Saturday Poster Sessions, November 3, 2007

HCV Treatment

 

Topic: Treatment - Pegasys

 

233. An Open Label, Comparative, Multicenter Study Of Peginterferon Alfa-2a Plus Ribavirin in The Treatment Of Patients With Chronic Hepatitis C/Hepatitis B Co-Infection Versus Those With Chronic Hepatitis C

Monoinfection C. Liu; W. Chuang; C. M. Lee; S. S. Wu; L. Y. Liao; H. T. Kuo; Y. C. Chao; C. L. Chen; P. J. Chen; D. S. Chen 

 

Introduction:

Pilot studies using conventional interferon plus ribavirin (RBV) for 6 months to treat patients with dual chronic hepatitis C and B infection suggested that sustained hepatitis C virus (HCV) clearance rate comparable to that observed in HCV monoinfected patients could be achieved. We have conducted a multicenter clinical trial in mono and co-infected patients using peginterferon-based combination therapy in Taiwan.

 

Methods:

Eligible patients with active HCV (serum ALT level >=1.5 X ULN and HCV RNA ≥100,000 copies/mL), with (n=161) or without (n=160) detectable HBsAg, were enrolled. Patients infected with HCV genotype 1 received 48 weeks of peginterferon alfa-2a 180 μg weekly plus 1000–1200 mg RBV daily. HCV genotype non-1 patients received 24 weeks of peginterferon alfa-2a 180 μg weekly plus 800 mg RBV daily. The primary efficacy endpoint was sustained HCV RNA clearance 24 weeks post-treatment (SVR) determined using an in-house real-time PCR assay (lower limit of detection ~100–1,000 copies/mL). Secondary efficacy parameters included HBV DNA response (<1,000 copies/mL) and normalization of serum ALT at end of treatment and 24 weeks post-treatment. Interim analyses are based on 275 patients (86%) who have completed treatment and follow-up.

 

Results:

Patients were recruited from June 2004.  The treatment and follow-up was completed in August 2007 and reported in September 2007.  The majority of dually infected patients were male; The group containing HCV genotype non-1 mono-infected patients had a higher proportion of female

patients enrolled than the other patient groups. 

 

The ITT analysis included all patients that received at least one dose of study treatment; withdrawn cases with missing data at 24 weeks post-treatment were counted as treatment failure.  A total of 26 (8.1%) patients were withdrawn prematurely from the study

 

HCV response

HCV genotype non-1 infected patients had a slightly better sustained response than genotype 1 patients in both HCV and HBV dually infected and HCV mono-infected patients.  HCV clearance rates were comparable at the end of treatment (88% vs 94%) and 24 weeks posttreatment (86% vs 88%) for dually infected and HCV mono-infected patients with non-1 genotype infection, respectively.  The majority of HCV genotype 1 infected patients with dual HCV/HBV infection achieved a sustained response (73%) after 24 weeks of treatment-free follow up and an even higher rate of HCV clearance was achieved in HCV mono-infected patients (77%).  A per protocol analysis, including data for all patients completing 12 weeks of treatment, shows comparable end-of-treatment and sustained responses.

 

HBV response

Virological

·        Of the 145 dually infected patients with available data for analysis, 68 (46.9%) had detectable serum HBV DNA pre-treatment

·        Of the 68 patients with baseline detectable serum HBV DNA, HBV virologic response (VR) was obtained in 47 (69.1%) at the end of treatment and in 38 (55.9%) at the end of follow-up

·        Of the 77 patients with baseline undetectable serum HBV DNA, rebound of HBV DNA was found in 28 (36.4%), including 16 (20.8%) and 17 (22.1%) at the end of treatment and follow-up, respectively

·        None of the HBV rebounds was associated with an elevation of serum ALT >200 IU/L, and almost all showed an HCV SVR

 

HBsAg clearance

·        10% of the dually infected patients cleared HBsAg at the end of treatment-free follow-up

 

Summary:

·        A sustained HCV clearance rate of 73% was achieved at 24 weeks post-treatment in the most difficult-to-treat patients dually infected with HCV genotype 1 and HBV

·        In HCV genotype non-1 dually infected patients, HCV clearance (86%) was achieved to an extent comparable to that observed in HCV mono-infected patients (77% and 88% for genotype 1 and non-1 infected patients, respectively)

·        In general there was little difference between HCV response rates between genotype 1 and non-1 infected patients at end of treatment and 24 weeks post-treatment

·        HBV virologic response was obtained in 56% of the patients with dual HCV/HBV infection

·        Importantly, HBsAg clearance was observed in 10% of the dually infected patients

·        36% of the dually infected patients whose serum HBV DNA were undetectable pre-treatment experienced rebound of HBV DNA

 

Conclusion:

Combination therapy of PEGASYS and COPEGUS appears to be safe and effective for treatment of patients dually infected with HCV and HBV. Importantly, a substantial proportion of the dually infected patients

achieved HBsAg clearance – an important indicator of long-term treatment success.

 


Topic: Treatment - Pegasys

 

234. Early discontinuation of ribavirin in HCV-2 and HCV-3 patients responding to Peg-interferon alfa-2a and ribavirin

A. Andriulli; C. Cursaro; R. Cozzolongo; A. Iacobellis; M. R. Valvano; A. Mangia; N. Minerva; D. Bacca; M. Stanzione; A. Scuteri; G. Montalto; P. Andreone 

 

Background & Aims:

Half of patients with HCV-2 and HCV-3 infection attained sustained virologic response (SVR) following Peg-interferon alfa-2a (Peg-IFN) monotherapy. However, guidelines recommend Peg-IFN with ribavirin for 24 weeks in all patients. Efforts to select patients who might benefit from Peg-IFN monotherapy have not been pursued.

 

Methods.

In a multicenter trial, 144 HCV-2 and HCV-3 patients were started on Peg-IFN alfa-2a (180 μg/wk) and ribavirin (1000-1200 mg/day) for 12 weeks: those with RVR at week 4 were randomized to either discontinue ribavirin and remain on Peg-IFN alfa-2a, (n=59) or to continue combination therapy (n=61). To delineate patients’ features that might help identify individuals likely to benefit from ribavirin discontinuation, an SVR prediction model was developed including gender, age, HCV genotype, baseline HCV-RNA levels, BMI, ALT values, and advanced fibrosis. Stepwise logistic regression analysis was used to compare P values and odds ratios for the effect of prognostic factors on either SVR and RVR rates.

 

Results:

In the 24 patients with no RVR, 15 (63%) were end-of-treatment (EOT) responders, and 12 (50%) were SVR. Baseline features of RVR patients randomized to ribavirin withdrawn or to standard treatment were not different. All but one RVR patients had EOT response. As expected, SVR rates were lower after discontinuation of ribavirin: 54% versus 82% (p<0.001). Twenty-seven (46%) and 10 (17%) EOT patients, respectively, relapsed during the follow up (difference, 29%, CI 27.5–30.6; p<0.001). In the discontinuation group, low body weight (p=0.022), low BMI (p=0.034), low viremia (p<0.01) genotype 3 (p=0.031) and mild liver disease (p<0.01) were associated with SVR; in the multivariate analysis, low viremia and mild liver disease remained significant predictors with respective odds ratios of 56.8 (C.I.4.3-745) and 27.3 (CI 1.4-521). In patients who did or did not discontinue ribavirin, SVR rates were similar in those with < 300,000 IU/ml viremia (86% vs. 81%) and in patients with intermediate viremia (70% vs. 71%), but disappointingly low in those with >700,000 IU/ml viremia (37% vs. 88%, p=0.004).

 

Conclusions:

·        In HCV-2 and HCV-3 patients, withdrawn of ribavirin and continuation with Peg-IFN alfa-2a monotherapy may be appropriate to attain SVR, providing viremia is cleared early during therapy and associated with low baseline viral load.

·        Our investigation warrants future prospective testing, since it can give rise to considerable saving in cost and quality of life related to over-treatment

 


Topic: Treatment - Pegasys

 

235. Randomized, double-blind, placebo-controlled trial of Peginterferon alfa-2a (40kD) and ribavirin with and without 400 mg amantadine-sulphate for 48 weeks in treatment naïve HCV genotype 1-infected patients

M. von Wagner; W. Hofmann; G. Teuber; T. Berg; T. Goeser; U. Spengler; H. Hinrichsen; H. Weidenbach; G. G. Gerken; M. P. Manns; P. Buggisch; S. Zeuzem 

 

Background:

The impact of amantadine on virologic response of interferon-based treatment of chronic hepatitis C is controversial. Dose-dependent increase in HCV RNA decline was observed for amantadine during first weeks of interferon-based treatment.

 

Objectives:

Assessment of virologic response rates in patients with chronic HCV 1-infection treated with 400mg amantadine or placebo in combination with Peginterferon alfa-2a (40kD) and ribavirin for 48 weeks.

 

Patients and Methods:

Seven hundred and four previously untreated chronically HCV genotype 1-infected patients (mean age 46 ± 12 yrs.) received amantadine-sulphate (400 mg/day) (n=352) or placebo (n=352) in combination with 180 µg peginterferon alfa-2a once weekly and ribavirin (1000-1200 mg/day) for 48 weeks. End of treatment and sustained virologic response after a 24-week follow-up period were assessed by qualitative RT-PCR (Cobas Amplicor HCV, sensitivity 50 IU/mL).

 

Results:

Demographic and baseline virologic parameters were similar in both treatment groups. For 61 patients (9 %) liver cirrhosis or transition to liver cirrhosis were reported. No significant differences were observed between patients receiving amantadine or placebo regarding end of treatment and sustained virologic response, respectively. Intent-to-treat virologic response rates are given in the Table. On-treatment drop-out rate in the amantadine-group was significantly higher than in the placebo-group (32% vs. 23%; p=.01). However, adverse events and laboratory abnormalities were similar between both groups and per-protocol analysis revealed similar virologic response rates in both treatment groups (52.8% vs. 54.5%).

 

Conclusion:

In this large placebo-controlled multicenter study, amantadine even at a dose of 400mg/day did not improve virologic response of antiviral treatment with peginterferon alfa-2a and ribavirin.

 

Virologic response

All

Peg-IFN + Ribavirin Amantadine

Peg-IFN + Ribavirin Placebo

end of treatment

487/704 (69.2%)

231/352 (65.6%)

256/352 (72.7%)

end of follow-up

357/704 (50.7%)

171/352 (48.6%)

186/352 (52.8%)

 


Topic: Treatment – Extrahepatic Manifestations

 

236. Rituximab combined with Peg-Interferon-Ribavirin in refractory HCV-associated cryoglobulinemia vasculitis.

D. Saadoun; M. Resche rigon; D. Sene; L. Perard; J. Piette; P. Cacoub 

 

Background:

Treatment of hepatitis C-related mixed cryoglobulinemia (HCV-MC) remains difficult and one-third of patients continue to have active disease while receiving anti-CD20 monoclonal antibody or antiviral therapy.

 

Objective:

To report the results of a prospective open study using rituximab combined with Peg-Interferon (IFN)α2b-ribavirin in HCV-MC vasculitis.

 

Patients:

Sixteen consecutive HCV-MC patients were treated with rituximab (intravenously weekly for 4 weeks) combined with Peg-IFNα2b-ribavirin (for 12 months). All patients had severe active disease which was resistant to previous combination antiviral therapy.

 

Results:

Fifteen patients (93.7%) showed rapid clinical improvement, 10 of whom (62.5%) were complete responders. Compared with clinical complete responders, the partial or non responders had a 3.6 times longer duration of vasculitis prior to therapy and a lower rate of early virologic response. Complete response was associated with a significant reduction of cryoglobulin, rheumatoid factor activity and HCV RNA and increased C4. Treatment was well tolerated with no infectious complications. Flare-up of psoriasis and worsening of peripheral neuropathy occurred in one patient each. Clinical relapse occurred in two patients, which was associated with the simultaneous reappearance of HCV RNA and cryoglobulin and an increase in the number of peripheral blood B-cells.

 

Conclusion:

·        Rituximab combined with Peg-IFNα2b-ribavirin may act synergistically and represents a safe and effective therapeutic option in severe HCV-MC.

·        This therapeutic schedule should be considered as induction therapy for HCV-MC patients.

 


Topic: Treatment - Pegasys

 

237. Twice vs Once Weekly Dosing of Peginterferon Alfa 2a in Chronic HCV Genotype 1 Infection: Analysis of Early Viral Kinetics

J. J. Feld; G. A. Lutchman; R. Loomba; A. A. Modi; Y. Rotman; P. Nagabhyru; M. Ghany; T. Heller; V. Haynes-Williams; T. Liang; A. U. Neumann; J. H. Hoofnagle 

 

Background:

Treatment outcomes in chronic hepatitis C are highly correlated with early viral kinetics. Pegylation of interferon greatly improved treatment responses and allowed for once weekly dosing. However viral kinetic data have shown that many patients receiving peginterferon weekly have a rebound in HCV RNA between doses. This may result in suboptimal viral inhibition and prolong time to clearance of viremia.

 

Aim:

To compare early viral kinetics between once and twice weekly dosing of peginterferon in patients with chronic HCV genotype 1.

 

Methods:

Consecutive patients with HCV genotype 1 were divided into 2 groups: Group A received peginterferon alfa 2a 180μg once weekly and weight-based ribavirin for 4 weeks and Group B received an initial 180μg dose of peginterferon followed by 90μg twice weekly plus ribavirin for 4 weeks. Both groups were then treated with peginterferon 180μg once weekly and ribavirin for an additional 44 weeks. HCV RNA was measured at 0, 12, 24, 48 and 72 hrs and at days 7, 9, 14, 21 and 28. Early viral kinetics and baseline characteristics were compared.

 

Results:

Patients in Group A (n=25) had similar baseline characteristics to those in Group B (n=25): sex (56% vs 62% male), race (76% vs 80% Caucasian) and HCV RNA level (6.18 vs 6.29 log IU/ml). The groups had similar first phase (day 0-3) kinetics (Group A -0.76 log vs Group B -0.10 log), but starting at day 3, HCV RNA levels diverged (Figure).

 

Note:  1 patient in Group B became HCV negative and were not counted in the results.

 

Treatment outcome

 

Group A

Group B

P value

PCR( – )at Day 28

12 %

17 %

0.70

PCR (+) at week 12

61 %

78 %

0.37

EVR

83 %

83%

1.0

SVR

56 %

47 %

0.75

Relapse

26 %

24 %

1.0

 

Conclusions:

·        Twice-weekly dosing of peginterferon alfa 2a improves early viral kinetics in HCV genotype 1 infection.

·        There was a trend towards improved second phase slope, which translated into a significant difference in absolute decrease in HCV RNA at all time points from day 7 to 28.

·        The change in HCV RNA did not differ before day 7 or after day 28, suggesting that this difference was due to the twice weekly dosing regime during the first month of therapy.

·        Although there was no improvement in early or sustained viral clearance the study was underpowered and not designed to evaluate these endp9oints.  Furthermore, it may require longer than 1 month of twice weekly dosing to affects rates of EVR and SVR.

·        Base on these data a larger study to assess the benefit of twice weekly dosing of peginterferon alfa-2a is warranted. 

 


Topic: Treatment - PEG-Intron

 

238. Sustained Virological Response Is Associated with Eradication of Hepatitis C Virus and Decrease in anti-HCV Titer in Patients Treated for Chronic Hepatitis C with Interferon alpha 2b or Pegylated Interferon alpha-2b+ribavirin.

S. Maylin; M. Martinot-Peignoux; N. Boyer; M. Ripault; A. C. Cardoso; N. Giuily; C. Castelnau; M. Nicolas-Chanoine; P. Marcellin 

 

It is unclear whether hepatitis C virus (HCV) is eradicated in patients with chronic hepatitis C who achieve a sustained virological response [SVR). In this study, HCV-RNA was measured in serum, and peripheral blood mononuclear cells (PBMCs) and a follow-up of anti-HCV antibodies were performed in patients with chronic hepatitis C who achieved an SVR.

 

PATIENTS–METHODS:

215 patients with an SVR after a treatment with IFN alpha-2b or PEG-IFN alpha-2b+ribavirin (PEG-IFN 1.5μg/kg/week, plus ribavirin 800-1200 mg /day according to weight), were included in this study. HCV-RNA was tested: -(1) in serum for all the 215 patients every year and at the time of PBMCs collection, -(2) in PBMCs collected in 71 patients 3.9±3.4 (0.5-10) years after treatment. HCV-RNA was detected with the VERSANT HCV-RNA Qualitative assay (Qual TMA, Siemmens) (sensitivity 10 IU/ml). In 70 patients HCV antibody titers were measured with the Axsym HCV 3.0 (Abbott), and with the third-generation HCV recombinant immunoblot assay (RIBA) (CHIRON RIBA HCV 3.0 SIA).

 

RESULTS:

Patients were followed up for a mean of 2.7±1.4 years (range, 0.5 -10) years. Serum HCV-RNA remained undetectable in all the patients (1125 samples). HCV-RNA was detectable in the PBMCs sample for 1 patient (3 years after treatment cessation). The kinetics of antibodies is shown on the figure. The mean titers were 93±20 IU/ml and 41±20 IU/ml, before therapy and on the last serum sample available, respectively (p<0001). A significant decrease was observed for anti-NS5 and anti-NS3 with the RIBA assay (p=0.01).

 

CONCLUSION:

In our 215 patients with chronic hepatitis C and SVR, evaluated up to 10 years after treatment cessation, none demonstrated late relapse. HCV-RNA was detectable, by a very sensitive assay (TMA), in PBMCs in 1 patient. HCV antibody titers showed a marked decrease. These results demonstrate a durable response to IFN alpha 2b or PEG-IFN alpha-2b+ribavirin and indicate that SVR is associated with HCV eradication

 


Topic: Treatment – Liver Transplantation

 

239. Preemptive Treatment of HCV After Liver Transplantation Is Unjustified Except for Genotype 3a.

H. J. Merhav; L. Mieles; M. Ottman; S. Pappas; R. C. Botero 

 

Background:

Preemptive treatment (PT) of HCV after Liver Transplantation (LT) is controversial due to the high morbidity, high cost and unclear efficacy.

 

Methods and patients:

75 consecutive HCV LT recipients were followed prospectively in a preemptive intent to treat protocol with pegylated interferon (PegI) and ribavirin (Rib) for 48 weeks. Viral load and protocol biopsies were followed in all treated patients Preemptive treatment was defined as starting less than 180 days after LT and before the onset of histologically proven recurrent HCV (>Grade 1 Stage1). Viral genotype, pretreatment viral load, time to initiation of treatment, immunosuppression, rejection episodes and completion of treatment were analyzed for their effect on response.

 

Results:

Demographics: Pts. – n = 75. Age - 52±7. Sex – 50 m, 25 f. HCC – 23. Follow up – 27 ± 13 m. Actuarial Survival (patient and graft) – 1 year = 91 & 88%, 3 year = 84 & 81%

 

Of 75 LT patients (pts.) with HCV 29 (39%) qualified for PT. 14 pts. were treated after HCV recurrence was histologically documented. 32 pts. (43%) received no treatment against HCV. Reasons for exclusion were: preoperative viral clearance – 9;. early death – 3; psychosocial – 6; re-LT – 3; medical – 15; noncompliance – 5; early HCV recurrence - 3. Of the 29 who started PT only 13 (17 & 45 %) completed treatment. Of the 29 on PT 17 had complete response, 11 end of treatment response and 6 sustained viral response (SVR). Of the patients with SVR non were genotype 1a (3-3a, 1-2b, 1-1b, 1- indeterminate). Of 5 pts. with genotype 3a in the PT group all cleared the virus with one recurrence. Of 15 pts. with advanced recurrence (Grade >1 stage > 1) 12 had genotype 1a. No pts. With genotype 1a achieved SVR. 2 pts. And 3 (4%) grafts were lost to recurrent HCV. Of 15 pts. with moderate to severe recurrent HCV (>Grade 1 Stage1) 12 were 1a, 2 2a and 1 4e. After censuring for early death and early recurrent hepatitis there was no survival advantage in the non treated vs. the PT group. There were no deaths, graft loss or rejection episodes associated with treatment for HCV. 75% of PT patients required growth factor treatment. Intent to treat SVR was 6% for the cohort, 20% for the PT group and 45% for the pts. that completed treatment.

 

Conclusions:

1.PT for HCV after LT is expensive, time consuming and associated with considerable (though not lethal) morbidity. With an SVR of 6% it appears to be unjustified to expose all HCV pts. to treatment. 2. Genotype 3a appears to respond favorably and consistently to treatment and may be an indication for PT.

 


Topic: Treatment – Disease Progression

 

243. Positive Impact of Antiviral Therapy on the Long Term Outcome of Chronic Hepatitis C Patients with Cirrhosis

Ana-Carolina Cardoso, Rami Moucari, Nathalie Boyer, Tarik Asselah, Asma Laatar, Marie-Pierre Ripault, Michèle Martinot-Peignoux, Sarah Maylin, Pierre Bedossa and Patrick Marcellin. Service d’Hépatologie et INSERM CRB3, Hôpital Beaujon, France Service d’Anatomie Pathologique et de Microbiologie, Hôpital Beaujon, France A. C. Cardoso; R. Moucari; N. Boyer; T. Asselah; A. Laatar; M. Ripault; M. Martinot-Peignoux; S. Maylin; P. Bedossa; P. Marcellin 

 

Background and Aim

The major consequence of chronic hepatitis C (CHC) is the progression to cirrhosis and its potential complications: haemorrhage, ascites and hepatocellular carcinoma (HCC). The influence of antiviral therapy on the long-term outcome of CHC has not been determined. The aim of this study was to evaluate the influence of antiviral therapy on the long-term outcome of CHC patients with bridging fibrosis or cirrhosis.

 

Patients and Methods

278 consecutive patients with CHC and bridging fibrosis or cirrhosis (METAVIR F3-F4) were retrospectively evaluated. They had all received at least one treatment course with interferon (conventional or pegylated) with or without ribavirin for at least 12 weeks. Sustained virological response (SVR) was defined as undetectable HCV RNA in serum 24 weeks after treatment discontinuation. Cumulative incidence of haemorrhage, ascites, and HCC were compared between patients who developed or not SVR. The influence of treatment response on histology was also assessed on paired-liver biopsies in 118 patients.

 

Results

The baseline characteristics of the study population were: male gender (67%), mean age (55±10 years), mean BMI (25.8±4.8 kg/m2). Mean serum HCV RNA ±  SD, log 10 IU/mL ± 0.6.  Genotype distribution was: 1 (60%), 2(8%), 3 (16%), 4 (14%), and 5 (2%). Median follow-up period was 5 years (1-18) after the first biopsy, and 2 years after the last treatment (1-15).

 

Sustained Virological Response (SVR)

·        35% of F3 and F4 patients achieved SVR, and SVR rates were similar (F3,39%; F4, 32%) regardless of METAVIR fibrosis score.

 

Predictors of Sustained Virologic Response

·        Gentoype (G1/4 vs. G2/3), baseline viral load ≥ 400,000 IU/mL vs. ≤ 400,000 IU/mL), and baseline count (<100,000 cells/mL vs. ≥ 100,000 cells/mL) were significantly associated with SVR.

Liver Decompensation

·        Hemorrhage and ascites occurred significantly less often in patients who achieved SVR than in those who did not attain SVR.

Cumulative Incidence of Hepatocellular Carcinoma (HCC)

·        HCC occurred significantly less often in patients who attained SVR than in those who did not attain SVR.

Liver Histology

Significantly more patients who attained SVR experienced improvement in fibrosis score than did patients who did not attain SVR.

Conclusion

·        Antiviral therapy is associated with SVR in more than 30% of chronic hepatitis C patients with cirrhosis.

·        SVR is associated with lower rates of complications of liver disease and HCC and with significant regression of fibrosis and long-term improved outcome.

 


Topic: Treatment – Disease Progression

 

244. Long-term prognosis of elderly patients with hepatitis C virus-related chronic liver disease --- A cohort study of 2,379 Japanese patients

K. Ikeda; Y. Arase; Y. Kawamura; H. Yatsuji; H. Sezaki; T. Hosaka; N. Akuta; M. Kobayashi; S. Saitoh; F. Suzuki; Y. Suzuki; H. Kumada 

 

Background:

Interferon therapy is effective in reducing hepatocarcinogenesis and in improving survival rate of patients with HCV-related chronic hepatitis, but the clinical influence of interferon is considered less advantageous in elderly patients because of short longevity. In order to elucidate the prognosis of elderly patients of 60 years or older, and to evaluate the advantage of interferon treatment in the elderly, we analyzed a large cohort of patients with chronic hepatitis type C from viewpoints of hepatocellular carcinogenesis and survival period.

 

Patients and Method:

Among 7,235 patients with hepatitis C virus related chronic liver disease in our hospital, prognosis of 2,379 elderly patients was analyzed. A total of 459 elderly patients began interferon therapy before development of liver cancer. The elderly cohort was observed for a median of 6.3 years (25% 2.6years, 75% 10.8years).

 

Results:

(1) Cumulative survival rates in untreated elderly patients without overt cirrhosis were 94% at the end of 10th year and 79% at the 15th year in high platelet (>=150,000/mm3) group, 87% and 73% in intermediate (100,000-149,000/mm3) group, and 71% and 36% in low platelet group (<100,000/mm3), respectively. (2) Fifth- and 10th-year hepatocarcinogenesis rates in the intermediate and low platelet group (<150,000/mm3) were 12% and 22% in interferon therapy group (N=85) and 19% and 43% in untreated group (N=474), respectively (P=0.028). Multivariate analysis disclosed that interferon independently decreased carcinogenesis risk with a hazard ratio of 0.53 (P=0.012) in the subgroups. In the high platelet group (>=150,000/mm3), on the contrary, 5th and 10th-year carcinogenesis rates were 3% and 9% in interferon-treated group (N=96), and 5% and 13% in untreated group (N=598), respectively (P=0.88). (3) Interferon treatment significantly increased cumulative survival rates in the subgroup of lower platelet group (P=0.0028), but did not affect in the subgroups of higher platelet (P=0.20). Multivariate analysis also showed interferon was significantly associated with a longer survival in the lower platelet subgroup (hazard ratio 2.44, P=0.011).

 

Conclusions:

Initial platelet count was significantly associated the survival time of the elderly patients with chronic hepatitis C. Interferon for a subgroup of intermediate and low platelet count had significant advantages from the viewpoints of hepatocarcinogenesis and survival.

 


Topic: Treatment - Pegasys

 

245. Efficacy and Safety of Escitalopram for the Prevention of Depressive Episodes Induced by Peg-Interferon Alpha2a and Ribavirin in Chronic Hepatitis C Patients. A Double-Blind, Randomized, Placebo-Controlled Trial.

C. Diez-Quevedo; R. Planas; P. Castellvi; R. M. Morillas; M. Gimenez; H. Masnou; R. Solà; P. Giner; R. Martín-Santos 

 

Introduction:

Interferon is associated with a high prevalence of major depression, which is one of the main reasons for treatment withdrawal and failure. The aim of this study was to determine the efficacy and safety of an antidepressant for preventing depression induced by pegylated interferon (PegIFN) alpha2a in chronic hepatitis C (CHC).

 

Method:

Multicenter (15 Spanish hospitals) double-blind study of CHC patients who were eligible for PegIFN-alpha2a and ribavirin (RBV) therapy. Patients with mental disorders at baseline were excluded. They were randomly assigned to receive the antidepressant escitalopram (15 mg/day) or placebo. Treatment was begun 2 weeks before PegIFN therapy and continued for the following 12 weeks. Main variables studied were the presence of a major depressive episode, according to DSM-IV diagnostic criteria, and scores on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hospital Anxiety and Depression Scale (HADS). The study protocol conformed to the guidelines of the Declaration of Helsinki and was approved by the Ethic’s Committees of all centers involved and the Spanish Agency of Medicines. All patients signed a written informed consent before entering the study.

 

Results:

A total of 133 patients were included (74% genotype 1), 67 treated with escitalopram and 66 with placebo. Eighty-three (62%) patients were male, mean age 47 years. Seventeen patients (13%) had a past history of major depression and 22 (17%) of substance abuse. Placebo and escitalopram groups did not differ significantly in any measure at baseline.

 

During the first 12 weeks of treatment, only 1 patient (2%) in the placebo group and 5 (8%) in the escitalopram group developed a major depressive episode (Chi square = 2.67, p = 0.11). Total score of the MADRS increased between baseline and week 12 in 2.2 points in the placebo group and 3.1 in the escitalopram group. Figures for the depression subscale of the HADS were 0.7 and 1.0 respectively. Differences between both groups were not statistically significant.

 

Conclusions:

·        Treatment of chronic hepatitis C with pegylated interferon alpha 2a and ribavirin is associated with a very low incidence of major depressive episodes (6 out of 133 pts, 4.5%)

·        In CHC patients, pretreatment with an antidepressant is not an effective strategy for reducing depression induced by PegIFN and RBV, at least in a population of patients with low psychiatric risk.

·        On the other hand, the use of escitalopram in CHC patients is safe regarding biochemical and virological response to treatment at week 12.

This study has been supported by a grant from Roche.

 


Topic: Treatment - PEG-Intron

 

246. Response to Peginterferon alfa-2b + Ribavirin Combination Therapy in Genotype 2 and 3 Patients With Poor Baseline Prognostic Factors: Results of the Canadian POWeR Program

R. J. Bailey; D. K. Wong; C. Cooper; N. Hilzenrat; K. Peltekian; J. Daiter; N. Abadir; P. Marotta 

 

Background:

This subanalysis of the POWeR study evaluated the effect of fibrosis and baseline viral load on sustained virologic response (SVR) rates in treatment-naive genotype 2 (G2) and G3 patients with chronic hepatitis C treated with weight-based peginterferon (PEG-IFN) alfa-2b and weight-based ribavirin (RBV).

 

Methods:

POWeR is an open-label observational trial conducted in community and academic clinics across Canada between 2002 and 2006. G2/G3 patients received PEG-IFN alfa-2b (1.5μg/kg/wk) plus RBV (800–1200mg/d) for 24 weeks. SVR was undetectable HCV RNA levels 24 weeks posttreatment.

 

Results:

276 G2 and 389 G3 patients enrolled in POWeR (38% of all patients). Baseline viral load and fibrosis scores were available in 72% and 37% of G2 and G3 patients, respectively. Numerically, more G3 than G2 patients had high viral load (HVL; 49% vs 54%) and advanced fibrosis/cirrhosis (F3-F4) (40% vs 33%). G3 patients had lower SVR rates than G2 patients (72% vs 79%, P=.04) due to a lower end-of-treatment response (77% vs 86%, P=.01); relapse rates were 7.6% (Geno 2), and 6.4% (Geno 3). G2 patients responded well regardless of baseline viral load and fibrosis score (Table). G3 patients with low viral load (LVL) attained SVR more often than those with HVL (76% vs 64%, P=.03). An inverse relationship between SVR and fibrosis score was observed in G3 patients; 47% of G3 cirrhotic patients attained SVR.

 

Conclusions:

G2/G3 patients respond very differently to combination PEG-IFN alfa-2b plus RBV therapy. G2 patients respond well regardless of baseline characteristics. Conversely, lower response rates are observed in G3 patients who have poor prognostic factors. The lower response rate in the G3 population after 24 weeks’ treatment may not be detected in smaller studies that combine G2/3 patients for analysis purposes. New treatment strategies such as increased dose or duration of treatment are needed for G3 cirrhotic patients. Future studies should avoid combining G2/3 patient populations when reporting results.

 

SVR Rates Stratified by Baseline Viral Load and Fibrosis Score

 

SVR,*%

 

G2 (n=276)

G3 (n=389)

HVL†

83

64

LVL

79

76

F0-F1

79

81

F2

81

68

F3

80

71

F4

76

47

*113/276 G2 and 136/389 G3 with fibrosis score, 201/276 G2 and 281/389 G3 with baseline viral load data. †HVL=baseline HCV RNA levels >600,000 IU/mL or >2×106 copies/mL.

 


Topic: Treatment – Predictors of Treatment Response

 

249. Pretreatment insulin sensitivity contributes to the treatment response to peginterferon plus ribavirin combination therapy for patients with chronic hepatitis C

J. Huang; M. Yu; C. Dai; M. Hsieh; L. Lee; Z. Lin; S. Chen; W. Chang; W. Chuang 

 

Introduction:

Insulin resistance plays a key role in the entire suite of glucose abnormalities. The impact of insulin resistance on the treatment response of pegylated interferon-alpha plus ribavirin has not been fully clarified. This study aimed to evaluate the role of insulin sensitivity and the related viral factors in the treatment response in patients with HCV infection in Taiwan.

 

Methods:

A total of 430 patients (243 males) were included (between 2/2003-3/2007). All patients were treated with 24-week course of peginterferon alpha-2a (180 µg/week) and weight-based ribavirin 1000-1200 mg/day, with a 24-week follow-up period. We assessed insulin sensitivity and beta-cell function of these patients in a fasting state (homeostasis model assessment of insulin resistance [HOMA-IR] and homeostasis model assessment of beta-cell function [HOMA-beta]) before treatment and 24 weeks after treatment.

 

Results:

Sustained virological response (SVR) were observed in 336/430 (78.1%) patients. The rates of SVR in genotype-1 and non-1 patients was 64.5% (118/183) and 88.3% (218/247), respectively. The baseline HOMA-IR of those patients achieving an SVR was significantly lower than that of those without (2.28 vs. 3.40, P=0.002). Multivariate logistic regression analysis demonstrated that high baseline HOMA-IR (>=2.5) was a significant negative factor regarding to SVR in all patients (OD=2.22, 95% CI= 1.26-3.91, P=0.006). For 172 non-diabetic patients with genotype-1 HCV infection, the SVR rate (49.0%, 25/51) of those with high baseline HOMA-IR was significantly lower than those without (72.3%, 87/121, P=0.004). Meanwhile, multivariate logistic regression analysis demonstrated high baseline HOMA-IR was the most significant negative factor associated with SVR in genotype-1 patients (OD=2.91, 95% CI= 1.38-6.58, P=0.006), followed by viral load and age.

 

Conclusions:

Pretreatment insulin sensitivity contributes to treatment response in chronic hepatitis C patients, especially for those with genotype-1 infection.

 

Correlation between pretreatment HOMA-IR and SVR in non-diabetic chronic hepatitis C patients receiving peginterferon plus ribavirin

 

Total, n=389

G-1, n=172

G-non-1, n=217

SVR+

SVR-

P

SVR+

SVR-

P

SVR+

SVR-

P

HOMA-IR

 

 

 

>=2.5

85 (69.1%)

38 (30.9)

0.002

25 (49.0)

26 (51.0)

0.004

60 (83.3)

12 (16.7)

0.064

<2.5

220 (82.7)

46 (17.3)

 

87 (71.9)

34 (28.1)

 

133 (91.7)

12 (8.3)

 

 


Topic: Treatment – Pegasys

 

251. Response to high ribavirin dose in combination with peg-INF alfa-2a for treatment of HCV genotype 1 previous non-responders

E. Hornfeldt; L. Stahle; R. Schvarcz; O. R. Weiland; T. Carlsson; A. Hollander; K. Lindahl 

 

BACKGROUND:

Patients with hepatitis C (HCV) genotype 1 and previous non-responders to treatment with pegylated interferon (peg-INF) and ribavirin (RBV) are a difficult-to-cure group. We have previously shown that high doses of RBV (mean 2550 mg/d) offered high sustained virological response (SVR) in treatment-naïve patients with hepatitis C genotype 1. The aim of this controlled study was to evaluate the efficacy, safety and tolerability of high doses of RBV in combination with standard dosed peg-INF in previous non-responders.

 

METHODS:

20 patients with HCV genotype 1 and previous non-responders to peg-INF alfa-2a and RBV therapy received treatment with individualized high dose of RBV in combination with peg-INF a-2a 180mg/week for 48 weeks. Non-responders were defined as not achieving HCV-RNA <50 IU/mL at any time during previous treatment. The initial RBV dose was individualized and calculated from a pharmacokinetic formula based mainly on renal function aiming at a high steady state concentration of RBV of >15 mmol/L. Plasma RBV concentrations were measured during treatment by HPLC and if necessary the RBV dose was adjusted to reach the target concentration. All patients received erythropoietin (epo) at doses 10,000-60,000 IU, once weekly, starting 2 weeks prior to initiation of antiviral treatment.

 

RESULTS:

We enrolled 10 patients (9 males), mean age 52 years (range 34-61)  and 7 of 10 with fibrosis stage 3 on a 4-grade scale. The mean initial RBV dose was 2400 mg/d (range 1600-2800). To reach the target concentration within 6 weeks the dose was raised to a mean RBV dose of 3000 mg/d (range 2400-4000). The mean baseline haemoglobin level was 15.3 g/dL, at treatment week 6 mean haemoglobin level was 13.4 g/dL and at week twelve 10.9 g/dL. Two patients have required blood transfusions. Mean baseline viral load was 7.4 x 106 IU/mL, at treatment week 12 median viral load dropped to 1400 IU/mL (mean drop 3.6 log). Ten patients have reached treatment week 24 of whom 8 have HCV-RNA <15 IU/mL (COBAS TaqMan).

 

CONCLUSION:

·        High-dosed RBV in combination with peg-INF alfa-2a seems to offer a mean 3.6 log HCV-RNA decline within 12 weeks in previous non-responders to standard-dosed combination therapy with the same drugs.

·        High-dosed RBV treatment is feasible and seems to be safe, but requires strict attention regarding anemia.

·        Epo probably contributes to tolerability, especially during the first 12 weeks. The initial virological response is encouraging and the results from the completed trial, including SVR will show if the response is sustained.

 


Topic: Treatment – Methadone

 

253. Opioid maintenance therapy is not associated with treatment failure to hepatitis C therapy in a large German multicentre cohort

S. Mauss; D. Hüppe; E. Zehnter; M. Manns; G. Teuber; T. Dahhan; U. Meyer; B. Möller; N. Dikopoulos; T. Witthöft; J. Brack; M. Stern; S. Kaiser; R. Prinzing; . The bng hepatitis study group 

 

Objective:

The largest group of newly infected individuals with chronic hepatitis C in the Western world are intravenous drug users. Emerging data support treating individuals with peginterferon and ribavirin for chronic hepatitis C after stabilisation on opioid maintenance therapy (methadone or buprenorphine). However these data are based on small cohorts or substrata from trials with small patient numbers. Here we report data from a cohort of 4130 patients including 391 patients on opioid maintenance therapy.

 

Methods:

A total of 3547 patients treated with at least one dose of peginterferon alfa-2b and weight based ribavirin are currently included in a German multicentre cohort. Only patients included in this cohort beyond 72 weeks of baseline were included in this analysis (n=2016). Patients with missing data at week 72 were counted as treatment failures. Univariate analysis was performed for comparison of demographics in patients on opioid maintenance vs. remaining patients (age, sex, ALT, BMI, HCV-RNA, genotype, ribavirin dose, peginterferon dose). For logistic regression analysis sex, age, baseline HCV-RNA, HCV-genotype, BMI and opioid maintenance were used as independent variables. The dependent variable was being HCV-RNA negative (<600 IU/mL) or positive at week 72 (SVR).

 

Results:

Patients on opioid maintenance were younger 36 (range 18-63) vs. 42 (range 18-78), p<0.0001), more had genotype 3 (51% vs. 35%, p<0.0001), and median HCV-RNA levels were lower (66% vs. 50% <600.000 IU/mL, p<0.0001). SVR in all patients on opioid maintenance 64% vs. 59% in the not receiving opioid maintenance therapy (p<0.133). In logistic regression analysis, variables positively associated with SVR were younger age, HCV-genotype 2/3 and baseline HCV-rna <600.000 IU/mL (all p<0.0001). Female sex was not significantly associated with SVR (P=.1).

 

Conclusion:

·        The efficacy of PEG-IFN alfa-2b plus RBV was not different between chronic hepatitis C patients receiving opioid maintenance therapy and patients not receiving opioid maintenance therapy.

·        Because of favorable factors for SVR such as HCV G3 infection, young age, and low baseline HCV RNA, patients undergoing opioid maintenance therapy showed a trend for better unadjusted SVR rates.

·        However, after adjusting for variables associated with treatment outcome (age, genotype, baseline HCV RNA), treatment outcome did not differ between patients receiving and not receiving opioid maintenance therapy.

·        In conclusion, treatment of chronic hepatitis C patients undergoing opioid maintenance therapy in daily clinical practice is feasible, and success rates are not inferior to results from prospective, controlled studies.

 


Topic: Treatment – PEG-Intron

 

254. Final Results of the Canadian POWeR (Peginterferon alfa-2b Prospective Optimal Weight-based Dosing Response) Program. Sustained Virologic Response (SVR) to Weight-Based Peginterferon alfa-2b + Ribavirin in a Large, Mixed Community and Academic Observational Study

P. Marotta; S. V. Feinman; C. Ghent; L. Scully; M. Varenbut; J. Daiter; H. B. Witt-Sullivan; J. Robert; B. Romanowski; J. Farley; N. Abadir; R. J. Bailey 

 

Background:

To determine the impact of hepatitis C virus (HCV) genotype (G), baseline viral load, weight, and fibrosis stage on SVR rates in treatment-naive patients with chronic hepatitis C who were treated with weight-based peginterferon (PEG-IFN) alfa-2b and weight-based ribavirin (RBV) in a “real-life” observational setting. We report final SVR results from the POWeR program.

 

Methods:

POWeR was an open-label observational trial conducted in academic and community clinics ( total = 138) across Canada between 2002 and 2006. All patients received PEG-IFN alfa-2b (1.5μg/kg/wk) plus RBV (800–1200mg/day) for either 24 (G2 and G3) or 48 weeks (G1). SVR (defined as undetectable HCV RNA 24 weeks posttreatment) was stratified by genotype, baseline viral load, and fibrosis score.

 

Results:

1977 patients initiated treatment. Patients were excluded if they had undetectable HCV RNA at end of treatment but no 6-month follow up, had no treatment data available, or had HIV/HCV coinfection. This analysis was based on 1800 patients, including those who discontinued because of side effects, lack of response, or personal reasons. Most patients were infected with G1 (60%), followed by G3 (22%) and G2 (15%). Three percent of patients had G4/G5/G6 or no specified genotype. Baseline viral load was available in 1477 patients; 52% had high viral load (HVL; >600,000 IU/mL or 2×106 copies/mL). Liver biopsy specimens were available in 946 patients (53%), revealing F0-F2 fibrosis in 60% and F3-F4 fibrosis/cirrhosis in 40%. SVR rates were higher in patients with minimal (F0-F2) fibrosis than in those with advanced (F3-F4) fibrosis/cirrhosis (60% vs 35% P<.001) and in patients with low viral load than in those with HVL (57% vs 50% P=.009). Baseline viral load and fibrosis score were negative predictive factors for SVR in G1 and G3 patients but not G2 patients.

 

Conclusions:

·        Successful treatment outcomes that match those from rigorous clinical trials can be achieved in routine clinical practice

·        Despite poor predictive factors (advanced fibrosis and high baseline viral load) in this patient population, excellent SVR rates and low relapse rates with PEG-IFN alfa-2b plus RBV were attained in a real-life observational setting

·        Observational trials include a more heterogeneous patient population than populations observed in controlled trials and provide useful information to practitioners and regulators on postapproval drug use

·        Low virologic relapse rates were observed with combination therapy with PEG-IFN alfa-2b plus weight-based RBV

EOT, SVR, and Relapse Rates Stratified by Genotype

Genotype*

EOT, %

SVR, %

Relapse, %

All (n=1800)

61.7

54.3

11.9

G1 (n=1078)

50.2

41.6†

17.2

G2 (n=276)

85.5

79.0†

7.6

G3 (n=389)

76.9

72.0†

6.4

G4/G5/G6 (n=41)

70.7

65.9

6.8

*16 patients no genotype data. †P<.001. EOT=end of treatment.

 


Topic: Treatment – Side Effects

 

258. Assessment of the impact of psychiatric disorders on safety, compliance, and sustained virological response after hepatitis C treatment (CHEOBS)

J. Lang; P. Melin; D. Ouzan; M. Rotily; T. Fontanges; P. Marcellin; M. Chousterman; P. Cacoub 

 

Purpose :

The CHEOBS study is a French multicenter, prospective, observational study designed to analyze the factors related to compliance with the combination treatment with Peginterferon α-2b and Ribavirin in patients (pts) with chronic hepatitis C virus (HCV) infection. This analysis evaluates mental safety, quality of life, compliance to treatment and sustained viral response (SVR) in pts presenting psychiatric disorders (ppd) before the start of HCV treatment and compares them with those of pts not presenting psychiatric disorders (nppd).

 

Methods :

From Jan 2003 to Dec 2004, 1,972 pts with chronic HCV infection were included in CHEOBS and began antiviral therapy: 444 ppd pts and 1,528 nppd pts. Among ppd pts, 232 (53%) had depressive disorders, 179 (40%) anxiety disorders, 21 (5%) schizophrenia and 7 (2%) bipolar disorders. Baseline characteristics and the impact of ppd on compliance, virological response and quality of life (QoL, SF-36) were analysed.

 

Results :

At baseline (Day 0), ppd and nppd populations were different as the ppd population was younger (45 years vs 47 years), with a lower educational level (68% vs 53%), less well paid jobs (48% vs 61%), higher debts (13% vs 5%), more chronic diseases (32% vs 26%), higher alcohol intake (31% vs 23%), higher tobacco (66% vs 42%) and drug consumption (9% vs 2%), and higher rate of genotype 3 infection (30% vs 23%)(p<0.05). At the end of HCV treatment, there was no significant difference between ppd and nppd populations for compliance, duration of combination antiviral therapy (35 ± 17 vs 36 ± 17 weeks), premature antiviral therapy discontinuation due to adverse events or the pts request (53% vs 52%). The results of SVR, mental adverse events and QoL are shown in the Table.

 

Conclusion:

In a real life study, pts infected by HCV and starting HCV treatment frequently present with psychiatric disorders. The ppd profile did not have a negative impact on compliance, duration, premature treatment discontinuation or SVR. The QoL was impaired by HCV treatment and its adverse effects that was even more pronounced in nppd pts.

 

 

PPD

NPPD

P

schizophrenia

bipolar disorders

depressive disorders

anxiety disorders

Total

Mental Adverse events,%

 

 

 

 

 

 

 

M3

63

75

62

59

60

35

<.001

M6

63

17

64

58

62

40

<.001

M9

50

86

64

49

56

37

<.001

M12

70

33

66

69

64

37

<.001

SVR,%

44

50

52

48

50

48

.486

QoL*

 

Physical score

-3.3 ± 8

-20.9 ± 7

-6.5 ± 10

-3 ± 11

-5.2 ± 10

-5 ± 10

.710

Psychic score

7.3 ± 19

-11.3 ± 5

-1.5 ± 12

-0.7 ± 13

-1.5 ± 13

-6.8 ± 12

<.001

*between Day 0 and Month 12

 


Topic: Treatment – HIV/HCV Coinfection

 

259. Five years assessment of the risk of end-stage liver disease in HIV/HCV co-infected patients treated for a chronic HCV infection

F. Bani-Sadr; I. Goderel; C. Berendjem; C. Goujard; L. Piroth; F. Lunel; P. Morand; E. Rosenthal; D. Salmon; G. Pialoux; P. Bedossa; C. Perronne; P. Cacoub; F. Carrat; S. Pol 

 

Background:

Long term benefit of HCV therapy in HIV/HCV co-infected patients is unknown.

 

Methods:

We prospectively followed 383 patients who were enrolled in a randomized controlled trial of interferon-ribavirin combination (RIBAVIC) and who took at least one dose of study medication. The median follow-up in the cohort was 60 months. We studied the risk of end-stage liver disease (ELD) event defined as a liver decompensation, liver transplantation, hepatocellular carcinoma, or death. A Cox’s regression analysis was performed with treatment and HCV viral response entered as time-dependent covariate.

 

Results:

At entry, patients (40y, 73% male, 79% IVDU) belonged to the CDC class A, B & C in 51, 34 & 14%, respectively, and were given HAART in 83% with a mean CD4 cell count of 545/mm3, HIV RNA < 400 cp/ml in 66%. The mean Metavir score was A 1.25, F 2.2; 33% had F3-F4. 97 patients (25%) had a sustained viral response (negative PCR 6 months after therapy), 232 (61%) were HCV genotype 1 or 4 and 51 (39%) HCV genotype 2 or 3 infected non responders. Twenty one patients (5.5%) experienced ELD events during the follow-up (13 died). No patient had AIDS-related death. CD4 cell count < 350/mm3 (Hazard Ratio (HR) 2.7- IC95% 1.1-6.7; p=0.03), Metavir fibrosis score (F3 or F4) (HR 3.2- IC95% 1.0-9.8; p=0.046), prothrombin time <94% (HR 6.4- IC95% 1.4-28; p=0.01), platelets count < 190 000/mm3 (HR 4.6- IC95% 1.1-20; p=0.04) were independently associated with the risk of ELD. HCV sustained viral response was associated with a decreased risk of ELD although the effect did not reach statistical significance (HR 0.18- IC95% 0.02-1.33; p=0.09).

 

Conclusions:

·        Our results suggest that HCV SVR achieved by interferon-ribavirin combination may decrease the incidence of ELD in HIV/HCV Co-infected patients.

·        A longer period of follow-up is necessary to reach a firm conclusion.

 


Topic: Treatment – Side Effect Management

 

260. Danazol Increases the Platelets Count in Thrombo-Cytopenic Patients with Chronic Hepatitis C and Liver Cirrhosis Treated With Peg-Interferon Alfa 2a and Ribavirin.

G. Cabrera-Alvarez; L. Cañedo-Dorantes; J. Reyes-Esparza; L. Rodríguez-Fragoso; N. Mendez-Sanchez; A. Burguete; V. Madrid-Marina 

 

Backgorund and Aim:

Chronic hepatitis C (HCV) infection has been associated with the development of several extrahepatic alterations, including thrombocytopenia. Currently it remains unresolved. Danazol, an attenuated androgen has been succesfully used in patients with autoimmune thrombocytopenia. The aim of the present study was to investigate the effects of Danazol treatment for thrombocytopenia associated to peginterferon alfa-2a and ribavirin therapy in naïve HCV patients.

 

Methods:

A prospective study carried out in patients with chronic hepatitis C or liver cirrhosis patients who were under antiviral therapy. The protocol was approved by the Review Board/Ethics committee of the Hospital. The inclusion criteria including both gender, age (20 to 70 yr), without co-infection with hepatitis B virus or human immunodeficiency virus (HIV-1/2), thrombocytopenia during peginterferon alfa-2a and ribavirin therapy was defined when the count was ≤ 90,000 platelets/mL in the last month. Danazol 300-600 mg/day was administered until the end of therapy. We considered as a control patients those on antiviral therapy who did not receive adjuvant danazol due to only mild thrombocytopenia on antiviral therapy, matched for baseline platelet count, presence of cirrhosis, age, sex and HCV genotype. Efficacy was evaluated as the capacity to increase in platelet counts until the end of the treatment period.

 

Results:

A total of 41 patients with HCV-associated thrombocytopenia with PEG IFN/ribavirin treatment were studied: 26 patients (20 females, 6 males), mean age of 54.57± 8.40 yr who received danazol and 15 controls (9 females, 6 males), mean age of 55.8 ± 13 yr. Ninety percent of 41 patients had cirrhosis and the HCV genotypes were similar between groups. The platelet count increases in the Danazol group from baseline (75300 ± 11502) after treatment (123,900 ± 30411 p=0.0063). Whereas in the control group the mean count range from (238953.3 ± 141962.9 to 174200± 91643, p=0.9246) respectively. No association between genotypes and thrombocytopenia was observed (P>0.05). Danazol safety was assessed by the absence of collateral negative effects, except colestasis reversible in two patients.

 

Conclusions:

·        Adjuvant use of danazol is associated with increased platelets counts in patients on antiviral therapy with interferon and rivabirin for HCV infection and cirrhosis.

·        Although the mechanisms of danazol’s action is unclear we believe that maybe it involves impairment of macrophage-mediated clearance of antibody-coated platelets via decreased Fc receptor expression like in autoimmune thrombocytopenia.

·        This is new therapeutic option to treat thrombocytopenia and maximize the sustained virologic response.

 


Topic: Treatment – PEG-Intron

 

261. Relapse rates among HCV Genotype 1 early virological responders in a retrospective community-based cohort of patients treated with PEGETRON® in British Columbia, Canada

A. Yu; W. D. Hill; H. Mah; A. Mak; M. Krajden 

 

PURPOSE:

Response profiles from a community-based cohort of HCV genotype 1 infected patients undergoing a 48 wk course of Peginterferon alfa-2b plus Ribavirin (PEGETRON®) in British Columbia were assessed for the impact of residual viremia at wk 12 during Early Virological Response (EVR) determination. End of Treatment (EOT) response, Sustained Virological Response (SVR) and relapse rates were categorized with respect to whether a partial virological response or early virological clearance was achieved at wk 12.

 

METHODS:

Databases maintained by BC PharmaCare and the British Columbia Centre for Disease Control were used to calculate EOT, SVR and relapse rates among genotype 1 patients whose wk 12 EVR result was reported between June 12, 2003 and February 6, 2005. Patients were required to have a HCV RNA baseline viral load of > 61,500 IU/mL (Versant HCV 3.0 assay) and achieved an EVR. EVR was defined as either a > 2- log10 drop in viral load at wk 12 with residual viremia (wk 12 > 615 IU/mL or a positive qualitative HCV RNA (Roche, Cobas AMPLICOR), i.e. partial virological response); or a > 2-log10 drop in viral load at wk 12 with aviremia (wk 12 < 615 IU/mL or a negative qualitative HCV RNA, i.e., early virological clearance). Viral relapse was defined as a negative qualitative HCV RNA at EOT and detectable HCV RNA 24 wks after EOT. Relapse rates were reported as ranges to include or exclude missing SVR data. Lower range estimate was defined as EOT responder and SVR non-responder, and higher range estimate as EOT responder and SVR missing and/or non-responder.

 

RESULTS:

A total of 696 HCV genotype 1 patients underwent wk 12 testing during PEGETRON® treatment between June 12, 2003 and February 6, 2005. Of these, 507/696 (73%) had baseline viral loads > 61,500 IU/mL and achieved an EVR. 380/507 (75%) demonstrated early virological clearance and 127/507 (25%) had a partial virological response at wk 12. EOT results were available for 248/507 (49%) of whom 204/248 (82%) were aviremic at wk 12 and 44/248 (18%) were viremic at wk 12. 197/248 (79%) were EOT responders; EOT response rate was 183/204 (90%) for aviremic at wk 12 and 14/44 (32%) for viremic at wk 12. Relapse rates for aviremic patients were 10% to 32% (low and high ranges) whereas for viremic patients at wk 12, the relapse rates were 50% to 79%.

 

CONCLUSION:

·        Among patients treated with PEGETRON® for 48 wks, EVR aviremic patients had an EOT response rate of 90% and relapse rates of 10% to 32%.

·        In contrast, EVR viremic patients had an EOT response rate of 32% and relapse rates of 50% to 79%. The presence of residual viremia at wk 12 has an unfavourable outcome with fixed duration therapy.

 


Topic: Treatment – PEG-Intron

 

262. Viral and STAT kinetics in patients with chronic hepatitis C treated with pegylated interferon a-2b plus ribavirin.

G. Malizia; G. Giannuoli; E. Gallo; S. Madonia; E. Aragona; O. Dino; G. Pietrosi; A. Rizzo; S. Patti; M. Vitale; P. Mondello; F. Tinè 

 

Background:

Treatment with pegylated interferon-a (PEG-IFN-a) and ribavirin (RBV) induces sustained virologic response (SVR) in about 55% of patients with chronic hepatitis C (HCV). Among several factors, HCV interference with IFN-a signal transduction Jak-STAT pathway has been proposed as a possible determinant of treatment failure. Viral kinetic studies have shown that early viral response predicts SVR.

 

Aims:

To evaluate kinetics of STAT proteins in peripheral blood mononuclear cells (PBMC) in comparison to viral kinetics and to assess whether STAT kinetics may predict the outcome in HCV patients with low probability of response.

 

Methods:

15 patients with HCV genotype 1 (n=12) or 4 (n=3) treated with PEG-IFN-a 2b (1.5 mg/kg once weekly) plus RBV (1,000-1,200 mg daily) were prospectively evaluated one hour before treatment (T0) and at days 1 (T1), 2 (T2), 7 (T7) and 14 (T14) for quantitative serum HCV-RNA and PBMC cytoplasmic and nuclear STAT1 and STAT2. PBMC protein extracts were analyzed by Western blot and EMSA.

 

Results:

Six patients (40%) achieved SVR, two (13.3%) were relapsers and seven (46.7%) were virologic non responders (NR). HCV-RNA levels fell ≥1 log in many patients, mostly responders, at T1 and T2, with an intermediate increase at T7. At T14, only seven patients showed a renewed ≥1 log HCV-RNA decline (5 SVR, 1 NR, 1 relapser). PBMC analysis showed that STAT1-STAT2 nuclear translocation was restricted to the SVR patients and one relapser with a proportion that progressively increased from T1 to T14. Among the seven patients showing STAT1-STAT2 in the nucleus of PBMC at T14, EMSA analysis showed both STAT2 and STAT1 DNA binding only in the six SVR. Comparing early viral and STAT kinetics during the first two weeks, we found that whereas the occurrence of a ≥1 log fall of HCV-RNA at T1 was in most cases not associated to STAT1-STAT2 nuclear localization in PBMC, the rate of this association increased through time, being highest at T14 (5 SVR, one relapser). When we compared STAT kinetics at T14 and virologic response at week 24, we found that among the eight HCV-RNA negative patients (six SVR and both relapsers), only the six SVR showed also STAT1-STAT2 nuclear import and DNA binding, whereas none of the seven HCV-RNA positive patients showed nuclear STAT1-STAT2.

 

Conclusions:

Our data suggest that the variability of virological response to treatment with PEG-IFN-a and RBV is associated with intrinsic differences in the pattern of IFN signaling pathway and that STAT1-STAT2 nuclear translocation and DNA binding in PBMC may predict SVR as early as two weeks after treatment start.

 


Topic: Treatment – General

 

263. Morphological analysis and assessment of HCV-RNA and ribavirin concentration in seminal fluid of chronic hepatitis C patients undergoing antiviral combination therapy

H. Hofer; J. Donnerer; K. Sator; K. Staufer; T. Scherzer; C. Dejaco; M. Sator; J. Huber; H. Kessler; P. Ferenci 

 

Background:

At present, combination therapy with pegylated interferon-alpha and ribavirin is the treatment of choice for patients with chronic hepatitis C (CHC). Due to the possible teratogenic effect of ribavirin effective contraception is mandatory during antiviral therapy.

 

Aim:

Aim of the study was to evaluate seminal parameters, ribavirin and HCV-RNA concentration in seminal fluid and serum prior to and during antiviral treatment.

 

Patients and Methods:

So far, 10 male patients (mean age: 43±9 (years±SD) with CHC who were treated with pegylated interferon-alpha-2a (Pegasys®, Roche, Austria) in combination with ribavirin (Copegus®, Roche, Austria) were investigated. All patients were negative for HIV or HBV co-infection. The HCV genotype distribution was HCV-1 (n=5), HCV-2 (n=1), HCV-3 (n=1), HCV-4 (n=3). Seminal fluid (sperm concentration, motility and morphology) was analyzed morphologically. HCV-RNA and ribavirin concentration (serum and seminal fluid (diluted 1:10)) were determined by quantitative PCR (TaqMan®, Roche Austria; LOD: 10 IU/mL) and HPLC, respectively. Examinations were carried out at baseline, at week 4 and at week 12 of antiviral therapy

 

Results:

HCV RNA was detectable in the seminal fluid of only one patient prior to antiviral therapy (with a serum viral load of 4.04 MU/ml) and was undetectable in all patients after 4 and 12 weeks of combination therapy. Ribavirin concentration was substantially higher in the seminal fluid (week 4: 4.7±1.9 µg/ml, [mean±SD]; week 12: 4.3±0.4) than in serum (week 4: 2.2±0.3 [p=0.01]; week 12: 1.9±0.3 [p=0.02]). Morphological semen abnormalities were common at baseline (asthenoteratozoospermia: n=4, asthenozoospermia: n=1, teratozoospermia: n=3). Sperm density (BL: 70±31x106/ml, Week 4: 50±32, week 8: 59±43 [n.s.]), percentage of sperms with progressive motility (BL: 45±25%, Week 4: 30+28, week 8: 30+23 [n.s.]), and percentage of sperms with normal morphology (BL: 21±14%, Week 4: 19±11, week 8: 11±6 [n.s.]) tended to further decrease during antiviral therapy.

 

Conclusion:

·        HCV RNA is detectable in seminal fluid only in a low proportion of CHC patients. In contrast, pre-treatment semen abnormalities with reduced percentage of spermatozoa with normal progressive motility and normal morphology are common in patients with chronic HCV infection with further impairment during antiviral therapy.

·        Ribavirin concentration is twofold elevated in seminal fluid compared to serum levels, which reinforces the need of contraception during antiviral combination therapy.

 


Topic: Treatment – HIV/HCV Coinfection

 

264. Fosamprenavir in HAART schedule induces a rapid virological and biochemical response to HCV coupled to Th1 boosting in HIV/HCV coinfected patients.

A. Perrella; S. Grattacaso; M. Gnarini; C. Sbreglia; L. Atripaldi; A. D'Antonio; O. Perrella 

 

Objectives:

Pegylated recombinant Interferon plus ribavirin after HAART induced immune system restoration is the treatment schedule in HIV/HCV patients (pts). We aimed to evaluate the effect of Fosamprenavir on immune function in naïve-drug coinfected patients before to start treatment with Interferon plus ribavirin.

 

Methods:

We studied 10 naïve pts ( 4 F and 6 M) with HIV/HCV infection with at least one year history of HCV persistent infection and treated with: [(AZT 300mg + 3TC 300mg Twice) + (Fosamprenavir 700mg twice) + (RTV 100mg)], assaying CD3+/CD4+, INF-γ and IL-4 ELISpot specific response (HCV-core peptides; Pro-Immune,Oxford,UK), HIV and HCV Viral Load (Amplicor Roche system) and Transaminasis before to start HAART treatment (T0) and every month. Sign Test was used for statistic analysis.

 

Results:

At Time 0: CD4+ =186 ± 23 (mean ± s.d.); ALT= 121 ± 44; AST =93 ±31; HCV-RNA = 569x103 ± 236x103 IU/mL; HIV-RNA = 90x103 ± 19x103 IU/mL, while Elispot was IFN-γ 62 ± 10 SFC and IL-4 93 ±12 Spot Forming Colonies (SFCs). At T1: CD4+ = 414± 63; HIV-RNA = 209 ± 427 IU/mL but more surprisingly we had ALT = 22 ± 9; AST = 25 ±8; HCV-RNA = 13x103 ± 30x103 IU/mL (two out of ten pts had become negative at Viral load). Concerning ELISpot we had IFN-γ 112 ± 14 SFC and IL-4 = 52 ±16 SFCs. At T3: CD4+ 486 ± 48, with negative HIV and HCV viral load and normal transaminasis serum levels. Differences were statistically significant (p <.01).

 

Conclusion:

Fosamprenavir treatment in HAART schedule induces a decrease of HIV-RNA with CD4+ increasing within the first month, but more interestingly also a rapid HCV virological and biochemical response with a boost of Th1 immune network. Fosamprenavir treatment may be an important strategy in the therapy of HIV/HCV naïve coinfected patients.

 


Topic: Treatment – General

 

265. Improved Response Rates with Treatment Extension to 72 weeks in Slow Responders to Peginterferon and Weight-Based Ribavirin in Chronic Hepatitis C Virus (HCV) Infection

B. Pearlman; C. Ehleben 

 

Background:

For therapy-naïve, chronic hepatitis C- genotype 1-infected patients, treatment with pegylated interferon and ribavirin for 48 weeks has become the standard of care. For slow responders to treatment, there has been interest in extending therapy duration in hopes of improving rates of sustained virologic response (SVR). Two recent studies suggested that slow responders to treatment enjoy improved SVR rates with 72 weeks of therapy compared to 48 weeks, because of a diminution in rates of relapse; however, both studies used suboptimal doses of ribavirin (800 mg daily) (Gastroenterol 130:1086, 2006; Gastroenterol 131:451, 2006). It is unclear if therapy prolongation in slow responders would be beneficial, if weight-based ribavirin were utilized.

 

Methods:

We analyzed data from two studies in which slow responders received either a customary treatment duration of 48 weeks or treatment extension to 72 weeks. One study was from the U.S. (Hepatology, In-press, 2007), and the other was from Europe (AASLD 2006, abs #390; EASL 2007, abs #641). The U.S. cohort was 48% African American and 52% Caucasian; the European cohort was 90% Caucasian. Slow response was defined by at least a 2-log decrement in baseline serum HCV RNA yet detectable viremia at 12 weeks of therapy with undetectable serum HCV RNA at 24 weeks. Slow responders in the European study also had detectable viremia at 4 weeks. The lower limits of RNA detection for the U.S. and European studies were 10 and 50 IU, respectively.

 

Results:

Rates of SVR were significantly superior in slow responders when treated for 72 weeks compared to 48 weeks, largely because of an improvement in relapse rate (Table)

 

Conclusions:

·        Treatment extension to 72 weeks relative to 48 improved SVR rates in slow-responders to peginterferon and weight-based ribavirin, in two disparate patient populations.

·        SVR was improved because of a decrement in relapse rate.

·        Results should be confirmed in larger prospective trials.

 

 

Study Onea

Study Twob,c

Interferon

type

Peg alpha

2-b

Peg alpha

2-a

Ribavirin

dose

800-1,400 mg/day

1,000-1,200

mg/day

Study

population

U.S.*

100% genotype 1

Europe

>90% genotype 1

<10% genotype 4

Total sample size

361

373

Slow responders analyzed (percentage total sample)

101(28)

41(11)

SVR

(48 weeks)

18% (9/49)

52% (13/25)

SVR

(72 weeks)

38% (20/52)

69% (11/16)

Relapse rate

(48 weeks)

59%

32%

Relapse rate

(72 weeks)

20%

18%

*48% African American; aHepatology, In-press, 2007; bAASLD 2006, abs #390; cEASL 2007, abs #641.


Topic: Treatment – General

 

268. Treatment of recently acquired hepatitis C infection in injecting drug users: Preliminary results from The Australian Trial in Acute Hepatitis C (ATAHC)

G. J. Dore; M. E. Hellard; G. V. Matthews; P. S. Haber; D. R. Shaw; B. Y. Yeung; K. Petoumenos; I. A. van Beek; G. W. McCaughan; Y. Pan; R. A. Ffrench; W. D. Rawlinson; A. R. Lloyd; J. M. Kaldor 

 

Introduction:

Short duration treatment for acute hepatitis C virus (HCV) infection with pegylated interferon monotherapy has been shown to be highly effective, but has been investigated to a very limited extent in injecting drug users (IDUs), even though they are the population most at risk of infection in many high-income countries. The Australian Trial in Acute Hepatitis C (ATAHC) was funded by the US National Institutes of Health to examine the natural history and treatment of recently acquired HCV in IDUs.

 

Methods:

A longitudinal cohort was defined by having a first positive anti-HCV antibody test within 6 months of screening, plus either a negative antibody test within the preceding 24 month period or acute clinical hepatitis within the prior 12 months. Those in the cohort with detectable HCV RNA at screening were assessed for treatment with PEG-IFN α-2a (180 mcg weekly for 24 weeks), and follow up was undertaken in parallel protocols for both treated and untreated participants. Treatment outcomes among the initial 50 HCV monoinfected subjects commenced on treatment are presented on all subjects, and separately on only those subjects with available HCV RNA assessment at week 24.

 

Results:

Since August 2004, 132 participants have been enrolled, with 85 (64%) commencing treatment, including 59 with HCV infection and 26 with HIV/HCV co-infection. Of the initial 50 participants with HCV only who received treatment (mean age 30 years, 66% male), 41 (82%) became infected via injecting drug use.  Fifty percent had HCV genotype 1, the median HCV RNA was 380,000 copies/ml, and 23 (46%) had symptomatic acute infection. HCV treatment commenced a median 35 weeks (range, 18 – 81 weeks) after the estimated date of infection.

 

In the initial 50 HCV monoinfected subjects undergoing treatment, SVR rate was 56% by IIT.  Poor adherence (<80%) was seen in 34% of subjects.  Factors associated with improved SVR were treatment adherence (>80%) and absence of injection drug use during treatment and post treatment follow-up.  Among 24 subjects with undetectable HCV RNA at week 24 and with week 48 assessment, one case of HCV RNArecurre3nce occurred and was consistent with reinfection by HCV RNA sequencing.

 


Topic: Treatment – General

 

269. Short-term prolongation of peginterferon plus ribavirin combination therapy is a safe and effective treatment strategy for genotype 1b chronic hepatitis C patients

H. Ikeda; M. Suzuki; C. Okuse; M. Kobayashi; H. Takahashi; N. Matsumoto; H. Yotsuyanagi; T. Yasuda; S. Iino; F. Itoh 

 

Introduction:

It has been shown that 72 weeks (wks) of peginterferon plus ribavirin combination therapy (PEG/R) for genotype 1 chronic hepatitis C (CHC) patients, whose serum HCV RNA was positive at 4 wks of treatment increases sustained viral response (SVR) rate. However, the prolongation of treatment duration increases therapy discontinuation because of the decrease of medication tolerability and the increase of medical expense. This result suggests 72 wks of PEG/R is difficult for some patients to complete.

 

In this study, we focused on the patients with early viral response. Since they represent about a half of patient population, an increase of SVR rate of these patients should greatly affect the overall SVR rate. We set short-term prolonged treatment durations of PEG/R for genotype 1b CHC patients, depending on the time point when serum HCV RNA turned negative. And its efficacy was evaluated.

 

Methods:

Total of 52 genotype 1b CHC patients (30 male, 22 female, mean age 55±11years) were enrolled in this study from December 2004 to September 2005. They were treated with peginterferon alpha 2b (1.0-1.5µg/kg/wk) and ribavirin (600-1000mg/day) and serum HCV RNA levels were estimated every 4 wks. The viral response was defined and the treatment durations were determined by the time point when serum HCV RNA turned negative. 1) 4 wks; rapid viral response (RVR); 48wks duration, 2) 8 wks; early viral response (EVR); 52wks duration, 3) 12 wks; EVR; 56 to 60 wks duration, 4) 16 to 24 wks; late viral response (LVR); 72 wks duration. Patients with positive serum HCV RNA at 24 wks finished treatment without prolongation of PEG/R. And we prospectively investigated SVR rates of these groups.

 

Results:

Numbers of the patients achieved RVR, EVR and LVR were 4 (7.6%), 28 (53.2%) and 6 (11.5%), respectively. Only two patients (3.8%) could not complete this treatment protocol. SVR rates of the RVR, EVR and LVR patients were 100% (4/4), 78.6% (22/28) and 66.7% (4/6), respectively. The SVR rate of these 3 groups was 78.9% (30/38). While 86.4% (19/22) of male and 85.7% (6/7) of female under age of 55 achieved SVR, only 44.4% (4/9) of female aged 55 or over achieved SVR.

 

Conclusion:

Our results suggest that the short-term prolonged treatment duration of PEG/R determined by the time when serum HCV RNA turned negative is a safe and effective treatment strategy for genotype 1b CHC patients. However, this treatment is insufficient for female age 55 or over.

 


Topic: Treatment – Pegasys

 

271. Predictors of Response to Pegylated Interferon-α2A and Ribavirin in a Cohort of Patients Infected with the Same Strain of HCV: The O’Brien Project

V. I. Descalzi; S. E. Yantorno; S. M. Soria; F. M. Cairo; N. Massenzio; J. E. Gonzalez; M. S. Munne; G. Picchio; F. G. Villamil 

 

O'Brien is a small rural town of Argentina (2200 inhabitants) with a high prevalence of HCV infection (102/1832 (5.6%), 12.6% in >40 years, 23.4% in >60 years). All viremic patients (n=83)were infected with genotype 1b and showed 90.4-97.5% homology in NS5b nucleotide sequencing (Hepatology, 2002: 1660A). The presumed common source of infection, present in all patients, was the administration of unsafe injections a mean of 35 years before diagnosis.

 

Goals:

to analyze results of combined pegylated interferon α-2A (PEG) and ribavirin (RIB) therapy for 48 weeks and to identify predictors of sustained virological response (SVR).

 

Methods:

the study included 32 patients (50% males) aged 51±10 years. Viral load was investigated by Amplicor Monitor 2.0 and HCV RNA by RT-PCR. At baseline 21 patients (75%) had high VL (>800000 IU, mean 6.4±0.8 log IU) and only 9 (28%) elevated ALT. Liver biopsy showed stage 0 in 2, I in 5, II in 12, III in 6 and IV (cirrhosis) in 5 patients by METAVIR score. Patients received 180μg/week of PEG and 1000-1200 mg/day of RIB according to body weight (> or <75 Kg).

 

Results:

Two patients discontinued therapy (weeks 2 and 8) due to adverse effects and the remaining 30 completed 48 weeks. Dose reductions of PEG were required in 5/30 (17%) patients and of RIB in 8/30 (27%). However, all fulfilled the 80%/80%/80% rule at all time points of treatment. Thirteen patients (43%) received G-CSF and 6 (20%) EPO. On an intention-to-treat basis, virological responses were: 91% (29/32) at week 12 (EVR), 91% at week 24, 91% at week 48 (ETR) and 59% (19/32) at week 72 (SVR). Predictors of SVR by univariate analysis were age (48±2 vs. 56±2 years, p=0.039), significant alcohol (>80 grams in males and >50 grams in females) consumption (10.5% vs. 45.5%, p=0.029), low fibrosis stages (p=0.008) and cirrhosis (0% vs. 45.5%, p=0.001). Female gender (63% vs. 27%, p=0.058), lower BMI (25±1.5 vs. 29±1, p=0.08) and low VL (42% vs. 9%, p=0.057) were more frequent among patients with SVR but the differences were not significant. Fibrosis stage was the only independent predictor of SVR by multivariate analysis (OR: 0.275, 95% CI: 0.101-0.752, p=0.012).

 

Conclusions:

1) Treatment with PEG-RIB of patients from O'Brien was associated with a SVR of 59% despite that the majority had elevated VL (75%)and a significant proportion (34%) advanced disease with fibrosis stages III or IV; 2) In this unique cohort of patients infected with the same strain of HCV genotype 1b, histological severity was the only independent predictor of SVR

 

This study was supported in part by the Foundation for Research and Education in Liver Diseases (FUNDIEH) and by Productos Roche SA

 


Topic: Treatment – PEG-Intron

 

272. Time to HCV RNA Negativation in Hepatitis C Virus (HCV) Type 1-Infection During PEG-Interferon-alpha-2B plus Ribavirin Therapy: Differences in Relation to the Assay Sensitivity (Indiv-1 Study Group)

T. Berg; V. Weich; G. Teuber; H. Klinker; B. Möller; J. Rasenack; H. Hinrichsen; T. Gerlach; U. Spengler; P. Buggisch; H. Balk; M. Zankel; C. Sarrazin; S. Zeuzem 

 

Introduction:

Exact determination of early virologic response has great implication for designing a more refined treatment strategy in HCV infection. To achieve this goal one needs accurate information regarding parameters which govern the time to HCV RNA negativation. A disadvantage relies in the fact that the available virologic tests differ in their sensitivity, i.e. they only give an estimate whether viral replication is completely suppressed. In a prospective study we therefore analysed the time to virologic response by determining HCV RNA levels either by the quantitative bDNA or the highly sensitive TMA test.

 

Methods:

433 patients received 1.5 ug/kg PEG-IFNa-2b per week plus 800-1400mg RBV for at least 18-48 weeks. All patients were examined by bDNA (detection limit 615 IU/mL) weekly until week 8 and at weeks 12, 24 and 48. bDNA-negative patietns were additionally analysed by the TMA test (detection limit 5.3 IU/mL).

 

Results:

There is clear evidence that the frequency and time of response observed during therapy was significantly lower when the HCV RNA levels were calculated by the TMA assay. Thus a few clear answers can be given from these data: 1. at week 12, 71% of the patients were negative by bDNA but only 51% by TMA; 2. the average time necessary to induce HCV RNA negativity was 7.4 weeks for bDNA and 12.6 weeks for TMA (p< 0.05); 3. for patients being already bDNA negative it still took 5.6 weeks (0-40) to also become TMA negative. Forth: by bDNA testing, a steady increase of complete virologic responses (<615 IU/mL) of around 10% per week (9-11%) was observed within the first 4 weeks of therapy, but after the fourth week this phenomenon became less pronounced. In contrast, as estimated by TMA, the HCV RNA negativity rates remained constant within the first 12 weeks showing frequencies of around 3.5-6.7% per week.

 

Conclusion:

The most important discrepancies between the two test systems (bDNA vs TMA) with respect to frequency and rate of virologic response can be observed within the first 12 weeks of therapy. At the end of treatment, however, frequencies of undetectable HCV RNA levels did not differ greatly and reached around 70% independently whether bDNA or TMA was used. From all these data it emerges that there is a risk to overestimate virologic response rates when HCV RNA levels are only assessed by the quantitative assay.

 


Topic: Treatment – Disease Progression

 

273. Impact of antiviral therapy and response to treatment on long-term outcome of chronic hepatitis C (CHC):a propensity score analysis in a population-based cohort of 1159 patients

E. Monnet; J. Crouzet; A. Minello; T. Thévenot; A. Gagnaire; V. Jooste; P. Hillon; V. Di Martino 

 

Background:

The effect of antiviral therapy and sustained virological response (SVR) on the long-term outcome of CHC has never been assessed through population-based cohort study reflecting usual medical practice using clinical endpoints. Concerns can be raised for clinical trials and observational studies which suggested the clinical benefit of antiviral therapy regarding representativeness of the studied population, follow-up duration, or selection biases associated with treatment allocation.

 

Aim:

The aim of this study was to assess treatment and SVR effects on the outcome of 1159 HCV monoinfected viremic patients recruited in a well-defined population of 1,005,817 inhabitants, using the propensity score technique to reduce bias in the comparison of non-randomized treatment groups.

 

Methods:

All HCV mono-infected viremic patients diagnosed in the study area between 1994 and 2001 were included and followed for 4.9±2.6 years. 409 patients (35.2%) received antiviral therapy ((peg)-interferon-α ± ribavirin), of whom 142 (34.7%) achieved SVR. The effects of antiviral therapy and SVR on the risk of decompensated cirrhosis, hepatocellular carcinoma and death (liver-related or not) were estimated separately by time-dependent Cox regression analyses including a propensity score to adjust for observable differences between treated and untreated patients and considering all the demographic variables known to influence the natural history of CHC.

 

Results:

Treated and untreated patients were significantly different for age, gender, place of residence, route of infection, self-reported excessive alcohol consumption, and liver damage according to the Metavir score. Using Kaplan-Meier estimates, the 5-year rates of decompensated cirrhosis and of all-causes and liver-related deaths were 6.0%, 18.5% and 6.5% in untreated patients, 2.6%, 4.9% and 2% in treated patients who did not achieve SVR, and 0.7%, 0% and 0% in treated patients who achieved SVR, respectively (p=0.019 and p<0.0001 by log-rank tests). Propensity-adjusted multivariable Cox regression failed to demonstrate a better outcome in patients who received antiviral therapy, despite lower RR of cirrhosis decompensation (0.45) and hepatocellular (0.29) and the 0% rate of death in patients who achieved SVR. Interestingly, the risk of all-causes death was 0.48 for treated patients without SVR (p=0.06).

 

Conclusion:

This population-based study suggests a benefit of antiviral therapy on the long-term outcome of CHC. Using propensity-adjusted Cox regression analysis, the complete demonstration should be given with a larger studied population and/or a longer follow-up duration to increase the number of events.

 


Topic: Treatment – General

 

275. Insulin Resistance (IR) defined by the homeostasis model of assessment insulin resistance (HOMA-IR) index has a direct effect on early viral kinetics during Pegylated-Interferon therapy for Chronic Hepatitis C.

G. Bortoletto; S. Realdon; F. Dal Pero; M. Gerotto; L. Scribano; S. Boninsegna; D. Martines; A. Alberti 

 

Background:

Insulin resistance (IR), a central feature of the metabolic syndrome, has emerged as a key factor reducing the response to Pegylated-Interferon (PEG-IFN) based therapy in chronic hepatitis C. The pathogenic mechanisms underlying this association are still unclear.

 

Aim:

To examine the relationship of baseline serum insulin and of homeostasis model of assessment insulin resistance (HOMA-IR) index with the early virological response to PEG-IFN, taken as a measurement of the intracellular response to Interferon (IFN) signaling.

 

Methods:

In 30 patients treated with weight-based doses of PEG-IFN plus Ribavirin, baseline serum, insulin and HOMA-IR were measured the same day of the first IFN injection. HCV-RNA levels were measured by RealTime PCR (Abbott m2000, LoD 12 IU/mL) in all patients at baseline, as well as 24 hours and at week 1, 4, 12 after treatment initiation to define the individual kinetics of response.

 

Results:

Mean baseline insulin level was 13.38±7.21 mIU/L (range: 1.5-28) while, mean baseline HOMA-IR was 3.11±1.64 (range: 0.36-6.29). No statistically significant association was found between baseline insulin levels and baseline viremia or HCV-RNA decay at the different time-points during therapy. On the other hand, when patients were stratified by baseline HOMA-IR, those with high insulin resistance index showed a significant reduction in virus decay already at 24 hours and thereafter compared to cases with lower HOMA-IR (see Table).

 

By Kaplan-Meier analysis, patients with HOMA-IR>=4 had 0% rate of HCV-RNA negativity during the first 12 weeks of treatment while, the percentage of HCV-RNA negative cases among those with HOMA-IR<4 was 20% at week 1, 40% at week 4 and 50% at week 12.

 

Baseline body weight and body mass index did not show a significant association with virus decay.

 

 

HCV-RNA Log decay

HOMA-IR

24 Hours

Week 1

Week 4

Week 12

<3

1.11±0.52

p=0.04

0.44±0.61

p=0.12

1.68±1.84

p=0.12

3.29±2.46

p=0.05

 

 

 

 

 

>=3

0.55±0.71

0.14±0.43

0.71±0.70

2.34±2.36

<4

1.08±0.58

0.44±0.57

1.61±1.57

3.54±2.31

 

p=0.02

p=0.13

p=0.006

p=0.006

>=4

-0.05±0.35

-0.06±0.32

0.30±0.20

0.74±0.36

 

Conclusions:

We have demonstrated a direct effect of HOMA-IR on the early response during PEG-IFN based therapy for chronic hepatitis C, independently of insulin levels and BMI, suggesting that insulin resistance is the key factor in reducing the cellular response to IFN in hepatitis C infected patients.

 


Topic: Treatment – Pegasys

 

276. Treatment of chronic hepatitis C with peginterferon alfa-2a (40KD) (PEG) and Ribavirin (RBV) in naïve patients with HIV-HCV co-infection in the real-life setting in Germany

E. Zehnter; S. Mauss; K. Boeker; T. Lutz; S. Racky; W. Schmidt; R. Ullrich; I. Sbrijer; R. Heyne; A. Schober; C. John; K. Hey; B. Möller; B. Bokemeyer; B. Kallinowski; S. Pape; U. Alshuth; D. Hüppe 

 

Background:

HCV co-infection and related concomitant diseases, especially of the liver, have become more important since antiretroviral therapy has reduced morbidity and mortality associated with HIV. Clinical trials have demonstrated that treatment with PEG and RBV can achieve high rates of SVR in co-infected patients, but less is known about what happens in real life.

 

Methods:

The Association of German independent Gastroenterologists (bng) in cooperation with Roche conducted an observational study. From March 2003 to May 2007 data from >20 000 patients were collected from >500 centers. Efficacy, safety and compliance data were recorded. An analysis for naïve patients with HCV-mono (MONO) - or HCV/HIV coinfection (CO) who have been treated with PEG and RBV, was performed.

 Due to the ongoing character of the study, the status of data was frozen on May 15th, 2007, including queries solved.

 

Results:

·        Between March 2003 and May 2007 data from more than 20,000 patients have been documented.

·        A total of 13,596 treatment naïve patient screensings have been completed and 4,063 of these patients (29.9%) have been treated with peginterferon alfa-2a (40KD).

·        679 patients (5.0%) of the cohort had a HCV/HIV coinfection.

·        Of them 156 (23.0%) received a complete treatment with peginterferon alfa-2a (40KD), in almost all cases plus ribavirin, whereas HCV patients without HIV were treated in 30.2% of the patients (N=3907/12917).

·        Demographic data of treated patients with HCV/HIV coinfection were: mean age 39.0 years.  76.9% of patients were male, the mean BMI was 23.3 kg/m2.

·        Genotypes (HCV/HIV coinfection /HCV without HIV) for patients with HCV therapy:  Genotype 1 (59.0% / 58.3%), genotype 2/3 (34.6%/38.6%) and genotype 4/5/6/ (6.4%/3.1)

 

Treatment

·        The mean duration of HCV treatment for patients with genotype 1 was 34.3 weeks in patients with HCV/HIV coinfection vs. 38.3 weeks for HCV patients without HIV coinfection.  For genotype 2/3-patients the mean treatment durations were 31.9/24.0 weeks, respectively.

·        Discontinuations:  A total of 66.156 patients with HCV/HIV coinfection and 1062/3906 HCV patients without HIV coinfection (42.3%/27.2%) have discontinued therapy:  37.9%/39.5% due to virological non-response, 27.3/26.4% for poor tolerability, 13.6%/16.4% were lost to follow-up, 15.2%/10.8% for personal reasons and 12.1%/9.4% for lack of compliance.

 

Virological Response

·        Sustained Virological Response (SVR):  Complete treatment data is available for 156 patients with HCV/HIV coinfection and 3906 HCV patients without HIV coinfection, who were treated according to consensus recommendations.  An SVR was achieved by 61/156 with HCV/HIV coinfection (39.1%) and 2104/3906 HCV patients without HIV coinfection (53.9%).

 

Conclusion:

·        Although HIV co-infection is a serious and hepatitis-accelerating disease only a third of CO patients had been treated with PEG and RBV.

·        Although patients with HCV/HIV coinfection urgently need HCV treatment, 40% of these patients cannot be convinced of the indication.  The most frequent reasons for declining HCV treatment are fear of therapy and missing understanding of the urgency of the therapy. 

·         In this population, combination therapy was found to be reasonable safe and sufficiently effective even under real-life conditions.

·        A challenge will be to convince co-infected patients of the need for therapy, whilst minimizing the discontinuation rate and hence the extension of treatment duration.

 

Characteristics of Treatment patients

Co-infected (N=156)

Mono-infected (N=3907)

Age (mean yrs)

Male (%)

BMI (kg/m2)

Duration of HCV (mean yrs)

39.0

76.9

23.3

8.0

42.2

59.7

25.0

12.0

Genotype (%)

G1

G2/3

Other

 

59

38.6

3.1

 

58.3

34.6

6.4

SVR (%)

39.1

53.8

 

 


Topic: Treatment – General

 

277. Does prolonged therapy in HCV-genotype 3 patients with high viral load improve sustained viral response rates?

S. Mauss; D. Hüppe; E. Zehnter; M. Manns; G. Teuber; T. Dahhan; U. Meyer; B. Möller; N. Dikopoulos; T. Witthöft; J. Brack; M. Stern; S. Kaiser; R. Prinzing; . The bng hepatitis study group 

 

Objective:

The sustained viral response (SVR) in HCV-genotype 3 patients differs substantially depending on baseline viral load and viral response to therapy. Whereas patients with rapid viral response and low viral load show SVR rates >80%, patients with high viral load and no rapid viral response may reach SVR <50% after 24 weeks of therapy. These patients may be candidates for longer treatment durations. Here we report SVR data from a cohort of 3547 patients including 1148 patients with HCV-genotype 3 treated for 24 vs. 48 weeks with peginterferon and ribavirin.

 

Methods:

All patients were treated with at least one dose of peginterferon alfa-2b and weight based ribavirin as part of a German multicentre cohort. Only patients who were beyond 24 weeks of follow up after planned end of therapy (24 or 48 weeks) were included in this analysis (n=571). Patients were stratified according to HCV-RNA below or above/equal to 600.000 IU/mL. Patients with missing data at end of follow up were counted as treatment failures. Statistical analysis was performed using chi-square test.

 

Results:

157/207 (76%) of patients with genotype 3 and HCV-RNA <600.000 IU/mL reached SVR after 24 weeks of therapy versus 82/115 (72%) after 48 weeks of therapy (p>0.05, n.s.). 123/160 (77%) of patients with genotype 3 and HCV-RNA >600.000 IU/mL reached SVR after 24 weeks of therapy versus 66/89 (74%) after 48 weeks of therapy (p>0.05, n.s.).

 

Conclusion:

Extending therapy from 24 weeks to 48 weeks for HCV-genotype 3 did not improve SVR rates regardless of baseline viral load. These results confirm findings from the initial prospective, controlled study by Hadziyannis et al. Ann Intern Med. 2004; 140(5):346-55. In addition SVR was comparable for patients with low and high viral load. However it can not be excluded from this study that a more targeted approach based on viral kinetics, i.e. slow viral response, may be beneficial for a smaller subgroup of patients.

 


Topic: Treatment – PEG-Intron

 

279. Treatment of Hemodialysis (HD) Patients With Chronic Hepatitis C (CHC) Using an Escalating Dose Regimen of Pegylated Interferon (PEG-IFN) alfa-2b

S. Tan; M. Abu Hassan; A. Abdullah; B. Ooi; S. Rampal; T. Korompis; M. Merican 

 

Background:

CHC is a prevalent condition among patients receiving HD, and post-renal transplant CHC patients have poorer treatment-related outcomes. Additionally, treatment with IFN therapy has been associated with graft rejection. In this study, we evaluated the efficacy and safety of PEG-IFN alfa-2b in CHC patients receiving HD.

 

Methods:

This study included treatment-naive CHC patients aged 18-70 years with compensated liver cirrhosis and adequate hematologic parameters. Patients with coinfection, significant cardiovascular dysfunction, uncontrolled diabetes, and any contraindications to IFN therapy were excluded. Of the 46 CHC patients undergoing HD who were screened, 34 enrolled in the study. All patients received PEG-IFN alfa-2b 0.5μg/kg/wk; doses were increased by 0.25μg/kg/wk every 4 wks if well tolerated. Maximum dose was defined as 1μg/kg/wk at 48 wks in patients with genotype (G) 1 and 24 wks in those with G2/3. Patients unable to tolerate study medication were discontinued from the trial.

 

Results:

Baseline patient characteristics included mean age of 41.4±11.9 years (61.8% ≥40 years); males, 44.1%; G1, 70.6%; G3, 29.4%; mean body mass index, 22.6±4.4 kg/m2; median HD duration, 5.8 years (range, 3.8-8.2 years); normal alanine aminotransferase (ALT) levels, 55.9%; HCV RNA ≥700,000 IU/mL, 50%; and fibrosis ≥2 (modified Histology Activity Index score), 26.5%. In total, 97% (33/34) of patients reached maximum dose; however, 21% were unable to maintain that dose. Early virologic response (EVR; undetectable HCV RNA [<50 IU/mL] at wk 12) was attained in 15 of 20 G1 patients; end-of-treatment (EOT) and sustained virologic responses (SVRs) were attained in 10 of 15 and 9 of 18 G1 patients, respectively. Conversely, 8 of 10 G3 patients attained EVR, and EOT and SVRs were attained in 8/9 and 8/10 G3 patients, respectively. Almost 30% (11/34) of patients discontinued treatment early because of adverse events (AE). The most commonly reported AE was anemia; 64.7% of patients required blood transfusions. Low-dose epoetin was administered to 85.3% of patients during the trial. One patient died during the study of acute coronary syndrome after the 41st dose.

 

Conclusions:

In total, SVRs were attained in 37.5% (9/24) of G1 patients undergoing HD who were treated for 48 wks with an escalating dose regimen of PEG-IFN alfa-2b monotherapy. In contrast, 80% (8/10) of G3 patients, who received only 24 wks of this therapy, attained SVR. These results indicate that G3 patients undergoing HD can be successfully treated with short-term PEG-IFN alfa-2b monotherapy. Because PEG-IFN alfa-2b can be associated with AEs, supportive therapy may be necessary.

 


Topic: Treatment – General

 

281. Real-life Rates of Treatment Completion for HCV

A. A. Butt; M. Skanderson; K. A. McGinnis; C. K. Kwoh; A. C. Justice 

 

Background:

Rates and factors predicting treatment completion for HCV infection in real-life settings are unknown.

 

Methods:

We assembled a national cohort of HCV-infected veterans from 1998-2003, using the VA National Patient Care Database for demographic and clinical information, Pharmacy Benefits Management database for pharmacy records and the Decision Support Systems database for laboratory data. We studied the rates and factors predicting treatment completion for HCV.

 

Results:

For the 134,934 veterans with at least 1 inpatient or 2 outpatient codes, 16,043(11.9%) were prescribed treatment. Among the 10,641 veterans with > 1 year of follow-up, 22.5% completed a 48 week course of treatment. Non-completers were more likely to be black, have pre-treatment anemia, coronary artery disease, depression and more aggregate comorbidities. In multivariable analyses, non-completion was associated with baseline anemia (OR 0.66, 95%CI 0.56-0.78 for hemoglobin 10-14mg/dl) and depression (OR 0.78, 95%CI 0.69-0.89). Pegylated interferon was associated with higher rates of treatment completion. HIV-coinfection did not affect completion rates.

 

Conclusions:

A minority of HCV-infected persons are prescribed treatment and less than one-quarter complete a 48-week course. Anemia and depression are potentially modifiable factors that must be addressed at a population level before universal use of pharmacotherapy is advocated.

 

 

Baseline characteristics of HCV infected persons who completed a 48 course of treatment for HCV, and a flow sheet of analysis for the current study

 

Note:  complete lab data was available for 6,838 in ‘At least one year of follow-up.’  Complete lab data was available in 5,854 in ‘At least one year of follow-up’ data.

 


Topic: Treatment – Predictors of Treatment Response

 

282. Clinical Relevance of Rapid Virological Response (RVR) in Decompensated HCV-Related Cirrhosis Treated with PEG-Interferon and Ribavirin

A. Iacobellis; B. Annicchiarico; M. Siciliano; G. Niro; L. Accadia; N. Caruso; G. Bombardieri; A. Andriulli 

 

Background:

Recent studies provided positive data on the impact of HCV clearance by antiviral therapy in improving hepatic function in decompensated cirrhosis. However, low tolerability of therapy and the risk for severe infections render useful to single out those patients with a higher likelihood of achieving a sustained virological response (SVR).

 

Aim:

to determine whether in decompensated cirrhotics naïve to previous combined antiviral therapy RVR could predict SVR. Methods: 104 cirrhotics underwent treatment with peginterferon alfa-2b (1.5 mcg/kg/wk) and ribavirin (800 or 1000 mg) for 24 weeks.

 

Patients:

mean age was 62 +/- 7 yrs; 63% of patients were infected by geno 1/4; and 96% were staged in Child-Pough class B. Results: SVR was achieved in 29 patients (28%), overall; 10 of them (15%) with genotype 1 or 4, and 19 (48,7%) with genotype 2 and 3 (P < 0.01). On-treatment viral clearances, according to HCV genotypes, are given in the table. At treatment week 4, 36 patients cleared HCV (RVR), and 23 of them achieved SVR (63,8%) at a significant difference between genotypes: 9 of 18 genotype 1 and 4 patients (50%), and 14 of 18 genotypes 2 and 3 (78%; P < 0.01). All RVR patients who achieved SVR had a pre-treatment viral load < 350.000 copies/mL.

 

Conclusion:

Decompensated patients with HCV-related liver cirrhosis achieve on-treatment viral clearance at different time. Achieving the RVR status may guide tailoring length of treatment. Two-thirds of patients infected by genotypes 2 and 3 may achieve SVR with a treatment length as short as 24 weeks, provided they clear HCV at treatment week 4. In non-RVR patients with the latter genotypes and in those infected by genotypes 1 and 4, the adopted duration of therapy appears insufficient to attain optimal SVR rates. The present study further supports the feasibility of antiviral treatment with Peg-interferon alfa-2b and ribavirin in Child-Pugh class B cirrhotics.

 

 


Topic: Treatment – Predictors of Treatment Response

 

284. Iron Depletion and Response to Interferon in Chronic Hepatitis C (HCV) : A Meta-Analysis

R. r. Mummadi; K. S. Kasturi; G. Sood 

 

Background and Aim:

Hepatic iron content is known to influence the response to interferon (IFN) in chronic Hepatitis C (HCV) patients. Several studies have reported effect of Iron depletion on response to IFN in HCV. These studies are heterogeneous in design and outcome measures. We performed a meta-analysis of available studies (1995 through May 2007).

 

Methods:

Electronic database Medline, CINHAL and Science Citation index were searched. RCTS comparing Interferon treatment (IFN) with Interferon and Phlebotomy (IFN and Phlebotomy) were chosen for the meta-analysis. Sustained Virologic Response (SVR) was the primary out come. Sustained biochemical response (biochemical SR) and end of treatment Virologic response (ETR) were also analyzed. Data was pooled using Fixed effects (Peto odds Ratio) and Random effects (DerSimonian-Laird) method.

 

Results:

A total of 231 studies were identified among which 52 studies were selected and reviewed.The studies with known causes of iron overload ( Hemochromatosis, alcohol abuse, Porphyria cutanea tarda or transfusion related overload )were excluded. There were fifteen published studies evaluating effect of IFN with phlebotomy as an adjuvant therapy. The data was extracted from 5 studies (N=334) which met the inclusion criteria (RCTS). IFN with phlebotomy compared with IFN alone increased the probability of achieving SVR (Peto OR= 2.43 95 % CI 1.41-4.16)Virologic ETR (Peto OR=2.34 95%CI 1.48-3.70), and biochemical SR (Peto OR = 2.02 95% CI = 1.22-3.33).There was no significant heterogeneity among the studies included in meta-analysis. Sensitivity analysis excluding study with previous treatment failures did not impact the resuts. None of these studies were done using Pegylated IFN or ribavirin as treatment options.

 

Conclusions:

·        Phlebotomy increased the probability of achieving SVR, Virologic ETR, biochemical SR in patients with chronic hepatitis C.

·        A RCT to assess the influence of phlebotomy on treatment with Pegylated IFN and Ribavirin is needed.

 


Topic: Treatment – Pegasys

 

285. Efficacy of peginterferon alfa-2a and ribavirin in 2101 patients with HCV infection in real-life clinical practice: results of the French Hepatys study

M. Bourliere; D. Ouzan; M. Rosenheim ; M. Doffoel; P. Marcellin; J. Pawlotsky; L. Salomon; F. Fagnani; C. Hayem; I. Lonjon-Domanec; M. Vray 

 

Objectives:

Previous studies conducted in Europe and in the US have shown similar efficacy of peginterferon alfa-2a plus ribavirin in real-world setting compared to randomized controlled trials. A nationwide observational study was also conducted in France to determine the characteristics of hepatitis C patients under treatment, histology assessment and rates of sustained virological response (SVR).

 

Methods:

Between November 2003 and December 2004, 324 physicians recruited chronic hepatitis C patients treated with peginterferon alfa-2a (40KD). Patient demography and liver histology assessment were recorded at baseline and treatment and compliance were recorded every 3 months. Efficacy outcome was evaluated with qualitative PCR more than 3 months after the end of treatment.

 

Results:

Among the 2101 patients analyzed, 62% were male, the mean age was 47±12 years, the mean body weight was 71±14 kg and 17% had cirrhosis. Distribution of genotypes: GT1 53%, GT2 12%, GT3 25%, GT4 8%, GT5 2%. The majority of the patients in the cohort were HCV treatment naïve (70%). Liver biopsy and fibrosis markers were performed in 69% and 35% of the patients respectively but the relative proportions changed during the conduct of the study in favour of evaluating fibrosis markers. GT1 patients were biopsied more often than GT2 and 3 patients (77% and 56% respectively). The overall SVR rate was 57% (783/1377) in all patients and 63% (596/949) in naïve patients. Among naïve patients, SVR rate was 52% in GT1 (227/438), 80% in GT2 (115/144), 74% in GT3 (194/262), 55% in GT4 (42/76) and 59% in GT5 (10/17). Age below 40 years (p<0.001; odds ratio (OR) [95% confidence interval (CI)] = 2.4 [1.7-3.2], genotype 2 and 3 (p<0.001; OR [95% CI] = 2.7 [2.0-3.5], fibrosis less than F2 (p<0.001; OR [95% CI] = 1.7 [1.3-2.2], and naïve status (p<0.001; OR [95% CI] = 3.2 [2.2-4.6], were found to be independently associated with a higher response rate in multivariate analysis.

 

Conclusions:

This large study confirmed the efficacy of peginterferon alfa-2a plus ribavirin in the French clinical practice setting compared to randomized controlled clinical trials*. The increasing role of fibrosis markers rather than liver biopsy in the management of hepatitis C patient in France is confirmed.

 

*Fried NEJM 2002; Hadziyannis Annals 2004

 


Topic: Treatment – Predictors of Treatment Response

 

290. Predictors of Sustained Virological Response to Interferon-based Treatment in Hemodialysis Patients with Chronic Hepatitis C Virus Infection - a Patient Level Meta-analysis

C. E. Gordon; K. Uhlig; J. Lau; C. H. Schmid; A. S. Levey; J. B. Wong 

 

Background

Hepatitis C virus (HCV) infection has a prevalence of 13% in hemodialysis (HD) patients and increases mortality. Interferon (IFN) and pegylated-interferon (PEG-IFN) may eradicate HCV infection. We studied predictors of sustained virological response rate (SVR) to IFN in HD patients with HCV.

 

Methods

After performing a systematic review of IFN and PEG-IFN treatment in HCV-infected HD patients published between 1966 and December 2006, we extracted individual patient data (IPD) from included articles and acquired additional data by contacting study authors. We used univariate and multivariate logistic regression to identify predictors of SVR.

 

Results

Twenty studies of IFN monotherapy with 461 patients met inclusion criteria and provided IPD for 428 patients. Three studies of PEG-IFN involved 38 patients but did not supply IPD. The overall SVR was 41% (95% CI, 33-49%) with IFN and 37% (9-77%) with pegylated-IFN (PEG-IFN). Factors associated with statistically significantly higher SVR with IFN using IPD included: 3 MU or higher dose three times weekly (OR 3.3, 1.2-9.1), intended treatment duration of at least six months (2.0, 1.1-3.9), treatment completion (4.1, 2.4-6.8), lower HCV RNA at baseline (3.6, 1.9-6.7 per log10 lower RNA), and female gender (2.1, 1.3-3.4). Early virological response (EVR), measured as HCV RNA negativity 1-3 months into treatment, was also associated with significantly higher SVR (5.1, 2.6-10.0). HCV genotype 1 and cirrhosis were not associated with SVR. Despite limitations involving missing and clustered data, multivariate analysis documented independent associations of SVR with dose, duration, treatment completion, HCV RNA, and female gender.

 

Conclusions

HCV treatment in HD patients resulted in an overall SVR of 41% with IFN and 37% with PEG-IFN. SVR is higher in women, with low baseline HCV RNA, or with early virological response, and with IFN antiviral therapy at 3 MU for at least 6 months and completion of intended treatment duration.

 


Topic: Treatment – General

 

291. Bezafibrate treatment for chronic hepatitis C after failure of previous combination therapy with Interferon and Ribavirin

V. Weich; B. Schlosser; J. Halangk; A. Bergk; F. van Bömmel; T. Berg 

 

Introduction:

Lipoproteins have been reported to be involved in the infection cycle of hepatitis C virus. Former studies from Japan could demonstrate a significant reduction of liver enzymes and viral load after treatment with the lipid lowering agent bezafibrate. Bezafibrate exerts multiple effects on lipid metabolism by activating the peroxisome proliferator-activated receptor-alpha (PPAR-α) which modulates the expression of key genes of lipid transport, hepatic fatty acid and lipoprotein metabolism as well as inflammation.

 

Aim:

The aim of the present observational study was to assess the efficacy and safety of bezafibrate monotherapy in patients with advanced chronic hepatitis C who failed previous combination therapy with (peg)-interferon alpha and ribavirin.

 

Patients and Methods:

36 patients from our university hospital (mean age 61 years, HCV type 1 [n=34], HCV type 3 [n=1],HCV type 4 [n=1], stage 2 = 4 patients, stage 3 = 14 patients, advanced fibrosis [n=18]) received daily oral bezafibrate treatment (400 mg per day) on the basis of a prospective observational open-label study design. Clinical, biochemical and virological data were evaluated during a mean treatment duration of 12 months (range 2-49 months).

 

Results:

Three patients dropped out of the study complaining about vertigo or palpitations within the first days of treatment. In the remaining 33 patients no significant adverse events were observed. During the treatment course, a significant improvement in gamma-glutamyl transpeptidase levels (p<0.0001) as well as alanine aminotransferase levels (p<0.001) could be demonstrated in all patients. In 3 patients liver enzymes normalized completely. No significant effect on viral load was observed.  Only one patient showed viral decline of 1 log after 11 months of treatment.

 

Conclusion:

·        This observational study provides evidence that bezafibrate is effective for patients with chronic hepatitis C by reducing significantly ALT and GGT levels and could be therefore a therapeutic option, especially for those, in whom peg-interferon combination treatment was previously unsuccessful.

·        Further larger and randomized clinical trials including also histological endpoints are required to confirm these findings.

 


Topic: Treatment – General

 

293. Early reduction of Ribavirin leads to retardation of viral clearance and affects SVR

Y. Karino; J. Toyota; T. Arakawa; Y. Kuwata; J. Akaike; K. Yamazaki; T. Sato; T. Omura; S. Iino 

 

Background:

It is said a reduction of ribavirin (RBV) will not impact the SVR rate, but no examination has included the effect of the timing of the reduction of RBV while it is known that the timing of HCV RNA loss strongly relates to the SVR rate.

 

Aim:

To review the antiviral activity of RBV from the effect of the timing of reduction of RBV on the timing of HCV RNA loss.

 

Methods:

One hundred and twenty-four patients with genotype 1b and high viral load (62 males, 62 females; mean age 55.9 years old) who received PEG IFNα-2b plus RBV combination therapy for 48 weeks were included in analysis. All patients received RBV by a total clearance of RBV (CL/F)-based dose (we set 2250ng/ml as target blood concentration and calculated the dose of RBV from CL/F, 2005AASLD). The dose of PEG IFNα-2b of 1.5μg/kg/week was not reduced for the duration of administration. We determined the factors affecting the timing of HCV RNA loss in patients for whom RBV was not reduced (group A) by multiple regression analysis and prepared of a predictive formula. Appling this predictive formula to patients in whom RBV was reduced, we examined whether the timing of RBV reduction affects the timing of HCV RNA loss.

 

Results:

Predictive formula based on multiple regression analysis was: Estimated time of HCV RNA loss (week) = 1.8960 x Log HCV RNA (2W) + 8.5722, where HCV RNA (2W) is HCV RNA level (KIU/ml) 2 weeks after the start of treatment. This predictive formula allowed the good prediction of the actual timing of HCV loss. When applied to patients with RBV reduced after 8 weeks of treatment (group B) and in the first 8 weeks of treatment (group C), the fit was 100% (group B) and 69% (group C) that of the actual timing of HCV RNA loss with less than +/-4 weeks of predicted. With patients showing greater than +/-4 weeks difference between predicted and actual timing of HCV RNA loss (group C), the actual timing was delayed from the predicted time. In other words, delay in HCV RNA loss was statistically significant compared to without RBV reduction in patients with early RBV reduction. SVR rate with group A, B, and C was 60%, 62.5%, and 38.5%, respectively, and reflected the difference in the timing of HCV RNA loss.

 

Conclusions:

·        We reviewed patients with genotype 1 and high viral load with and without RBV dose reduction and correlation with the timing of HCV loss.

·        Because HCV RNA loss was delayed in patients for whom RBV was reduced early in treatment, it was thought that antiviral activity of RBV was expressed from a relatively early stage in IFN + RBV combination therapy.

·        A method of administration to avoid reducing RBV is important to improve the SVR rate.

 


Topic: Treatment – IDU

 

295. Treatment Uptake and Outcomes Among Current and Former Injection Drug Users (IDUs) Receiving Directly Observed Therapy Within a Multidisciplinary Group Model for the Treatment of Hepatitis C Virus (HCV) Infection

K. Genoway; J. Grebely; F. Duncan; M. Viljoen; L. Gallagher; D. Elliott; M. Khara; J. D. Raffa; S. deVlaming; B. Conway 

 

Purpose:

We evaluated HCV treatment uptake and outcomes among current and former IDUs attending a weekly peer-support group and receiving directly observed HCV therapy (DOT).

 

Methods:

Beginning in March 2005, patients interested in receiving treatment for HCV infection were referred to a weekly peer-support group and evaluated for treatment. Utilizing the existing infrastructure for addiction disease management, we have developed a model whereby the treatment of addiction, HCV and other medical conditions are integrated under the DOT model of care. Patients received directly observed therapy with pegylated interferon alpha 2a or alpha 2b (PEG-IFN alpha 2a or alpha 2b), both in combination with self-administered ribavirin (RBV).

 

Results:

Overall, 129 subjects were referred to the support group over a period of 108 weeks, with the mean attendance being 15 subjects per week (range 3-32). Overall, 10 (8%) did not medically qualify for treatment, 39 (30%) were lost to follow-up and 8 (6%) had completed or initiated treatment for HCV infection prior to attending the group. We observed a high uptake of HCV treatment among attendees, with 30% of subjects (39/129) currently under evaluation and 26% (33/129) having initiated or completed treatment for HCV infection. In a comparison of subjects that had initiated or completed treatment for HCV infection (n=33) and those lost to follow up (n=39), those having received treatment for HCV infection had a higher median attendance [34 meetings (Interquartile range, IQR = 11-33) vs. 2 meetings (IQR=1-3, P<0.001)] and were more likely to attend >3 clinic visits (97% vs. 23%, P<0.001) than those lost to follow up. To date, 31 patients (PEG-IFN alpha 2a/RBV = 15; PEG-IFN alpha 2b/RBV = 4) have initiated treatment for HCV infection at our site and 18 have completed therapy, with 67% (12/18) of subjects achieving an end of treatment response (Genotype 1 – 40%, Genotypes 2- 100%, Genotype 3 – 67%), despite ongoing drug use in 72% of patients during treatment and early discontinuation in 56%.

 

Conclusion:

·        These data demonstrate that with the appropriate programs in place, a high uptake of HCV treatment can be achieved among IDUs referred to a peer-support group.

·        Depression was a major cause of discontinuation, despite prophylactric antidepressant use in 78%.

·        Moreover, the treatment of HCV in current and former IDUs within a multidisciplinary DOT program can be successfully undertaken, resulting in end of treatment responses similar to those reported in randomized controlled trials.

 


Topic: Treatment – IDU

 

296. Infrequent Hepatitis C Virus (HCV) Re-infection after Sustained Virological Response (SVR) Among Current and Former Injection Drug Users (IDUs) Having Received Treatment for HCV Infection

J. Grebely; J. D. Raffa; K. Genoway; G. Showler; F. Duncan; M. Viljoen; M. Khara; S. deVlaming; C. Fraser; B. Conway 

 

Purpose:

To evaluate HCV re-infection following SVR among IDUs having received directly observed IFN alpha-2b or PEG-IFN alpha-2a/b in combination with self-administered ribavirin in a directly observed therapy program.

 

Methods:

Viremic HCV-infected IDUs, with ALT >1.5x ULN, received 24 or 48 week therapy (based on HCV genotype) with ribavirin and interferon alpha-2b, replaced by PEG-interferon alpha-2a/2b. Following treatment, subjects were encouraged to return to the clinic at follow-up intervals of ~1 year and were asked about their use of illicit drugs. HCV RNA testing by PCR was performed and positive results were genotyped.

 

Results:

Overall, 28/51 subjects (55%) receiving IFN alfa-2b (n=12), PEG-IFN alpha-2b (n=32) or PEG-IFN alpha-2a (n=7) achieved an SVR. Illicit drugs were used by 21/51 (41%) in the 6 months preceding therapy and by 29/51 (57%) during treatment. In total, 28 subjects were followed for a mean of 1.1 years (range, 0-3.2 years) following SVR. In this period, 13/28 (46%) reported using illicit drugs:

o       Illicit drug use post-SVR (%) – 13 (46)

o       Injection drug use post-SVR (%)

o       Injection cocaine – 3 (11%)

o       Injection heroin – 3 (11%)

o       Combined injection drug – 5 (18%)

o       Eleven subjects (39%) reported injection drug use.

o        

Overall, 25/28 (89%) remained HCV RNA negative, 1 died of hepatocellular carcinoma, 1 was lost to follow-up and 1 was positive for HCV RNA. This subject received 17 weeks of PEG-IFN alpha-2b therapy and had viral reoccurrence with the same genotype (G1), consistent with re-infection or viral relapse. Therefore, viremia re-occurred in 1/28 (3.6%), providing an estimated rate of re-occurrence of 4.0 cases per 100 person-years.

 

Conclusions:

o       Overall, 55% of current and former illicit drug users obtained an SVR.

o       Occurrence of HCV viremia was 3.6% (2.6 cases/100 person-years).

o       This is despite relapse to injection drug use in 46% of subjects.

o       Study is limited given that no longitudinal data on equipment sharing available. 

o       IDUs with treatment-induced clearance may be protected from HCV re-infection either through:

o       reduced risk behaviors for acquisition; or

o       partial protective immunity following successful treatment and enhanced clearance after reexposure

o       These data need to be confirmed in larger, prospective studies designed to evaluate HCV reinfection in IDUs following treatment induced viremia.

 


Topic: Treatment – PEG-Intron

 

297. Pegylated Interferon alfa-2b plus Ribavirin reduces insulin resistance and improves glucose metabolism in patients with chronic hepatitis C

M. Korenaga; K. Korenaga; K. Uchida; T. Yamasaki; K. Hino; I. Sakaida 

 

Background:

Hepatitis C Virus (HCV) infection is linked to insulin resistance which may contribute to fibrogenesis and carcinogenesis in chronic hepatitis C. Glucose intolerance setting of chronic HCV infection could be related etiologically to viral factors. However, IFN has been reported to acutely induce insulin resistance and glucose intolerance. Although HCV is a candidate for the development of insulin resistance, the effects of antiviral treatment on impaired glucose metabolism remain unclear. The aim of this study was to clarify whether insulin resistance was improved on Pegylated Interferon alfa-2b Plus Ribavirin (PegIFN/RBV).

 

Methods:

Plasma glucose (PG) level and immunoreactive insulin (IRI) level in the course of 75g oral glucose tolerance test (OGTT) were measured to evaluate glucose intolerance in 0, 4 and 12 weeks after initial PegIFN/RBV. The OGTT was performed after an overnight fast, and blood samples were taken at 0, 30, 60, 90 and 120 min following glucose ingestion. Then PG area under the curve (AUC-G), IRI area under the curve (AUC-I) and HOMA-IR were calculated. Simultaneously, oxidation rate of carbohydrate (%CHO), fat (%FAT) and nonprotein respiratory quotient (npRQ) were calculated by using an indirect calorimeter.

 

Results:

We examined 25 biopsy-proven patients who received PegIFN/RBV. Twelve patients (48%) were found to have diabetes while five (20%) showed impaired glucose tolerance (IGT) at the pretreatment according to OGTT as based on the revised diagnostic criteria of the American Diabetes Association (1997). In the patients of diabetes and IGT (n=17), the AUC-G was significantly decreasing (0w: 582±33 4w: 453±22: p<0.05) at week 4.Although HOMA-IR did not change at week 12 (0w: 2.4±0.3, 12w: 2.3±0.5), the AUC-I was decreased (0w: 212±25, 12w: 158±20: p<0.05). The %CHO increased (0w: 40±4, 12w: 50±6) and %FAT decreased (0w: 47±4 12w: 36±5), as a result, npRQ increased (0w: 0.837±0.015, 12w 0.871±0.017: p<0.05) at week 12. No one shows severe weight loss (5% down at pretreatment) and patients with normal glucose tolerance did not change by week 12. Finally, patients with glucose intolerance were divided into two groups by IFN response: Eleven were under detectable in HCVRNA at week 12 as an EVR group and six were non EVR group. The AUC-G and AUC-I were reduced by 35% (p<0.05) in EVR. However, the AUC-I did not change in nonEVR, although the AUC-G was decreased by 17%.

 

Conclusions:

Insulin resistance and energy metabolism improved by the administration of PegIFN/RBV, which had strongest effect against HCV. The effects of rapid viral reduction might be important for restoring of glucose tolerance in chronic hepatitis C.

 


Topic: Treatment – Predictors of Treatment Response

 

298. Whole-body, not only liver, insulin sensitivity is strongly associated with an early and sustained virologic response to peginterferon plus ribavirin treatment in patients with chronic hepatitis C genotype 1b and high viral load

T. Mizuta; Y. Eguchi; Y. Kawaguchi; K. Ario; H. Takahashi; S. Iwane; N. Oza; I. Ozaki 

 

Aim:

Recent studies have indicated that insulin resistance (IR) might be an important factor associated with the virologic response to interferon treatment for chronic hepatitis C, but little is known about its mechanism. IR consists of hepatic IR (central IR) and muscle IR (peripheral IR). We analyzed the effect of hepatic and whole-body (hepatic + muscle) IR on the efficacy of peginterferon plus ribavirin treatment.

 

Methods:

Forty-three chronic hepatitis C patients with genotype 1b and high viral load treated with peginterferon alpha-2b plus ribavirin for 48 weeks were examined. Early virologic response (EVR) and sustained virologic response (SVR) were obtained in 22 patients (51%) and 18 patients (42%), respectively. We used two methods to evaluate IR; HOMA-IR, a marker of hepatic IR, and the ISI composite, which indicates whole-body insulin sensitivity and is calculated as 10000/√FPG × FIRI × mean BS (0-120) × mean IRI (0-120) from a 75 g oral glucose tolerance test. Serum adiponectin levels were measured and visceral fat areas at the umbilical level were evaluated by computed tomography. We analyzed whether the HOMA-IR and ISI composite values before treatment were associated with EVR or SVR

 

Results:

There were significant differences in HOMA-IR and ISI composite values before treatment between EVR and non-EVR patients (HOMA-IR: 1.7 vs 3.0 , p=.0005; ISI composite: 5.7 vs 3.3, p=.02). Similarly, there were significant differences in both between SVR and non-SVR (HOMA-IR: 1.6 vs 2.8, p=.009; ISI composite: 6.0 vs 3.4, p=.003). Analyzed according to HOMA-IR classes, EVR and SVR rates were 76% and 62% in <2 (n=21), 32% and 26% in 2~4 (n=19), 0% and 0% in >4 (n=3), respectively. According to ISI composite classes, EVR and SVR rates were 20% and 13% in <3 (n=15), 60% and 45% in 3~6 (n=20), 100% and 80% in 6~9 (n=5), 67% and 100% in >9 (n=3), respectively. A positive predictive value for EVR and SVR when ISI composite was >6 was 87.5% for both. Multivariate analysis showed that >6 in ISI composite was the only factor associated with SVR. ISI composite values were significantly positively correlated with serum adiponectin levels and negatively with visceral fat areas.

 

Conclusions:

Whole-body, predominantly liver and skeletal muscle, insulin sensitivity is strongly associated with the efficacy of peginterferon plus ribavirin treatment. These data suggest that life-style interventions might enhance the effect of anti-viral therapy in patients with chronic hepatitis C.

 


Topic: Treatment – General

 

299. Evaluation of a multidisciplinary support program in hepatitis C treatment

M. Garcia-Retortillo; M. Giménez; C. Márquez; P. Castellvi; R. Navinés; E. Clot; I. Cirera; E. Salas; R. Martín-Santos; R. Solà 

 

Introduction:

Adherence to antiviral treatment has been cited as a potentially important factor in determining the outcome of therapy in hepatitis C patients.

 

Aims:

To evaluate the multidisciplinary support program (MSP) efficacy and its impact on the health-related quality of life (HQL) during HCV treatment.

 

Method:

One hundred eighty-eight HCV naive patients were consecutively treated in the Liver Section of the Hospital Mar: Group 1, 91 patients included in the MSP (2005), and Group 2, 97 patients with conventional control (2003-2004). All patients were treated with Peg-IFN alpha-2a and ribavirin (RBV). The MSP team includes hepatologists, nurses, a pharmacist, a psychologist and a psychiatrist. Uniform patient informing, open and flexible visits scheduling, continued evaluation of psychiatric risk (PHQ and HADS), active medication control, and standardized management of the secondary effects were carried out during MSP. Patients receiving ≥ 80% of each assigned drug for ≥ 80% of the expected duration therapy were considered as adherent to the treatment. HQL was evaluated by SF-36 before and at 1, 3, and 6 months during treatment.

 

Results:

No differences were observed between either group in terms of age, gender, HCV-genotype, viral load and fibrosis degree.

 

Anti-depressives or anxiolytics were prescribed in 34 (37,4%) and 21 (21,6%) patients in each group, respectively (P 0.02). Patients in Group 1 showed better scores in all domain scales of health status than the patients in Group 2. However, the differences only reached statistical significance in terms of bodily pain, and in general and mental health scores.

 

Conclusions:

The multidisciplinary support program (MSP) increases the adherence to the antiviral therapy and improves the perception of the quality of life during treatment.

 

 

Group 1

Group 2

P

Adherence (%)

95.6

80.4

0.0002

Withdrawal / drop-out (%)

4.4

6.2

NS

Drug dosages < 80% (%)

0

13.4

0.0003

Mean hemoglobin decrease (mg/dL)

3.1

2.9

NS

Peg-IFN dosage 100% (%)

100

89

0.02

RBV dosage 100% (%)

98.8

80.2

0.0001

Erythropoietin (%)

3.3

1

NS

End of treatment response (%)

86.8

78.3

0.1

 


Topic: Treatment – Predictors of Treatment Response

 

301. The Impact Of Steatosis And Steatohepatitis On The Response To Treatment In Patients With Chronic Hepatitis C Infection.

T. J. Cross; A. Quaglia; J. Nolan; I. Fletcher; K. Agarwal; P. M. Harrison 

 

Background:

The impact of steatosis on sustained virological response (SVR) in patients treated with pegylated interferon and ribavirin for chronic hepatitis C (CHC) infection is controversial.

 

Aims:

We studied whether finding steatosis with or without steatohepatitis on a pre-treatment liver biopsy (LB) influenced SVR in patients with CHC subsequently treated with pegylated interferon and ribavirin.

 

Patients:

We assessed 204 consecutive patients treated for CHC between January 2001 and January 2005. LB was performed in all patients before treatment. The method described by Ishak was used to grade necro-inflammation and stage fibrosis. Steatosis and steatohepatitis were graded using the modified Brunt score. Patients were classified according to the presence or absence of steatosis and steatohepatitis. Patients achieving SVR were labeled as responders and those failing to achieve SVR as non-responders

 

Results:

179 patients were included in the final analysis after exclusions, 72% male, median age 46 years (interquartile range 40 – 52). 127 patients had Ishak Fibrosis stage 3 or less (71%), and 31 patients (17.3%) were cirrhotic (Ishak stage 5-6). 106 patients achieved an SVR (59%); the SVR rates by genotype were: genotype 1 (35%), genotype 2 (82%), genotype 3 (79%), and genotype 4 (57%). 98 patients had steatosis (51.9%). The Χ2 test for trend demonstrated different rates of steatosis between the genotypes (P=0.14). Steatosis was most prevalent in genotype 4, 6/7 (86%), although the numbers were small. Genotype 3 had a high level of steatosis 34/54 (63%, p=0.053) and genotype 2 had a low level, 12/37 (32%, p=0.008). Steatohepatitis was present in 34 patients (19%), who were older (49 years vs. 44 years, p=0.03) and more likely to have severe steatosis (grade 2-3 vs. 0-1, p<0.0001), and cirrhosis (p<0.0001). Genotype had no effect on the likelihood of steatohepatitis (p=0.69). Responders did not differ from non-responders in respect to gender, age, the presence or severity of steatosis, necroinflammatory grade or pre-treatment ALT. In a univariate analysis, reduced SVR was associated with genotypes 1 and 4 (p<0.0001), cirrhosis (p<0.0001), steatohepatitis and heavier patient weight (both p=0.009). But on multivariate analysis only genotypes 1 and 4 (p<0.001), pretreatment weight (p=0.002) and cirrhosis (p=0.06) were found to be associated with SVR.

 

Conclusion:

·        In CHC, steatosis has no effect on SVR. Steatohepatitis is associated with severe steatosis and liver disease progression but not SVR, which is mainly determined by genotype, patient weight and the presence of cirrhosis

·        Therapeutic strategies aimed at treating steatohepatis may improve SVR in at risk patients

·        Patients at risk should have liver biopsy to assess for steatohepatitis

 


Topic: Treatment – PEG-Intron

 

302. Consistency of Sustained Virologic Response (SVR) Across Weight Categories: Results From the Canadian POWeR (Peginterferon alfa-2b Prospective Optimal Weight-based Dosing Response) Program

S. V. Feinman; C. Ghent; H. B. Witt-Sullivan; L. Scully; M. Poliquin; W. Ghesquiere; R. Arlen; P. Marotta 

 

Background:

This analysis examines the impact of body weight on SVR rates in patients with chronic hepatitis C who received weight-based peginterferon (PEG-IFN) alfa-2b plus weight-based RBV in the POWeR program.

 

Methods:

POWeR is an open-label, observational trial conducted in academic and community clinics across Canada between 2002 and 2006. Treatment-naive patients received PEG-IFN alfa-2b (1.5μg/kg/wk) plus RBV (800–1200mg/day) for either 24 (genotype [G] 2 and G3) or 48 weeks (G1). SVR was defined as undetectable HCV RNA 24 weeks posttreatment. SVR rates were stratified by weight category (according to Canadian approved dosing of PEG-IFN alfa-2b + RBV), genotype, and fibrosis score.

 

Results:

1977 patients initiated treatment. Patients were excluded if they had undetectable HCV RNA at end of treatment but no 6-month follow-up, had no treatment data, or had HIV/HCV coinfection. Patients (n=1800) in this analysis included those who discontinued because of side effects, lack of response, or personal reasons. Most patients were infected with G1 (60%), followed by G3 (22%) and G2 (15%); 3% had other genotype.  Liver biopsy specimens, available in 946 patients (53%), demonstrated varying degrees of fibrosis (F0-F2 [60%]; F3/F4 [40%]). There was no significant difference in fibrosis score or genotype distribution across weight categories. There was a trend toward a higher incidence of F3-F4 fibrosis/cirrhosis in heavier patients. No statistically significant differences in overall SVR, SVR by genotype, or SVR by fibrosis score were observed among weight categories (Table). Overall SVR rates were higher in persons with F0-F2 fibrosis than in those with F3-F4 fibrosis/cirrhosis (60% vs 35%, P<.001).

 

Summary:

• No statistically significant differences were observed in overall SVR rates across patient body weight categories when a weight-based PEG-IFN alfa-2b plus RBV regimen was used

 

Conclusions:

·        Weight-based dosing of PEG-IFN alfa-2b (1.5 μg/kg/wk) plus RBV (800-1200 mg/d) is appropriate for all body weights and produces consistent SVR rates across all patient body weights

·        Community and academic physicians can expect excellent SVR rates, regardless of patient body weight

Consistency of SVR Rates Across Weight Categories

 

SVR,%

 

 

<50 kg

50-<64 kg

64-<75 kg

75-<85 kg

≥85 kg

P

Overall (n=1796)*

64

57

53

51

56

NS

*4 patients no weight data; 16 no genotype data.

 


Topic: Treatment – Predictors of Treatment Response

 

303. Rapid Virological Response at Week 4 is the Best Predictor of Treatment Outcome in Patients with Chronic Hepatitis C: A Multivariate Analysis

M. Martinot-Peignoux; S. Maylin; R. Moucari; M. Ripault; N. Boyer; N. Giuily; C. Castelnau; T. Asselah; P. Marcellin 

 

Introduction:

It is well established that HCV genotype and baseline HCV-RNA are good predictors of sustained virological response (SVR) in selected patients included in clinical trials of pegylated interferon alpha (PEG-IFN)+ribavirin (RBV). Limited knowledge is available on predictors of SVR in the general population managed in routine clinical practice.

 

Methods:

408 patients consecutively treated with PEG-IFN α-2b+RBV, were studied (221 naïves; 125 non-responders (NRs); 62 relapsers (RRs). Patients with genotypes 1 or 4 and non-naive were treated 48 weeks and patients with genotypes 2 or 3 for 24 weeks (PEG-IFN 1.5μg/kg/week; RIBA 800-1200 mg/day). Serum HCV-RNA was measured at baseline, week 4, week 12, end of treatment and 6 months after the end of treatment with the quantitative VERSANTR HCV 3.0 Assay (bDNA)(Siemens). Samples below limit of quantification were tested with the VERSANTR HCV-RNA Qualitative Assay (TMA)(Siemmens). SVR was defined as undetectable serum HCV-RNA by TMA at the end of 6-month post-treatment follow-up. The characteristics included in the logistic regression analysis were: baseline viral load (≤vs>400x103IU/ml), HCV genotype (1, 2, 3, 4, 5), gender, age (≤vs>45y), histology grade (A0-1≤vs>A2-3), fibrosis stage (F0-2≤vs>F3-4) assessed with Metavir score, serum ALT, pretreatment status, rapid virological response at week 4 (RVR4)(TMA undetectable) and rapid virological response at week 12 (RVR12) (>2 log viral drop) of therapy. Early viral kinetic was analyzed at weeks 1 to 4 in a subgroup of 78 patients.

 

Results.

Overall SVR rate was 46%; SVR rates were 53%, 25% and 65% in naives, NRs and RRs, respectively.

Univariate Analysis:

o       All parameters, except sex, were significant predictors in treatment-naive patients

o       RVR and EVR were significant predictors in all patient groups

o       Sex was not a significant predictor for any patients

o       Age was a significant predictor for treatment-naive patients and RRs but not NRs

o       Fibrosis (activity grade and fibrosis score) was a significant predictor for treatment-naive patients but not for RRs or NRs

 

Conclusions.

o       For treatment-naive patients, RVR (undetectable HCV RNA at week 4 of therapy) is the strongest independent factor for prediction of SVR

o       For patients who were NRs to previous therapy, high initial viral load (>5 log10 IU/mL) and absence of EVR (<2 log10 decrease in HCV RNA from baseline at week 12 of therapy) are the strongest predictors of non-SVR

o       Therefore, the following should be assessed during anti-HCV therapy:

 

Timing

Assessment

Treatment initiation

Quantification of serum HCV RNA

Week 4 of therapy

Qualitative detection of serum HCV RNA to predict SVR

Week 12 of therapy

Quantification of serum HCV RNA to predict non-SVR

 


Topic: Treatment – Predictors of Treatment Response

 

304. Assessment of Both Virological Response at Week 4 and at Week 12 Optimizes Prediction of Treatment Outcome in Patients with Chronic Hepatitis C Treated with Peginterferon alfa-2B Plus Ribavirin

M. Martinot-Peignoux; S. Maylin; M. Ripault; R. Moucari; N. Boyer; N. Giuily; C. Castelnau; P. Marcellin 

 

Introduction:

Pretreatment viral load is an important predictor for treatment outcome in patients with chronic hepatitis C. Recently, Zeuzem et al. (AASLD 2006) proposed 400 000 IU/ml (assessed with the COBAS TaQMan HCV assay) as the optimal cut-off to best discriminate low and high VL, based on the probability to achieve SVR in patients treated with peginterferon (PEG-IFN) alpha 2a+ribavirin (RBV).

 

Aim:

Our study aimed to analyze the positive predictive value (PPV) of this cut-off value at baseline, the PPV of rapid virological response at week 4 (RVR4) and the negative predictive value (NPV) of non early virological response at week 12 (non-EVR12), in patients treated with PEG-IFN alpha 2b+RBV.

 

Patients-Methods:

408 patients (221 naive; 187 non-naive) consecutively treated with PEG-IFN alpha-2b+RBV (PEG IFN 1.5μg/kg/week, plus RIBA 800-1200 mg /day according to weight), were included in this study. Patients with genotypes 1, 4 or 5 or non-responders were treated 48 weeks; naive patients infected with genotypes 2 or 3 were treated 24 weeks. Serum HCV RNA was measured at baseline, week 4, week 12, end of treatment and 6 months after the end of treatment with the quantitative VERSANTR HCV 3.0 Assay (bDNA) (Siemens Medical Solution Diagnostics). Samples below the limit of quantification were tested with VERSANTR HCV RNA Qualitative Assay (TMA) (Siemens Medical Solution Diagnostic). SVR was defined as undetectable serum HCV RNA by TMA at end of 6 months post-treatment follow-up. At treatment initiation PPV was defined with a cut-off set up at ≤ 400 103IU/ml; at week 4 the PPV was defined as TMA undetectable or ≥ 2 log drop baseline viral load; at week 12 the NPV was defined as TMA detectable or < 2 log drop baseline viral load.

 

Results.

The overall SVR rate was 46% (53% in naïve patients and 38% in non-naïve patients).

 

Conclusions.

·        Undetectable HCV RNA at week 4 (RVR) when assessed with a sensitive assay (TMA) is more accurate (96%-100%) than baseline cut-off (≤400 103IU/ml) to predict SVR both in naive and in experienced patients.

·        The absence of EVR at week 12 (less than 2 log reduction of HCV RNA) is a strong predictor (96%-100%) of non response to therapy independently of the patients pretreatment status.

·        Monitoring of patients during therapy with PEG-IFN plus RBV should include

o       Qualitative detection of serum HCV RNA at week 4 to predict SVR

o       Quantification of serum HCV RNA at treatment initiation and week 12 to predict non-SVR (no EVR and no SVR)

 

 

PPV

PPV

PPV

NPV

NPV

 

Baseline

Week 4

Week 4

Week 12

Week 12

Viral Load

<400000

IU/ml

TMA negatif

≥ 2 log drop

TMA positif

< 2 log drop

All the patients

62%

97%

70%

87%

98%

Naives

63%

96%

78%

83%

100%

Non-Responders

27%

100%

50%

90%

96%

Relapsers

76%

100%

70%

76%

100%

 


Topic: Treatment – Predictors of Treatment Response

 

305. Predictability of Response: Positive and Negative Predictive Values of Rapid and Early Virologic Responses to Peginterferon alfa-2b and Ribavirin in the Treatment of Chronic Hepatitis C

F. Poordad; C. Kambili 

 

Background:

Assessing viral kinetics in response to peginterferon (PEG-IFN) alfa and ribavirin (RBV) can help predict treatment response among patients with chronic hepatitis C. Hepatitis C virus (HCV) RNA levels decrease rapidly after initiation of treatment with PEG-IFN alfa-2b/RBV. To determine the value of assessing early viral kinetics during PEG-IFN alfa-2b/RBV therapy, positive and negative predictive values (PPVs; NPVs) of rapid and early virologic response (RVR; EVR) for sustained virologic response (SVR) were culled from PEG-IFN alfa-2b articles or abstracts.

 

Methods:

Published PEG-IFN alfa-2b data were evaluated for PPVs and NPVs for RVR and/or EVR. PPVs and NPVs were calculated if not reported but RVR and/or EVR rates and SVR rates were available. RVR was defined as undetectable HCV RNA at wk 4 of treatment (lower limit of detection <50 IU/mL in most studies). EVR was defined as undetectable HCV RNA or a ≥2 log10 decrease from baseline at wk 12 of treatment.

 

Results:

Patients from applicable trials (N>2000) were monoinfected with HCV or coinfected with HCV/HIV and were treated with PEG-IFN alfa-2b (1.0 or 1.5μg/kg/wk or 50-150μg/wk) and various doses of RBV (800-1400mg/d). Treatment duration was 48 or 24 weeks, generally depending on genotype (G). Attaining RVR was highly predictive of attaining SVR in patients with any genotype who were treated for 48 wks (PPV 89%), in G1/4 patients treated for 48 wks (PPV 81%), and in G2/3 patients treated for 24 wks (PPV 85-90%). Not attaining RVR was a less reliable predictor of not attaining SVR for all genotypes (NPV 59%); NPVs were 84% among G1/4 and 44-63% among G2/3 patients. G2/G3 patients were analyzed separately in 1 study; the PPV and NPV for RVR were 89% and 50%, respectively, for G2 patients and 100% and 57%, respectively, for G3 patients. Failure to attain EVR was a consistent indicator of failure to attain SVR (NPV 95-100%), whereas attaining EVR was a less reliable predictor of attaining SVR (PPV 67-72%) for all genotypes. Among African Americans, NPVs and PPVs for EVR were 100% and 48-83%, respectively. Studies in G4 patients revealed NPVs for EVR of 86-100% and PPVs for EVR of 76-100%.

 

Conclusions:

Predictability of response to PEG-IFN alfa-2b/RBV applied to mono- and coinfected patients. EVR was a better negative than positive predictor of SVR and can be used to guide treatment cessation in G1/4 patients who do not respond by week 12 of treatment. RVR was an excellent positive but poor negative predictor of SVR for all genotypes. RVR can be used as a patient motivator and can reliably be used as part of the treatment algorithm for future studies and in clinical practice.

 


Topic: Treatment – Predictors of Treatment Response

 

308. High predictive value of early viral kinetics in peginterferon plus ribavirin combination therapy of genotype 1 infected patients with chronic hepatitis C.

T. Oze; N. Hiramatsu; Y. Inoue; N. Kurashige; M. Kurokawa; T. Yakushijin; T. Igura; K. Imanaka; M. Oshita; H. Hagiwara; E. Mita; T. Ito; T. Hijioka; H. Yoshihara; Y. Imai; E. Hayashi; M. Kato; Y. Minami; K. Ohkawa; S. Kiso; T. Kanto; T. Takehara; A. Kasahara; S. Tamura; N. Hayashi 

 

Background & Aim:

The early viral response, defined as undetectable or at least a 2-log decrease in HCV RNA level after 12 weeks of treatment, is very important for predicting which hepatitis C patients are not likely to display a sustained viral response (SVR) to peginterferon (Peg-IFN) plus ribavirin (RBV) combination therapy. In this study, we investigated the relationship between the viral kinetics during the first 8 weeks and the antiviral outcome to identify factors with a high positive predictive value (PPV) or negative predictive value (NPV) for SVR. Patients & Methods: This study was conducted at Osaka University Hospital and institutions of participating in the Osaka Liver Forum. A total of 551 patients with chronic hepatitis C (332 males, 218 females; mean age 55.6 ± 10.2 y.o.) were treated with combination therapy of Peg-IFN alfa-2b at a dose of 1.5 µg/kg/week and RBV each at 600 mg/day (body weight (BW) ≤ 60 kg) or 800 mg/day (60 < BW ≤ 80 kg) or 1000 mg/day (BW < 80 kg) for 48 weeks. All had HCV genotype 1b with over 100 KIU/ml HCV RNA. Serum HCV RNA level was assessed at week 2 and every 4 weeks during therapy and 24 weeks after the therapy by COBAS AMPLICOR HCV test, v2.0 (<50 IU/ml), and COBAS AMPLICOR GT HCV MONITOR test, v2.0 (5 - 5000 KIU/ml).

 

Results:

At week 2, 33 out of 39 patients who had undetectable (<5 KIU/ml) or at least a 2-log decrease in HCV RNA achieved SVR (PPV = 85%). Ninety-one of 93 patients with less than a 1-log decrease in HCV RNA did not achieve SVR (91/93, NPV = 98%). At week 4, 21 patients had undetectable serum HCV RNA (<50 IU/ml), and achieved SVR (21/21, PPV = 100%). Seventy-five patients had less than a 1-log decrease in HCV RNA, and none achieved SVR (75/75, NPV = 100%). Similarly, at week 8, 73 patients had less than a 2-log decrease in HCV RNA, and none achieved SVR (NPV = 100%).

 

Conclusion:

Early viral kinetics in the first 8 weeks can predict PPV and NPV for SVR; especially useful are the 1-log decrease in HCV RNA at week 4 and 2-log decrease at week 8, which are excellent markers for NPV in Peg-IFN and RBV combination therapy.

 

PPV and NPV for SVR

change in HCV RNA

week of therapy

PPV for SVR

NPV for SVR

2-log decrease or <5 KIU/ml

2

85% (33/39)

87% (101/116)

1-log decrease or <5 KIU/ml

2

74% (46/62)

98% (91/93)

PCR negative (<50 IU/ml)

4

100% (21/21)

64% (240/376)

2-log decrease or <5 KIU/ml

4

67% (102/152)

94% (99/105)

1-log decrease or <5 KIU/ml

4

59% (108/182)

100% (75/75)

PCR negative (<50 IU/ml)

8

82% (111/135)

79% (220/278)

2-log decrease or <5 KIU/ml

8

64% (156/242)

100% (73/73)

1-log decrease or <5 KIU/ml

8

59% (156/265)

100% (50/50)

 


Topic: Treatment – PEG-Intron

 

309. Impact of reducing peginterferon alfa-2b and ribavirin on early viral response in genotype 1 infected patients with chronic hepatitis C.

T. Oze; N. Hiramatsu; Y. Inoue; N. Kurashige; M. Kurokawa; T. Yakushijin; T. Igura; K. Imanaka; M. Oshita; H. Hagiwara; E. Mita; K. Katayama; H. Yoshihara; A. Inoue; Y. Imai; E. Hayashi; M. Kato; M. Nishikawa; Y. Minami; T. Tatsumi; T. Kanto; T. Takehara; A. Kasahara; S. Tamura; N. Hayashi 

 

Background & Aim:

Patients with early viral response (EVR), defined as undetectable or at least a 2-log decrease in HCV RNA level after 12 weeks of treatment, show a high probability of SVR in pegylated interferon (Peg-IFN) and Ribavirin (RBV) therapy for chronic hepatitis C patients with genotype 1. We evaluated the effect of Peg-IFN alfa-2b and RBV dose reduction on EVR in patients with genotype 1 and high viral load.

 

Patients & Methods:

This study was conducted at Osaka University Hospital and institutions of participating in the Osaka Liver Forum. A total of 839 patients with chronic hepatitis C (476 males, 362 females; mean age 56.3 ± 10.0 y.o.) were treated with combination therapy of Peg-IFN alfa-2b and RBV for 48 weeks. All had HCV genotype 1b with over 100 KIU/ml HCV RNA. All were evaluated based on the amounts of Peg-IFN alfa-2b and RBV given during the first 12 weeks of treatment. The mean doses of both drugs were calculated as the average dose per body weight: Peg-IFN, µg/kg/week; RBV, mg/kg/day. We also calculated the complete EVR (c-EVR) rate, defined as undetectable serum HCV RNA, by COBAS AMPLICOR HCV test, v2.0 (<50 IU/ml) at week 12.

 

Results:

Of the 839 patients, 45 discontinued therapy due to side effects before week 12. Of those who completed 12 weeks of treatment, 48% (326/675) achieved c-EVR. Of the c-EVR patients, 75% achieved SVR, while 29% with late viral response, defined as undetectable serum HCV RNA from 13 to 24 weeks, achieved SVR. In patients who received 12 - 14 mg/kg of RBV, the c-EVR rate was 36% (5/14) for those given 0.75 µg/kg (50%) - 1.2 µg/kg (80%) of Peg-IFN, 54% (15/28) for those given 1.2 - 1.5 µg/kg of Peg-IFN, and 61% (42/69) for those given 1.5 - 1.8 µg/kg of Peg-IFN. Similarly, the c-EVR rate was 30% (13/43), 56% (104/186), 53% (34/64) in patients who received 10 - 12 mg/kg of RBV, 42% (11/26), 49% (35/71), 56% (22/39) in those who received 8 - 10 mg/kg of RBV, and 36% (5/14), 50% (9/18), 60% (6/10) in those who received 6 - 8 mg/kg of RBV. No decline in c-EVR rate was observed among patients with more than 1.2 µg/kg of Peg-IFN, but the c-EVR rate declined among those with less than 1.2 µg/kg of Peg-IFN (p < 0.001, Fisher exact test).

 

Conclusion:

Peg-IFN reduction up to 80% (≥1.2 µg/kg/week) can maintain approximately 50% of EVR regardless of the RBV dosage.

 


Topic: Treatment – Pegasys

 

310. Effects of systematic nurse-provided therapeutic education on adherence and efficiency of PEG-Interferon-a2a(Pegasys®)-ribavirin treatment in chronic hepatitis C (Pegobs Protocol).

D. Larrey; A. Salsé; G. Pageaux; N. Funakoshi; D. Ribard; O. Boutet; V. Hyrailles; B. Niang; E. Vaucher; J. Arpurt; A. Rémy; S. Dahmouni; N. Kharlova; J. Daurès 

 

Introduction:

Failures of PEGIFN-a2a/b-ribavirin combination in chronic hepatitis C are mainly due to a poor adherence and side effects. TT optimization is currently recommended. However no prospective study has still been performed for assessing the effect of systematised therapeutic education.

 

Aim:

To assess the effect of systematic nurse-provided therapeutic education on adherence and efficiency of PEGIFN-a2a (Pegasys®)-ribavirin in pts with chronic hepatitis C.

 

Patients and methods:

Multicentric, prospective study, randomized in 2 groups: GrA: systematic nurse consultation after medical consultation at D0, W4, 8, 12, 24, 36; performed with a standardised questionnaire for the assessment and education on the disease and its TT; GrB: pragmatic follow-up. Comparison was made between an experimented center (center 1) and newly formed nurses.

 

Results:

239 randomized pts: GrA 123 ; GrB 116 ; center 1 : 128 pts. Baseline : no difference between groups for age, sex ratio, BMI, alcohol intake, contamination type, previous PEGIFN TT 42,6 vs 36%, genotypes prevalence, mean viremia and ALT, fibrosis score.

 

Adherence to TT better (p<0,05) (GrA vs GrB) at W24 : 75,6 vs 64,5%, end of treatment (EOT) 73,7 vs 61,9% ; it was even better for center 1 : W12 : 90,8 vs 74,6% ; W24 : 86,2 vs 65,1% ; EOT 83 vs 60,3%. Accordance of TT duration with protocol for 24W : 83,6 vs 76,7% ; 48W : 69,7 vs 53,2% ; center 1 : 24W : 94,1 vs 90% ; 48W : 79,1 vs 48,8%.

 

HCV RNA disapparence was more frequent (p<0,01) in GrA vs GrB at W12 : 72,8 vs 57,1% ; W24 : 75,2 vs 59,8% ; EOT : 70,6 vs 52%. For center 1 : W12 : 76,9 vs 55,7% ; W24 : 86,1 vs 62,9% ; EOT : 80 vs 55%.

 

Sustained virological response (SVR) was significantly higher : 37,7 vs 25% for all pts ; naïve : 46,4 vs 31% ; re-TT : 25 vs16% ; center 1 : overall 48,4 vs 24% ; naïve : 66,7 vs 37% ; re-TT : 32,3 vs 7%. SVR according to genotypes: HCV1, 4, 5 : 30,7 vs 14% ; HCV 2, 3 : 50 vs 43%. Center 1 : HCV1, 4, 5 : 41,9 vs 10% ; HCV 2, 3 : 61,9 vs 52%. No difference according to the stage of fibrosis.

 

Conclusion:

The systematic nurse-provided therapeutic education is significantly associated with a better adherence to the TT and a better virological response. The beneficial effect was more significant in pts treated 48 W and in center with nurse particulary experimented for therapeutic education (center 1).

 

Comments:

These results show : 1) the importance of therapeutic education in the TT of hepatitis C particularly in the most difficult groups with relatively resistant genotypes and previous therapeutic failures ; 2) the importance of nurse experience in therapeutic education.

 

We thank Roche Laboratory for its support.

 


Topic: Treatment – PEG-Intron

 

312. Viral kinetics can quickly predict sustained virological response in HCV patients with normal ALT treated with pegylated ifn α2b and ribavirin: a prospective study

P. Deltenre; V. Canva; A. Louvet; S. Dharancy; L. Bocket; A. Hollebecque; J. Boitard; C. François; S. Castelain; G. Duverlie; J. Henrion; P. Mathurin 

 

Introduction:

Treatment is recommended in HCV patients (pts) with normal ALT only for viral eradication. HCV viral kinetics during antiviral therapy comports a two phase decline. The second slow δ phase is related to infected cell loss. δ phase is predictive of sustained virological response (SVR) and may be estimated by reduction of viral load (VL). In pts with normal ALT, a good estimate of the δ phase is required to determine as soon as possible the need to continue treatment.

 

Aim:

to determine the earliest and optimal time when decline of logVL becomes the best estimate of δ phase in HCV patients with normal ALT prospectively treated with peginterferon α2b and ribavirin for 6 or 12 months.

 

Methods:

The prediction of viral kinetics was expressed by the AUROC curves. Viral load were assessed at 1, 4, 8 hours, days 1 to 4, 7, 14, 21, 28 and 2 and 3 months during treatment.

 

Results:

24 pts (17 with genotype 1) were included. On overall patients, the median ALT level was 26±6 IU/L. There was no significant fibrosis. Median baseline VL was 284500 IU/ml (95% CI: 119000-413000). SVR was achieved in 62% (53% for genotype 1 pts). On overall patients, reduction of VL at day 21 was the earliest time estimating SVR (AUROC curve of logVL: 0.848±0.086, p<0.0001) but day 28 has the highest AUROC curve of logVL for estimating SVR (0.981±0.02, p<0.0001). Months 2 and 3 didn’t have better AUROC curves of logVL than day 28. In a sensitivity analysis restricted to pts with genotype 1, reduction of VL at day 28 had a better predictive value of SVR than reduction of VL at day 21 (AUROC curves of logVL: 0.962±0.04 vs 0.759±0.13, p=0.02). No SVR was observed in genotype 1 pts with a decline of VL <1 log from baseline to day 28. In terms of optimal cut-off in genotype 1 pts, a decline of VL ≥2 log at day 28 was the best predictor of SVR (sensibility 95%, specificity 76%, PPV 85%, NPV 91%). 40% of the pts were below this cut-off and had <10% of probability of SVR and 60% were above and had >80% of probability of SVR.

 

Conclusions:

In HCV genotype 1 pts with normal ALT, reduction of VL at day 28 is the best estimate of the δ phase. As viral eradication is the only aim, the use of this endpoint may avoid waiting until 3 months to decide treatment discontinuation in genotype 1 pts with low probability of SVR.

 


Topic: Treatment – General

 

315. Hepatitis C treatment outcomes in the Rhode Island Department of Corrections

K. Chew; S. A. Allen; L. E. Taylor; J. D. Rich; E. Feller 

 

Introduction:

As many as 83% of the USA’s 2 million injection drug users are incarcerated at some time. An estimated 29-43% of hepatitis C virus (HCV)-infected people in the USA are released from prisons or jails yearly. We report our experience with pegylated interferon (PEG-INT) plus ribavirin treatment of 71 HCV RNA-positive male inmates at the Rhode Island Department of Corrections (RIDOC).

 

Methods:

We reviewed charts of all male inmates identified as having initiated HCV treatment between October 2000 and April 2004. HCV-infected individuals were identified by HCV antibody screening at intake for known risk factors, elevated aminotransferase levels, or per individual request. Treatment followed standard guidelines with weight-based dosing of both PEG-INT alfa-2b and ribavirin. End of treatment response (ETR) was defined as undetectable serum HCV RNA at end of treatment, and sustained virologic response (SVR) as undetectable serum HCV RNA 6 months post-treatment. Endpoints were completion of therapy plus 6 months for SVR, therapy discontinuation, and loss to follow-up.

 

Results:

At data collection, 71 patients had reached an endpoint as defined above. The majority was white (80%). The cohort included genotype 1 (65%), genotype 2 (17%), genotype 3 (13%), genotype 4 (5%). Ninety-nine percent had a history of substance use (drug injection, non-injection drug use, or alcohol use). All 13 African-Americans (AA) had genotype 1. Of 59 patients having liver biopsy, 41 (70%) had early stage disease, defined as stage 0-1, 1-2, or 2. Overall ETR was 39% (28 of 71) and SVR, 28% (20 of 71). Response rate was lower for genotype 1 (ETR 33%, SVR 18%) compared to genotype 2 (ETR 64%, SVR 60%) and genotype 3 (ETR 56%, SVR 50%). Of inmates with genotype 1, no statistical difference existed in ETR or SVR by race (33% ETR in AA vs. 34% in whites; 22% SVR in AA vs. 18% in whites). Thirty-three patients completed treatment and 31 stopped for reasons including side effects (26) or initial non-response (5); 7 did not return for follow-up.

 

Conclusion:

Our results support the limited data available that acceptable HCV treatment outcomes can be achieved in prisons. Our small study indicates a difference in treatment response by genotype, but no difference by African-American vs. white race for genotype 1. Incarceration may be the only time that this difficult-to-access population intersects with the health care system long enough for evaluation and treatment. The correctional system has unique potential for HCV management and reducing the reservoir of infection, targeting those at high risk of transmission.

 


Topic: Treatment – Side Effects

 

316. The cerebral metabolic and cognitive effects of Pegylated Interferon (PIFN) and hepatitis C viral (HCV) clearance.

V. M. Byrnes; A. Miller; E. Hill; C. Weinstein; D. Alsop; R. E. Lenkinski; N. H. Afdhal 

 

Background:

Altered cerebral metabolites and cognitive dysfunction are common findings in chronic HCV infection. The neurologic benefit of HCV clearance has not been well described.

 

Aim:

To assess the effect of PIFN and HCV clearance on cerebral metabolites, cognition and mood.

 

Methods:

Fifteen patients with non-cirrhotic HCV were evaluated by MRI/MR spectroscopy, neuropsychometric testing and Beck’s depression inventory before, during and after treatment with PIFN. Three cerebral metabolites, including choline (Cho), myoinositol (MI) and N-acetyl aspartate (NAA), were measured from 3 different brain regions (basal ganglia, left frontal cortex and left dorso-lateral prefrontal cortex) and expressed as a ratio to the control metabolite creatine (Cr). Seven HCV positive controls (not taking PIFN) were also assessed at 2 time points, 3 months apart to determine (i) the variability of cerebral metabolites over time and (ii) the ‘practice effect’ of repeat cognitive testing.

 

Results:

At 12 weeks, 13/15 patients had undetectable HCV RNA (<600IU/ml). Of these, 8 were persistently negative for HCV RNA, 5 relapsed, and 1 was lost to follow up. PIFN therapy had no effect on cerebral metabolites. Cerebral Cho/Cr and MI/Cr were significantly reduced in the basal ganglia at the time of follow up when compared to baseline in sustained virological responders (SVR) but not in non-responders/relapsers (NR/R), p=0.03 and p=0.03, respectively. There were no significant differences observed in cerebral metabolites over time in controls.

 

Memory and executive functioning significantly improved on PIFN when compared to baseline in treated patients (p=0.006, p= 0.002) and in controls (p=0.03 and 0.02). This improvement was preserved in SVRs (p=0.02 and p=0.04) but not in NR/R. Attention significantly improved on PIFN in treated subjects (p=0.03). Language and motor skills were unaffected by PIFN or viral clearance. There was a significant increase in depression scores on PIFN (p=0.02) but no change when compared to baseline in SVRs and NR/R.

 

Conclusion:

PIFN does not alter cerebral metabolites but improves cognition in HCV patients. HCV clearance decreases metabolic markers of cerebral inflammation and activation and improves cognition in SVRs, likely due to the clearance of HCV from brain tissue. This study demonstrates the cerebral benefit to HCV clearance.

 


Topic: Treatment – PEG-Intron

 

318. The level of pretreatment HCV core antigen is a new and useful predictor for the efficacy of peginterferon alpha-2b and ribavirin in patients with chronic hepatitis C

S. Shakado; D. Morihara; S. Nishizawa; A. Anan; T. Tanaka; S. Inomata; S. Ueda; T. Matsumoto; Y. Takeyama; M. Irie; K. Iwata; T. Sohda; S. Sakisaka 

 

Aim:

The aim of this study was to clarify the most useful predictors for the therapeutic effects of a combination therapy with peginterferon alpha-2b (PEG) and ribavirin (Rib) in patients with chronic hepatitis C.

 

Patients and methods:

In patients infected with the hepatitis C virus (HCV) genotype 1b with a high viral load, we investigated 54 patients (26 males and 28 females) who completed treatment with PEG+Rib for 48 weeks and followed up for more than 6 months. We compared a group of serum HCV RNA-negative patients at 6 months after the end of treatment (SVR) with a group of serum HCV RNA-positive patients at 6 months after the end of treatment (NR), regarding age, gender, body mass index, alanine aminotransferase levels, HCV RNA levels (RT-PCR method), HCV core antigen levels (Lumispot EIKEN HCV antigen kit, EIKEN CHEMICAL, Tokyo, Japan), the time when HCV RNA became negative and the administration rate of PEG and Rib.

 

Results:

SVR was obtained in 21 patients (38.9%), NR in 24 (44.4%), and withdrawal in 9 (16.7%). Although the pretreatment HCV RNA levels were not statistically different between the SVR and NR groups, the pretreatment levels of the HCV core antigen were significantly lower in the SVR group than those in the NR group (4099.7 vs 7868.8 fmol/L, p<0.05). The rate of HCV core antigen loss after one month of treatment was significantly higher in the SVR group in comparison to that of the NR group (100 vs 50.0%, p <0.05). In the SVR group, there were significantly more cases with a level of pretreatment HCV core antigen less than 7000 fmol/L (83.3 vs 41.2%, p <0.05). The dose reduction rate of PEG and/or Rib was significantly lower in the SVR group than those in the NR group (p<0.05). An administration rate of PEG and/or Rib of more than 80% of a dose adjusted for body weight was significantly higher in the SVR group (p <0.01).

 

Conclusion:

A pretreatment HCV core antigen level of less than 7000 fmol/L and a loss of the HCV core antigen after one month of treatment are both valuable predictive markers of SVR of PEG+Rib in Japanese patients with chronic hepatitis C. An extended treatment duration to obtain an administration rate of PEG and Rib of more than 80% of a dose adjusted for body weight may increase the SVR rates in patients with chronic hepatitis C by reducing the rate of relapse.

 


Topic: Treatment – Disease Progression

 

319. Hepatocellular carcinoma in long-term sustained virologic responders to antiviral treatment for chronic hepatitis C

T. Scherzer; K. Reddy; K. Staufer; H. Hofer; P. Steindl-Munda; P. Ferenci 

 

BACKGROUND:

Antiviral treatment results in a sustained virologic response (SVR) in 50 to 75% of patients with chronic hepatitis C. Long term follow up studies have observed ongoing SVR in the overwhelming majority. Thus chronic hepatitis C is considered “cured” if a SVR is achieved. Consequently, it is expected that in SVRs long term complications of HCV related chronic liver disease including HCC are eliminated or have a decreased incidence.

 

RESULTS:

We report on 5 patients (#1-3 from Austria, #4-5 from USA) who developed HCC during follow up after achieving SVR. During follow up and at diagnosis all were HCV-RNA neg. The key clinical details are summarized in Table 1.

 

#1: After a relapse following a six months interferon (IFN) monotherapy he achieved a SVR after one year treatment with IFNα-2b TIW and ribavirin (RBV) in 1999. Ultrasonography in 12/05 showed a normal liver, but a tumour in the right adrenal. The biopsy revealed a metastasis from HCC. At resection the macroscopic appearance of the liver was normal. 8 months later a tumour in the right adrenal was resected and was a metastatic HCC.

 

#2: After two 48 week courses (relapse after 1. treatment) of pegIFNα2a/RBV she achieved a SVR in 2001.4 years later an elevated AFP level (47ng/ml) was noted; liver sonography was normal, but revealed a 5 cm HCC in segment 5/6 a year later. At segmental resection the liver was firm but macroscopically did not have cirrhosis. HCV-RNA was undetectable in the tumour tissue.

 

#3: Following two courses (relapse after 1. treatment) of pegIFNα2a/RBV she achieved a SVR in 2004. In 2007 she complained of upper abdominal discomfort and sonography showed a multifocal HCC.

 

#4: After 2 years treatment with 60 μg/week PEG-IFN-2b and 800mg/d RBV he achieved an SVR in 2001. A large HCC was detected in 2006. It was unresectable and he was placed on chemotherapy.

 

#5: Pretreatment liver biopsy showed stage 0 fibrosis. He achieved SVR following 1 year PEGIFN alfa-2b/RBV in 2003. HCC was diagnosed in 2006. A staging laparoscopy revealed a non-cirrhotic liver, but tiny peritoneal implants in the peritoneum. He was placed on chemotherapy.

 

CONCLUSION:

·        Successful antiviral treatment in HCV patients does not prevent development of HCC even in non-cirrhotic livers.

·        Long-term follow up of patients with SVR is mandatory and should include screening for HCC.

 

Table 1

Pat.

Fibrosis Grade*

Genotype

Mode of infection

SVR

HCC detected year (age)

#1/m

2

3a

i.v. drugs

1999

2006 (54)

#2/f

3

1b

BloodTx

2002

2007 (67)

#3/f

4

1b

Unknown

2004

2007 (51)

#4/m

4

1a

BloodTx

2001

2006 (53)

#5/m

0

1b

i.v.drugs

2003

2006 (52)

*pretreatment

 


Topic: Treatment – Predictors of Treatment Response

 

320. Systemic Factors Associated with Virologic Nonresponse to Peginterferon/Ribavirin Retreatment of Chronic Hepatitis C

K. L. Lindsay; C. Morishima; E. C. Wright; J. L. Dienstag; M. L. Shiffman; G. T. Everson; A. S. Lok; H. L. Bonkovsky; W. M. Lee; T. R. Morgan; M. Ghany; H.

 

BACKGROUND:

Peginterferon with ribavirin therapy leads to a sustained loss of serum hepatitis C virus (HCV) RNA in at least half of patients with chronic hepatitis C. Viral kinetic studies, which describe profiles of patients who respond to treatment, suggest hypotheses to explain the mechanism of action of interferon alpha and ribavirin. Very little information is available to explain why virologic suppression does not occur in some patients.

 

METHODS:

We evaluated potential factors associated with the lack of a week-20 virologic response in a cohort of previous nonresponder patients with advanced fibrosis undergoing retreatment with peginterferon alfa-2a and ribavirin. Among 1,145 patients enrolled in the HALT-C Trial, 588 who received more than 80% of prescribed therapy for 20 weeks were analyzed. Medication compliance was assessed at each visit by patient self-report, interviews, and returned peginterferon vial counts. Factors related to null response in univariate analyses were entered into a multivariate logistic regression with backward stepwise selection to assess their relative importance. Analyses were performed with the SAS version 9.1.

 

RESULTS:

By week 20, 245 patients (41.7%) had undetectable HCV RNA (full), 186 (31.6%) had >1 log decrease (partial), and 157 (26.7%) had <1 log decrease (null) virologic response. Virologic null response was associated independently with African American race, genotype-1 infection, and less reduction in body weight, platelets, and WBC – markers of systemic responses to interferon – during treatment (all p < 0.005).

 

CONCLUSIONS:

On-treatment variables associated with virologic null response to peginterferon with ribavirin suggest the lack of a systemic response to interferon, perhaps related to host genetic or environmental factors. These data have important implications for the design and analysis of retreatment trials and trials to evaluate new specifically targeted antiviral therapy for hepatitis C. Further studies are needed to discern whether interferon resistance, viral resistance, or both are playing a role in treatment-adherent patients who have no virologic response to interferon treatment.

 


Topic: Treatment – Pegasys

 

321. High rates of sustained virological response (SVR) in patients >50 years infected with HCV genotype 1 with positive prognostic factors treated with peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®)

R. Reddy; D. Messinger; M. Popescu; S. J. Hadziyannis 

 

Background:

The prognosis of pts with chronic HCV is influenced by viral factors such as HCV genotype (G) and HCV RNA level as well as pt factors such as age, gender, race, cirrhosis and drug adherence. The demographics of HCV infection are shifting with an increasing number of pts now in their 50’s. To assess the impact of age on SVR rates we analyzed the data from two large phase III studies of PEG-IFN alfa-2a (40KD) plus ribavirin (RBV) (Fried et al. NEJM 2002 and Hadziyannis et al. Ann Intern Med 2004).

 

Methods:

We included pts who had HCV G1 and were randomised to 48 wks of treatment with PEG-IFN alfa-2a (40KD) 180µg/wk plus RBV 1000/1200mg/d. SVR was defined as undetectable HCV RNA by qualitative PCR after 24 wks of untreated follow-up.

 

Results:

Overall, the SVR rate in pts ≤50 years was 52.3% (n=438) and 38.9% in the 131 pts who were >50 (p=0.007). SVR rates in pts aged >50 years were heterogeneous and varied according to previously well-established prognostic factors (Table). In particular, SVR rates were higher in pts without advanced fibrosis, those with low baseline serum HCV RNA levels, those pts who received ≥80% of the planned dose of PEG-IFN and those patients who received ≥60% of the planned dose of RBV. Overall, age did not influence whether pts completed therapy (75.6% of pts ≤50 vs 73.3% of pts >50 years [p=0.5954]). However, there was a trend towards lower cumulative PEG-IFN exposure in older pts (7235µg in pts ≤50 vs 6868µg in pts >50 [p=0.0986]) and a significantly lower cumulative RBV exposure in older pts (304g in pts ≤50 vs 252g in pts >50 [p<0.0001]). Decreasing RBV exposure to <60% of target has been associated with a dramatic reduction in SVR rates (Reddy et al. Clin Gastro Hepatol 2007). In our study more pts >50 years had dose reductions resulting in <60% of target RBV exposure than pts ≤50 years (38% vs 22%). Discontinuation rates due to any AE was similar in those ≤50 (11.4%) compared to those >50 years old (11.5%).

 

Conclusions:

·        Subgroups of HCV genotype 1 patients >50 years can achieve high SVR rates (particularly those with a low baseline viral load or without cirrhosis).

·        Older patients (>50 years) had more ribavirin dose reductions due to laboratory abnormalities.

·        Maintaining exposure to peginterferon alfa-2a (40KD) and/or ribavirin during treatment is essential to achieving high SVR rates, particularly in older patients.

·        More attention is required when modifying dose of ribavirin in older patients; small decrements are advisable in order to maintain the highest tolerable ribavirin exposure.

·        The assessment of virologic response at weeks 4 and 12 can be used to predict which patients are most likely to achieve an SVR, regardless of age as high SVR rates are achieved by all patients with an RVR or cEVR.

·        In summary, older HCV patients are an important population and a full treatment course with pegylated interferon plus ribavirin should be considered based on their on-treatment week 4 and week 12 response.

Characteristics and treatment outcomes in 131 pts aged >50yrs

Characteristic

Prevalence (%)

SVR

(%)

Male : Female

White : Black : Other race

BMI <30 : ≥30

60 : 40

81 : 5 : 15

84 : 16

36.7 : 42.3*

38.7 : 16.7 : 47.4*

40.0 : 33.3*

Cirrhosis/bridging : Minimal fibrosis

34 : 66

28.9 : 44.2

HCV RNA <400 000 : ≥400 000 IU/mL

23 : 77

56.7 : 33.7**

ALT Quotient ≤3 : >3

63 : 37

38.6 : 39.6*

<60 : 60–<80 : ≥80% planned exposure to:

PEG-IFN

RBV

25 : 14 : 61

38 : 20 : 42

18.2 : 16.7 : 52.5**

16 : 42.3 : 58.2**

*p=NS; p<0.01; **p<0.05


Topic: Treatment – Pegasys

 

322. Low dose peginterferon alfa-2a and ribavirin for chronic hepatitis C, genotype 2 & 3: viral kinetics, efficacy and safety

Y. Rotman; B. B. Borg; A. Soza; R. Loomba; A. A. Modi; J. J. Feld; E. Rivera; E. Doo; T. Heller; M. Ghany; A. U. Neumann; T. Liang; J. H. Hoofnagle 

 

Introduction:

Chronic infection with hepatitis C virus (HCV) genotypes 2 & 3 is highly responsive to the combination therapy with peginterferon and ribavirin. Use of lower doses of peginterferon and ribavirin may reduce side effects without loss of efficacy.

 

Aim:

To determine whether a lower dose of peginterferon is better-tolerated and just as effective as the standard dose and to compare the viral kinetics of the two regimens.

 

Methods:

Patients were treated with peginterferon alfa-2a (kindly provided by Roche Laboratories, Nutley, NJ) in a dose of 90 μg/week (low-dose regimen, LD) or 180 μg/week (standard dose, SD) in combination with ribavirin (800 mg/day) for 24 weeks. Patients who failed to become HCV RNA negative by week 12 or who relapsed after treatment were eligible for a 48-week course of standard dose (extended treatment, ET).

 

Results:

30 patients were treated with the LD and, to date, 18 of a planned 30 patients with the SD regimen. Among those receiving LD, 19 (63%) achieved an SVR compared to 10 of 12 patients (83%) receiving SD who have completed treatment and follow up. The 3 non-responders and 4 of 8 relapsers after LD therapy were retreated with ET, and all but one (86%) achieved an SVR. Viral kinetic analyses showed that the mean reduction in HCV RNA levels at 48 hours (first phase) was -1.1 log with LD vs. -2.5 log with SD (p<0.001). This difference persisted up to day 14 (-2.6 vs. -3.6, p=0.04) and the mean second phase slope was less with LD (-1.2 log/week) than SD (-2.3 log/week) (p=0.08). Patients receiving SD became HCV RNA negative earlier than those in the low-dose group (log rank, p<0.01), such that by week 12, all patients treated with SD (100%) but only 86% treated with LD were HCV RNA negative. Viral kinetics could not predict relapse, the most common cause for treatment failure. In the 7 LD patients who were retreated with ET, viral kinetic measurements were superior with the standard dose of the ET regimen than the initial low dose. Side effects were measured using a visual analogue scale. Patients on LD peginterferon had significantly less fatigue and felt better overall during therapy than patients receiving SD. Depression scores, however, did not differ. Serious adverse events occurred in 2 patients in both groups (sarcoidosis and acute coronary event with LD; fatal drug overdose, and severe mastoiditis and anemia in SD group).

 

Conclusion:

Although better tolerated, a reduced dose of 90 μg/week of peginterferon is significantly less potent and, in combination with 800 mg of ribavirin, provided an unacceptably lower SVR rate in patients with chronic hepatitis C, genotypes 2 and 3.


Topic: Treatment – General

 

324. Prevalence of Bipolar Affective Disorder in Patients with a Positive Depression Screen at the Initiation of Interferon Therapy for Chronic Hepatitis C

J. S. Olson ; A. Zaman; K. D. Ingram; J. R. Phelps 

 

Purpose:

Interferon therapy is associated with worsening of underlying depression, and clinicians frequently screen for depression before starting interferon. Bipolar affective disorder (BAD) patients often present with symptoms of depression rather than mania, and as a result these patients can be misdiagnosed with unipolar depression if a positive depression screen is not followed up with an appropriate screen for subtle or inactive manic traits. Our aim was to assess the prevalence of BAD in hepatitis C patients with a positive depression screen, and to determine if BAD is associated with an increased rate of psychiatric complications during interferon therapy.

 

Methods:

Retrospective study performed at the OHSU Hepatology Clinic from 12/04 to 9/06. All adult patients initiating interferon therapy (n=112) were given the Physicians Health Questionnaire (PHQ-9); a validated, self-administered survey of depressive symptoms used as a sensitive screening tool for unipolar depression. Patients with a positive PHQ screen were asked to complete the Mood Disorders Questionnaire; a validated, sensitive and specific screening tool for BAD. Chart review was performed on all 112 patients for the six month period following initiation of interferon. Psychiatric complications (change in psychiatric medications, referral to psychiatry, visits to the ER, hospital admissions, and discontinuation of interferon therapy) were recorded.

 

Results:

Three groups were formed:

·        Group A: 89 patients had a negative PHQ depression screen; and adverse psychiatric events occurred in 28 patients (31.5%).

·        Group B: 16 patients had a + PHQ depression screen, but a negative MDQ screen for manic traits; and adverse events occurred in 5 patients (31.3%).

·        Group C: 7 patients had a + PHQ depression screen, and a + MDQ screen for manic traits; and adverse events occurred in 5 patients (71.4%).Chi Square comparison of groups showed a statistically significant increase in adverse events in group C compared with group A (p=.045). The increased rate of complications in group C compared with group B approached statistical significance (p=.169).

 

Conclusions:

This is the first study of its kind to evaluate the rate of BAD in interferon patients with a positive depression screen. BAD as defined by a + MDQ screen was common (7/23 patients), and was also associated with a markedly higher rate of psychiatric complications during interferon treatment when compared to both patients without depression, and to patients with depression without manic traits. This preliminary study highlights the importance of follow up screening for BAD in patients with a positive depression screen.

 


Topic: Treatment – PEG-Intron

 

325. Patient education improves adherence to peginterferon α-2b and ribavirin in chronic genotype 2 or 3 hepatitis C virus infection: A prospective, real-life study (CHEOBS Study)

P. Cacoub; D. Ouzan; T. Fontanges; J. Lang; P. Melin; M. Rotily; M. Varastet; P. Marcellin; M. Chousterman 

 

Objective:

The CHEOBS study is a French multicenter, prospective, observational study designed to analyse the factors related to compliance with the combination treatment with peginterferon α-2b (peg-IFN) and ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Main results in patients with a genotype 2 or 3 infection are presented.

 

Patients and Methods:

From January 2003 to December 2004, 705 out of 2001 patients included were infected with a genotype 2 or 3 virus among which 674 patients had sufficient data to be analyzed: 370 patients (group 1) received an educational program to optimize the tolerance and the efficacy of HCV treatment whereas 304 pts (group 2) had no specific formation. Baseline characteristics, impact of the educational program on compliance and sustained virological response (SVR = 6 months after stopping therapy) were assessed.

 

Results:

The mean age was 45 ± 11 years, 59% were male, 17% were unemployed and 6% had poor socio-economic conditions. Patients were excessive alcohol consumers (170, 25%), smokers (354, 53%), drug abusers (current [28, 4%], past [332, 50%]), had past depression (180, 27%) and/or current psychiatric disorders (158, 24%). HCV viral load was >800,000 IU for 173 patients (38%) and genotype was 2 (202, 30%) or 3 (472, 70%). A high stage of fibrosis was frequent: Metavir F2–F3 (211, 42%), cirrhosis (69, 14%). Co-morbidities included HIV co-infection (26, 4%), HBV co-infection (9, 1%), or other chronic diseases (153, 23%).

 

At baseline, there were no significant differences between groups in sociodemographic characteristics, except indebtedness (P = .02). Depression, psychiatric disorders, current drug abuse, and METAVIR F2 or F3 fibrosis stage were significantly greater in the education group than in the no-education group

 

Patient-Reported Adherence to PEG-IFN alfa-2b and RBV Combination Therapy

·        The overall rate of adherence to combination therapy was 65% (301/466) at 3 months and 55% (209/383) at 6 months

·        Therapeutic education given during the first 3 months of treatment significantly helped stabilize the proportion of patients adherent to combination therapy until the end of treatment (Figure 2)

o       At 3 months of treatment, the proportion of adherent patients was similar in the 2 groups (66% in the education groups vs 63% in the no-education group)

o       At 6 months, the proportion of adherent patients decreased in the no-education group (to 47%) but not in the education group (61%; P = .01)

 

Virologic Response ≥21 Weeks After the End of Treatment

·        The overall SVR rate was 72% (367/511)

o       15% of patients were nonresponders

o       14% of patients were relapsers

·        Virologic response (Figure 2) was more favorable in the education group than in the no-education group; however, the difference was not statistically significant

o       SVR rates were higher (75% vs 68%) and relapse rates were lower (11% vs 16%) in the education group than in the no-education group

·        Therapeutic education benefited patients infected with G2 or G3, especially those infected with HCV G2 and low baseline viral load (data not shown)

o       Patients with baseline viral load ≤800,000 UI/mL attained higher SVR rates (80% vs 59%; P = .07) than those with baseline viral load >800,000 UI/mL; relapse rates were also lower (4% vs 21%; P = .05)

 

Conclusion:

·        This is the first prospective study to evaluate adherence in patients infected with HCV G2 or G3 and the first study to assess adherence in real life

·        Therapeutic education improved the proportion of patients adherent to combination therapy at 6 months

·        There was a beneficial impact of education on virologic response—increased SVR rate and lower relapse rate—however, the differences were not statistically significant

·        In clinical practice, the proportion of patients with psychiatric disorders or drug addiction was substantial, and therapeutic education may provide a benefit to these difficult-to-treat patients

 


Topic: Treatment – PEG-Intron

 

326. Peginterferon alfa-2b and ribavirin treatment of patients with chronic hepatitis C and normal versus elevated aminotransferase levels – final results of a prospective open trial

W. Vogel; H. Brunner; A. Maieron; I. Graziadei; M. Rosenbeiger; K. Jilek; R. E. Stauber; D. Wolkersdorfer 

 

Introduction:

Prognosis of chronic hepatitis C (CHC) seems to be similar in patients with persistently normal transaminases (PNALT) and in those with elevated (EALT). In addition, the response to therapy with interferon and ribavirin is similar in both groups of patients. However, further studies are needed. In this prospective, multi-center, open-labeled clinical trial 231 treatment-naive patients with biopsy-proven CHC with normal or elevated ALT levels received PegIntron 1,5 µg/kg/wk & Rebetol 0,8-1,2g/d for 48 weeks (genotype 1/4) or 24 weeks (genotype 2/3).

 

Study design:

Patients were stratified according to elevated or normal (median of 3 measurements over >3 months) ALT, high or low viral titer (cut-off 800.000 IU/ml, bDNA HCV RNA 3.0 assay; Bayer Diagnostics) and genotypes (GT) 1/4 or 2/3. From these 231 patients 47,6% had PNALT and 52,4% had EALT. 76,6% with GT 1 or 4 (77,3% of the PNALT and 76% in the EALT group) and 23,4% patients with GT 2 or 3 (22,7% of the PNALT and 23,9% in the EALT group) were enrolled. The median ALT in the PNALT group was 28 U/ml (GT 1 or 4) and 24 U/ml (GT 2 or 3) and 78 U/ml (GT 1 or 4) and 131 U/ml (GT2 or 3) in the EALT group.

 

Results:

The pretreatment characteristics were comparable between the two groups. 65.5% of patients with PNALT had a viral load lower or equal 800,000 IU/ml vs. 63,6% of patients with EALT.

 

Results of liver biopsies at baseline were available from 147 patients. 46,4% in the PNALT group had Metavir score F0-F1, compared to 31.4% for EALT group. 

 

Virologic Response

o       Virologic response (undetectable HCV RNA) was similar in patients with PNALT and EALT levels throughout treatment and at the end of follow-up

o       Week 4 response

o       119 of 231 patients were evaluated (64 PNALT; 55 EALT)

o       In 45.4% of patients, HCV RNA was undetectable (response rate: 46.9% PNALT and 43.6% EALT)

o       Week 12 response

o       177 of 231 patients were evaluated (83 PNALT; 94 EALT)

o       In 74.6 % of patients, HCV RNA was undetectable (response rate: 80.7% PNALT and 69% EALT)

o       End-of-treatment response (110 PNALT patients; 121 EALT patients)

o       In 70.6% of patients, HCV RNA was undetectable at end of treatment

§        Response rate: 73.6% PNALT and 67.8% EALT

§        Response rate: 65.5% G1/4 and 87% G2/3

o       SVR

§        In 49.4% of patients, HCV RNA was undetectable 24 weeks after treatment cessation

o       Response rate: 50.9% PNALT and 47.9% EALT

o       Response rate: 44.6% G1/4 and 64.8% G2/3

§        End-of-treatment and SVR rates were higher for G2/3 patients than G1/4 patients, regardless of baseline ALT levels

• SVR rates were significantly higher for patients in the PNALT group with baseline viral load <800,000 IU/mL than for patients with baseline viral load ≥800,000 IU/mL (58.3% vs 36.8%, P = .03)

 

Conclusions:

o       Fibrosis scores (F0-F1) were significantly lower in patients with chronic hepatitis C and PNALT levels than in those with EALT levels

o       SVR rates were similar in patients with PNALT and EALT levels

o       SVR rates were higher for G2/3 patients than G1/4 patients, regardless of baseline ALT levels

o       When treated with PEG-IFN alfa-2b plus ribavirin, attainment of SVR is independent of baseline ALT level in patients with chronic hepatitis C.

 


Topic: Treatment – Pegasys

 

327. Comparison of efficacy of treatment with peginterferon alfa-2a plus ribavirin vs peginterferon alfa-2b plus ribavirin among patients chronically infected with non 2/3 HCV genotypes with low and high pretreatment viral load.

H. Berak; A. Kolakowska-Rzadzka; M. Wasilewski; J. Stanczak; K. Szamotulska; K. Bardadin; A. Horban 

 

PATIENTS:

212 patients chronically infected with non 2/3 HCV genotypes were treated 48 weeks with peginterferon alfa-2a (Pegasys, group A) and peginterferon alfa-2b (Pegintron, group B), both plus standard doses of ribavirin. A and B pts were divided into groups with low ( ≤600,000 IU/mL) and high (>600,000 IU/mL) pretreatment viral load (VL) to compare the efficacy of treatment. 17 pts were lost to observation (9 in group A and 8 in group B). The analysis concerned 195 (92%) pts: 92 (91,1%) treated with Pegasys and 103 (92,8%) treated with Pegintron.

 

METHODS:

Liver biopsies were analyzed according to the Knodell’s and Scheuer’s scores. The main study outcome was undetectable HCV RNA on week 72 (SVR), 24 weeks after end of treatment. HCV RNA was performed, determined with HCV RNA ASSAY and viral load (VL) with CA HCV MONITOR TEST (both of ROCHE DIAGN SYS.). Statistical analysis was performed with Chi-squared.

 

RESULTS:

No statistically significant difference was found on the positive SVR in group A vs B and low pretreatment VL: 20 (66,7%) pts in group A and 17 (58,6%) in group B (p=0,523). Ten (33,3%) pts in group A and 12 (41,4%) in group B had detectable HCV RNA. Thirty (48,4%) pts with high pretreatment VL in group A and 32 (43,2%) in group B had positive SVR (p=0,549), and 32 (51,6%) in group A and 42 (56,8%) in group B had detectable HCV RNA.

 

Conclusion:

There were higher proportions of patients with SVR treated with peginterferon alfa-2a (Pegasys). The low pretreatment VL is a good predictor of SVR.

 

 

PEGASYS (group A)

PEGINTRON (group B)

OVERALL

92

103

HCV RNA baseline viremia

≤ 600 000 IU/mL

> 600 000 IU/mL

≤ 600 000 IU/mL

> 600 000 IU/mL

 

30

 

62

 

29

 

74

SVR

HCV RNA

HCV RNA

(-)

(+)

(-)

(+)

(-)

(+)

(-)

(+)

20 (66,7%)

10

(33,3%)

30 (48,4%)

32

(51,6%)

17 (58,6%)

12

(41,4%)

32 (43,2%)

42

(56,8%)

gender:

male

female

 

15*

15*

 

32**

30**

 

15*

14*

 

48**

26**

fibrosis score:

1-2

3-4

unknown

 

 

28*

1*

1

 

 

49**

10**

3

 

 

23*

6*

0

 

 

51**

18**

5

gender: *p=0,895, **p=0,118 fibrosis score: *p=0,044, **p=0,213

 


Topic: Treatment – Pegasys

 

328. PEG Interferon ALFA-2A Monotherapy in Dialysis Patients Infected with Hepatitis C Virus

R. Zachoval; P. Buggisch; P. Reinke; R. Woitas; A. Michelsen; M. Fuchs; W. Böcher; E. Schulte-Frohlinde; J. Encke; B. Kallinowski 

 

AIM:

Hepatitis C is an important cause of liver related morbidity and mortality under hemodialysis. Data about the efficacy of antiviral treatment with pegylated interferons (Peg-IFNs) are limited in this difficult to treat patient group. Theoretically Peg-IFN alfa-2a should be preferable to Peg-IFN alfa-2b due to the fact that <10% is eliminated by the kidneys. We conducted a multicenter controlled trial to assess the efficacy and tolerability of Peg-IFN alfa-2a monotherapy 135µg s.c. qw for 48 weeks in treatment naïve patients with hepatitis C virus(HCV) infection under hemodialysis.

 

PATIENTS & METHODS:

Thirty-eight patients were included: 23 males(61%), mean age 48 years(25-68), mean HCV-RNA 872.749 IU/ml(1523-5.560.000), 29 patients(83%) genotype 1, 3 patients(8%) fibrosis stage 3/4.

 

Patients received 135µg Peg-IFN alfa-2a s.c. qw after dialysis for 48 weeks. Treatment was discontinued at week 24 in those patients without HCV-RNA decline ≥ 2 log. The primary end-point was sustained viral response(SVR) defined as undetectable HCV-RNA(<50 IU/ml) after 24 weeks of follow-up. In a subgroup the pharmacokinetics of 2 different doses of Peg-IFN alfa-2a (135µg N=5, 180µg N=6) during the first 12 weeks of treatment were assessed by weekly serum measurements (ELISA).

 

RESULTS:

36.8% (14/38) of the patients had a sustained viral response, 17/38(44.8%) were nonresponders and 7/38(18%) had a viral relapse. Dose reduction of Peg-IFN alfa-2a was necessary in 4 patients due to hematologic abnormalities; in 10 patients treatment was discontinued (SAEs N=8, patients’ decision N=2). Twelve SAEs were noted during the study including fatal myocardial infarction, coronary bypass operation, retinal infarction, seizures, pneumonia, decompensation of cirrhosis (1 patient each).In the pharmacokinetic substudy tolerability was comparable in both dosage groups. The observed side effects in this patient cohort were comparable to those observed in patients with normal renal function. Stable concentrations of Peg-IFN alfa-2a were reached within 4-7 weeks in both groups (13 ng/ml with 135µg and 24 ng/ml with 180µg respectively).

 

CONCLUSION:

·        Peg-IFN alfa-2a monotherapy (135µg qw) has a good efficacy in hemodialysis patients (SVR 36.8%).

·        The 180µg weekly dose which might be even more efficient should be evaluated in a larger trial; repeated injections of Peg-IFN alfa-2a lead to safe and constant drug concentrations in the serum of patients with end stage renal disease.

·        The high rate of SAEs even with Peg-IFN-monotherapy in this group of patients with considerable comorbidity warrants meticulous patient selection and calculation of the potential risk versus the benefit.

 


Topic: Treatment – Side Effects

 

330. GM-CSF May Modulate the Response to Therapeutic IFN-α in Chronic Hepatitis C Virus (HCV) Infection

T. Tajuddin; E. Ryan; J. Hegarty; C. O'Farrelly 

 

Introduction:

Haematological growth factors, particularly GM-CSF and G-CSF, are frequently used to treat anaemia in HCV-infected patients receiving therapeutic interferon alpha. However, targeted use of these factors may also have important immunoregulatory roles in patients who fail to respond to conventional therapy. Previous studies have shown that these non-responsive patients can be identified, prior to treatment, by high levels of the chemokine, CXCL10. It has also been shown that GM-CSF can inhibit CXCL10 expression. In preliminary studies, we found that PBMCs from non-responsive HCV patients secreted low levels of the haematological growth factor GM-CSF compared with patients who responded to interferon alpha.

 

Aim:

The aim of this study was to determine the relationship between GM-CSF, CXCL10 and HCV infection in chronically infected patients with a view to developing a rationale for targeted therapeutic use of GM-CSF.

 

Methods:

Circulating GM-CSF was measured in twenty-seven women who had been exposed to HCV-contaminated anti-D immunoglobulin and thirteen healthy controls by ELISA. HCV infected patients had detectable levels of circulating GM-CSF (controls: 0 pg/ml ± 3.4, PCR- 5pg/ml ± 20.7, PCR+ 25 pg/ml ± 18.7); the PCR+ group had significantly more circulating GM-CSF than the healthy controls (p= 0.04), although there was significant inter-individual variation in levels. Peripheral blood mononuclear cells (PBMCs) stimulated with toll-like receptor (TLR-3 and TLR-7) agonists secreted significant quantities of GM-CSF indicating that the raised levels of circulating growth factor in HCV-infected patients were virally induced. GM-CSF suppressed interferon alpha-mediated induction of the chemokine CXCL10 by PBMCs.

 

Conclusions:

These data suggest that targeted use of therapeutic GM-CSF may overcome CXCL10-mediated inhibition of interferon alpha responsiveness in chronic HCV infection.

 


Topic: Treatment – Extrahepatic Manifestations

 

331. Hepatitis C Associated Systemic Cryoglobulinemia: Successful Treatment With Plasma Exchange.

J. C. Hofmann; R. G. Gish 

 

Introduction:

Acute treatment of mixed cryoglobulinemia associated with hepatitis C is indicated for systemic disease characterized by renal dysfunction, cutaneous vasculitis, or peripheral neuropathy.

 

Methods:

We reviewed the medical records of 21 patients (pts) who were diagnosed with moderate to severe hepatitis C associated cryoglobulinemia from January, 2005 to May, 2007 and referred for plasmapheresis treatment. The mean age of pts was 54 years (46-64 years old); 11 pts (52%) were male. 18 pts (86%) had HCV genotype 1A or 1B. The median HCV RNA was 733,900 IU/ml (73,620-9,370,000 IU/ml). All pts had positive cryoglobulin studies; median cryocrit was 1.7% (0.3-5.0%). 18 pts (86%) had significant elevation of rheumatoid factor (RF). 79-90% of pts had low complement levels.

 

Clinical Presentation:

17 pts (81%) presented with renal disease. 11 pts (52%) had chronic renal insufficiency and 6 pts (29%) presented with acute renal failure requiring hemodialysis (HD). Of 17 pts with renal disease, thirteen (76%) had a renal biopsy; 12 pts (92%) had MPGN. 17 pts (81%) had elevated 24-hour urine protein; 13 of these pts (76%) had nephrotic range proteinuria. 13 pts (62%) presented with active vasculitic skin lesions. 7 pts (33%) had peripheral neuropathy.

 

Treatment:

19 pts (90%) received a course of inpatient plasma exchange (PE) every other day; mean number of PE treatments (txs) was 8.4 (5-12 txs). 2 pts (9.5%) received outpatient PE. After completion of inpatient PE txs, 8 pts (38%) received low dose cyclophosphamide to prevent rebound of immune complex production. 5 pts (24%) underwent weekly rituximab (4-6 doses). 15 pts (71%) started weekly pegylated alpha interferon after completion of PE txs; 12 pts (57%) started daily ribavirin.

 

Results:

20 pts (95%) experienced clinical improvement. Of 13 pts with nephrotic range proteinuria, 9 pts (69%) had significant decline in urinary protein. 3 of 6 pts (50%) on HD were able to stop dialysis. 17 pts (94%) had a marked decrease in RF with twelve pts (67%) normalizing their RF levels. 12 pts (92%) demonstrated significant improvement in vasculitic skin lesions. 6 pts (86%) experienced slight improvement in symptoms of peripheral neuropathy. 3 pts (14%) with refractory disease required several inpatient courses of PE. 6 pts (29%) received weekly maintenance PE txs.

 

Conclusion:

Plasma exchange is an effective therapy for hepatitis C associated cryoglobulinemia, especially in acute treatment of progressive renal disease and cutaneous vasculitis. Some patients may require maintenance plasmapheresis treatment. Successful long-term response to antiviral therapy is essential in controlling this disease.

 


Topic: Treatment – Pegasys

 

334. Eight-week oral administration of meloxicam, a COX-II specific non-steroidal anti-inflammatory drug, prevents dose reduction of pegylated interferon alfa-2a in the treatment of chronic hepatitis C

T. Kagawa; H. Shiozawa; S. Kojima; S. Takashimizu; N. Nagata; M. Numata; F. Morino; Y. Nishizaki; N. Watanabe; S. Matsuzaki; T. Mine 

 

Background & Aim:

Reduction or discontinuation of interferon (IFN) dosage by adverse effects leads to unfavorable results in the treatment of chronic hepatitis C. To prevent dose reduction by alleviating adverse effects is important to increase sustained virological response (SVR). Granulocyte colony-stimulating factor (G-CSF) is often used to increase neutrophils, but is costly. We conducted a trial to evaluate whether 8-week oral administration of meloxicam, a COX-II specific non-steroidal anti-inflammatory drug, would decrease the rate of patients requiring dose reduction of pegylated (PEG) IFN in the treatment of chronic hepatitis C.

 

Patients & Methods:

The enrollment criteria was (1) presence of serum HCV-RNA, (2) neutrophil count ≥ 1,500 /μl, (3) platelet count ≥ 90,000 /μl, and (4) serum hemoglobin ≥ 10 g/dl. Sixty patients given weekly subcutaneous administration of PEG-IFN alfa-2a (180 μg) for 48 weeks were allocated into the meloxicam group (n = 22) and the control group (n = 38) before treatment. Meloxicam was given orally at a dose of 10 mg once a day for 8 weeks since IFN treatment started. Patients were not allowed to receive G-CSF. Dose of PEG-IFN was reduced to 90 μg when neutrophil and platelet counts fell down below 750 /μl and 50,000 /μl, respectively.

 

Results:

Age, pretreatment neutrophil and platelet counts, and body weight were not significantly different between groups. Any adverse effects of meloxicam were not observed. Cumulative rate of patients who required dose reduction was significantly lower in the meloxicam group (Kaplan-Meier plot, P < 0.05). In the meloxicam group, 9.1% and 40% of patients required dose reduction until week 8 and throughout the treatment, respectively. On the other hand, 44.7% and 71.9% of the control group required dose reduction until week 8 and throughout the treatment, respectively. Major cause of dose modification was neutropenia. Meloxicam relieved a decline of neutrophils within first 8 weeks from 54.2% to 44.2% (P < 0.05). The COX proportional hazards regression model revealed that lower pretreatment neutrophil count (adjusted HR: 3.0 per 1,000 /μl-decrease, 95% C.I.: 1.5-6.1, P = 0.002) and not receiving meloxicam (adjusted HR: 3.6, 95% C.I.: 1.4-8.9, P = 0.007) were significantly associated with dose reduction. SVR was obtained in 42.9% of the control group and 68.2% of the meloxicam group, however, multivariate logistic analysis revealed that viral serotype and viral load were only independent factors associated with SVR.

 

Conclusions:

Eight-week administration of meloxicam prevented dose reduction of PEG-IFN by relieving a decline of neutrophil count in the treatment of chronic hepatitis C.

 


Topic: Treatment – PEG-Intron

 

336. Treatment and outcome of genotype 4 chronic hepatitis C patients with PegInterferon alfa 2b and Ribavirin in the clinical setting in Germany

D. Hüppe; E. Zehnter; M. Manns; S. Mauss; G. Teuber; T. Dahhan; U. Meyer; B. Möller; N. Dikopoulos; T. Witthöft; J. Brack; M. Stern; S. Kaiser; R. Prinzing; . The bng hepatitis study group 

 

BACKGROUND:

Pegylated interferon (PEG-IFN alfa) and Ribavirin (RBV) are standard of care for hepatitis C (HCV) treatment. Since there are no large controlled studies for genotype (GT) 4 patients (pts), available cohort data are of interest in order to better define response rates and suitable treatment strategies.

 

METHODS:

A total of 285 sites (75 with GT 4 pts) have treated a total of 4130 HCV pts, of whom 126 were GT 4. The results of GT 4 pts who had reached an observational period beyond 72 weeks after baseline are described. Pts without available HCV-RNA data 24 weeks post therapy were counted as treatment failures. Data are analyzed using standard summary statistics.

 

RESULTS:

GT 4 pts had a mean age of 41 years, 61% (n=75) were male. 48% (n=59) were German, 6% (n=8) Italian, 12% (n=15) Egyptian, 4% (n=5) Ethiopian, and 6% (n=5) Turkish.  Three percent (n=4) of the pts showed cirrhosis and 5% were coinfected with HIV and 2% were coinfected with HBV.

 

88% (111/126) of the pts received PEG-IFN and RBV as primary therapy, 12% (15/126) were retreated after unsuccessful IFN mono-therapy. 38% (48/126) received standard PEG-IFN dose (1.5 mg/kg body weight), 35% (44/126) received lower and 25% (31/126) higher doses. 72% (91/126) received standard weight-dosed RBV (1000/1200 mg/day).

 

As of yet, 58 pts have reached the 24 weeks follow-up after end of therapy. Normalization of ALT was seen in 55% (32/58) of the pts at follow-up. 47% (27/47) of the pts analyzed thus far showed sustained virologic response (SVR), 16% (9 pts) relapsed, 22% (13 pts) were non-responders, and 16% (9 pts) were lost to follow-up or missing.

 

In patients with baseline HCV-RNA <600.000 IU/ml (LVL) SVR rate was 67% (16/24) and 48% (10/21) in the HVL group (<600.000 IU/mL). More nonresponders were seen in the HVL group (38%; 8/21) than in the LVL group (13%; 3/24).

 

CONCLUSION:

·        Efficacy of PEG-IFN alfa-2b plus RBV in patients with HCV G4 infection is comparable, but not superior, to results in patients with HCV G1 infection within this German cohort of patients

 


Topic: Treatment – Pegasys

 

337. PEG-IFN alfa-2A plus Ribavirin is Superior Compared to High Dose Consensus Interferon (CIFN) and Ribavirin in the Treatment of Patients with Chronic Hepatitis C

T. Witthoeft 

 

Introduction:

Pegylated IFN alfa plus ribavirin is the standard treatment in patients with chronic hepatitis C. However, so far not all patients can be cured due to different genotypes, disease history, stage of fibrosis and resistance to interferon.

 

Methods:

We conducted a single center study comparing pegylated IFN alfa-2a (180ug) plus ribavirin (800-1200mg) and high dose induction therapy with Consensus interferon (CIFN) plus ribavirin (800mg) in a therapy-naive cohort. CIFN was given at 18ug daily for 8 weeks followed by 9ug per day subcutaneously. RBV was added from the beginning at 800mg daily. Pegylated IFN was given at the recommended dosage and RBV was added in a weight based manner in patients with GT 1 and 4 and 800mg in GT 2 and 3. 52 patients received pegylated IFN and ribavirin and 50 patients received CIFN and ribavirin. PCR was performed by using the Cobas Amplicor assay. Treatment was stopped if HCV-RNA PCR was positive at week 24. Both groups were well matched in regard to age, sex and genotype.

 

Results:

The treatment was well tolerated on both treatment groups. However, patients in the CIFN treatment group experienced significantly more side effects (e.g. fever, muscle pain, weight loss, depression, lower WBC) compared to patients treated with pegylated IFN plus RBV due to the higher amount of daily interferon. Patients with low viral load (< 800 000 IU/ml) and women did respond better in both treatment groups in regard to SVR.

 

Conclusions:

Treatment regimen with pegylated interferon and ribavirin is superior in regard to SVR and tolerablitiy. Side effects are more common and severe in patients taking CIFN daily resulting in a higher drop out rate and lower SVR. CIFN might be favourable for difficult to treat patients with high viral load or non response to conventional standard therapy.

Demographics and results

 

PEG-IFN a-2a plus RBV

CIFN plus RBV (800mg)

Male (n)

29

26

Female (n)

23

24

GT 2 / 3 (n)

26

30

GT 1 / 4 (n)

26

20

SVR 2 / 3 (%)

85

73

SVR 1 / 4 (%)

58

48

Cirrhosis (n)

4

3

Drop offs (n)

0

4

 


Topic: Treatment – Disease Progression

 

338. Bone mineral density and metabolism in non-cirrhotic patients with chronic hepatitis C before and after antiviral therapy with pegylated interferon α and ribavirin: a prospective controlled study

W. P. Hofmann; B. Kronenberger; J. Bojunga; B. Stamm; U. Mihm; M. von Wagner; E. Herrmann; S. Zeuzem; C. Sarrazin 

 

Introduction:

The importance of osteoporosis as a complication of end-stage chronic liver disease is well known. However, significant osteopenia may already be present in non-cirrhotic patients with chronic hepatitis C (CHC). Furthermore, the administration of antiviral therapy may have an influence on bone metabolism. While interferon alfa has been shown to decrease bone resorption in vitro and may be beneficial for bone mineral density in vivo, less consistent data are available for ribavirin.

 

Patients and Methods:

Thirty non-cirrhotic patients with CHC genotype 1 infection were treated with peginterferon alfa and ribavirin for 48 weeks. Dual-energy x-ray absorptiometry was performed at baseline, after 48 weeks of therapy, and at the end of a 24-week follow up period. Bone mineral density (BMD), and T-scores / Z-scores were assessed. Additionally, levels of serum C-terminal propeptide of type I collagen, bone-specific alkaline phosphatase, and osteocalcin were measured.

 

Results:

Thirteen of the 30 non-cirrhotic patients had osteopenia (43%) and manifest osteoporosis was present in 4 patients (13%). Antiviral therapy led to a significant increase of femur neck and hip BMD (baseline vs end of treatment, p<0.05) as well as T-scores (p<0.05) and Z-scores (p<0.01). While in patients with sustained virologic response (n=19) most parameters remained highly above baseline values by the end of the 24-week follow up period, patients with virologic relapse (n=11) had a decrease of BMD, T-scores and Z-scores thereafter that did not differ from baseline values. Levels of osteocalcin decreased significantly during antiviral therapy, remained below the baseline levels in sustained responder, but showed an increase in relapser patients by the end of the 24-week follow up period (p=0.05).

 

Conclusion:

·        Osteopenia is detectable in a substantial proportion of non-cirrhotic patients with CHC.

·        Antiviral therapy with peginterferon alfa and ribavirin leads to a lasting increase of bone mineral density in those patients who achieve a sustained virologic response.

 


Topic: Treatment – Predictors of Treatment Response

 

340. Factors Impacting SVR in HCV Genotype 1 Patients with EVR and Week 24 Negativity

R. H. Ghalib; C. Levine; A. Steephen; A. Mubarak; J. Weinstein 

 

Background:

Current guidelines for treatment of chronic HCV utilize the EVR with ≥2 log decrease in virus as an indicator of patients who are likely to respond to therapy. Reports indicate a 72% SVR rate in patients with an EVR. The purpose of this study was to evaluate factors impacting the SVR rate in chronic HCV genotype 1 patients who have achieved an EVR at treatment week 12 with viral negativity at week 24.

 

Methods:

This was a retrospective cohort analysis of HCV genotype 1 patients treated with PEG IFN plus ribavirin. All patients who achieved an EVR and were HCV RNA undetected at week 24 of treatment were included. “Slow viral responders” had a ≥2 log decrease with detectable virus at week 12 achieving undetectable virus at week 24.

 

Results:

Total number of patients was 143 (92 men, 51 women). Age range was 22-70 (mean 47.1 ± 8.4). Race was White 112 (78%), Black 17 (12%), and Hispanic 14 (10%). Fibrosis was stage 0-1 in 21, stage 2 in 47, stage 3 in 31, and stage 4 in 34 patients. At treatment week 12, 107 (75%) patients achieved an undetectable HCV RNA with the remaining 26 (25%) patients being slow viral responders (Table 1). SVR rate in the group with undetectable virus at week 12 was 78% (p=0.0001). In patients with slow viral response, the most important factor impacting SVR was the week 12 HCV RNA <100 IU/ml vs. ≥100 IU/mL with 10/20 (50%) and 0/16 (0%), respectively (p=0.006). Additional factors demonstrating a trend in different SVR rates were race, baseline viral count, and PEG IFN used. Racial differences comparing White with non-White demonstrated a trend with 9/18 (33%) and 1/9 (11%), respectively (p=0.2). Patients with high baseline viral load (>400,000 IU/mL) had lower SVR than those with low viral load (0/4 and 10/32, respectively, p=0.25). In slow viral responders, SVR rate with PEG IFN alfa-2a vs. alfa-2b were 9% and 36%, respectively (p=0.10).

 

Conclusions:

·        Slow viral responders, with a ≥2 log decrease but delayed viral clearance until week 24, have a significantly reduced chance of SVR with standard 48 week treatment than those with undetectable virus, 27% vs. 78% respectively.

·        Significantly higher SVR rates were found in patients who were virus positive with HCV RNA level <100 IU/mL vs. ≥100 IU/mL at week 12.

·        Trends toward lower SVR rates were also seen in difficult to treat patients: non-White race and high baseline viral count.

·        Further investigation is needed to improve SVR rates in patients who are slow viral responders.

Number of Patients With Undetectable HCV RNA

Week 12 Viral Response

n

Week 48

SVR

p Value

≥2 log decrease and viral clearance at week 24

36

26 (72.2%)

10 (27.7%)

 

0.001

HCV RNA negative

107

95 (88.8%)

83 (77.6%)

 


Topic: Treatment – HIV/HCV Coinfection

 

342. Negative Impact of Abacavir on Response to pegIFN plus RBV in HIV/HCV Coinfected Patients

P. Barreiro; E. Vispo; I. Maida; J. Pineda; J. Mira; I. Santos; J. Girón; D. Merino; A. Rivero; V. Soriano 

 

Background:

The choice of antiretrovirals may influence outcome of pegylated-interferon (pegIFN) plus ribavirin (RBV) therapy. While didanosine and zidovudine have to be avoided due to greater risk of side effects, little is known on the influence of abacavir, which is a guanosine analog as RBV.

 

Methods:

All HIV/HCV patients receiving first-line pegIFN plus RBV therapy between 2002 and 2005 in three Spanish hospitals were retrospectively analyzed. Main demographics, HCV features and antiretrovirals were recorded. Baseline liver fibrosis and RBV plasma levels at week 4 were also available for a large subset of patients.

 

Results:

A total of 426 HIV/HCV patients (80% males, mean age 41 years, 80% on HAART, mean CD4 count 567 cells/µl) received at least one dose of pegIFN plus RBV. At baseline, mean HCV-RNA 5.8 log IU/ml, 65% genotypes 1 or 4, and 40% Metavir ≥F3. The SVR was 38% (G1/4, 26%; G2/3, 61%). Factors associated with non-SVR in the multivariate analysis (OR [95% CI] p) were: higher baseline HCV-RNA (10.31 [3.70-28.57] <0.001), HCV genotype 1/4 (7.75 [2.56-23.25] <0.001), Metavir ≥F3 (4.03 [1.32-12.50] 0.01), and lower RBV plasma trough levels (1.64 [1.03-2.56] 0.04). The use of abacavir predicted non-SVR (2.04 [1.08-3.85] 0.03) when RBV levels were not included in the model. The negative impact of abacavir on HCV suppression was recognized at weeks 4, 12, 48 and 72. However, it was not appreciable in the subset of patients with RBV plasma trough levels >2.2 µg/ml.

 

Conclusions:

·        Treatment with peg-ifn plus weight adjusted doses of RBV provided SVR in 38% of HIV infected patients.

·        Baseline HCV RNA, HCV-genotype and plasma levels of RBV have a strong influence the rate of SVR.

·        The use of ABC as part of HAART is associated with reduced chances for SVR.

·        The negative effect of ABC was:

o       Particularly evident in patients with lower exposure to RBV

o       In part influenced by greater degrees of liver fibrosis at baseline

·        As RBV and ABC share phosphorylation pathways, a possible intracellular interaction between both drugs may explain these findings.

 


Topic: Treatment – HIV/HCV Coinfection

 

343. Sustained Virologic Response (SVR) To Peg-Interferon Plus Ribavirin In Genotype-4 HCV-HIV Coinfected Patients

L. Martín-Carbonero; M. Puoti; J. García-Samaniego; M. Romero; E. Losada; A. Mariñó; K. Abiguerrengoa; M. Núñez; P. Barreiro; V. Soriano 

 

Background:

HCV Genotype 1 and 4 respond worse to pegylated interferon (pegIFN) + ribavirin (RBV). For this reason most of the studies joint patients with these genotypes for SVR rates and factors associated with response. However, in most trials genotype 4 sample is small, and real factors associated with response can be biased.

 

Methods:

All genotype 4 HIV-HCV infected patients who received treatment with pegIFN+RBV in two different multicentric studies (PRESCO and ROMANCE) were retrospective analyzed. Baseline viral load (BVL), undetectable HCV-RNA at week 4 (RVR), decrease of 2 log at week 12 (EVR) were assessed as predictive factors of response. Results are given as median (IQR) and percentage. Univariate and multivariate logistic regression analysis was performed.

 

Results:

Overall, 75 patients (60 men) were evaluated. Median age and CD4 cell count were 40 and 598, respectively. 49% of patients had HIV-RNA < 50 copies/ml, 71% had elevated aminotransferase levels and 31% had F3-4 fibrosis. Median HCV BVL was 5.7 log/ml. RVR was obtained in 10 (20%) patients and EVR in 26(42%). In an intention to treat (ITT) and on-treatment analysis (OTT), sustained virological response (SVR) was achieved in 21/75 (28%) and 21/62 (34%) of patients, respectively. In the multivariate analysis (OTT) BVL (OR for every log increment 0.08 95%IC:0.008-0.8) and EVR (OR 6.5 95%CI:1.3-30.8) were independently associated with SVR. HCV baseline cut-off to predict response could not be established, as sensitivity was low: the best cut-off was 5.7 log HCV-RNA with a sensitivity of 0.3.

 

Conclusion:

In this large series of patients with HCV-4/HIV coinfection treated with pegIFN+RBV we confirm than genotype 4 is a difficult to treat genotype. BVL and RVR are the best predictors of response. However, we could not establish a good baseline HCV-RNA cut-off to predict response.

 


Topic: Treatment – HIV/HCV Coinfection

 

345. Re-treatment with Pegylated Interferon plus Weight-Adjusted Ribavirin in HIV+ Patients with Chronic Hepatitis C: The PILOT-NR Study

P. Labarga; E. Vispo; P. Barreiro; J. García-Samaniego; S. Rodriguez-Novoa; C. Castellares; A. Amor; V. Soriano 

 

Background:

The efficacy of IFN-based therapy is lower in patients with chronic hepatitis C and HIV coinfection. The number of HCV/HIV patients who failed to clear HCV with suboptimal therapy in the past has increased rapidly. They might be good candidates for re-treatment with pegIFN plus weight-adjusted RBV.

 

Methods:

Prospective study of therapy with pegIFN-α2a (180 μg weekly) plus RBV (<75 kg: 1000/d; >75 kg: 1200 mg/d) for 12 months in HIV/HCV patients non-responders or relapsers to a suboptimal IFN-based therapy. Main endpoint was the achievement of SVR. Advanced liver fibrosis (ALF) was defined as >9.5 kPa using FibroScan. RBV plasma trough levels were measured by UV-HPLC.

 

Results:

A total of 51 patients were included (80% males; mean age 42 years; mean CD4 count 696 cells/μl; 90% on HAART; 89% with undetectable HIV-RNA; mean HCV-RNA 6.1 log IU/ml; 72% G1-4; 59% with ALF). Prior suboptimal regimens were IFN monotherapy (23%), IFN+RBV (27%) and peg-IFN+RBV 800 mg/d (50%). Mean length of these treatments was 6.6 months. Overall, 64% were non-responders and 36% relapsers.

 

Re-treatment with pegIFN+RBV provided SVR in 39% of patients (27% for G1-4 vs 70% G2-3; p=0.02 ). SVR was lower in non-responders than relapsers (30 vs 58%; p=ns), as in patients with ALF vs non-ALF (18 vs 60%; p=0.02). RBV plasma trough levels at week 4 were comparable between SVR and non-SVR (2.53 vs 2.13 ug/ml). In the multivariate analysis, factors independently associated with the attainment of SVR (OR [95% CI] p) were: non-ALF (50 [2.12-100] p=0.02), lower baseline HCV-RNA log IU/ml (16 [1.5-166] p<0.05) and G2-3 (33.3 [1.03-166] p<0.05).

 

Conclusions:

Re-treatment with pegIFN-α2a plus weight-adjusted RBV for 12 months allows HCV clearance in a significant proportion of HIV/HCV patients. The better chances of HCV eradication were seen in patients with mild liver fibrosis, low HCV-RNA, and G2-3.

 


Topic: Treatment – IDU

 

346. Feasibility of combination therapy for chronic hepatitis C in IVDU in the framework of an heroin detoxification protocol.

A. Ciaccio; D. Ferraro; G. Alaimo; A. Maggio; A. Craxì; P. L. Almasio 

 

Background and aims.

HCV infection is highly prevalent among intravenous drug users (IVDU), but only few receive standard-of-care antiviral treatment albeit small-scale studies suggest feasibility of treatment in this cohort, but also high rates of withdrawal from therapy affecting its efficacy. We aimed to assess adherence and sustained viral response (SVR) to therapy in a cohort of HCV-infected drug addicts within the framework of an heroin detoxification protocol.

 

Patients and protocols.

Sixty-seven consecutive anti-HCV positive IVDU patients currently on methadone or buprenorphine were referred to a Liver Unit by 4 Addiction Centres, to considered for antiviral therapy. PEG-interferon alfa-2b 1.5 μg/wk and Ribavirin 800-1,400 mg/day according to body weight were given for 24 (genotype 2 or 3) or 48 weeks (genotype 1 or 4), and observed for 24 weeks thereafter. Patients were followed for the entire period directly by the Addiction Centre.

 

Results.

Seven patients were excluded (3 being HCV RNA negative, 3 because of alcohol abuse, one for morbid obesity) and 60 were treated. This analysis is conducted on 41 subjects who have completed treatment and follow-up at the current time. Thirty-nine were males (mean age 32.4 yrs, mean duration of IVDU 9.1 yrs). Sixteen patients had HCV genotype 1, 2 genotype 2, 17 genotype 3 and 1 genotype 4. The overall withdrawal rate under therapy was 44%. Seventeen out of 22 (77%) patients who prematurely discontinued therapy were classified as early drop-outs (discontinuation within the fourth week): in all cases but one, the cause of discontinuation was primary non-compliance. Sustained viral response was 34% (18% in G1-4 and 41% in G2-3) on intention to treat analysis and 73% (40% in G1-4 and 100% in G2-3) by per protocol analysis. None of the patients enrolled was lost to the heroin detoxification program. Both the mean time of abstinence from IVDU and the mean duration of former IVDU were comparable between the patients with adequate and those with suboptimal adherence. Remarkably, adherence to the antiviral regimen was higher in the group treated with buprenorphine than in methadone maintenance (8 out of 14, 57.1% vs. 4 out 17, 23.5%, p 0.06).

 

Conclusions.

Patients with chronic hepatitis C on an heroin detoxification regimen may be effectively treated with PEG-Interferon and ribavirin, without any unexpected side effect or loss of efficacy of the opioid maintenance regimen. The high rate of voluntary discontinuation (mostly within he first 4 weeks of therapy) cannot be predicted by sociodemographic factors, but buprenorphine may be more effective than methadone in helping the patients to adhere to the schedule.

 


Topic: Treatment – General

 

347. Description of Patients with Viral Breakthrough During PEG IFN and Ribavirin Treatment for Chronic HCV Genotype 1

R. H. Ghalib; C. Levine; A. Steephen; A. Mubarak; J. Weinstein 

 

Purpose:

The purpose of this study was to evaluate factors impacting viral breakthrough in patients undergoing PEG/RBV treatment for hepatitis C genotype 1.

 

Methods:

This was a retrospective cohort analysis of HCV genotype 1 patients treated with pegylated interferon plus weight-based ribavirin from 2003 to present. All genotype 1 patients who were HCV RNA undetected prior to week 24 of treatment were included in the sample.

 

Results:

The total number of genotype 1 patients who underwent treatment was 431 with 209 achieving an undetectable HCV RNA prior to week 24 of treatment. The number of patients with documented viral breakthrough was 22 (17 males and 5 females). Age range was 24-58 (mean 45.8.1 ± 6.6). Race distribution was White 13 (59%), Black 7 (32%), Hispanic 1 (5%) and Asian 1 (5%). Fibrosis was stage 0-1 in 3, stage 2 in 11, stage 3 in 4, and stage 4 in 4 patients. BMI was normal in 6 (27%), overweight in 6 (27%), and obese in 10 patients (45%). Baseline viral load was <400,000 IU/mL in 6 (27%) and >800,000 IU/mL in the remaining 16 (73%). At treatment week 4, 1 patient was HCV RNA undetectable with a viral breakthrough prior to week 12. At week 12, 9 patients had HCV RNA undetectable with viral breakthrough in 4 prior to week 24, 2 prior to week 40, and 3 at week 48. The other 12 patients had undetectable virus on or before week 24 with viral breakthrough in 1 prior to week 24, 8 prior to week 40 and 3 at week 48.

 

During treatment, 7 patients (32%) were noncompliant with dosing (2 with ribavirin, 1 with IFN and 4 with both), 9 patients (41%) had dose reductions (5 with ribavirin, 1 with IFN and 4 with both), and the remaining 5 (23%) patients were all viral undetectable by week 12 and had no known noncompliance or dose reductions of medications.

 

Conclusions:

·        The majority of patients who suffered a viral breakthrough during treatment with Peg/RBV for chronic hepatitis C had experienced either dose modifications or were noncompliant with dosing of one or both medications.

·        However, viral breakthrough happened in some genotype 1 patients with favorable predictors of SVR, including low viral load and week 4 and 12 negativity, when neither dose modification nor noncompliance to medications occurred.

·        This data emphasizes the importance of maintaining compliance during HCV treatment even when undetectable levels of virus have been attained.


Topic: Treatment – General

 

348. Extending antiviral treatment for 12 months after HCV-RNA clearance is associated with a high response rate in difficult-to-treat HCV patients.

A. Riili; A. Gramenzi; C. Cursaro; M. Salerno; F. Felline; A. Scuteri; R. Vukotic; G. Vitale; L. Pirillo; M. Bernardi; P. Andreone 

 

Background:

difficult-to-treat patients with chronic hepatitis C constitute a large number of heterogeneous patients characterized to resistance to standard antiviral treatment mainly due to a slow HCV-RNA clearance. Recently, it has been suggested that extension of treatment to 72 weeks improves the response in this subset of pts.

 

Methods:

we enrolled 65 difficult-to-treat genotype 1 HCV pts (38 males, mean age: 54±11 yrs) defined by at least one of the following criteria: HCV-RNA serum levels ≥6x105 UI/ml (36 pts), presence of cirrhosis (10 pts), non-response to previous antiviral treatment (31 pts). Patients were treated with PEG-IFNα2b 1.5 mg/kg plus Ribavirin 800-1,200 mg/day. HCV-RNA was assayed monthly during the first 6 months and pts resulting HCV-RNA negative (<50 UI/ml) continued the treatment for further 12 months starting since the moment of HCV-RNA negativization. After 6 months pts who did not achieved a HCV-RNA negativization, withdrew from the study and were considered non-responders. Study end-point was undetectable HCV-RNA 6 months after treatment cessation (SVR).

 

Results:

HCV-RNA was negative in 5 pts (8%) after one month of treatment, in 8 (12%) after two, in 25 (39%) after three, in 6 (9%) after four, in 4 (6%) after five and in 9 (14%) after six months. Eight pts (12%) did not achieved HCV-RNA negativization within the first six months and stopped treatment. Up to now 61 patients completed the treatment period and 58 the 6 month of follow-up. A SVR was obtained in 40/58 pts (69%). The absence of cirrhosis and the naive status were the only predictive factors of SVR (p=0.009 and p=0.005, respectively).

 

Conclusions:

·        Extending antiviral treatment for 12 months after HCV-RNA negativization is a rational approach to treat HCV difficult-to-treat patients.

·        Although the study population was heterogeneous, this type of patients are not selected and very commonly encountered in the medical practice and it is crucial to define a treatment strategy in this setting.

 


Topic: Treatment – Predictors of Treatment Response

 

349. Ultra Rapid Virologic Response Predicts Sustained Virologic Response in HCV Infected Patients with Genotype 3 and High Viral Load: The Get-C Study

S. Pianko; W. Sievert; E. Gane; H. Harley; S. D. Bowden; R. McCaw; P. Palmer; M. Perlman; K. McLelland; C. Law; G. Investigators 

 

Aim:

To assess the impact of viral clearance at week 2 of therapy on the sustained virologic response (SVR) rate of HCV genotype 3 infected patients with a high viral load.

 

Methods:

The GET-C study is an ongoing study designed to evaluate extended therapy in genotype 3 patients with a baseline viral load >400,000IU/ml. Patients were randomized to receive Peg IFN alpha 2b 1.5ug /kg per week plus weight based ribavirin for 24 or 48 weeks. We assessed the predictive value of a week 2 and week 4 virologic response on the sustained virologic response rate. Viral load was determined using the Versant HCV RNA 3.0 bDNA assay (Bayer Diagnostics) (limit of detection 615 IU/ml) at baseline, week 2, 4, 12, 24, 36, 48 and 72 where applicable. All data was collected in an electronic case record form. Statistical analysis was performed using the Fisher's Exact Chi Square two-tailed test.

 

Results:

Baseline demographics were similar in responders and non responders. To date, of the first 43 patients who have completed therapy and follow up, 42 patients had week 2 virologic data available. Of 42 patients, 30 (71%) achieved viral suppression to below 615 IU/ml at week 2. Of those who achieved this, 28 had an SVR with a positive predictive value (PPV) of 93%. 12 patients did not clear virus by week 2, of these, 5 did not have an SVR with a negative predictive value (NPV) of 42%. The impact on SVR of achieving a viral load reduction to <615IU/ml at week 2 was statistically significant (p=0.011). Of 42 patients, 39 (93%) were below 615 IU/ml at week 4. Seven patients who were positive at week 2 were negative at week 4 and 4/7 achieved a SVR (57%).

 

Conclusion:

An ultrarapid virological response at week 2 was highly predictive of SVR (PPV 93%). These data in 42 genotype 3 patients with high viral load suggest that week 2 may be a useful time for predicting SVR. Patients who fail to attain an undetectable viral load by week 2 have a significantly reduced chance of achieving a SVR and may benefit from extended therapy, which is being evaluated in the GET-C study.

 


Topic: Treatment – Side Effects

 

351. Incidence and management of psychiatric disturbance in hepatitis C patients treated outside of sponsored research protocols with peginterferon and ribavirin

D. Evon; A. Verma; K. Simpson; K. Dougherty; M. W. Fried 

 

Background:

The incidence of psychiatric symptoms among patients treated with peginterferon and ribavirin (pegIFN/RBV) in registration trials ranges from 20%-30%. However, rigid entry criteria in these studies often excluded participation by patients with histories of mental health and substance use disturbance (MH/SUD). This may underestimate the burden of psychiatric side effects in the general HCV population who undergo HCV treatment. The purpose of this study was to investigate the incidence and outcomes of psychiatric symptoms in patients treated for HCV who were not enrolled in sponsored research studies.

 

Methods:

Electronic medical records were reviewed from 215 patients who underwent treatment with PegIFN/RBV from 2002-2006 at a university-based hepatology center. Logistic regressions, adjusted for gender, age, and race, explored the relationship between history of MH/SUD and the development of psychiatric symptoms on treatment.

 

Results:

Patients were mostly male(59%), Caucasian 79%), with a mean age of 45.

1)     The cumulative history of any MH/SUD was 67%. History of SUD was present in 48%, history of depression in 47%, and 14% had a history of anxiety.

2)     Prior use of psychotropic medication: 39% had taken psychotropics previously, and 80% continued on meds during therapy. A total of 39% were taking meds at the start of treatment.

3)     Development of psychiatric symptoms on therapy: 46% endorsed depressive symptoms, 19% endorsed anxiety symptoms, and 46% endorsed irritability. Cumulatively, 64% of patients indicated mood disturbance on therapy. The majority of psychiatric symptoms developed between weeks 2-18 (median=7), and rarely after week 20. Logistic regressions, adjusted for demographics, showed that a history of depression predicted the development of depression on therapy. The association was similar for developing anxiety and irritability.

4)     Management of psychiatric symptoms: Of those who developed mood symptoms, 60% required an intervention such as prescribing an antidepressant, dose reductions (14%), or treatment discontinuation (12%). 40% of patients who developed symptoms did not require interventions beyond close observation.

 

Conclusions:

This large observational study provides important insights into the incidence and management of psychiatric symptoms in an unselected sample of patients treated for HCV. Those treated outside of study protocols have higher rates of MH/SUD comorbidity, psychotropic med use, and exhibit higher rates of mood disturbance on therapy compared to previous reports in the literature. Despite this, most patients are able to complete therapy with specific interventions to manage psychiatric symptoms.

 


Topic: Treatment – Pegasys

 

352. The depression induced by peginterferon alfa-2a and ribavirin in the treatment of chronic hepatitis C is under-diagnosed by the clinician.

J. Bronowicki; P. Melin; N. Talbodec; D. Capron; J. Raabe; I. Beurthon; V. Canva; A. Weiss; D. Lucidarme; S. Fratte; C. Chandelier 

 

The occurrence of depression was reported in 20-30 % of cases in the studies which assessed peginterferon alfa and ribavirin in chronic hepatitis C. However, in these studies the diagnosis of depression was based only on the clinical impression of the investigators.

 

Aims:

The aims of our study were to evaluate the incidence of depression during the treatment with peginterferon alfa-2a plus ribavirin in chronic hepatitis C in the real life with the help of the Mini-International Neuropsychiatric Interview (MINI), a short structured diagnostic interview for DSM-IV and ICD-10 psychiatric disorders and to make the correlation between the MINI results and the diagnosis made by the clinician and with the Beck Depression Inventory score (BDI).

 

Patients and methods:

150 HCV mono-infected patients treated with peginterferon alfa-2a plus ribavirin are expected to be enrolled in this multicentric study. The incidence of depression will be assessed at baseline, at weeks 4, 12, 24, at the end of the treatment and at the end of follow up with the MINI, the clinician feeling and the BDI score.

 

Results:

The results from baseline to week 12 of the 123 first enrolled patients are presented in this intermediate analysis. The baseline patients characteristics were as follows: mean age: 48 years, male: 73 (59 %), history of IVDU: 53 (43 %), history of alcohol abuse: 29 (24 %), history of psychiatric events 30 (24 %), genotype 1: 67 (54 %), F3-F4 fibrosis: 45 (37 %), naïve patients: 73 (59 %). At baseline, the MINI revealed a current major depression in 9 patients (7 %), 7 received anti-depressant therapy before (n=5) or after (n=2) the beginning of peginterferon. Between the baseline and week 12, 21 (18 %) major depressions were diagnosed by the MINI. In 16 cases (76 %), the clinicians considered that there was no depression. Finally, an anti-depressant therapy was started in 17 cases (81 %). On the other hand, in 7 cases (6 %) the diagnosis of major depression was made by the clinician but not confirmed by the MINI. The correlation between the MINI and the BDI was poor.

 

Conclusion:

·        The incidence of depression between the baseline and week 12 was of 18 %. Major depression seems to be under-diagnosed by the clinicians.

·        The systematic use of Mini-International Neuropsychiatric Interview (MINI), a short structured diagnostic interview for DSM-IV psychiatric disorders may be of interest during peginterferon therapy.

This study was supported by Roche

 


Topic: Treatment – PEG-Intron

 

353. Combination therapy with pegylated interferon alfa-2b and ribavirin for patients with chronic hepatitis C and normal aminotransferase levels

Y. Katano; M. Ishigami; I. Nakano; K. Hayashi; T. Honda; H. Goto 

 

Background/Aim:

Combination therapy with pegylated interferon (PEGIFN) and ribavirin is standard therapy for patients with chronic hepatitis C (CHC). There is evidence that patients with CHC and persistently normal alanine aminotransferase (PNALT) levels respond similarly to those with elevated alanine aminotransferase (ALT) levels to treatment with interferon and ribavirin, however, such data with PEGIFN alfa-2b and ribavirin are currently few. The aim of this study was to evaluate whether patients with PNALT levels and patients with elevated ALT levels respond similarly to the combination therapy with PEGIFN alfa-2b and ribavirin.

 

Methods:

299 chronic hepatitis patients infected with hepatitis C virus (HCV) genotype 1 were treated with PEGIFN alfa-2b 1.5 µg/kg/wk plus ribavirin 600-1000 mg/d for 48 weeks. Among this group 54 patients, had at least 3 normal ALT levels over the 3 months prior to treatment, were defined as patients with PNALT levels. The evaluation of efficacy was sustained virologic response (SVR), defined as undetectable serum HCV RNA at 24 weeks after completion of treatment.

 

Results:

Liver histology in patients with PNALT levels were significantly milder compared with that in patients with elevated ALT levels. Overall, 50.0% of patients with PNALT levels and 43.7% of those with elevated ALT levels were SVR (p=0.395). In male, SVR rates of 46.4% and 51.8% were obtained in the PNALT group and elevated ALT group, respectively (p=0.605). In female, SVR rates of 53.9% and 31.7% were obtained in the PNALT group and elevated ALT group, respectively (p=0.036).

 

Conclusions:

·        The efficacy of PEGIFN alfa-2b and ribavirin combination therapy in CHC patients with PNALT levels is similar to that in patients with elevated ALT levels.

·        In particular, female patients with PNALT levels should be considered for curative therapy.

 


Topic: Treatment – Predictors of Treatment Response

 

354. The Role of Steatosis and Diabetes as a Predictor of Treatment Response to Interferon Based Therapies in Latino Americans with Chronic Hepatitis C.

E. A. Mena; O. E. Ventura; L. M. Blatt; M. J. Tong 

 

Background:

The role of nonalcoholic steatohepatitis (NASH) must be considered as a predictor of response to interferon based therapies in the Latino population. The aim of this study is to determine if steatosis and diabetes influence sustained virologic response (SVR) rates. Understanding the pathophysiology of NASH could help clarify pharmacological options and defining the role of treatment of NASH in overall treatment of HCV.

 

Methods:

Retrospective chart review of 205 Latino Americans referred to the HMRI Liver Center. Steatosis was defined as having fatty infiltration or balloon degeneration on liver biopsy. Diabetes was defined as having a fasting sugar greater than 126. SVR was defined as being RNA negative 6 months after interferon based therapy. Chi-square t-test and logistic regression were performed.

 

Results:

Of the 205 patients, 67% were born in the USA, 23% born in Mexico, and 10% were from a country in Central or South America. The mode of acquisition were: 42% tattoo, 40% transfusion, 37% IVDA, and 37% cocaine. The mean age this population was 52 yrs (range 25-82), mean weight 178 lbs (range 114-296), and the mean BMI was 28 (range 21-44). In 136 with liver biopsies; 67% had steatosis. Also ultrasound reports in 177 patients showed that 50% had radiographic evidence of steatosis. The most common genotype was 1 65%, 2 24%, and 3 10%. There were 79 patients treated for Hepatitis C. The majority of patients received pegylated interferon with weight based ribavirin 66%. The sustained virologic response rate to interferon based therapies for all genotypes was 36%. The nonresponder rate (NR) was 44% and the rebound rate (RR) was 14%. In Genotype 1 the SVR 23%, NR 60%, RR 17%. For Genotype 2 the SVR 76%, NR 18%, RR 6%. In Genotype 3 the SVR 38%, NR 50%, RR 13%. We found no statistical difference for SVR between age, weight, BMI, steatosis, diabetes, and cirrhosis. However there were trends of clinical relevance. Table 1

 

Summary:

There were no statistical differences in SVR with respect to weight, BMI, diabetes. This may be due the low samples size of the population. However, there were trends that need to be further analyzed. 67% of our population had steatosis on liver biopsy. Patients with steatosis on biopsy tended to have a lower SVR (33%) compared to those with no steatosis (46%). The diabetic patients had a lower SVR of (26%) compared to our nondiabetic patients with an SVR of (40%).

 

 

SVR (%)

NR (%)

RR (%)

Steatosis

33

53

14

W/o Steatosis

46

42

13

Diabetes

26

47

26

W/o Diabetes

40

49

11

 


Topic: Treatment – Consensus Interferon

 

355. Hepatitis C Virus (HCV) Treatment Outcomes with Consensus Interferon with or without Ribavirin in Peginterferon/Ribavirin Non-responders/Relapsers: Results from National Clinical Practice Settings

H. S. Yee; K. Tortorice; S. Chapman; F. Cunningham; S. Currie 

 

Background:

Approximately 50% of chronic hepatitis C patients who receive current standard of therapy (peginterferon alfa plus ribavirin) are nonresponders to treatment. Currently, there is no FDA-approved treatment for HCV nonresponders or relapsers to peginterferon alfa plus ribavirin. Despite limited published data and limited criteria for use, some providers may consider using consensus interferon (CIFN, Infergen®) in combination with ribavirin as a treatment option in these patients. To date, there have not been any large studies evaluating provider practice patterns and treatment outcomes of CIFN in HCV nonresponders or relapsers to peginterferon alfa plus ribavirin.

 

Objective:

To evaluate treatment outcomes and utilization patterns of CIFN with or without ribavirin in chronic HCV nonresponders and relapsers to peginterferon alfa plus ribavirin.

 

Methods:

A retrospective review was conducted in veterans who were prescribed CIFN with or without ribavirin in the national VA Healthcare system from October 1st, 2003 to September 1st, 2006. Data collected included HCV treatment history, time between HCV treatments, CIFN dose, frequency and duration, and HCV RNA results.

 

Results:

776 patients were prescribed CIFN, mostly in combination with ribavirin. The majority who received CIFN were prior nonresponders/relapsers to peginterferon plus ribavirin. Patients were predominantly male (95.4%), with a mean age of 55.4 ± 5.57 years; 40.3% were Caucasian, 25.5% were African American, 3.9% were Hispanic, and 30.3% were Other/Unknown. In 134 VA medical facilities, 73 (54.5%) did not prescribe CIFN. In the remaining 61 prescribing facilities, there was a 15-fold difference in patients receiving CIFN between the lowest and highest quartiles of prescribers (14.96 OR, 9.83-22.77 95%CI). 766 patients received consensus interferon plus ribavirin with a mean treatment duration of 3.1 months.  Virological data were available and 23.5% of patients treated with consensus interferon/ribavirin were HCV RNA negative ≥ 3 months post treatment.

 

Conclusion:

o       Consensus interferon is used frequently, primarily in combination with ribavirin in prior nonresponders/relapers to peginterferon and ribavirin.

o       Over 57% of patients discontinued consensus interferon use in less than 3 months of starting treatment.

o       12% (28/237) remained HCV RNA undetectable at least 3 months post-treatment with consensus following treatment with peginterferon and ribavirin.

o       Further analysis is needed to compare consensus interferon response in prior peginterferon and ribavirin nonresponders versus relapsers.

o       24% (12/51) of treatment-naïve patients remained HCV RNA undetectable at least 3 months post-treatment with consensus interferon.

o       Factors associated with outcomes and consensus interferon +/- ribavirin and other practice variations need to be further assessed.