There Is a Trend to Improved SVR for African-Americans Receiving High Dose Induction IFN alfa 2b + Ribavirin Therapy for Chronic HCV: Final Results of a Prospective, Randomized, Controlled, Multicenter Trial in a VA Population

Steve Flamm, Charles Mendenhall, David A. Johnson, Maher Azzouz, Lawrence Lumeng, Vivek Huilgol, Ena Bromley, Kimberly Sipich

 

Background

Chronic HCV has increased prevalence in the VA population and is responsible for great morbidity and mortality. There is evidence that IFN alfa 2b antiviral treatment regimens in standard dosages are less effective in the African-American (AA) grp. There is a large AA population in the VA system. It is postulated that high dose induction rx with IFN alfa based medication regimens may benefit the AA population.

 

Aim

We sought to determine the efficacy of standard dosage IFN alfa 2b + ribavirin in the AA population in comparison to the Caucasian (C) population and determine SVR to a HD induction IFN alfa 2b + ribavirin regimen.

 

Methods

VA pts with chronic HCV infection (+ HCV RNA & elevated ALT) who were not previously treated were identified in this prospective, randomized, controlled, multicenter trial. Demographic information (including race), serological parameters (viral load and genotype) and histological data were obtained. Pts were randomized to receive standard (SD) IFN alfa 2b (3 MU TIW) + ribavirin for 48 wks vs. high-dose induction (HD) IFN alfa 2b (5 MU daily 6 wks followed by 3 MU TIW 42 wks) + ribavirin. Sustained response rate (SVR) data (undetectable HCV RNA) are reported. 273 pts including 84 AA and 157 C were enrolled. SVR data are available in 70 AA and 136 C.

 

Results

15/70 (21%) of AA and 27/136 (20%) of C discontinued treatment and were considered non-responders. Overall SVR in the AA group was 4/70 (5%) in comparison to 36/136 (26%) in the C group (p<0.05). In the AA population 1/40 (2.5%) achieved SVR vs. 3/30 (10%) in the HD group. In the C population 18/69 (26%) in the SD group achieved SVR in comparison to 18/67 (27%) in the HD group. Of note, significantly more AA had GT 1,4 (93%) vs. C 62%). As previously reported, the VA population in general had significant psychosocial discord (low income, significant hx of IV drug use, incarceration and significant hx of alcohol abuse).

 

Editor’s note:  Of note, significantly more African Americans had genotype 1 (93%) than did Caucasians (62%).  The cirrhosis (F4) scores for African Americans was 16% for African Americans and 18% for Caucasians.

 

Conclusions

1)     There was a trend to increased SVR in the AA population with HD induction IFN alfa 2b + ribavirin therapy;

2)     The C population had significantly improved SVR in comparison to the AA population;

3)     The VA population has poor treatment response (SVR) to antiviral medications in comparison to the general population.

4)     There is a high drop-out rate among pts in the VA population receiving antiviral therapy. This is likely secondary to psychosocial comorbidity and may be responsible for lower SVR.

 

Psychiatric Side Effects of Pegylated Interferon Alfa-2b as Compared to Conventional Interferon Alfa-2b in Patients with Chronic Hepatitis C

Arne Schaefer, Michael Scheurlen, Herbert Csef, Michael R. Kraus

 

Background Aims

Psychiatric side effects of interferon alfa are frequently observed during therapy of patients with chronic hepatitis C infection. When introduced in 2000, peginterferon was suggested to be better tolerable than unmodified interferon.

 

Aim

The goal of the present study was to assess systematically the spectrum and extent of psychiatric symptoms (especially depression and anger/hostility), comparing patient groups receiving peginterferon or conventional interferon, respectively.

 

Methods

Ninety-eight patients with chronic hepatitis C and interferon-based therapy (+ribavirin) were consecutively enrolled in a longitudinal study. According to the respective therapy standards, patients were treated with conventional interferon alfa-2b (48/98 patients; 5 MIU interferon alfa-2b thrice weekly) or peginterferon alfa-2b (50/98 patients; 80-150 μg peginterferon alfa-2b). Repeated psychometric testing was performed before, three times during and once after antiviral therapy: Depression was evaluated by the Hospital Anxiety and Depression Scale (HADS), anger/hostility by the Symptom Checklist-90 Items Revised (SCL-90-R).

 

Results

Therapy with pegylated interferon alfa-2b produced comparable scores (with respect to time course and extent) for depression (ANOVA main effect treatment P > 0.05; main effect time course within treatment P < 0.001) as compared to conventional interferon. Observed maximums of depression scores were even higher (however, statistically not significant) and cases of clinically relevant depression were frequent during therapy with peginterferon and ribavirin. Scores for anger/hostility were comparable for both therapy subgroups (P > 0.05).

 

Conclusions

Our findings suggest that the extent and frequency of depressive symptoms (and symptoms of anger/hostility) in total are not reduced by peginterferon as compared to conventional interferon alfa. Therefore, monitoring and management of neuropsychiatric toxicity - especially depression - have to be considered as much as in former antiviral therapy with unmodified interferon

 

Two-Weeks Induction Therapy with Pegylated Interferon Decreases Early Viral Load Without Improving Sustained Virological Response Rate in Patients with Chronic Hepatitis C - Prospective, Randomized, Open Label Phase III Clinical Trial

Wolfgang Vogel, H. Brunner, W. Lin, Rudolf Stauber, Michael Gschwantler, Bernhard Stadler, Hans J. Ulmer, Austrian Hepatitis Study Group

 

Introduction /Aim

High-dose induction therapy may improve the outcome of interferon/ribavirin combination therapy in genotype 1 patients (Hepatology 2001;34:1006-11).

 

Methods

In this multicenter, open-labelled clinical trial 163 de novo genotype 1 patients (66 women), with biopsy-proven chronic hepatitis C were randomly allocated to 4 induction treatment arms lasting 2 weeks each at d7 after receiving a test dosis of 10 MU Intron A once at d1. Group A (n=41) = 200ug pegylated Ifn-alpha2b (PegIntron,PEG) 1x/wk + Ribavirin (Rib) 1-1,2g/d; Group B (n=43-1=42 for wrong allocation) = 100ug PEG 1x/wk + Rib 1-1,2g/d; Group C (n=41)= 200ug PEG 1x/wk; Group D (n=38) = 100ug PEG 1x/wk. After induction treatment, all patients received PEG 100ug 1x/wk + Rib 1-1,2g/d for 12 months. Viral titers were measured on d0 (prior to test dose), d 1 (24 hours after injection), ds 7 and 8 (prior to and 24 h after first PEG), d11, d14 and d20. Viral titers were measured by the Clinical Molecular Biology Lab of the Schering-Plough Research Institute. Primary outcome measure was defined as virus elimination at d21, secondary at 3 and 6 months after start of routine treatment, at month 12 and 6 months after end of treatment.

 

Results

In group A, virus load decreased by -4.41+/-3.08 log units from d 0 (baseline) to d 21 (n=26), in group B by -2.46+/-2.82 (n=28), in group C by -2.81+/-2.47 (n=26) and in group D by -1.81+/-2.19 (n=27). Differences were statistically significant over all groups (p=0.005, one-way ANOVA). Only group A revealed to be significantly different (A vs. B p=0.008; A vs. C p=0.032; A vs. D p=0.001; all p-values corrected for multiple comparisons using the LSD-procedure) in pair-wise comparisons. High dose PEG (200 ug vs. 100 ug, p=0.005) and use of Rib (p=0.031) showed significant effects in a two-way ANOVA, considering the factorial design of the trial. At month 3, 72.4% patients in group A, 63.6% in group B, 75.8% in group C and 60.0% in group D were PCR negative (p=0.504, chi-square test). At month 6, 88.5% patients in group A, 65.4% in group B, 76% in group C and 58.3% in group D were PCR negative. P=0.072, indicating a trend. At month 12, 84.2% patients in group A, 82.6% in group B, 89.5% in group C and 81.3% were PCR negative (p=0.214). SVRs differed not significantly between groups: A 52.4%, B 68.2%, C 70.6% and D 57.1%. The odds ratio to achieve a SVR for patients with a >2 log drop in viral load after the test dose was 1.38 (95% CI 1.03-1.95; p=0.003).

 

Conclusion

The authors concluded that 2 weeks of induction therapy with pegylated interferon decreases early viral load without improving SVR in patients with chronic hepatitis C.

 

End of Treatment Response for PEG-IFN + Weight-Based Ribavirin Nonresponders Retreated with IFN alfacon-1 + Weight-Based Ribavirin

Carroll B. Leevy, G. Ramaraju, Chris P. Chalmers, Lawrence M. Blatt

 

Background

Recent studies suggest that IFN alfacon-1 with ribavirin may be effective in re-treating interferon α2 and RBV non-responders when compared to re-treated with a PEG-IFN-α2 containing regiment. We report the end of treatment virological response and safety of IFN alfacon-1 and weight based ribavirin in HCV patients who were non-responders to PEG IFN α-2b and weight based ribavirin.

 

Methods

We conducted a retrospective review of 137 consecutive PEG IFN α-2b/RBV non-responders re-treated with daily IFN alfacon-1 and RBV. All patients had previously received PEG IFN α-2b 1.5 mcg/kg SQ Q week and weight based dosed RBV, and did not have at least a 2 log decline in HCV RNA at week 12 of therapy (Null Responders). With no washout period, patients were started on IFN alfacon-1 at 15 mcg SQ daily and RBV 1000-1200mg QD for 12 weeks, if they were HCV RNA negative the dose was reduced to 15 mcg SQ TIW for the remainder of the 48 weeks, if they were not HCV RNA negative, no dose reduction was implemented. Patients were monitored for constitutional symptoms and bloods were collected for serum chemistries and hematological evaluations.

 

Results

The population was 57% male, mean age was: 47.5 ± 9 years, mean weight was 79 ± 15 kg. Ninety-four percent of the patients were HCV genotype 1 and 4. The mean HCV RNA at baseline and after 12 weeks of therapy of PEG IFN α-2b /RBV was 3.245 ± 4.11 million copies/ml, and 1.67 ± 1.82 million copies/ml. At the end of 12 and 24 weeks of therapy with daily IFN alfacon-1/RBV, the mean HCV RNA was 247,000 ± 314,000 copies/ml and 189,902 ± 254,500 copies/ml respectively, a significant reduction from the baseline(P<0.05 for both observations). By the end of therapy with IFN alfacon-1/RBV (week 48) 59/137 (43%) of patients were HCV RNA negative. Therapy was well tolerated in all patients with flu-like symptom and fatigue reported in most patients, but no patients discontinued therapy. Sixteen percent (22 patients) had ANC drop below 0.75 X 109 /L, and required growth factors.

 

Conclusions

In these difficult to treat nonresponding HCV patients, retreatment with bioengineered IFN alfacon-1/RBV resulted in a clinically significant end of treatment virologic response (43%). Daily-dose consensus interferon with weight-based ribavirin dosing was generally well tolerated.  The authors stated that their data suggest that the time to response may be longer for nonresponders than for treatment-naïve patients.  Patients will be monitored for HCV RNA response 6 months post treatment to determine the rate of SVR. These initial data are highly promising and warrant more study of IFN alfacon-1/RBV in difficult to treat chronic Hepatitis C patients.

 

Improved Medical Adherence and QOL with Cognitive Behavioral Therapy in Pts Receiving PEG IFN alfa 2b (1.5 mcg/kg/wk) + Ribavirin (800-1400 mg/day) Persists Through 48 Wks of Therapy: Results of a Prospective, Randomized, Controlled, Multicenter Trial

Steve Flamm, Anne Eshelman, Michael Lyons, Arnold Levin, Stuart R. Gordon, Andrew J. Muir, Geronimo Sahagun, Jeffrey Medoff, Scott Strohecker, Ken Flora, Kenneth Kohagen, Wayne Weng, Tina Jackson

 

Background

Improved medication adherence significantly increases SVR. Thus, techniques are sought to improve medication adherence and QOL for pts treated for HCV. We have previously reported improved medication adherence and QOL with active intervention through wk 12 of rx.

 

Aim

We sought to determine if improved medication adherence and QOL persist through wk 48 of rx utilizing pt education, aggressive side-effect management and expanded supportive nursing intervention with cognitive behavioral rx by telephone in patients treated with PEG IFN alfa 2b + ribavirin.

 

Methods

Pts with HCV for whom medical rx was planned were eligible. 10 GI/hepatology groups were selected for participation. 5 grps were randomized to the active intervention (AI) arm and 5 grps to the standard of care (SC) for that group. Patients enrolled prior to receiving PEG IFN alfa 2b (1.5 mcg/kg/wk) + ribavirin (800-1400mg/day) for 48 wks. The AI arm consisted of the following: Experienced nurses who help pts with HCV on medical rx by telephone (Be In Charge) were taught behavioral rx techniques by an experienced therapist. Pts in the AI arm were to call these nurses on 10 defined occasions from prior to beginning medical rx until week 12 of rx. Aggressive medication side effect management was undertaken. Pts in the SC arm received routine supportive care used by their physician. SVR rates, AE profiles, and QOL measurements (SF 36) were determined in both groups. Drop-out rates and quality of life measurement results through wk 48 are reported.

 

Results

The 5 groups randomized to SC enrolled 39 patients. One group randomized to AI group did not recruit pts and was eliminated. The other 4 groups randomized to AI enrolled 38 pts. 30% in SC discontinued rx by wk 48 vs 11% in AI. 19% discontinued in
SC due to AE at week 24 versus vs. 6% in AI. Regarding health-related QOL, substantial improvement (33-75%) in 5/8 domains of SF 36 persisted through wk 12 and 48.

 

ETR 48 week

G1       AI = 33%

            SC = 20%

G 2/3   AI = 67%

            SC = 73%

Overall SVR   AI = 47%

                        SC = 36%

Conclusions

1)     AI utilizing pt education, aggressive side-effect management and nursing support by telephone, using cognitive behavioral therapy yields a decrease in overall drop-out rate and drop-outs related to AE through wk 48 of rx

2)     AI results in improvements in physical-related and mental health-related QOL which persist through wk 48 of rx.

3)     There is a trend to improve SVR in HCV genotype 1 patients in AI

4)     More breakthrough/relapsers were noted in SC than AI in genotype 1 patients.  In genotype 1 patients there were 7/25 (28%) breakthrough/relapsers in SC and 2/21 (10%) in AI.

 

Treatment of Patients with Chronic HCV Infection and Normal Liver Enzymes with PEG IFN alfa 2b + Ribavirin Is Effective: Results from a Prospective, Randomized, Controlled, Multicenter Trial

Steve Flamm, Jeffrey Goldman, Joel Cahan, Gregory Nelligan, David Chua, Bradley Shapiro, Mohammad Bawani, Rockford Yapp, Edward Jurkovic, Tina Jackson

 

Introduction

Approximately 30% of patients with chronic HCV have persistently normal liver enzymes, some of whom have progressive liver disease. The efficacy of pegylated interferon alfa 2b + ribavirin in HCV patients with normal liver enzymes is unknown. AIM: We sought to determine the efficacy of pegylated interferon alfa 2b + ribavirin in HCV patients with persistently normal liver enzymes.

 

Methods

Patients with chronic HCV (+HCV RNA) and persistently normal or abnormal ALT were evaluated within the context of a prospective, randomized, controlled, multicenter trial comparing pegylated interferon alfa 2b 1.0 mcg/kg/wk + ribavirin (800-1400mg/d) vs. pegylated interferon alfa 2b 1.5 mcg/kg/wk + ribavirin (800-1400mg/d). Demographic, serological (ALT), virological (HCV viral load and genotype) and histological data were obtained. Patients were randomized to one treatment group and were administered the medications for 24 weeks (genotypes 2, 3) or 48 weeks (genotype 1). Sustained response rate (HCV RNA negativity) will be assessed after a 24-week follow-up period. Preliminary 24 week response data in the patients with persistently normal ALT are reported.

 

Results

300 patients were enrolled including 76 with persistently normal ALT. 1 patient was d/c before receiving medication and not included in the analysis. 31/75 (41%) were men and 45/75 (60%) were women. 54/75 (72%) had fibrosis stage 0-1 and 22/75 (28%) had fibrosis stage 2-4. 53/74 (70%) of patients were GT 1 and 21/75 (28%) were GT 2, 3. Genotype was undetermined in 1 patient.  48 week response rates are based on 66 patients and follow up response rates are based on 58 patients.

Overall ETR was 34/366 (52%).  G1 ETR was 21/48 (44%) and G2/3 13/28 (72%).  Overall SVR is 26/58 = 45%.  G1 SVR is 14/40 (35%) and G2/3 is 12/18 (67%).  Relapse rate was 3/58 (5%).  12/75 (16%) patients discontinued by 24.  5 discontinued due to AE/ASE

 

Conclusions

1)     PEG IFN alfa 2b +RBV are effective in genotype 1 and 2/3 patients with chronic HCV and persistently normal ALT in regards to HCV RNA negativity at ETR and SVR

2)     There was significant medication discontinuation due to AE/SAE in this population which is similar to that reported in the registration trial.

 

The Outcome of Hepatitis C Therapy in African Americans and Hispanics with Persistently Normal Transaminases

Eric J. Lawitz, Norma S. Cantu, Stephen A. Harrison, Shailesh C. Kadakia, Frank Adams, Mitchell Davis, Richard Sperling, Naoky Tsai, Andrei Gasic, Tarum Kothari, K. P. Ganeshappa, James Cox, Barry Sanders, Bruce Silverman, Elias Ghandour, Jeffrey Medoff, Nezam Afdahl, Mark Mailliard, Michael Curry, Alamo Study Group

 

Background

Those with persistently normal transaminases (PNLT) have been shown to have similar sustained viral responses(SVR) to those with elevated transaminases. Ethnic groups may have a differential response to interferon-based therapy. African Americans have consistently shown a lower SVR. Emerging data suggests Hispanics may also have a less robust response to combination therapy. There has been no description of the outcome of African Americans and Hispanics with PNLT.

 

Aim

To describe the outcome of pegylated interferon and Ribavirin therapy in African Americans and Hispanics with normal transaminases. Methods: Data from a completed large multicenter trial evaluating the effectiveness of Amantadine as a third agent was retrospectively evaluated to determine the sustained viral response of African American and Hispanic subjects with PNLT. PNLT was defined as three consecutive normal ALT's over a 6 month period. Ethnicity was determined by subject self-report. Participants in the trial were randomized to receive either Pegylated Interferon Alfa 2b (PEG-IFN) 1.5 mcg/kg/wk + Weight Based Ribavirin (Riba) (800-1400mg) for 48 weeks + Amantadine 100mg bid for 32-48 weeks versus PEG-IFN 1.5 mcg/kg/wk + Riba for 48 weeks. HCV-RNA was obtained at 0, 24, 48 & 72 weeks.

 

Results

Eight hundred and seventy two treatment naive participants were treated. Nineteen percent of Caucasians (114 subjects), 16% of African Americans (9 subjects), and 12% of Hispanics (11 subjects) had PNLT. Subjects with elevated transaminases compared to those with PNLT showed no significant differences in age, gender, genotype 1 percentage, early discontinuation rates, or dose modification rates. Advanced liver disease (Metavir F3-4) was seen in 14% of PNLT subjects, compared to 38% of elevated transaminases subjects. The sustained viral responses are seen in the chart below.

 

Conclusions

African Americans and Hispanics with PNLT were significantly less likely than Caucasians with PNLT to achieve a SVR. Both Hispanics and African Americans with PNLT were less likely to achieve an SVR compared to the same ethnicity with elevated transaminases. There is no difference in SVR in Caucasians with PNLT or elevated transaminases. Small numbers limit conclusions but suggest prospective trials should be undertaken to validate these findings.

 

Sustained Viral Response

 

PNLT 

Elevated Transaminases 

Caucasian 

38% (43/114) 

39% (223/572) 

Hispanic 

9% (1/11) 

29% (24/82) 

African American 

0% (0/9) 

27% (13/48) 

 

Topic:  Treatment, IDU

High Relapse Rate of Former I.V. Drug Users with Hepatitis C Treated with Consensus-Interferon (Infergen) and Ribavirin

Thomas Witthoeft, Andreas Bruening, Diether Ludwig

 

Background

Chronic hepatitis C is the most common infectious disease among injection drug users (IDUs). Treatment is important to prevent spreading of the disease, but IDUs are difficult to treat since their lack of compliance.

 

Aims

We did treat former IDUs infected with HCV to proof tolerability and efficacy of a high dose induction protocol with Infergen and ribavirin primarily. Secondly we did look at the compliance rate of this difficult to treat patients.

 

Method

Patients were submitted to our outpatient clinic for further diagnostic and treatment of HCV-infection. 50 patients were former i.v. drug users and off drugs for at least for 4 months. 41 patients did participate in an inpatient detoxification program and 11 patients were either methadone- or codeine-substituted. 32 showed genotype 2 and 3 and 18 patients showed genotype 1 or 4. Viral load, subtype and liver enzymes were quantitated. Patients received 18ug of CIFN s.c. QD and 800mg of ribavirin QD for the first 8 weeks followed by CIFN 18ug (s.c.) tiw and ribavirin(800mg daily) for 16 weeks in the case of subtype 2 and 3, and 40 weeks for subtype 1 and 4. Haematology and liver enzymes were controlled every two weeks. Viral load was controlled qualitatively and quantitatively at week 12, 24 and 48.

Male    n=39    female=11

Fibrosis

0                 n=5

1                 n=27

2                 n=10

3                 n=5

4                 n=3

 

Results

Only 44% of patients did finish antiviral therapy within the recommended time frame. 46% did not complete the treatment due to relapse of i.v. drug use (6 patients), death (1), side effects (8) or lost to follow up (8). 20 patients who did succeed and showed negative HCV-PCR at end of treatment (ETR) did participate in a detoxification program while all patients who came outside the program failed to finish therapy due to different reasons. All patients who were on substitution either with methadone or codeine did finish therapy as well. Nearly 90% of patients who showed a negative PCR at ETR have been off i.v. drug use for more than 9 months.

 

Genotype                                 1                      2          3          4

N=                                           16                    17        15        2

Lost to f/u                                6(+1 death)      6          7          1

Stop due to SEs                       5                      3          2          -

Neg HCV PCR at ETR            4                      8          5          1

                                                (25%)              (47%)  (33%)  (50%)

 

Conclusions

High-dose-CIFN and ribavirin is a well tolerated treatment regimen in patients with HCV. 23 out of 32 patients with subtype 2 or 3 showed SVR. All patients who failed therapy due to relapse or i.v. drug use were off drugs initially for less than 1 year. These data support the need for more trained counsellors who help IDUs and provide psychological support while on therapy. The duration of being off i.v. drugs is positively correlated with negative HCV-PCR by the end of treatment. Close monitoring and counselling during therapy may be essential for the outcome of antiviral treatment in IDUs.