Outcome Study on Hepatitis C Therapy with Mistletoe (Viscum Album L.; Abnobaviscum) and Solanum Lycopersicum

Harald Matthes, Friedemann Schad, Burkhard Matthes, Silke Biesenthal-Matthes, Gesa Schenk

 

Introduction

Combined therapy with pegylated Interferon-alpha and Ribavirin reaches sustained response rates of 45-70%, depending on the genotype. The wide range of side effects which often lead to an interruption of this therapy. In cases where Interferon- a therapy has failed and high rates of side effects occur a study on a complementary therapy with mistletoe extract (Abnobaviscum) in combination with Solanum lycopersicum and Hepatodoron was initiated.

 

Aim

Aims are to achieve HCV-RNA-PCR negativity after 1 or 2 years of treatment and 6 months of follow up, documentation of side effects, fibrosis -parameter (PIIIP) and the quantitative course of HCV-RNA-PCR.

 

Methods

Up to now 85 patients with chronic hepatitis C (> 6 months) with increased transaminases and positive HCV-RNA-PCR values are included. 43 patients had a liver biopsy before therapy; 27 patients failed Interferon therapy before. Genotype was determined in all patients. Initially mistletoe was administered 3x per week subcutaneously, concomitantly Hepatodoron 3x2 tablets were given. After 14 days Solanum lycopersicum Herba D3-4 (tomato plant extract) tablets were applied. Duration of therapy was 12 (78 patients) - 24 months (64 patients).

 

Results

7 of 85 patients terminated the therapy. 14 patients (18%) were HCV-RNA-PCR negative after 12 months. After 24 months 20 patients (25%) showed a sustained response. 44 patients (56%) were non-responders. No essential side effects were observed. Transaminases and PIIIP-values decreased significantly during therapy (p<0,05). Virus load did not decrease continuously but in those patients with HCV-RNA-PCR negativity it decreased below the detection limit, independent of the initial level. 2 patients had shown a so-called 'break through' phenomenon.

 

Conclusion

Combined therapy of mistletoe and Solanum lycopersicum showed a virus elimination and sustained response in chronic hepatitis C. The responder rates of combination therapy lay below the results of the standard therapy. Advantage of mistletoe therapy is the absence of side effects and its cost effectiveness. Therefore mistletoe therapy could be an alternative in non-responders of standard therapy or in patients with relative or absolute contraindications of Interferon therapy. Further studies will be necessary to optimize the therapy and to verify the results.

 

Superior Efficacy of Twice a Week Administration of Peginterferon Alfa-2b plus Ribavirin in Obtaining SVR in HCV Genotype 1

Francesca Lodato, Francesco Azzaroli, Maria R. Tame, Antonio Colecchia, Marco Montagnani, Rosangela Muratori, Silvia Giovanelli, Anna Miracolo, Giovanni Nigro, Constance Mwangemi, Enrico Roda, Giuseppe Mazzella

 

Introduction

Once a week administration of Peginterferon alfa-2b (Pegintron) produce an exponential decrease of serum drug's level being almost undetectable at days 6 and 7 after administration.

 

Aim

To evaluate whether twice a week administration may improve sustained virological response (SVR) in hepatitis C patients.

 

Materials and Methods

Sixty five patients (38 men/27 women, age range 20-65) with chronic hepatitis C were subsequently enrolled among outpatients.

 

       Group A - Twenty two patients (7 genotype 2, 15 genotype 1) received Pegintron 1.5 mcg/Kg once a week -

       Group B forty-three patients (17 genotype 2, 26 genotype 1), received Pegintron twice a week (mean dose 2.4 mcg/Kg/week)

       Both groups received ribavirin 11 mg/kg/day.

 

Groups were comparable for rate of naive, non responders and relapsers, for prevalence of genotype 1, for male/female ratio and for age of patients. Genotype 1 patients were treated for 48 weeks, genotype 2 for 24 weeks. The follow-up period was 24 weeks. Statistical differences between groups were calculated with chi-square test.

 

Results

SVR was higher in group B for genotype 1 (46% vs 27%, p= 0.033). Overall early response was higher in group B than group A (53% vs 27%, p= 0.044). Among naive patients SVR was higher in group B (72% vs 25%, p=0.024). Total drop outs were 7 on 15 (32%) and 8 on 35 (19%) for group A and B respectively.

 

Conclusions

In a non selected population of patients with chronic hepatitis C, twice a week administration of Pegintron is more effective than once a week administration in genotype 1 naive patients. Tolerability and adherence to treatment was higher for the twice a week group (B), probably because the twice a week administration is able to induce tachyphilaxis, producing a continuous drug exposure.

 

Viscum Album L and Solanum Lycopersicum Inhibit Fibrosis in Chronic Hepatitis C (HCV): A Pilot Study

Friedemann Schad, Burkhard Matthes, Silke Biesenthal-Matthes, Dirk Buchwald, Harald Matthes

 

Introduction

Untreated HCV leads to liver cirrhosis and hepatocellular carcinoma in 20-30% of cases after 25 years of infection. No treatment is known in failure or contraindications to standard therapy (pegylated interferon and ribavirin).

 

Aim

We investigated the effect on fibrosis in a pilot study using a complementary concept with viscum album L (mistletoe) and herbal extracts of Solanum lycopersicum, Fragaria vesca/Vitis vinifera (Hepatodoron).

 

Methods

8 patients with HCV (genotype 1) were treated with Viscum album (ABNOBAviscum aceris or Helixor M) 3 x weekly 1 Amp. sc., Solanum lyc. D4-D6 2-6 Tbl. and Hepatodoron 2-6 Tbl. daily. Mean duration of therapy was 13.3 months. A liver biopsy was conducted before and 6-10 months after treatment and the modified HAI score was calculated and compared with the paired Wilcoxon Test.

 

Results

In 8 patients (5 female, 3 male; mean age 43, mean duration of HCV 20 years) the HAI score before treatment was 7.75; after 18 - 23 months (>12 months of treatment and 6-11 months follow-up) the score was 5.25 (p=0.05). The fibrosis stage decreased from 2.375 to 1.375 (p=0.09). In 4 patients, fibrosis decreased by 1-3 score points, 1 patient increased by 1 scored point and 3 were stable. Also peri-portal inflammation decreased but not significantly.

 

Discussion

Progression of fibrosis leads to the natural endpoint of cirrhosis in chronic HCV infection which is the most frequent indication for liver transplantation in western countries. Inhibition or decrease of fibrosis is the leading therapeutic aim in chronic HCV therapy. Interferon therapy inhibits inflammation and fibrosis in the liver. Viscum Album L has shown positive effects on viral load, levels of ASL and ALT and HRQOL in HCV therapy. In cirrhotic livers of rats antioxidative and antifibrotic effects have been seen with solanum lycopersicum. Morphological findings show a significant decrease in total HAI with a decrease in fibrosis due to a decrease of pro-fibrotic cytokines like FGF , TGF and TNF α found in the liver cells of HCV + patients under viscum album L therapy. In cancer treatment viscum album L decreases tumor in HCC and improves QOL in breast, ovarian and non-small cell lung cancer. It may be discussed that viscum album L has an effect of cancer prevention in HCV infection. Viscum album L is an immunomodulatory and immuno-stimulatory substance which induces apoptosis. Solanum lycopersicum can induce apoptosis in a high amount in HEP G2 cells by stimulation of caspase 8 (FLICE enzyme). Apoptosis is one of the leading mechanisms in hepatic viral clearance in HCV. Both effects may be responsible for decreasing inflammation and fibrosis shown here.

 

Conclusion

Viscum album and the herbal extract were able to inhibit and reduce fibrosis in liver biopsies scored by HAI. This therapy concept might be beneficial to non-responders and patients not compliant with standard HCV therapy. Further studies are necessary to confirm this preliminary data.

 

Treatment of Chronic Hepatitis C in Canadian Prison Inmates

Henry V. Chung, Victor Wong, Elizabeth Lim, Eric Yoshida, John Farley

 

Purpose

To assess the treatment compliance and sustained viral response in hepatitis C positive inmates in several Canadian penitentiaries.

 

Background

 

Methods

A retrospective chart review of all inmates that were treated with standard interferon and ribavirin therapy for chronic hepatitis C between March 2001 and February 2003.

 

Results

A total of 90 male patients were treated. There was incomplete data for 22 patients at the time of this abstract. The mean age at time of treatment was 37.6. There were 49 (55%) with genotype 1, 11 (12%) with genotype 2, 30 (33%) with genotype 3, and 1 person with unknown genotype.

 

Genotype 1

Complete Data Success Failure

38/49 (77.6%) 12 (31.6%) 26 (68.4%)

 

      Failures that completed therapy = 8 (30.8%)

      Failures due to HCV+ at week 24 = 9 (34.6%)

      Failures due to discontinuing due to ADR = 5 (19.2%)

      Failures due to discontinuing by own decision = 3 (11.5%)

      Failures due to palliative reasons = 1 (0.4%)

 

9/11 (82%) had an EOT

 

Genotype 2

11/11 (100%) achieved an SVR

 

Genotype 3

28/30 have completed data. SVR = 20/28 (71.4%)

 

Overall

Overall SVR = 55.8%

 

There was no difference in adherence in patients in different levels of security institutions

 

Conclusion

There was excellent compliance to treatment with interferon and ribavirin. To our knowledge this is the only study to assess the treatment of hepatitis C positive patients in a Canadian incarcerated population. This experience highlights a great opportunity to treat a population with high prevalence of hepatitis C positive persons who would otherwise likely not seek treatment. A standard screening and counseling program should be implemented for inmates to be able to more effectively address this important public health issue.

 

Outcomes of a Hepatitis C Screening Program at a Large Urban VA Medical Center

Holly Groom, Eric W. Dieperink, Mark L. Willenbring, Lori Tetrick, Janet Durfee, James Johnson, Stephen Ewing, Dave Nelson, Herbert Stockley, Rhonda von Drashek, Judith Garrard, Samuel B. Ho

 

Objectives

The Department of Veterans Affairs has issued guidelines calling for routine screening for hepatitis C and antiviral treatment for all eligible patients. The purpose of this study was to determine the effectiveness of a hepatitis C screening and referral program in a large urban VA Medical Center.

 

Methods

Retrospective review of all patients tested for hepatitis C at a VA Medical Center from 1/1/00 through 12/31/01. A series of logistic regression analyses were used to determine factors related to referral to hepatitis C clinic. The analyses considered the following variables: age, race, marital status, service connection, prior utilization, diagnoses of substance use disorders, psychiatric disorders, and medical comorbidities, and prior narcotic or psychiatric medication prescriptions. Criteria for antiviral treatment eligibility were based on the VA Hepatitis C Treatment Guidelines and the 1997 NIH Consensus Guidelines.

 

Results

During this two-year period 681 patients with positive HCV EIA tests were identified. A total of 670 received confirmatory testing for HCV RNA and 272 (40%) patients had multiple positive EIA testing. A total of 150/670 (22%) were HCV RNA negative. Of the 520 HCV EIA and RNA positive patients, 430 (83%) patients were referred for specialty care in the hepatitis clinic. The remaining 90 (17%) were neither referred nor scheduled. Patients referred to hepatitis clinic were found to have significantly less diagnosed medical comorbidities (OR=0.377, CI 0.225-0.635); and more psychiatric comorbidities (OR= 1.624, CI 0.956-2.841) than those not referred. Of the 430 patients referred to specialty care, 382 (89%) presented for at least one appointment and 48 (11%) patients did not attend any referral appointments. These 48 patients did not significantly differ on any variable from those who did show for referral appointments. The median amount of time between diagnosis and scheduled appointment was 63 days; 21% patients had scheduled follow-up more than 6 months after diagnosis. A total of 124/382 (33%) patients eventually received HCV therapy over 3.5 years of follow-up. Of 109 patients who have finished therapy, 36 (39.4%) achieved a sustained virologic response (SVR), representing 8% of the initial viremic cohort. Patients with an SVR include 17 patients with stage 3-4 fibrosis.

 

HCV Treatments and Outcomes

HCV Treatment Nave

Genotype 1 SVR NR Relapser Totals

Peg IFN/R 10 (31%) 17 5 32

IFN/R 11 (28%) 23 6 40

_________________________________________________________________

Total 21 (29%) 40 11 72

 

Genotype Non-1 SVR NR Relapser Totals

Peg IFN/R 0 (0%) 2 0 2

IFN/R 15 (68%) 7 0 22

_________________________________________________________________

Total 2 (62%) 9 0 24

 

Non Genotype Given SVR NR Relapser Totals

Peg IFN/R 0 (0%) 0 0 0

IFN/R 2 (67%) 0 1 3

_________________________________________________________________

Total 2 (67%) 0 1 3

 

HCV patients with prior IFN/R NR or Relapsers

 

SVR NR Relapser Totals

 

Genotype 1 Peg IFN/R 3 (23%) 10 0 13

Genotype non-1 Peg IFN/R 2(40%) 3 0 5

No genotype Peg IFN/R 0 2 0 2

Total 5 (25%) 15 0 20

 

Conclusions

The screening program resulted in 73% of HCV RNA positive patients attending a specialty HCV clinic and 24% receiving antiviral therapy. Improvements in avoiding duplicate EIA testing, increasing patient referral of all viremic HCV patients, and reducing waiting times and barriers for seeking care for hepatitis C are needed. The fact that only a small percentage of the total HCV viremic cohort was successfully treated indicates that improvements in clinical care and antiviral therapies are needed.

 

Hepatic Fibrosis Influences Early Virological Response Rates in Chronic Hepatitis C (CHC)

Anouk T. Dev, Keyur Patel, Andrew J. Muir, Dylan Matzinger, John G. McHutchison

 

Background

Early virological response (EVR), during HCV therapy is defined as undetectable HCV RNA or at least a 2-log decrease in HCV RNA at week 12. Failure to achieve EVR has been shown to accurately predict non response in genotype 1 patients. Hepatic fibrosis stage has previously been shown to significantly impact response to antiviral therapy. Advanced fibrosis is associated with a lower sustained virological response. It is not known whether hepatic fibrosis stage similarly influences EVR.

 

Aim

To determine the influence of hepatic fibrosis on EVR rates.

 

Methods

138 genotype 1 CHC patients who had received either combination peginterferon (1.5mcg/kg weekly) or standard interferon (3MU TIW) and ribavirin (1000-1200 mg/d) were retrospectively identified from the databases of 2 hospitals. Serum HCV RNA was measured at baseline, week 12, and at 24 weeks after completion of therapy using a quantitative PCR assay with a lower limit of detection of 100 copies/ml (NGI, Los Angeles, CA). Pre-treatment liver biopsies were scored for fibrosis by the METAVIR system. For analysis patients were classified as no or low grade fibrosis (Metavir 0-1) and medium to high fibrosis (Metavir 2-4).

 

Results

Of 138 patients, 95 (69%) were male, 81 (59%) were Caucasian, 47 (34%) were African American. 61 (44%) had Metavir stage F0-F1 and 77 (56%) had Metavir stage F2-F4. Overall 67 (49%) patients achieved EVR and 25 (18%) achieved SVR. Patients most likely to achieve an EVR were those with fibrosis stage F0-F1 compared with F2-F4 (62% vs 38%; p=0.0009), male patients with lower grades of fibrosis (66% vs 40%; p=0.02) and Caucasian patients with fibrosis scores 0-1 (74% vs 42%; p=0.0037). Only 32% of African American patients achieved EVR and 9/47(19%) achieved SVR. There was no difference in EVR between African American high and low grade fibrosis groups. In the low grade fibrosis group, Caucasians were more likely to achieve EVR than African Americans (74% vs 32%; p=0.012).

 

Patient Demographics and Baseline Characteristics

Characteristics Metavir F0-1 N=61 (44%) Metavir F2-4 N=77 (56%)

Age years (SD) 43 (5) 47 (4.4)

Gender N (%)

Males 38 (62) 57 (74)

Race N (SD)

Caucasians 43 (70) 38 (49)

African American 8 (13) 39 (51)

BMI (SD) 26.3 (2.8) 28.7 (2.9)

 

Treatment Regimen N (%)

IFN/RBV 29 (48) 13 (17)

PEG IFN/RBV 32 (52) 64 (83)

 

Conclusion

 

Factors That Improve the Efficacy of Epoetin Alfa for Maintenance of Ribavirin Weight-Based Dosing (RBV WBD)

Aijaz Ahmed, Cynthia Leung, Prista Charuworn, Judy Grossi, Ramsey C. Cheung, Emmet B. Keeffe

 

Background

Patients (pts) with chronic hepatitis C (CHC) treated with RBV WBD (>10.6 mg/kg/day) + peginterferon (PEG-IFN) often develop pronounced anemia. Improved compliance (80% or >) results in a higher incidence of anemia and potential need for dose reduction. During the initial 12 wks of therapy (Rx), dose reduction can result in impaired SVR. Epoetin alfa allows maintenance of RBV WBD.

 

Aim

Identify factors that may improve the efficacy of epoetin alfa in managing anemia associated with RBV WBD + PEG-IFN in the initial 12 wks of Rx.

 

Methods

Consecutive pts with CHC who were Rx with RBV WBD + PEG-IFN alfa-2a 180 mcg/wk or PEG-IFN alfa-2b 1.5 mcg/kg/wk over a 12-month period were identified. New onset RBV-induced anemia was defined as hemoglobin (Hb) <12 g/dl, >3 g/dl decline in Hb from baseline, or Hb decline >2 g/dl with fatigue. Pts had a complete blood count (CBC) every wk for the first 12 wks of Rx. Pts with anemia were treated with epoetin alfa 40K units/wk SQ until Hb returned to baseline. Pts with Hb between 10-11 g/dl despite epoetin alfa 40K units/wk SQ were treated with higher doses, 60-80K units/wk SQ until Hb returned to baseline.

 

Results

56 pts were identified. All pts had baseline Hb >13 g/dl. 4 pts (n=1, suicidal; n=2, platelets <30K; n=1, hyperthyroidism) were excluded due to premature discontinuation of Rx. 52 pts completed initial 12 wks of Rx. 34/52 (65%) pts met the criteria for anemia. 30/52 (58%) were managed with epoetin alfa (3/30 needed a higher doses of epoetin alfa, 60-80K units/wk SQ; 2/30 needed iron supplement). 4/34 (11%) pts with anemia were unable to obtain authorization for epoetin alfa and needed dose reduction. 18/52 (35%) remaining pts did not develop anemia. Most pts developed anemia between wk 3 and 6 (range, 2-10 wk). Insurance authorization and delivery of epoetin alfa varied from 0 to 21 days. Timing of authorization was dependent on polices of the insurance carrier and the experience of nursing staff. Late delivery of epoetin alfa lead to RBV dose reduction in 2/30 pts who received epoetin alfa. Weekly CBC facilitated early detection of anemia.

 

Conclusions

The following factors are crucial in improving the efficacy of epoetin alfa in treating anemia and maintaining RBV WBD: 1) weekly CBC check; 2) training of nursing staff to promptly request for epoetin alfa authorization and make necessary follow-up calls; 3) insurance carrier policies; 4) recognition of pts who may need higher doses of epoetin alfa; and 5) supplemental iron in pts with low iron and lack of response to epoetin alfa.

 

No Differences in Treatment Response to HCV in Mexican Americans

Ramsey C. Cheung, Sue Currie, Hui Shen, Ke-Qin Hu, Samuel Ho, Lennox S. Jeffers, Edmund J. Bini, Teresa L. Wright, VA-HCV-001 Research Group

 

Background

Previous smaller studies suggest that there are differences in patient characteristics, candidacy and Tx outcomes of Mexican Americans. This study examines variables and response rates of Mexican Americans (MA) vs non-Latino White (NLW) patients with chronic hepatitis C.

 

Methods

Data were prospectively collected in 421 MA and 2,510 NLW HCV RNA positive, Tx naive patients undergoing evaluation for HCV Tx in 24 VAMCs. A total of 88 MA and 481 NLW were subsequently treated with interferon and ribavirin combination therapy (Rebetron).

 

Results

Comparison was made between the two groups based on ethnicity (MA vs NLW). Univariate analysis showed no differences in age, BMI, and income vs NLW, nor in risk factors such as heavy alcohol use, injection drug use, or blood transfusion prior to 1990. However, they differed in blood contact during combat (18.5% vs 27.4%, OR = 0.6, p=.0002), history of surgery (77.1% vs 83.2%, OR = 0.68, p=.0026), needle stick injury (15.7% vs 22.3%, OR 0.65, p=.0023). MA were also significantly more likely to be HIV coinfected (20.4% vs 3.9%, OR = 6.44, p<.0001), have HAV antibody (39.9% vs 26.4%, p=.0001) but not HBsAg (4.5% vs 5.5% p=.4186). MA were more likely to be considered Tx candidates by criteria (49.8% vs 39.6%, p=.0001), and by physician (43% vs 37.8%, p=.0459), but there were no difference in the number who initiated Tx (20.2% vs 21.3%).

 

Liver biopsies in 123 MA and 743 NLW showed no statistical difference in fibrosis, but steatosis (54.7% vs 43.2%, p=.0382) especially of mixed pattern (47.6% vs 22.9%) was more common among MA. A total of 88 MA and 481 NLW were treated according to standard guidelines. There was no difference between the two groups treated in term of BMI, duration of infection, severity of liver disease on liver biopsy and genotype 1 (74.2% vs 68.7%, p=.3627). Univariate analysis suggested that MA were more likely to require dose reduction in ribavirin (26.1% vs 17.5%, p=.0575), and a lower EOTR (27.3% vs 37%, p=.0811). Multivariate analysis only identified genotype 1 (OR 0.31; 95% CI = 0.189-0.511), advanced fibrosis (OR 0.58; 95% CI = 0.340-0.988) and eliminated race as factors associated with SVR response in MA and NLW.

 

Conclusions

  1. When compared to non-Latino white, Latinos are less likely to have risk factors such as surgery and non-transfusion blood exposure as potential mode of HCV infection but more likely to have immunity to hepatitis A and HIV coinfection.
  2. Latinos are more likely to be treatment eligible both by criteria and physicians assessment, but overall only one of five ended up being treated, similar to NLW.
  3. Severity of liver disease is similar between the two groups but Latinos are more likely to have steatosis
  4. The response rates appear to be lower among Latinos but the difference was not statistically different. In the multivariate analysis, race (Latino versus NLW) was not a predictor of treatment outcome
  5. In contrast to the finding in African Americans, Latino patients with chronic HCV seem to be very similar to non-Latino whites.

 

The Effect of Amantadine on Sustained Virologic Response When Added to Pegylated Interferon Alfa 2b + Weight Based Ribavirin In Previous Nonresponders and Relapsers

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

 

Introduction

 

Aim

To determine if the addition of Amantadine to PEG-IFN and Ribavirin enhances the SVR in previous standard combination therapy nonresponders (Combo NR), IFN monotherapy nonresponders (Mono NR), and combination therapy relapsers.

 

Methods

Participants were randomized to receive either PEG-IFN 1.5 mcg/kg/wk + Weight Based Ribavirin (800-1400mg) (Riba) for 48 weeks + Amantadine 100mg bid for 32-48 weeks (due to a transient clinical hold) versus PEG-IFN 1.5 mcg/kg/wk + Riba for 48 weeks. HCV-RNA was obtained at 0, 24, 48 & 72 weeks.

 

Results

671 adult participants with compensated liver disease were enrolled. 396 standard combination nonresponders, 201 combination relapsers, and 74 monotherapy nonresponders. Eighty percent of enrollees were from community based investigators. Base line characteristics: African Americans - 12%, Genotype 1 - 84 %.

 

Combination Therapy Non-Responders

Double versus Triple

 

Combination Therapy Relapsers

Double versus Triple

 

Monotherapy Non-Responders

Double versus Triple

 

GENOTYPE 1 Combination Therapy Non-Responders

Double versus Triple

 

GENOTYPE 1 Combination Therapy Relapsers

Double versus Triple

 

GENOTYPE 1 Monotherapy Non-Responders

Double versus Triple

 

Ethnicity

Double versus Triple

 

Conclusion

Amantadine does not significantly increase the sustained viral response in the groups evaluated. Caucasians have higher sustained viral response than African Americans and Hispanics. Relapsers have a higher response rate than non-responders.

 

How Long Should We Retreat Non-Responders For? Final Results of the Frontier Trial

Matthew Nichols, Marcelo Kugelmas

 

Background

Improved SVR rates obtained with Peginterferon (Peg) and ribavirin (RBV) therapy has prompted retreatment of prior non-responders (NR) to interferon (IFN) or IFN + RBV. Aim: The Frontier trial was designed to test which is the appropriate length of treatment for prior IFN +/-RBV NR.

 

Methods

180 patients were treated with Peg (1.5 mcg/kg/week) + RBV 800 mg/d and randomized to three different lengths of treatment: 24 (n=57), 36 (n=61) or 48 (n=62) weeks. All patients were then followed up another 24 weeks to assess end of follow-up responses. Primary endpoint was SVR

 

Results

Of the 180 patients 59% were older than 40 years, 59% were male, 16% were black, 33% had a BMI >30, and 51% had high viral load. On an intention-to-treat analysis, 42/180 (23.3%) patients had an end-of-treatment viral response, 23 relapsed (54.8% relapse rate), and 19 (10.6%) had a sustained viral response. Included in the NR group were 41 drop-outs (23%), 21 with SAE, and 1 who died (MVA). The different lengths of therapy did not affect overall chances of achieving SVR: 10.5%, 9.8%, and 11.3% in the 24, 36, and 48 weeks of therapy groups, respectively. The relapse rate was lowest for patients treated for 48 weeks (22%) regardless of genotype (21%), prior treatment with IFN (20%) or IFN+RBV (25%), gender (males 29%, females= no relapse), or age (<40 had no relapse, >40= 29% relapse).

 

Conclusions

 

  1. Compared to nave HCV populations, prior IFN/RBV non-responders are more likely to have genotype 1, be older and obese.
  2. When retreating prior non-responders with PEG IFN/RBV, a week 4 response defined by a negative qualitative HCV RNA is associated with higher SVR.
  3. When retreating patients who have previously failed IFN +/- RBV, a treatment course of 48 weeks minimizes relapse rates.

 

Preemptive Therapy with Combination Pegylated Interferon and Ribavirin in Liver Transplant Recipients with Hepatitis C Virus

Guy W. Neff, Christopher B. O'Brien, Kamran Safdar, Phil Ruiz, Pablo Bejarano, Marzia Montalbano, Eugene R. Schiff

 

Background

% Treated for Depression

 

Drug Tolerability

Vogel PEG IFNα 2a 180g for 48 weeks n = 25

Khatib PEG IFNα 2b 0.5g/kg + RBV 400mg for 48 weeks n = 36

Levitsky PEG IFNα 2b 1.0g/kg + RBV 400mg for 48 weeks n = 31

Neff PEG IFNα 2b 1.5g/kg + RBV 60mg for 48 weeks n=29

Preemptive PEG IFNα 2b 0.5g/kg + RBV 20mg for 48 weeks

EOT and SVR

Khatib PEG IFNα 2b 0.5g/kg + RBV 400mg for 48 weeks n = 36

Neff PEG IFNα 2b 1.5g/kg + RBV 600mg for 48 weeks n = 29

Preemptive PEG IFNα 2b 0.5g/kg + RBV 200mg for 48 weeks n = 14

 

Introduction

The management protocols for recurrent HCV are diverse and the issues are complex, including the effectiveness of preemptive therapy. We present results of a retrospective review of liver transplant recipients receiving preemptive therapy of pegylated alpha-2b interferon and ribavirin within 4 months of transplant.

 

Aims

We wanted to determine if preemptive therapy with peginterferon alfa 2b and ribavirin for recurrent HCV post liver transplantation is safe and effective.

 

Methods

All recipients were started on combination pegylated alpha-2b interferon (0.5mcg/kg) and ribavirin (200-400 mg/d) therapy within 16 weeks of liver transplantation. Dose escalation was as follows: increase in pegylated alpha-2b interferon 0.5mcg/kg every 4 weeks until 1.5mcg/kg and ribavirin 200 mg/d every 4 weeks until 800-1000 mg/d. The therapy was followed for at least 48 weeks of therapy. The diagnosis of HCV recurrence was determined histopathologic findings with inflammation along with viral recurrence using COBAS AMPLICOR Hepatitis C virus Test, version 2.0 and COBAS AMPLICOR HCV MONITOR TEST-version 2.0 assays. Histology was graded and staged according to the Batts and Ludwig classification. The diagnosis of recurrent hepatitis was based on the presence of portal lymphocytic infiltrates, interface hepatitis, and lobular necroinflammatory injury in the absence of other findings that could indicated a different pathology.

 

Results

14 transplant recipients were included in the study: female 5(36%), males 9 (64%) mean age (50yrs), mean time from OLT was 6.7 weeks, Caucasians 8 (57%) and Hispanics 6 (43%). 3 patients remained serologically negative for HCV 3/15 (20%) for a 48 week period and 3 patients dropped their serum HCV PCR 2 logs (20%). The remaining 8 patients were viremic throughout the 48 week period. The side effects included: clinical depression 6 (43%) of which treatment was stopped in 2 while 2 improved to near baseline with SSRI therapy, thrombocytopenia (< 50K) 3 (20%), 1 (7%) require treatment cessation, neutropenia 3(20%) all responding to filgastrim. Serum ALT normalized in 5/14 (36%). 4 patients remained on therapy for 48 consecutive weeks. One death was noted as a result of fungal sepsis, and one patient experienced HAT. SVR was attained in 2/14 (14%), both tissue HCV PCR was negative at time of 48 week biopsy.

 

Conclusion

These results show that preemptive therapy was poorly tolerated while benefiting only a small portion of our cohort (20%).

 

Antioxidant Treatment Does Not Substantially Ameliorate the Fall in Hemoglobin in HCV Patients Treated with Pegylated Interferon Alfa-2b and Ribavirin

Bruce R. Bacon, Bradley L. Freilich, Joan M. Siegner, Rosemary O'Neill, Janay Kissinger, Joyce A. Hoffmann, Robert S. Britton, Adrian M. Di Bisceglie, Clifford A. Brass

 

Introduction

Ribavirin is commonly used in combination with pegylated alfa-interferon to treat patients with chronic hepatitis C (HCV). Ribavirin can cause hemolysis and a decrease in hemoglobin (Hb) levels is common. The mechanism of ribavirin-induced hemolysis is uncertain, but an increased susceptibility of erythrocytes (RBC) to membrane oxidative damage may play a role.

 

Aim

To test whether antioxidant (AO) treatment would ameliorate the fall in Hb levels in HCV patients treated with pegylated interferon alfa-2b and ribavirin.

 

Methods

A randomized, prospective, open-label study was designed to study the effects of AO treatment (vitamin E, 400 IU BID; vitamin C, 500 mg BID; S-adenosyl-L-methionine, 400 mg TID) in HCV patients treated with pegylated interferon alfa-2b (1.5 mcg/kg QW) and ribavirin (800-1400 mg QD). Treatment-naive, non-smoking patients with chronic HCV were divided into two groups: the AO group (n=22) received AO for a total of 28 w beginning 4 w before antiviral therapy, while the control group (n=32) received antiviral therapy alone.

 

This study was performed at two sites (St. Louis and Kansas City).

 

Patients with HCV genotype 1 received 48 weeks if they achieved a virologic response at 24 weeks otherwise they were discontinued at week 24. Patients with genotype 2/3 received antiviral therapy for 48 weeks. Evaluations continued for 24 weeks after discontinuation of therapy. Recombinant erythropoietin was given to patients whose hb levels fell below 10g/dl. This report focuses on measurements made at entry (6 w prior to antiviral therapy) and at 2, 4 or 12 w of antiviral therapy. RBC levels of malondialdehyde (MDA, a lipid peroxidation product) and glutathione (GSH) were also measured.

 

Results

The control and AO groups were well-matched with respect to age (45 1.6 vs 49 1.0), gender (62.5% vs 63.6% male), race (84.4% vs 95.5% Caucasian) (12.5% vs 4.5% Black) and (3.1% vs 0% Hispanic), HCV genotype (72% vs 91% type 1), (19% vs 4.5% type 2), (9% vs 0% type 3) and (0% versus 4.5% unknown).

 

Antiviral therapy resulted in decreases in hb, platelets and WBC. Antioxidant treatment significantly ameliorated the fall in hb only at 2 weeks (p<0.05). Recombinant erythropoietin use did not differ between the two groups (control = 32%, AO = 27% of patients).

 

Antiviral therapy resulted in decreases in ALT activity and haptoglobin, and an increase in reticulocytes. None of these effects was significantly different in the AO treatment group. Erythrocyte levels of PDA, GSH were not significantly altered by either antiviral therapy or antioxidant treatment.

 

Conclusion

This regimen of AO treatment with vitamin E, vitamin C and S-adenosyl-L-methionine did not substantially ameliorate the fall in Hb levels in HCV patients during the first 12 w of therapy with pegylated interferon alfa-2b and ribavirin. (Supported by Schering-Plough)

 

National Multicenter Study of Eligibility for Interferon and Ribavirin Therapy in Patients Coinfected with HIV and Hepatitis C

Edmund J. Bini, Sue Currie, Hui Shen, Norbert Brau, Warren Schmidt, Teresa L. Wright, VA HCV-001 Research Group

 

Background:

HIV and HCV coinfected patients progress to cirrhosis faster and more commonly than those with HCV monoinfection. However, many coinfected patients are not treated for HCV.

 

Aim

The aim of this study was to determine the proportion of HIV/HCV coinfected patients that were eligible for interferon (IFN) and ribavirin (RBV) therapy.

 

Methods

Data were prospectively collected in 4,364 HCV RNA positive patients undergoing evaluation for HCV therapy from 24 geographically diverse medical centers throughout the U.S. Treatment candidacy was determined by 2 methods (established inclusion/exclusion criteria and the opinion of the treating clinician). Information collected included demographics, determination of treatment candidacy, and reasons for non-candidacy.

 

Results

HIV status was known in 3,238 patients (72.6%), and 280 (8.6%) were coinfected with HIV. There were no significant differences in age or gender between the two groups, but coinfected patients were more likely to be African American (51.8% vs. 29.0%, p < 0.001). Coinfected patients were significantly less likely to be eligible for IFN/RBV therapy according to established criteria (25.0% vs. 32.5%; OR 0.7, 95% CI 0.5 - 0.9; p = 0.01) and in the opinion of the treating clinician (34.3% vs. 41.8%; OR 0.7, 95% CI 0.6 - 0.9; p = 0.02) compared to those with HCV monoinfection. Among coinfected patients, multivariate analysis identified ongoing or recent substance abuse (OR 26.0; 95% CI 5.2 - 128.8), comorbid medical disease (OR 19.4; 95% CI 6.4 - 58.9), albumin < 3.2 g/dl (OR 15.2; 95% CI 1.5 - 157.2), psychiatric disease (OR 5.7; 95% CI 1.2 - 26.6), and annual income < $10,000 (OR 2.6; 95% CI 1.0 - 6.4) as independent predictors of not being a treatment candidate according to the opinion of the clinician. Of those offered treatment, only 69.3% of coinfected and 75.9% of HCV monoinfected patients agreed to treatment (p = 0.16). The primary reasons for declining treatment in both groups included concerns over potential side-effects and deferring treatment until better therapies are available.

 

Patient Characteristic with Statistical Significance

HIV/HCV HCV p-value

N = 280 N = 2958

 

Race/Ethnicity <0.001

Caucasian (Non-Hispanic) 23.9% 57.5%

African American 51.8% 29.0%

Latino (Black) 4.3% 1.1%

Latino (Non-Black) 16.4% 7.8%

Asian 0.4% 0.3%

Native American 0.0% 2.2%

Other 2.5% 1.6%

 

Other Characteristics

Annual income<= $10,000 48.0% 39.6% 0.006

IDU 74.6% 64.8% 0.001

Blood Transfusion Prior to 1990 15.0% 20.2% <0.001

Blood Contact During Combat 17.3% 25.0% 0.005

Prior Surgery 72.5% 80.8% 0.001

Acupuncture 24.7% 13.4% <0.001

Tattoo 29.4% 42.6% <0.001

Body Piercing 50.2% 41.4% 0.005

Sex with Same Sex Partner 24.6% 8.1% <0.001

Sex with IDU 54.7% 38.2% <0.001

 

Conclusions

The majority of HCV infected patients are not suitable candidates for IFN and RBV therapy, and HIV/HCV coinfected individuals were even less likely to be eligible for therapy than those with HCV monoinfection. Multidisciplinary collaboration and better tolerated HCV therapies are needed to improve treatment candidacy in HIV/HCV