NATAP REPORTS

Current Review & Update on Hepatitis C & HIV/HCV Cection

SUMMER 2001

As stated above, the current standard of care for treatment of chronic HCV infection has been Rebetron: interferon alfa-2b (Intron A) given at a dose of 3 MU as a subcutaneous injection 3 times a week PLUS ribavirin (Rebetol) given orally at doses of 1,000-1,200 mg/day. Tolerability of taking this regimen has challenges, and SVR rates obtained with standard IFN/RBV are relatively poor, ranging from approximately 30% for genotype 1 patients after 48 weeks of therapy to 65% for genotypes 2 and 3 patients regardless of the duration of therapy (24 or 48 weeks). From a patient perspective, these response rates are suboptimal and tolerability is a concern, especially since adherence to the regimen is crucial to success. Clearly, better treatments are needed, particularly those that can be better tolerated and lead to a higher rate of SVR. The response rates seen in studies with pegylated interferon plus ribavirin are vastly improved: 76%-80% for genotypes 2/3, and 46% for genotype 1.

John McHutchison (Scripps Clinic, La Jolla, CA) reviewed at DDW 2001 the data on PegIntron monotherapy reported by Trepo at the EASL Spring 2000 Conference. In a study of 1200 patients, the End-Of -Treatment Response (ETR) was 41%, 6 months after stopping therapy the SVR (Sustained Virologic Response- SVR) was 23%. This compared to a 12% SVR in the control arm (standard IFN 3 MIU 3 times per week). The relapse rate was 39% and the discontinuation rate was 9-11%. Dose reduction rate was 15%. McHutchison concluded that PegIntron IFN monotherapy has similar side effects compared to standard IFN, double the SVR Sustained Virologic Response, a similar relapse rate as standard IFN, and most genotypes 1 do not respond (14% vs 49% for genotype 2).

At the same EASL Conference, Zuezem reported on 500 patients randomized to receive either Pegasys once weekly or an induction regimen of standard IFN 6 MIU 3 times per week for 12 weeks followed by the standard dosing of 3 MIU 3 times per week. Both studies were 48 weeks of treatment followed by a 24-week follow-up period to evaluate SVR. The Pegasys ETR was 69%, the SVR was 38%. In the control arm the SVR was 19%, also double the response rate observed in the control group. Genotype 1 SVR was 28% vs 64% for genotype 2. Patients with HCV viral load over 2 million did not respond as well as patients with viral <2 million (52% vs 27%). The discontinuation rate was 7%. Dose reduction was reported as 8% for adverse events, and 14% for lab abnormality in Peg arm and 9% in induction arm--mostly due to neutropenia (decreased neutrophils)- it was 11% in Peg arm and 7% in other arm.

The PegIntron montherapy study (23% SVR) described above is the only PegIntron monotherapy study reported. Several Pegasys monotherapy studies have been reported at conferences showing response rates ranging from 30% to 38%.

Comparing the two formulations of pegylated interferons

Pegasys- There has been only one study for each of the Peg IFNs in combination with RBV. There has not been a head to head comparison of the two formulations of pegylated interferon, and it is difficult to compare them across studies in which patient populations are different and control arms are different. In the study reported by Michael Fried (University of North Carolina) at DDW Spring 2001, approximately 1200 Patients received 1 of 3 treatment regimens:

1. Pegasys 180ug once weekly by subcutaneous injection plus Ribavirin 1000-1200 mg per day

2. Pegasys plus placebo

3. Standard interferon a-2b 3 MIU (Million International Units) 3 times per week plus Ribavirin 1000-1200 mg per day

Biopsy was performed before and after therapy and the results are being analyzed and will be reported in the near future. Patient characteristics at baseline were: average age 42; male 68-73%; weight approximately 78 kg in all 3 arms, 64-66% genotype 1; HCV viral load about 6 million in all 3 arms; cirrhosis 15% in Peg monotherapy arm and 12% in other 2 arms.

The Pegasys+RBV sustained virologic response (ITT analysis) was 56% (n=453) overall compared to 45% (n=444) for standard IFN/RBV and 30% (n=224) for Pegasys monotherapy). Genotype 1 SVR was 46% vs 76% for genotype 2/3. Cirrhotic patients had 43% SVR in Pegasys/RBV arm compared to 33% receiving IFN/RBV. For patients without cirrhosis SVR was 58% for those taking Pegasys/RBVcompared to 47% for those taking IFN/RBV. Fried said that any patient receiving at least one dose of study drug was included in the analysis (Intent-To-Treat). See the discussion below on ribavirin dosing by weight.

Pegasys + RBV Intl Study Presented by Michael Fried at DDW

ITT (Intent-To-Treat) analysis used, which is more stringent than as-treated analysis.

To read full Pegasys report from EASL:
http://www.natap.org/2001/ddw/pegylated052301.htm

Peg-Intron- At the AASLD 2000 Conference, Michael Manns (Hannover Medical School, Hannover, Germany) reported week 72 results (48 weeks treatment followed by 24 week follow-up) for about 1500 treatment-naïve patients receiving 1 of 3 arms:

1. PegIntron (1.5 ug/kg once weekly for 4 weeks) plus Ribavirin 1000-1200 mg/daily and 0.5 PegIntron ug/kg for the next 44 weeks (n=514)

2. PegIntron (1.5 ug/kg once weekly for 48 weeks) plus Ribavirin 800 mg/daily (n=511)

3. Standard IFN (3 times per week) plus Ribavirin 1000-1200 mg/daily (n=505)

Biopsies were performed before and after treatment and evaluations are expected to be reported in future. Patient characteristics at baseline were: age 43, about the same in each group; about 67% men in each group; 90% Caucasians in each group; weight about 82 kg in each group. About 68% genotype 1 in all 3 groups; 67-69% had >2 million viral load; Manns reported cirrhosis 10% in each group at AASLD, but at EASL 2001 reported 40-44% had "bridging fibrosis or cirrhosis" (F3/F4) while the Schering printed literature said liver biopsy by local pathologist reported 28-30% (F3/F4).

PegIntron/RBV (full dose 1.5 ug/kg) combined with 800mg RBV showed an overall 54% SVR. Patients receiving standard IFN with 1000-1200mg RBV had a 47% SVR. 42% for genotype 1 vs 82% genotype 2/3 (ITT analysis). Patients with less advanced liver disease tend to respond better to treatment, so this should be a factor considered in deciding when to begin therapy. Manns reported that lower baseline fibrosis scores were associated higher SVR rates, a trend that has occurred in previous studies. When comparing patients with F1/F2 to F3/F4 fibrosis scores there was a difference in SVR of 5-7 percentage points.

PegIntron + RBV Study Presented by M Manns at EASL

The data in the Table are an Intent-to-treat (ITT) analysis, which is a more stringent analysis rather than as-treated analysis.

* These data were reported in the recently issued (August 2001) FDA PegIntron/Ribavirin Label.

To read the full PegIntron reports from EASL:

http://www.natap.org/2001/36theasl/part4easl050101.htm
http://www.natap.org/2001/36theasl/part5easl050101.htm

Two studies find benefit in treating HCV during acute infection

There were two interesting poster abstracts at DDW 2001 addressing the unusual patient group--patients with acute HCV infection. They are unusual because they are hard to find. Therefore, treating this patient group has not been studied much. Just as in HIV its hard to identify patients with acute infection. It 's not until years later, in general, that patients get tested and find out they have HIV or HCV. In the Jaeckel study below, at the end of the 24-week treatment period, 97% of treated patients were virologic responders, whereas only 30% of untreated patients spontaneously cleared virus. I think that the sustained response at the end of the 24-week follow-up period in the treated group was 70%. This was using the standard interferon without ribavirin, so using pegylated interferon with ribavirin ought to yield better results. Jaeckel suggests interferon monotherapy is adequate I suppose because of the high response rates he saw. In the Chone study (n=14), at the end of treatment 71% (n=10) were responders (HCV-RNA negative and normal liver enzymes). 60% of the responders had an average follow-up of 17 months & all were sustained responders. The studies concluded that treatment during acute infection can prevent chronic infection in a high percentage of patients and unexpected side effects do not appear to occur.

Suggested dosing of ribavirin by weight

It was reported at AASLD (November 2000) from the PegIntron/RBV study that dosing ribavirin by weight may improve response to therapy, but these data had limitations and are controversial. Study investigators did a retrospective analysis to see how much RBV concentration patients were receiving based on their body weights. To be clear, study patients were not randomized to receive different doses of RBV, as everyone received 800 mg per day of ribavirin. In the AASLD reported study, the authors reported patients with higher concentrations of RBV had better virologic responses: patients who had <65 kg weight at baseline had a 62% SVR; patients with 65-85 kg at baseline had a 55% SVR; patients with >85 kg had a 49% SVR. But, Manns concluded weight adjusted dosing of ribavirin with peginterferon alfa 2b will be confirmed in prospective studies. Two reasons for the controversy regarding the findings reported at AASLD is that patients with lower weight tend to respond better to therapy and that all patients in this study received the same RBV dose of 800 mg at baseline. Schering is now conducting a large prospective study to address this question in which patients are receiving different RBV dosing based on weight.

Based on their study conclusions, Schering recommends the optimum Ribivarin dosing with Peg IFN a-2b 1.5 ug/kg (10.6 mg per kilogram):

<65 kg in weight ribivarin dose should be 800 mg/day

65-85 kg = 1000 mg/day

>85 kg = 1200 mg/day

European authorities approved PegIntron with weight based dosing of ribavirin. The FDA has not approved weight based dosing of ribavirin. In their recent approval of ribavirin being sold unbundled from interferon, the FDA approved ribavirin dosing only with 800 mg per day in combination with PegIntron. Pegasys studies have not yet analyzed or explored response by weight based dosing of RBV, but studies are expected to be exploring this. Data should be forthcoming soon.

Adherence is crucial to HCV treatment success; apparently more so in genotype 1

We are very aware of the importance of adherence in HIV. Study results suggest that taking less than 95% of HIV medications can impact on reaching full virologic suppression. Adherence to HCV treatment is just as important and it has been evaluated by several investigators. Fried reported compliance with treatment at week 12 is associated with the highest probability of achieving an SVR. Of the 86% responders at week 12, 75% (n=184) achieved SVR when adherence was >80%. While only 48% (n=69) with <80% adherence achieved a SVR.

At DDW (May 2001), John McHutchison discussed how adherence impacted response in the PegIntron+RBV study. Patients who received PegIntron 1.5 + RBV 800 had a 54% overall SVR, but patients with >80% adherence had a 63% SVR while patients with <80% adherence had a 52% SVR. In referring to data using the standard interferon + RBV, adherence also mattered: 41% had a SVR, but when compared to patients with >80% adherence 48% had a SVR, and compared to patients with <80% adherence only 29% had an SVR.

McHutchison reported that 63% of patients in the study were adherent as measured by taking 80% of the medications 80% of the time for 80% of the study length. Men were more likely to be adherent than women (67% vs 53%). As would be expected, the overall SVR rate was higher among patients who adhered to the "80/80/80" criteria, except for patients in arm 2 (PEG 1.5) with genotypes 2 or 3, for whom there were no significant differences when comparing adherent to specified, partially non-adherent patients. This finding is most likely secondary to the very high SVR in genotype 2/3 patients. For patients with all genotypes in arm 2 (PEG 1.5), those who were adherent 80% of the time had a significantly higher SVR rate of 63% ("as-treated" analysis), compared to partially, non-adherent patients (52%, as-treated analysis) and the 54% rate in the ITT ("intent-to-treat") analysis. When considering only genotype 1 patients in arm 2, "80% adherent" patients had a significantly higher SVR rate of 51% (as-treated), compared to 34% of partially, non-adherent patients (as-treated) and the 42% rate in the ITT analysis. When considering only patients with genotypes 2 or 3 in arm 2, "80% adherent" patients had a similar SVR rate of 90% (as-treated) as partially, non-adherent patients (89%, as-treated), compared to 82% in the ITT analysis.

Predictability Analysis: Initial viral load response may predict final viral response

Besides adherence, the HCV decline slope during the first few months after therapy initiation may predict which individuals are likely to achieve an SVR. From the Pegasys+RBV study reported at DDW 2001, Fried reported an analysis showing that the initial viral load response seen in the first few months after starting therapy as well as patient adherence appear to be key factors in achieving sustained virologic response. Two-thirds of patients with a 2 log drop or undetectable PCR at week 12 went on to achieve an SVR 24 weeks after stopping 48 weeks of therapy.

At week 12 (n=453), 86% (n=390) had a 2 log drop in HCV-RNA and 14% did not (n=63). Of these 14% only 2 (3%) went on to have a SVR 24 weeks after stopping treatment. Thus, Fried concluded that there is a 97% predictive value that if a patient does not have 2 log drop or negative PCR by week 12 they will not reach SVR. Of the 86% with the viral response, 65% (n=253) went on to SVR and 35% (n=137) did not.