Sunday Evening Update From EASL, April 27-May 3, Rotterdam

A company symposium this afternoon reported data on Consensus Interferon (Infergen) for non-responders. You'll recall that in a prior report I discussed that an EASL committee presented a meta-analysis for studies of treating HCV including interferon/ribavirin studies. Perhaps the most interesting data was that they found about a 20% virologic response (undetectable HCV-RNA) of treating Interferon non-responders with IFN+RBV, because at last year's EASL conference the Consensus Statement was unsure about recommending treatment for non-responders. In speaking with the researcher today, she told me that non-responders had a 2.2 increased chance of response with IFN+RBV compared to using IFN alone. Makes sense.

This afternoon at the Consensus Interferon (CI) Yamanouchi symposium data was reported on treating non-responders with CI. I assume outside the USA, Yamanouchi has the rights to market Consensus Interferon. In the CI retreatment trial, 337 patients were enrolled who had failed to respond (breakthrough while on treatment) or relapsed (after treatment) after an initial course of therapy with IFN alfa-2b 3MU TIW or Infergen 3ug or 9ug TIW during the phase 3 study with naÔve patients. Patients were randomized to receive either 6 or 12 months of 15ug Infergen TIW in a multicenter randomized clinical trial. Patients were then observed for an additional 6 months after therapy to assess the sustained response. Take note that the dose of Infergen was increased for the retreatment trial from 9ug in the naÔve study to 15ug. Overall for all genotypes, after 6 months the response rate was only 5% but increased to 13% after 12 months retreatment. Among those with genotype1 (72% in study had genotype 1), 12% responded virologically (undetectable) after 12 months of retreatment. Among those with genotype 2, the response rate was 25% but the number of patients in this group was relatively small. In general, relapsers do much better upon retreatment. Presenters claim that Infergen monotherapy has superiority to IFN alfa-2b montherapy in treating IFN naÔve patients with baseline viral load >4.8 million. In the study they presented individuals with a baseline viral load >4.8 million copies/ml had a 7% virologic sustained response compared to 0% sustained response for IFN alfa-2b. For all others with lower viral loads there was no statistically significant difference in sustained response between Infergen and Alfa-2b. However, how relevant is this data after Pegylated Interferon is available for treatment? Presenters also noted an 8% sustained response rate for Infergen for genotype 1 versus a 4% response with IFN Alfa-2b, but it was not statistically significant. The presenters were asked if there were plans to compare Infergen to Pegylated Interferon but there was no response from the panel of speakers. Transplants for HCV/HIV Coinfected. This is like Friday when during the sessions on liver transplantation I asked about offering liver transplants to HCV/HIV coinfected individuals. The speaker said he had not transplanted anyone who was coinfected and the session chairperson cut me off by saying it would be addressed later but it wasn't.

HIV Protease Inhibitor Therapy and Fibrosis. In an earlier EASL report I discussed the data presented at AASLD on a study comparing the fibrosis progression rates of HCV/HIV coinfected individuals who received a PI regimen for HIV to those who received non-PI therapy for HIV. The study found that the group with a slower fibrosis progression rate contained more individuals on a PI regimen than the other group. They found that the duration of  PI therapy was associated with a low FPR in HCV-HIV coinfected patients. I received an email saying that the non-PI regimen arm had a higher intake of alcohol than the individual's in the PI arm suggesting the difference in fibrosis. I inquired of Poynard today and he said that they adjusted for the difference in alcohol and the PI regimen still improved fibrosis compared to other arm. However, the study was a retrospective analysis. Here is the report.

Liver Fibrosis Progression (this report was taken from NATAP web site and from NATAP Reports Dec. '99 newsletter)

Christine Katlama and others in French HIV research group reported here in Dallas at AASLD Conference and also at ICAAC HIV Conference in September that individuals  co-infected with HIV and HCV who receive protease inhibitor therapy for  HIV can experience decreased liver fibrosis progression rates. The authors here said HCV related liver fibrosis progression is  accelerated in HIV infected patients. The objective of their study is to  examine the impact of combination anti-retroviral therapy for HIV  including a PI on liver fibrosis progression rates. 162 consecutive HCV-HIV coinfected patients (119 male; 36.7 yrs age)  were studied. At liver biopsy, HCV duration was 14.4 years, CD4s were  327, and HIV RNA was performed in 79 patients (17,823 copies/ml). 42  patients had self-recorded alcohol consumption (SRAC above 50g/day). At  liver biopsy, 49 patients were receiving PI therapy for 12 months.

Estimated FPR (fibrosis progression rate) was defined as ratio between  fibrosis stage (METAVIR scoring system) and HCV duration. Since the  linearity of liver fibrosis progression remains questionable only  non-parametric statistical tests were used for univariate and  multivariate analysis.

Patients receiving PI therapy had higher duration of HCV infection and  lower HIV viral load than patients who had never received PI treatment  (17 vs 14 years, p=0.04; 12,154 vs 22,332 copies/ml, p=0.03). Neither  CD4 count nor alcohol consumption showed significant difference between  the 2 groups. Patients with high FPR (above 2.0 fibrosis units/year;  that is, expected time from HCV infection to cirrhosis below 20 years , n=45) included more patients older than 20 years at HCV infection, with  a SRAC (alcohol consumption) above 50 g/day, and with a CD4 count below  200, and less patients treated with a PI compared to patients with low  FPR (equal to or below 2.0 fibrosis units/year, n=117).

Logistic regression analysis identified 2 independent factors associated  with high FPR: CD4 count below 200 (odds ratio=15; p below 0.0001)) and  no previous treatment with PI (odds ratio=3.8, p=0.02). The duration of  PI therapy is associated with a low FPR in HCV-HIV coinfected patients.  The independent association between PI therapy and liver fibrosis  progression is not explained by the studied factors, including the CD4  count.