 |
|
|
| |
Hepatitis C and HIV: incremental advances; plenary talk on HCV protease, new drug research & basic science; final results of 3 important co-infection studies
|
| |
| |
Reported for NATAP by David Margolis, MD, University of Texas, Southwestern Medical Center
Charles Rice of the Rockefeller University outlined the state of the Hepatitis C field. It has been difficult to make progress in understanding this RNA virus, and to devise therapies as available laboratory systems and animal models of hepatitis C are suboptimal. Although trillion HCV particles, with roughly 10-fold more variants than HIV are made in an infected person every day, HCV cannot persist without replication. Therefore, in distinction to HIV, HCV infection can be cured.
Important advances recently include the development of a replicon system, in which a DNA construct made from pieces of the HCV genome can be made to produce HCV particles. This replicon system has allowed the advances in the understanding of the function of some of HCV genes, and the testing of drug candidates. However, the system is not perfect, as mutations that increase replicon performance in cell lines inhibit replication in chimpanzees (the best animal model of HCV). One of the most critical insights into HCV biology was the discovery in the past year that one of the HCV protease genes also serves to block the host cells interferon innate antiviral response.
This offers the hope that if HCV protease inhibitors can be developed they will carry a double whammy for the virus: inhibition of viral particle formation and augmentation of the host antiviral response. A pilot HCV protease inhibitor, BILN-2061, was found to have potent short-term antiviral activity in humans this year, but toxicity problems in test animals have sent Boehringer back to the drawing board to find new candidates for testing. Success rates with peg-interferon and ribavirin are still inadequate, but modest improvements were reported in sustained viral remission (SVR) in two large trials of treatment for HIV/HCV coinfection were reported at this meeting. In ACTG 5071 (abstract 110) a total of 133 subjects were randomized to 180 _g of peginterferon-2a (PEG) weekly for 48 weeks or to interferon-2a (IFN) 6 million units 3 times weekly for 12 weeks followed by 3 million units 3 times weekly to complete 48 weeks of therapy. Both arms received ribavirin in a dose-escalation schedule from 600 mg/d to 1000 mg/d. At week 24, subjects who failed to achieve HCV clearance underwent liver biopsy, and medications were continued for virologic response (VR: HCV RNA < 60 IU/mL) or histologic response (HR: >2 point drop in hepatic activity index). At week 24 VR was 44% with PEG/ribavirin vs 15% with IFN/R. End of treatment virologic response was 41% with PEG/ribavirin vs 12% with IFN/ribavirin. However SVR dropped to 27% vs. 12%, due to a high relapse rate of patients with genotype 1 HCV. Within the PEG/rabivirin arm, SVR was only 14% for genotype 1, compared with 73% for genotype non-1. Importantly, failure to achieve >2-log HCV RNA reduction at week 12 uniformly predicted failure to obtain SVR. Therefore patients without 2 log response at week 12 may choose to spare themselves further toxicity and discontinue therapy. Continued interferon despite lack of response may offer other benefits such as amelioration of liver damage, and this hypothesis is under study in other trials. Receipt of PEG/ribavirin, HCV genotype non-1, no prior injection drug use, and a detectable HIV-1 RNA at entry all increased the likelihood of SVR. Improved liver histology was observed in 36% of virologic nonresponders and in 52% of virologic response who underwent liver biopsy.
The AIDS Pegasys Ribavirin International Co-infection Trial (APRICOT) randomized 868 HIV/HCV co-infected subjects in 19 countries to 48 weeks of treatment with IFN-2a three MIU 3 times a week plus 800 mg/day ribavirin, PEG 180 mg weekly (PEGASYS) plus placebo, or PEGASYS 180 mg weekly plus 800 mg/day RBV (Abstract 112). Eligible subjects were HCV RNA and HCV antibody positive, had compensated liver disease, a CD4+ count ≥100 cells/mL, and stable HIV disease, with or without antiretroviral therapy (ART). The primary endpoint, SVR, was defined as HCV RNA <50 IU/mL at the end of 24 weeks of treatment-free follow-up (week 72), determined by the COBAS AMPLICOR HCV Test v 2.0. Again PEG/RBV was superior, with a 40% overall rate of SVR, compared to 20% without RBV, and 12% with IFN/RBV. However, the SVR rate in genotype 1 was only 29%, due again to a high rate of relapse. HIV viremia was well-controlled throughout the trial, and the rate of drug-related severe adverse events was 8%. Certainly a glass less than half full, it is nice to know that almost a third of genotype 1 patients can achieve an SVR, but better and more tolerable therapies are needed.
MORE RETROVIRUS NATAP REPORTS ON HEPATITIS C
(APRICOT Study, 72-week results) Pegylated Interferon plus Ribavirin: Pegasys/RBV in Co-infection
http://www.natap.org/2004/CROI/croi_5.htm
RIBAVIC Study: Final 72 week data from co-infection study comparing PegIntron plus ribavirin to interferon plus ribavirin
http://www.natap.org/2004/CROI/croi_15.htm
ACTG 5071: Pegasys plus Ribavirin vs IFN/RBV in HCV/HIV Coinfection
http://www.natap.org/2004/CROI/croi_14.htm
Ribavirin-NRTIs Interaction Study
http://www.natap.org/2004/CROI/croi_7.htm
Hepatitis C and Neuropsychological Function In Treatment Naive HIV-1-infected
Subjects - A5097s Baseline Analysis
http://www.natap.org/2004/CROI/croi_3.htm
|
|
| |
| |
|
| |
|
|
|
|
|
