Hepatitis C treatment has moved forward subtantially in the past two years with the widespread adoption of combination therapy with pegylated interferon and ribavirin. What does 2004 hold for the treatment of hepatitis C, especially in people coinfected with HIV and hepatitis C?
The final results from three large trials of current hepatitis C therapy in people co-infected with HIV will be released in 2004. Several new therapies will move into early stages of clinical testing, mainly in people infected with hepatitis C (HCV) alone.
Co-infection and current therapy: Pegylated interferon and ribavirin
The standard of care for hepatitis C treatment combines a once-weekly injection of pegylated interferon (Roche’s Pegasys or Schering-Plough’s Peg-Intron) with daily ribavirin. Combination therapy for 24-48 weeks leads to a viral clearance (a sustained virologic response, defined as an undetectable viral load six months after treatment) in about 50% of people treated. However, response to treatment can vary widely depending on several factors, including viral genotype, hepatitis C viral load, and race. Pegylated interferon and ribavirin also have high rates of treatment-limiting toxicities, including anemia and depression.
Data on sustained virologic response rates from three major studies (RIBAVIC, A5071, and APRICOT) of hepatitis C treatment in co-infected persons will be presented in early 2004. Each study compares pegylated to standard interferon in combination with ribavirin. RIBAVIC, a 418-person study conducted by France’s ANRS, used Peg-Intron, while A5071 and APRICOT employed Roche’s Pegasys. A5071, sponsored by the United States’ Adult AIDS Clinical Trials Group, followed 133 subjects. The Roche-sponsored APRICOT (the AIDS PEGASYS and Ribavirin International Co-Infection Trial) is an international trial that enrolled 868 co-infected persons. Preliminary analyses of these trials indicated that treatment is less effective in people co-infected with HIV:
- Early results from RIBAVIC showed a high rate of severe side effects. 30% of the study population dropped out of the trial.
- In A5071, less than half of subjects receiving Pegasys had a virologic response mid-way through treatment.
Based on these results and findings from smaller trials, many expect that final data will document sustained virologic response rates well below those seen in hepatitis C mono-infection, in the range of 20-35% overall. Poor tolerability on top of lower response rates will complicate treatment decisions for people co-infected with HIV and HCV.
Future directions for improving treatment outcomes for co-infected people using current therapies are unclear. Options include intensifying treatment through higher doses of pegylated interferon or longer durations of therapy. The value of these approaches has not been established in people infected with HCV alone. Moreover, either strategy would increase the incidence of side effects, jeopardising adherence and impairing quality of life during treatment. Nevertheless, some clinicians have begun treating co-infected patients for an additional six months in order to increase the likelihood of sustained virologic responses. Others await new drugs, none of which are currently being tested in co-infected people.
HCV Protease Inhibitors
Hepatitis C, like HIV, uses a viral protease enzyme essential for replication. In the late 1990’s, a robust field of drug development targeting the HCV serine protease was stalled due to lawsuits and licensing disputes between Chiron, the patent-holder, and a host of other pharmaceutical companies. Most of the legal and financial issues have now been resolved, with Chiron reaching licensing deals with Boehringer Ingelheim, Gilead and Vertex in 2003. Several companies have been pursuing candidate HCV protease inhibitors, with a number of oral compounds in late pre-clinical testing and a few entering human trials.
The first published data from a human study of an HCV protease inhibitor appeared in the November 13, 2003 issue of Nature, (Lamarre) reporting on Boehringer Ingelheim’s BILN 2061. A two-day course of BILN 2061 resulted in a 2-to-3 log drop in HCV viral load in small groups of study subjects, demonstrating proof of concept. BI recently announced a halt in further development of this drug, reportedly due to animal toxicity data, but will proceed with another compound. Vertex is launching a phase I study of its HCV protease inhibitor, VX-950, in early 2004, and Schering-Plough has begun initial clinical trials of another protease inhibitor, SCH7.
Protease inhibitors are considered the most promising class of new anti-HCV agents, but they face some challenges. In vitro studies show that drug resistant-virus can rapidly emerge, so HCV protease inhibitors must be used in combination with interferon-based treatment. Protease inhibitors in development have been designed to target the HCV genotype 1 protease, reflecting the genotype most common in the United States, Europe, and Japan, but may be less effective against other HCV genotypes. Several important issues in clinical trial design have not been resolved, including whether these drugs will be tested in people co-infected with HIV, and whether they will be initially studied as first-line therapy or for non-responders to prior treatment. Under the most optimistic scenarios, an HCV protease inhibitor would not reach licensure until 2007 or 2008.
Other Investigational Drugs
Several other agents targeting another HCV enzyme, the RNA-dependent RNA polymerase (RdRp), are in early pre-clinical and clinical development, including drugs entering phase I and II trials from Rigel and Japan Tobacco. United Therapeutics has begun a phase I study of an imino sugar derivative, UT231B, that appears to block the activity of another HCV protein, p7. Isis Pharmaceuticals has an antisense oligonucleotide, ISIS 14803, in phase II.
Several nucleoside analogues with the potential to complement or replace ribavirin will be in clinical trials in 2004. Valeant Pharmaceucticals is developing viramidine, a less toxic pro-drug of ribavirin. Valeant is beginning two large phase III trials by the end of 2003 to compare viramidine to ribavirin, both in combination with pegylated interferon. Valeant (formerly ICN Pharmaceuticals) originally discovered ribavirin in 1970, but expects to face generic competition in the United States beginning in 2004. The pressure on ribavirin profits has spurred its research on viramidine and a similar drug, levovirin, an L-isomer of ribavirin. Valeant and Roche are collaborating on phase I/II trials of levovirin.
Other nucleoside analogues are in earlier stages of development. Vertex is conducting phase II trials in Europe of Merimepodib, an IMPDH inhibitor, in combination with pegylated interferon and ribavirin, with interim results showing favorable signs of safety and efficacy. Roche, Anadys and Idenix also have nucleoside analogues in early clinical studies.
Some research may advance the HCV vaccine field, still in its infancy. Chiron announced in late 2003 the initiation of a phase I study of an envelope-based vaccine to prevent HCV infection. Belgian-based Innogenetics is developing a therapeutic HCV vaccine based on an envelope protein, and recently published promising results in an uncontrolled phase II study that showed improvement in liver biopsy scores (Nevens). Long-term follow-up data is expected in 2004.