The closing CROI Symposium, Advances in the Understanding of HCV Biology and Treatment, included a detail of the HCV protease and polymerase inhibitor pipeline. Ann Kwong from Vertex Pharmaceuticals reviewed clinical development of protease inhibitors, describing the active site of the HCV protease as a lousy target: "landing an inhibitor on the top of that enzyme is like landing on a piece of pizza -- it's just greasy and [the inhibitor] flies right off." Previously, Boehringer Ingelheim had established proof-of-concept with BILN-2061, but development was halted in 2004 due to the drug's cardiac toxicity. Two candidates have recently completed early Phase I studies: Vertex's 950 and Schering's 503034. Data appears below in Table 1.
Promising results from these early trials have inspired considerable excitement and speculation. As indicated in Table 1, both PIs were active against HCV genotype 1, and in treatment na?ve persons (Vertex) and nonresponders (Schering). Genotype 1 requires 48 weeks of treatment and is less responsive to current therapy than genotypes 2, 3, and 4.
The spoiler is resistance. A single mutation at position A/156/T creates cross-resistance to HCV protease inhibitors. Additional mutations conferring low and high-level resistance to Vertex 950 have been identified. Vertex's early research suggests that the replicative capacity of resistant virus may be poorer than that of wild-type virus. The crucial question is whether an HCV protease inhibitor-based regimen can eliminate the virus before resistance develops.
Phase I data have been used to estimate the impact of HCV protease inhibitors on hepatitis C treatment duration. These models ambitiously predict a significant treatment abbreviation from 48 to 12 weeks, but more data are needed. As Kwong rightly noted, "we'll just have to see how it turns out."
Daria Hazuda from Merck closed the symposium with an update on preclinical development of HCV polymerase inhibitors. HCV's polymerase enzyme is a mother lode for anti-viral drug development; five classes of polymerase inhibitors have already been identified. Preclinical data indicate that these drugs may be combined with one another, and some may offer additive or synergistic effects. The drawback is resistance. In preclinical testing, a single amino acid change caused high-level resistance, although cross-resistance may be less likely with polymerase inhibitors than protease inhibitors.
These exciting developments bode well for the future of HCV therapy but contrast sharply with today's clinical reality for HIV/HCV coinfected patients. Several posters at CROI documented high rates of HCV treatment ineligibility, low response to HCV therapy, and significant liver-related morbidity and mortality among coinfected persons. In particular, two HIV clinics based in Baltimore and Seattle reported that less than one third of their coinfected patients had been evaluated for HCV treatment; of the third who underwent evaluation, less than 20% began treatment. Not surprisingly, at the end of the day, the number of patients who achieved SVR during treatment represented an abysmal .7 and 1.6 percent of the entire Baltimore and Seattle-based cohorts, respectively.
Sources: Mehta S, Lucas G, Torbenson M, et al. Barriers to referral for hepatitis C care among HIV/HCV coinfected patients in an urban HIV clinic. 13th Conference on Retrovurises and Opportunistic Infections; February 5-8th; Denver Colorado. 2006. Abstract 884;
Scott J, Wald A, Kitahata M, Drolette A, Corey L, Wang, C. HCV is evaluated and treated infrequently in an HIV/HCV coinfected population. 13th Conference on Retrovurises and Opportunistic Infections; February 5-8th; Denver Colorado. 2006. Abstract 882.
More effective, less toxic therapies will undoubtedly increase treatment uptake among coinfected people. Still, new drugs alone won't dispel existing barriers, particularly since the clinically demanding, and difficult-to-tolerate, pegylated interferon is likely to remain the therapeutic backbone of HCV treatment for the next few years. Successful HCV treatment programs offer integrated psychiatric care, drug treatment, and include strong peer education and support components. Such programs are few and far between. The infrastructure necessary for delivering HCV treatment to coinfected people must be developed now, in anticipation of improvements in therapy.
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