CROI's Hep C Treatment News
Dr. Mark Sulkowski presented treatment with boceprevir (BOC) in untreated patients with genotype 1 HCV. In this randomized study, all patients began with a lead-in of four weeks P/R therapy, followed by 64 and 34 patients continuing with P/R+BOC vs. P/R alone, respectively. At 12 weeks post-treatment 61% on P/R+BOC vs. 27% on P/R alone achieved an SVR.
HIV treatment failure occurred in three patients on boceprevir vs. four patients on P/R alone. In a separate abstract (Abstract 771LB), drug-drug interactions of boceprevir with boosted protease inhibitors showed that both ritonavir-boosted protease inhibitors and boceprevir inhibit the same CYP3A4 enzymatic systems and other complex enzyme transporter interactions. At the time of this study, these interactions were unknown; we now understand that boosted PIs should not be used with boceprevir. Boceprevir reduced steady-state exposure of Kaletra, Reyataz, and Prezista by 43, 49, and 59% respectively. There is also a significant reduction in boceprevir exposure with Kaletra and boosted Prezista. Healthcare professionals recently received a letter in which Merck stressed they do not recommend the co-administration of Victrelis (boceprevir) and ritonavir-boosted HIV protease inhibitors (see "Victrelis 'Not Recommended' With Some HIV Meds").
Side effects with boceprevir treatment included anemia, pyrexia, asthenia, decreased appetite, diarrhea, vomiting, flu-like illness, and neutropenia. However, serious adverse events were 17% in the BOC group vs. 21% in the group taking P/R alone.
In another presentation, Richard Barnard presented a Phase 1 study of Merck's next generation HCV protease inhibitor, MK-5172. Preliminary evidence shows activity against other protease inhibitor-resistant variants. In this Phase 1 trial, there were six treatment arms with doses ranging from 50 to 800 mg once daily administered to genotype 1 treatment-naive patients over seven days. Thirty out of forty, or 75%, achieved viral load reductions to below detection at seven days during which there were no viral breakthroughs (treatment failures) with viral load reductions persisting for several days beyond administration. During the conference, information released by Merck discussed the two higher doses being associated with an elevated liver enzyme signal. However, because the trial showed all arms, including 50 mg, to have superimposed viral load declines, we hope that further studies will move forward, expecting to use the lower doses.
In a much anticipated session, GS-7977 was presented. Gilead Sciences has recently acquired this agent from Pharmasset and it has been much in the news lately due to its ability to result in SVRs without need for interferon; it is also one of the agents that is ahead of others in development for treating HCV. Currently, the standard of care for hepatitis C treatment includes pegylated interferon despite its difficult side effects, so successful HCV treatment without the need for interferon is of keen interest to both clinicians and providers.
7977, a nucleotide analog with potent anti-HCV activity, is administered in one pill daily, with or without food. In the prior study, Electron, patients with genotype 2 or 3, naive to HCV treatment, were given 7977 at 400 mg daily plus ribavirin for 12 weeks, but importantly, without pegylated interferon. Continuing, in the Electron study, all 40 patients studied achieved an SVR out to 24 weeks. Moreover, one arm of the study had 7977 administered as monotherapy and 60% achieved SVR out to 24 weeks.
In the latest segment of Electron, the newest data studied HCV patients with genotype 1 in two groups: null responders (those who previously failed treatment) and patients naive to HCV therapy. All patients received 7977 with ribavirin for 12 weeks. At the conference only the results of the null responders were available. Remarkably, of the 10 patients, no patient rebounded while on the 12 weeks of treatment, demonstrating 7977 to have a high barrier for resistance. However, nine out of 10 patients relapsed soon after cessation of treatment. The authors concluded that these particular patients with genotype 1, also previously treatment failures, would probably require another direct acting agent, such as an NS3 inhibitor. From this writer's standpoint, patients who fail treatment with P/R probably develop resistance; thus being offered one new agent (7977), although together with ribavirin, would be tantamount to monotherapy. We anticipate the results from the naive patients to be presented at EASL (European Association for the Study of the Liver) in Barcelona this April.
Drug Interactions With Newer Agents: Daclatasvir, TMC 435 and Boceprevir
Daclatasvir (DCV) is a potent NS5A replication complex inhibitor of HCV, administered once daily, currently in Phase 3 trials in combination with P/R. PK data showed no effect on tenofovir (Viread), efavirenz (Sustiva), or boosted atazanavi r (Reyataz/Norvir). However, DCV dosage adjustments will be needed: 30 mg when used with boosted atazanavir, 90 mg with efavirenz. Both have equivalent exposure of DCV as in the 60 mg dose used alone.
TMC 435, another potent NS3/4A protease inhibitor, currently in Phase 3 for genotypes 1 and 4 HCV-infected patients, is about to begin trials in co-infection. Data of drug-drug interactions showed it to be not recommended for use with efavirenz due to the reduced exposure to TMC 435 in the presence of efavirenz. However, rilpivirine (Edurant), raltegravir (Isentress), and tenofovir (Viread) can be used with TMC 435 without dosage adjustment.
Lastly, for the first time, drug-drug interactions were presented regarding using raltegravir (Isentress) in combination with boceprevir (Victrelis) with the conclusions that boceprevir does not affect raltegravir exposure and can be used safely.
Dr. Daniel S. Berger is a leading HIV physician in the U.S. and is Clinical Associate Professor of Medicine at the University of Illinois at Chicago. He is founder and medical director of Northstar Healthcare, has published extensively in such prestigious journals as The Lancet and The New England Journal of Medicine, and currently serves as principle investigator at Northstar Healthcare. Dr. Berger has been honored by Test Positive Aware Network with the Charles E. Clifton Leadership Award. Dr. Berger can be reached at DSBergerMD@aol.com and www.Nstarmedical.com.
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