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CROI's Hep C Treatment News

By Daniel S. Berger, M.D.

May/June 2012

The revolution of treatment development with direct acting agents against hepatitis C virus (HCV) is moving faster than a speeding bullet. As it once was for treatment development of HIV, it is dramatic.

Thus, one of many reasons to attend the 19th Conference on Retroviruses and Opportunistic Infections (CROI), held this year in Seattle in March, was the intensity and new data regarding HCV treatment. This was unusual for a conference historically focused on the basic science of HIV.

There is a growing incidence of hepatitis C infection among HIV-positive individuals (co-infection) and it is becoming clear that HCV treatment is complicated. Treatments differ in regards to HCV genotype, therapy for treatment-naive vs. history of treatment failure, and drug-drug interactions for patients with co-infection. HIV specialists are accustomed to these kinds of complex issues while gastroenterologists, busy with endoscopic procedures, and hospital-based infectious disease specialists, with limited office hours, may not be able to tackle the rocketing numbers of patients with HCV infection growing to monumental proportions. With many future agents becoming developed, much heavy lifting treating HCV-infected patients will be left to physicians who manage HIV disease. However, there is a progressive decrease of physicians wanting to specialize in HIV disease treatment.

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A poster presented by the Swiss Cohort team showed staggering statistics in regards to the growing hepatitis C epidemic among those infected by HIV. Their investigation of the MSM (men who have sex with men) population excluded intravenous drug users and heterosexuals. Of 3,333 MSM patients followed, the incidence of new HCV infections in 2011 (compared to 1998) increased 18-fold. Identified risk factors were unsafe anal sex, history of syphilis, and chronic hepatitis B infection. Indeed, the take home message for clinicians is the need for increased testing for HCV and for gay men engaged in unsafe sexual practices, the message is beware and exercise prevention; one needn't be engaged in intravenous drug use to become infected.

The "Breakthroughs in HCV Treatment" session began with presentations of studies with telaprevir (Incivek) and boceprevir (Victrelis), both inhibitors of NS3/4A HCV protease. Both won FDA approval in 2011 for use with pegylated interferon and ribavirin in adults with genotype 1 chronic HCV and compensated liver disease. However, neither boceprevir nor telaprevir is licensed for use in HIV/HCV co-infection. At CROI, two co-infection studies were highlighted; both trial designs included combinations with pegylated interferon and ribavirin (P/R), and both included the conventional "futility rules" that have become standard for patients undergoing treatment. Protocols put futility rules in place so that patients who experience viral rebound or those who do not reach rapid declines in hep C RNA (viral load) or undetectability within a specified time frame are discontinued from treatment, avoiding resistance mutations or further side effects with failing treatment. Also discussed were HIV drug interactions, crucial for understanding their use with HIV treatment.


Telaprevir

Dr. Douglas Dieterich presented a trial of treatment with telaprevir (TVR) in genotype 1 HCV co-infected patients; genotype 1 is the most common and, unfortunately, the most difficult to treat HCV strain.

Patients were administered telaprevir (750 mg every 8 hrs)+P/R for 12 weeks followed by 36 weeks of P/R alone; in the P/R control group, patients were treated for 48 weeks with P/R alone. Further, the trial was divided into parts A and B. In part A, 13 patients were treated without ART (antiretrovirals); 7 randomized to P/R+TVR and 6 on P/R alone. In part B, 24 patients were on Atripla, 16 treated with P/R+TVR and 8 on P/R alone. Also, 23 patients were on ritonavir-boosted atazanavir (Reyataz/Norvir) with either Truvada (emtricitabine/tenofovir) or Viread/Epivir and of these, 15 were treated with P/R+TVR and 8 with P/R alone.

At 12 weeks post-treatment the overall SVR (sustained virologic response -- indicates treatment success), was 74% in the P/R/TVR-treated patients vs. 45% in controls. There were no HIV treatment failures; three HCV treatment failures occurred -- at week 4 with one patient in each of the Atripla and Reyataz groups and one at week 12 in the Atripla group. Patient discontinuations due to futility rules were more common in the P/R controls (32 vs. 5%) and discontinuations due to adverse events were 8% in the TVR group vs. 0% in the P/R group. The most common side effect was fatigue in both groups (41-42%) with pruritis (itchy skin), nausea, headache, and rash being more common in the TVR treatment groups. No dosage adjustments were necessary except for a higher dose of telaprevir (1,125 mg every 8 hours) required to offset reduced exposure of it with efavirenz (Sustiva, in Atripla).

Boceprevir

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.


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MK-5172

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.


GS-7977

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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