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Boceprevir vs. Telaprevir: What We Know and Don't Know

•A 4-week lead-in period of PR is given with boceprevir but not with telaprevir.
•In treatment-naive patients with genotype 1 HCV infection, both boceprevir and telaprevir improve SVR rates and, for many patients, reduce the duration of treatment. Neither drug is indicated for treatment of non–genotype 1 HCV infection.
•In previously treated patients, telaprevir improves SVR rates in both prior responders and prior null-responders. Boceprevir has been studied only in patients who had at least a partial response to PR therapy in the past — and has been shown to improve SVR rates in this population.
•Both boceprevir and telaprevir are approved for three-times-daily dosing, and the pill burden is considerable. Telaprevir may be effective when dosed at 1125 mg twice daily,10 but larger studies are needed.
•In a retrospective subgroup analysis of the boceprevir phase III trials, patients with the favorable IL28B genotype (C/C) had higher response rates than those with unfavorable genotypes. This was particularly true among previously untreated patients.1 In a retrospective subgroup analysis of the telaprevir trials, patients with any IL28B genotype appeared to have higher SVR rates with T+PR than with PR alone.4
•A head-to-head trial comparing the drugs has not been performed, so we do not yet know which one is better.

Drug Resistance: Stay Tuned
Not surprisingly, emergence of drug-resistance mutations has been observed in patients who have received these agents. Drug resistance may become undetectable after HCV protease inhibitors are stopped, but we do not yet know whether these resistant variants would reemerge if therapy were restarted.

Improving HCV Therapy for HIV-Coinfected Patients
HCV treatment in HIV-coinfected individuals has traditionally been challenging, given their low rates of SVR. However, emerging data from a recent phase II, randomized trial demonstrate that telaprevir may improve virologic responses in HIV-infected patients with genotype 1 HCV infection.11 In that study, 60 patients were treated with PR plus telaprevir or placebo for 12 weeks, followed by PR alone to complete 48 weeks of therapy. In an interim analysis involving 59 patients, 70% of those in the telaprevir group had undetectable HCV RNA at week 4, compared with 0% in the control group. At week 12, the numbers were 68% versus 14%. Table 3 shows results stratified by receipt of antiretroviral therapy (ART); notably, only those receiving tenofovir/FTC/efavirenz or tenofovir/FTC + ritonavir-boosted atazanavir were eligible for the portion of the study examining responses in ART-treated patients. Currently, neither telaprevir nor boceprevir is approved for treating chronic HCV infection in HIV-positive patients. Although these findings suggest that telaprevir may be beneficial, longer-term results are still pending.

Little is known about drug interactions between HCV protease inhibitors and ART. Use of efavirenz reduces telaprevir levels; as a result, in the ongoing phase II study summarized above, the dose of telaprevir was increased to 1125 mg every 8 hours in the efavirenz group. In healthy-volunteer studies, ritonavir-boosted atazanavir had less effect on telaprevir exposure than did other HIV protease inhibitors.12 Coadministration of efavirenz reduces trough concentrations of boceprevir, but the clinical implications are not clear.13 Interactions between boceprevir and commonly used HIV protease inhibitors have not yet been reported.

Conclusions and Future Challenges
Use of boceprevir or telaprevir together with PR will revolutionize HCV treatment, leading to improved outcomes and a shorter duration of treatment for many patients. As we take stock of this breathtaking advance, we should also pause to consider some unanswered questions:
•How will clinicians choose between these new agents?
•Do all patients need the new drugs, or can some patients, such as those with favorable host and viral factors, be treated with PR alone?
•Does boceprevir require the 4-week PR lead-in period for maximum effectiveness?
•Should prior null-responders be treated with telaprevir-based therapy — which is expected to have a response rate of approximately 30% — or should they wait for development of better therapies in the future?
•How should liver-transplant patients with graft HCV reinfection be treated?
•How should patients with decompensated cirrhosis, in whom PR therapy is contraindicated, be treated?

Furthermore, these drugs are not yet approved for HIV/HCV-coinfected patients, and we have only preliminary information from one study in this important group. Therefore, if possible, it is worth waiting until additional data are available before using these agents in coinfected individuals.

Finally, boceprevir and telaprevir are administered with peginterferon/ribavirin, and patients who cannot tolerate these medications will not benefit from the newly approved drugs yet. Fortunately, many new anti-HCV drugs — including polymerase and NS5A inhibitors — are being investigated in clinical trials. Hopefully, they will eliminate interferon from our HCV toolbox in the future.

— Isaac I. Bogoch, MD, and Rajesh T. Gandhi, MD

Dr. Bogoch is a Fellow in the Division of Infectious Diseases at Massachusetts General Hospital in Boston. He reports no conflicts of interest.

Published in Journal Watch HIV/AIDS Clinical Care May 27, 2011
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