Review Article: Specifically Targeted Anti-viral Therapy for Hepatitis C – A New Era in Therapy

C. M. Lange; C. Sarrazin; S. Zeuzem

Disclosures

Aliment Pharmacol Ther. 2010;32(1):14-28. 

In This Article

Conclusions

Numerous directly acting anti-viral agents are currently under clinical phase I-III evaluation. Results of phase II clinical trials evaluating the most advanced compounds telaprevir and boceprevir indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon-alfa and ribavirin substantially improves the chance to achieve a SVR in treatment-naive HCV genotype 1 patients as well as in prior nonresponders and relapsers to standard therapy. In addition, at least during treatment with telaprevir-based regimens, overall treatment durations can be shortened significantly.

Results of the milestone studies PROVE 1 and 2 indicate that 12 weeks of telaprevir-based triple therapy is too short because of the high rate of relapse after treatment completion. Moreover, ribavirin is necessary in therapies with telaprevir to achieve high SVR rates. However, 24 to 48 weeks of total therapy including 12 weeks of triple therapy with telaprevir in addition to standard treatment greatly improved SVR rates in treatment-naïve genotype 1 patients compared with the standard of care. The RVR during triple therapy is an important predictor for treatment success and can be applied for defining individualized treatment durations. Important side effects of telaprevir are, as observed during treatment with other protease inhibitors as well, anaemia, rash and gastrointestinal disorders. The SPRINT-1 trial demonstrated that SVR rates in treatment-naïve HCV genotype 1 patients can be enhanced by the addition of boceprevir to standard treatment as well. However, the lower anti-viral efficacy of boceprevir compared with telaprevir may require longer durations of boceprevir application.

PROVE 3 has shown that telaprevir is also highly effective in the treatment of prior nonresponders or relapsers infected with HCV genotype 1. In contrast, addition of boceprevir to standard treatment only revealed a minor impact on SVR rates in nonresponders, but further trials are awaited. In addition to telaprevir and boceprevir, many NS3/4A inhibitors with promising anti-viral activities are currently investigated in phase I and II trials.

Compared with NS3/4A protease inhibitors, most HCV polymerase inhibitors display a lower anti-viral activity during monotherapy. SVR data of triple therapies containing NS5B inhibitors need to be awaited. However, some polymerase inhibitors are equally effective against different HCV genotypes whereas it was shown that protease inhibitors such as telaprevir are less potent in other genotypes than HCV genotype 1. In addition, NS5B inhibitors at least of the nucleoside analogue family display a high genetic barrier to resistance.

Although it can be vastly reduced by addition of pegylated interferon-alfa and ribavirin, resistance development to directly acting anti-viral agents has to be kept in mind. R155 is the overlapping mutation conferring resistance to all clinically yet evaluated protease inhibitors. Although resistance against polymerase inhibitors needs to be better characterized, it is evident that their resistance profiles differ from those of protease inhibitors. Combination of different classes of STAT-C agents may therefore help to overcome limitations of resistance development. The impact of recently discovered polymorphisms near the IL28B gene on resistance development and SVR rates during STAT-C regimens needs to be characterized in future studies.[80–82]

A pivotal trial evidenced an additive anti-viral efficacy of the polymerase inhibitor R7128 in combination with the protease inhibitor ITMN-191 in an interferon- and ribavirin-free regimen. Whether SVR can be achieved with such interferon-free regimens needs to be addressed in future trials.

In conclusion, STAT-C compounds in addition to pegylated interferon-alfa and ribavirin are capable to improve SVR rates at least in HCV genotype 1 patients and will therefore be included in future treatment recommendations and guidelines.

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