Protease inhibitors: Silver bullets for chronic hepatitis C infection?

Telaprevir in previously treated patients with HCV genotype 1: The REALIZE trial

In this phase 3 placebo-controlled trial,⁵ 622 patients with prior relapse, partial response, or null response were randomly allocated into one of three groups:

• Telaprevir for 12 weeks plus pegylated interferon and ribavirin for 48 weeks
• Lead-in for 4 weeks followed by 12 weeks of triple therapy and another 32 weeks of pegylated interferon and ribavirin
• Pegylated interferon and ribavirin for 48 weeks (the control group).

The overall sustained virologic response rates were 66% and 64%, respectively, in the telaprevir groups vs 17% in the control group (P < .0001). The sustained virologic response rates in the telaprevir groups were 83% to 88% in prior relapsers, 54% to 59% in partial responders, and 29% to 33% in null-responders. Of note, patients did not benefit from the lead-in phase.

This was the only trial to investigate the response to triple therapy in null-responders, a group in which treatment has been considered hopeless. A response rate of approximately 31% was encouraging, especially if we compare it with the 5% response rate achieved with the current standard of care with pegylated interferon and ribavirin.

Telaprevir side effects

As with boceprevir-based triple therapy, the most common adverse events were related to pegylated interferon (Table 2).

Nearly 50% of patients who receive telaprevir develop a skin rash that is primarily eczematous, can be managed with topical steroids, and usually resolves when telaprevir is discontinued. Severe rashes occurred in 3% to 6% of patients in the ADVANCE trial,³ and three suspected cases of Stevens-Johnson syndrome have been reported to the FDA.

Other side effects that were more frequent with telaprevir included pruritus, nausea, diarrhea, and anemia. On average, the hemoglobin level decreased by an additional 1 g/dL in the telaprevir treatment groups compared with the groups that received only pegylated interferon-ribavirin. Erythropoietin use was not allowed in the phase 3 telaprevir studies, and anemia was managed by ribavirin dose reduction.

In the ADVANCE trial,³ study drugs were discontinued owing to adverse events in 7% to 8% of the patients in the telaprevir groups compared with 4% in the control group. In the ILLUMINATE trial,⁴ 17% of patients had to permanently discontinue all study drugs due to adverse events.

FDA-APPROVED TREATMENT REGIMENS FOR BOCEPREVIR AND TELAPREVIR

For treatment algorithms, see the eFigures that accompany this article online.

Boceprevir in previously untreated patients

• Week 0—Start pegylated interferon and ribavirin
• Week 4—Add boceprevir
• Week 8—Measure HCV RNA
• Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL
• Week 24—Measure HCV RNA; stop treatment if it is detectable
• Week 28—Stop all treatment if HCV RNA was undetectable at weeks 8 and 24
• Week 36—Measure HCV RNA; stop boceprevir
• Week 48—Stop all treatment (eFigure 1).

Boceprevir in previously treated patients

• Week 0—Start pegylated interferon and ribavirin
• Week 4—Add boceprevir
• Week 8—Measure HCV RNA
• Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL
• Week 24—Measure HCV RNA; stop treatment if it is detectable
• Week 36—if HCV RNA was not detectable at week 8, stop all treatment now; if HCV RNA was detectable at week 8, stop boceprevir now but continue pegylated interferon and ribavirin
• Week 48—Stop all treatment (eFigure 2).

Telaprevir in previously untreated patients and prior relapsers

• Week 0—start telaprevir, pegylated interferon, and ribavirin
• Week 4—measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL
• Week 12—Stop telaprevir; measure HCV RNA; stop all treatment if HCV RNA is more than 1,000 IU/mL
• Week 24—Stop pegylated interferon and ribavirin if HCV RNA was undetectable at week 12; measure HCV RNA and stop treatment if it is detectable; otherwise, continue pegylated interferon and ribavirin
• Week 48—Stop all treatment (eFigure 3).

Telaprevir in patients who previously achieved a partial or null response

• Week 0—Start telaprevir, pegylated interferon, and ribavirin
• Week 4—Measure HCV RNA; stop treatment if it is more than 1,000 IU/mL
• Week 12—Measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL; if less than 1,000 IU/mL then stop telaprevir but continue pegylated interferon and ribavirin
• Week 24—Measure HCV RNA; stop treatment if HCV RNA is detectable
• Week 48—Stop all treatment (eFigure 4).

Drug interactions with boceprevir and telaprevir

Both boceprevir and telaprevir inhibit cytochrome P450 3A (CYP3A) and thus are contraindicated in combination with drugs highly dependent on CYP3A for clearance and with drugs for which elevated plasma concentrations are associated with serious adverse events, such as atorvastatin (Lipitor), simvastatin (Zocor), sildenafil (Viagra), midazolam (Versed), and St. John’s wort. Giving potent inducers of CYP3A with boceprevir or telaprevir may lead to lower exposure and loss of efficacy of both protease inhibitors.

EMERGING THERAPIES FOR HCV

Thanks to a better understanding of the biology of HCV infection, the effort to develop new therapeutic agents started to focus on targeting specific steps of the viral life cycle, including attachment, entry into cells, replication, and release.²⁴

Currently, more than 50 clinical trials are evaluating new direct-acting antivirals to treat HCV infection.²⁵ Monoclonal and polyclonal antibodies that target the molecular process involved in HCV attachment and entry are being developed.²⁶ The nonstructural protein NS5B (RNA polymerase) is intimately involved in viral replication and represents a promising target.²⁷ Several nucleosides and nonnucleoside protease inhibitors have already entered clinical trials.

The low fidelity of the HCV replication machinery leads to a very high mutation rate, thus enabling the virus to quickly develop mutations that resist agents targeting viral enzymes.²⁸ Therefore, a novel approach is to target host cofactors that are essential for HCV replication. An intriguing study by Lanford et al²⁹ demonstrated that antagonizing microRNA-122 (the most abundant microRNA in the liver and an essential cofactor for viral RNA replication) by the oligonucleotide SPC3649 caused marked and prolonged reduction of HCV viremia in chronically infected chimpanzees.²⁹

Although we are still in the early stages of drug development, the future holds great promise for newer drugs to improve the sustained virologic response, shorten the duration of treatment, improve tolerability with interferon-sparing regimens, and decrease viral resistance.