Direct-acting antiviral agents in monoinfected patients
The advent of direct-acting antiviral agents (DAAs) active against different steps within the HCV lifecycle will dramatically change therapy, especially for difficult-to-treat patients. Both telaprevir (TVR) and boceprevir (BOC) are potent inhibitors of the HCV NS3/4A serine protease; both have been tested in combination with the standard-of-care (SOC; peginterferon plus ribavirin) in large Phase III trials.
The pivotal Phase III trials that included TVR are ADVANCE Citation[1] and ILLUMINATE Citation[2] in treatment-naive subjects, and REALIZE Citation[3] in treatment-experienced subjects. The Phase III trials for BOC are SPRINT-2 Citation[4] (naive) and RESPOND-2 Citation[5] (experienced).
The results of these trials highlighted the fact that the use of DAA significantly improves the sustained virologic response (SVR) rate when compared with the combination of peginterferon and ribavirin (PR), such as used in the existing SOC.
Moreover a significant proportion of DAA-treated patients may shorten the duration of therapy if they achieved a complete rapid virologic response (RVR).
Indeed, for treatment-naive genotype 1 HCV-infected patients, the results of the ADVANCE study show that significantly more patients in the T12PR or T8PR group than in the PR group had a SVR (75 and 69%, respectively, vs 44%; p < 0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with TVR were eligible to receive 24 weeks of total treatment.
The results from the ILLUMINATE trial support the strategy of response-guided therapy Citation[2]. Among patients who achieved an extended rapid virological response (eRVR), rates of SVR in those treated for 24 weeks were comparable to that obtained in the 48-week treatment group (92 vs 88%, respectively), The SVR rate was 64% in patients not obtaining the eRVR but who continued the treatment for 48 weeks.
REALIZE is still the only Phase III hepatitis C study of a DAA (TVR) designed to evaluate patients failing a prior treatment, including those who had a null response Citation[3]. The study had a three-arm complex design, one of which included a lead-in phase compared with a simultaneous starting one.
Rates of SVR were significantly higher in the two TVR groups than in the control group among patients who had a previous relapse (83 vs 88% in the lead-in group and 24% in the SOC group), a partial response (59, 54 and 15%, respectively), and no response (29, 33 and 5%, respectively; p < 0.001 for all comparisons).
SPRINT-2 included treatment-naive HCV genotype 1 patients to be treated with BOC Citation[4]. Participants were divided into cohorts according to race, as individuals of African descent do not respond as well to interferon-based therapy. BOC recipients were further allocated to receive either the triple combination for a fixed duration of 48 total weeks or response-guided therapy.
In an intent-to-treat analysis, SVR rates were significantly higher in the BOC arms – 66% with fixed-duration treatment and 63% with response-guided therapy – compared with the standard therapy arm (38%). In all arms, white patients had higher response rates than blacks. Among BOC participants who had detectable HCV viral load at least once during weeks 8–24, 74% still achieved SVR in both arms.
The RESPOND-2 study evaluated the use of BOC-PR in 403 patients who had failed prior dual therapy with peginterferon/RBV Citation[5]. Patients treated with BOC had significantly higher rates of SVR compared with those who were administered placebo. Responses rates were higher among those who had experienced prior relapse than among prior nonresponders. Even among patients who did not achieve a HCV RNA decline greater than 1 log at week 4, SVR was significantly higher in subjects receiving BOC.
TVR & BOC safety & tolerability
The safety and tolerability results of the TVR-based combination regimens were consistent across the Phase III studies. Rash and anemia occurred more frequently in the TVR-based treatment arms compared with the control group. Rash was primarily characterized as eczema-like, manageable and resolved upon stopping TVR.
Adverse events (AEs) in patients treated with BOC included anemia, which was reported in 49% of patients in the BOC arm compared with 29% of patients in placebo. Dysgeusia, a prolonged metallic taste, was also more common in patients receiving BOC than in patients receiving placebo.
TVR & BOC resistance
Minor resistant populations pre-exist at baseline, probably in all HCV-infected patients Citation[6]. Typical mutations are selected by protease inhibitor therapy; such as R155K. These mutations arise more quickly in patients who are infected with genotype 1a than in those infected with genotype 1b. Indeed, in a genotype 1a patient, only one nucleotide change is required to result in a change in the amino acid; in the genotype 1b patient, two changes are required Citation[7]. Emergence of resistance is reduced when a protease inhibitor is combined with peginterferon/ribavirin.
Currently, available data show that for both BOC and TVR, associated mutations can persist for at least approximately 2 years Citation[8,9].
Natural DAA resistance-associated mutations are frequently seen in HIV–HCV coinfected individuals. Changes polV499A and prQ80K seem to be natural polymorphisms and their effect on treatment outcomes warrants further examination Citation[10].
TVR in HIV–HCV coinfected patients
The study 110 was conducted in HCV–HIV coinfected patients who were receiving either no antiretroviral therapy, efavirenz (EFV)-based antiretroviral therapy or boosted atazanavir-based antiretroviral therapy Citation[11]. In patients who received TVR plus peginterferon and ribavirin, the RVR rates are in the 57–75% range, regardless of antiretroviral therapy regimen. The patients receiving only peginterferon plus ribavirin had RVR rates in the range of 5–12%. Therefore the addition of TVR boosted the RVR rate tremendously in this study, and patients with RVR are likely to clear the virus.
Similar results are seen in the 12-week data from the patients who had achieved a complete EVR. The reader should recall that a complete EVR is a predictor of higher rates of SVR.
Similar efficacy results were observed with or without concurrent antiretroviral therapy. Nausea, pruritus, dizziness and fever were more common in the TVR group then the placebo group, and the pharmacokinetic interactions between atazanavir and EFV and TVR were not clinically significant.
Interaction between DAA & antiretroviral drugs
Investigators found no clinically relevant changes in BOC exposure when it was coadministered with tenofovir (TDF). Slight reductions were observed in the area under the curve (AUC) of BOC (BOC AUC: 0–8h) and Cmax (19 and 8%, respectively) when it was coadministered with EFV. In addition, the BOC Cmin decreased 44% when coadministered with EFV. Coadministration with ketoconazole increased BOC exposure (AUC) by 131%, while coadministration with ritonavir and clarithromycin resulted in minimal effects on BOC exposure. Coadministration of BOC with TDF did not result in any notable effect on TDF AUC or renal clearance, but did increase TDF Cmax by 32%. The AUC (0–24 h) and Cmax of EFV were increased somewhat (20 and 11%, respectively) by coadministration with BOC. The data suggest no need to adjust BOC dosage with coadministration of peginterferon or TDF Citation[12].
Pharmacokineic data on TVR coadmistered with commonly used antiretroviral drugs showed that TVR AUC and Cmin decreased by only approximately 15% when administered 750 mg three-times daily with boosted atazanavir. TVR levels fell by approximately 50% when administered at the same dose with lopinavir/ritonavir. TVR levels decreased by approximately 30% when administered with darunavir/ritonavir or fosamprenavir/ritonavir. Conversely, darunavir and fosamprenavir levels fell by more than half when coadministered with TVR. Atazanavir Cmin nearly doubled when taken with 750 mg TVR. Therapeutic levels of all drugs were maintained when the TVR dose was increased to 1250 mg three-times daily in combination with EFV and TDF Citation[13].
Conclusion
These data provide some answers to relevant questions. First, the on-treatment HCV RNA response was substantially higher than the current standard of care. While further information is needed regarding SVR, the early results with TVR were certainly promising. Second, while many patients will not find this therapy easy to tolerate, the safety of the triple therapy in HIV–HCV coinfected patients was acceptable. Third, for TVR and BOC, drug–drug interactions with antiretrovirals, particularly HIV protease inhibitors and EFV, will be an important consideration for clinicians. Therefore, if we consider the pros and cons of treating with triple therapy using a protease inhibitor versus deferring, there are several points to discuss. Protease inhibitors added to peginterferon/ribavirin could clearly increase the chances of SVR in HIV–HCV patients; if treatment is successful, disease progress may be halted and complications may be avoided.
However, it is important to keep in mind the cons of treatment: the current regimens are very complex, and they have challenging adverse events. Newer drugs may be more tolerable with shorter durations of therapy.
We may have all-oral therapies that do not include peginterferon/ribavirin. There may be even better chances of SVR with combinations of DAAs. Finally, we must keep in mind the risk of resistance and the potential impact on future treatment options.
Expert commentary
The response rate to therapy with peginterferon/ribavirin in patients with HIV–HCV is actually unsatisfactory and these patients show an accelerate course of the disease. There is an absolute need for more effective therapies. The recent availability of DAAs also seems to be promising in coinfected patients, although the emergence of resistance and pharmacokinetic interactions may limit their performance.
Two-year view
In the next few years, the results of randomized controlled trials will became available in order to clarify the effective role that DAAs have to play in coinfected patients. The same trials will supply data on pharmacokinetic interactions between DAAs and antiretrovirals, and on the emergence of resistance in these patients.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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