First results from telaprevir in HIV/HCV coinfection
1 April 2011. Related: Conference reports, Antiretrovirals, Hepatitis coinfection, CROI 18 (Retrovirus) 2011.
Simon Collins, HIV i-Base
The most important study relating to hepatitis C coinfection was the late-breaker presentation of interim results from the first study using the HCV NS3/4A serine protease inhibitor telaprevir in people with HIV/HCV coinfection.
Community pressure led to earlier studies of the newest HCV drugs in people with coinfection than would have occurred otherwise, so the results are keenly awaited. Even though PEG-interferon and ribavirin are still required, there is hope that new treatments will improve response rates, especially in people with HCV genotype-1, and reduce duration of treatment. Telapravir has already shown impressive responses in HCV monoinfection in both naive and experienced patients.
Mark Sulkowski from Johns Hopkins School of Medicine, Baltimore presented initial results from a phase 2a study of coinfected patients with HCV genotype 1a/b, where some people were on HAART (part B, CD4 >300, viral load <50) and others were not (part A, CD4 >500 and viral load <100,000). Limited data about interactions between telaprevir and antiretrovirals limited choice of HAART to tenofovir/FTC plus either efavirenz or atazanavir/ritonavir. People using efavirenz used a higher telaprevir dose. [1]
In this 48-week study all participants used pegylated IFN-alpa2a (180 mg/week) plus ribavirin throughout. Ribavirin was dosed at 800mg/day in the US and but five patients at European sites used weight-based dosing (1000 mg/day if under 75 kg and 1200 mg/day if >75 kg). The randomisation in each group was to telaprevir 750 mg every 8 hours vs placebo for the first 12 weeks of the study.
Interim results were presented for 59/60 people who have so far enrolled (n=13 in part A ; n=46 in part B), with 12-week results available for 41 people. In part B roughly half the group used efavirenz and half used atazanavir/r.
The study also included detailed stopping rules at weeks 4, 8, 12, 24 and 36 for non-response or subsequent rebound based on HCV vireamia in order to limit the risk of developing resistance to telaprevir.
Baseline characteristics included: 88% male, 69% white, mean age 46 years, 68% genotype 1a, 83% baseline HCV RNA >800,000 IU/mL with 10% participants having advanced liver fibrosis based on biopsy.
Results were presented showing HCV viral suppression, at weeks 4 and 12. See Table 1. At week 4, by intent-to-treat analysis, approximately 70% (26/37) vs 5% (1/22) of people in the telaprevir vs placebo groups had undetectable HCV viral load. At week 12 these response rates were 68% (25/37) vs 14% (3/22) respectively.
| Part A: no ART | Part B: EFV/TDF/FTC | Part B: ATV/r + TDF + FTC/3TC | Total | |||||
|---|---|---|---|---|---|---|---|---|
| N (%) | TVR n = 7 |
PCB n = 6 |
TVR n = 16 |
PCB n = 8 |
TVR n = 14 |
PCB n = 8 |
TVR n = 37 |
PCB n = 22 |
| Undetectable HCV RNA* at wk 4 | 5 (71) | 0 (0) | 12 (75) | 1 (12) | 9 (64) | 0 (0) | 26 (70) | 0 (0) |
| Undetectable HCV RNA* at wk 12# | 5 (71) | 1 (17) | 12 (75) | 1 (12) | 8 (57) | 1 (12) | 25 (68) | 3 (14) |
| Undetectable HCV RNA* at wks 4 and 12# | 3 (43) | 0 (0) | 10 (62) | 0 (0) | 6 (43) | 0 (0) | 19 (49) | 0 (0) |
*determined by Roche Taqman v2, LLOQ of 25 IU/mL. #41 patients have reached week 12
Reponses in the HAART and no-HAART groups were similar and median trough levels of telaprevir were similar in the three groups. Variability in antiretroviral trough levels of efavirenz, atazanavir and tenofovir were similar to placebo.
Three people in each of the telaprevir and placebo groups were stopped early for failure to meet minimum viral responses or viral breakthrough.
HIV viral load remained stable for patients on HAART but reduced by approximately one log in the no-HAART group due to the anti-HIV action of interferon that has been previously reported.
Most patients experienced side effects, as would be expected from interferon/ribavirin treatment. Side effects reported more often in the telaprevir arm compared to placebo included nausea (35 vs 15%), pruritis (35 vs 5%), dizziness (32 vs 5%), anorexia and vomiting (both 19 vs 9%) and moderate rash (11 vs <1%). Severe rash was not seen.
There were 3 grade 3/4 events, all in the telaprevir arm: 2 bacterial infections and one case of anaemia. The two discontinuations of all drugs were for anaemia and jaundice (both in the atazanavir and telaprevir arm).
Based on this limited interim analysis, these very early responses in small groups of people with coinfection appear to show similar efficacy for people with coinfection compared to HCV monoinfection, with an indication that treatment can be used with HAART.
References
- Sulkowski M et al. Interim analysis of a phase 2a double-blind study of TVR in combination with pegIFN-a2a and RBV in HIV/HCV co-infected patients. Oral abstract 146LB.
http://www.retroconference.org/2011/Abstracts/42467.htm