Adding a first-generation hepatitis C virus (HCV) protease inhibitor to pegylated interferon/ribavirin dramatically increases the likelihood of 12-week sustained virological response to hepatitis C treatment among HIV/HCV coinfected people, researchers reported on Tuesday at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.
Last year's approval of the first direct-acting hepatitis C drugs has ushered in a new era of treatment. The HCV protease inhibitors telaprevir (Incivo, Incivek) and boceprevir (Victrelis) are licensed in the US and Europe for HCV monoinfected patients in combination with pegylated interferon and ribavirin. Studies are ongoing for the coinfected population, a group that urgently needs better treatment options.
Douglas Dieterich from Mount Sinai School of Medicine presented the latest findings from Study 110, a Phase 2 trial testing telaprevir in combination with pegylated interferon/ribavirin in previously untreated coinfected patients with difficult-to-treat HCV genotype 1. Initial data were presented at last year's conference, with further follow-up at the Liver Meeting last November.
The study consisted of two parts. Part A included 13 coinfected participants who had CD4 T-cell counts of at least 500 cells/mm3 and were not yet taking antiretroviral therapy (ART). Part B included 47 people on ART; 24 took efavirenz (Sustiva or Stocrin) plus tenofovir (Viread) and emtricitabine (Emtriva), while 23 took ritonavir-boosted atazanavir (Reyataz) with either lamivudine (Epivir) or emtricitabine.
Most participants were men, with an average age of about 45 years. Part A included a higher proportion of people of African descent (a group that does not respond as well to interferon-based therapy). About half in Part A and 75% in Part B had HCV genotype 1a, the rest 1b. Most had high baseline HCV viral load about 10% had advanced liver fibrosis or cirrhosis. Median CD4 counts in Part A and B were approximately 600 and 500 cells/mm3, respectively; patients on ART had suppressed HIV RNA below 50 copies/ml.
In both parts of the study, participants were randomly assigned to receive either telaprevir or placebo in combination with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus ribavirin. Triple therapy continued for 12 weeks, followed by pegylated interferon/ribavirin alone through week 48.
Patients taking atazanavir received the usual telaprevir dose of 750mg three times daily; to compensate for a known drug-drug interaction that lowers telaprevir levels, those taking efavirenz increased their dose to 1125mg three times daily.
Two patients (5%) in the triple therapy arm and seven (32%) taking pegylated interferon/ribavirin alone stopped treatment prematurely due to poor early response according to predefined "futility" rules.
Dieterich reported rates of sustained virological response, or continued undetectable viral load, at 12 weeks after completion of treatment, known as SVR12. This has been shown to be a good predictor of 24-week SVR, generally considered a cure.
Overall, 74% of patients taking telaprevir achieved SVR12, compared with just 45% of those taking pegylated interferon/ribavirin alone. Among participants off ART in Part A, SVR12 rates were 71% and 33%, respectively. By ART regimen, 69% using the efavirenz combination and 80% using boosted atazanavir achieved SVR12 with telaprevir, compared with 50% for both regimens with pegylated interferon/ribavirin alone.
One telaprevir recipient (3%) and two placebo recipients (15%) experienced HCV relapse after completing therapy. Three people on the telaprevir combination experienced HCV RNA breakthrough while on treatment. No participants showed evidence of HIV viral load rebound. Absolute CD4 cell counts fell in both arms – a known effect of interferon – but CD4 cell percentages did not change.
People taking telaprevir experienced more side-effects overall than those on pegylated interferon/ribavirin alone. Three people on telaprevir, but none in the control group, discontinued treatment early due to adverse events. Adverse events that occurred at least 10% more often among telaprevir recipients compared with placebo recipients included pruritis or itching (39% vs 9%), headache (37% vs 27%), nausea (34% vs 23%), skin rash (34% vs 23%), fever (21% vs 9%) and depression (21% vs 9%); insomnia and weight loss were more common in the control group. No patients in either arm experienced severe rash and anaemia was equally common in both groups (18%).
"Higher SVR12 rates were observed in chronic genotype 1 patients treated with telaprevir combination treatment," the researchers concluded. "Overall safety and tolerability profile was comparable to that previously observed in chronic genotype 1 HCV monoinfected patients."
Mark Sulkowski from Johns Hopkins University Medical School presented data on boceprevir triple therapy in HIV/HCV coinfected patients. Earlier findings were presented at last year's Infectious Diseases Society of America meeting.
In this Phase 2 trial, 100 previously untreated coinfected participants with HCV genotype 1 were randomly assigned to receive 800mg three times daily boceprevir or placebo plus 1.5mcg/kg/week pegylated interferon alfa-2b (PegIntron) and weight-adjusted ribavirin; two dropped out before receiving study drugs.
All participants started with a four-week lead-in period of pegylated interferon/ribavirin alone, followed by triple therapy for 44 more weeks. Here too, people with poor early response discontinued treatment according to predefined futility rules.
All patients in this trial were taking ART and had stable undetectable HIV viral load. Based on prior drug-drug interaction studies, they were limited to regimens containing a boosted HIV protease inhibitor plus two nucleoside/nucleotide reverse transcriptase inhibitors. Further analysis recently revealed that combining boceprevir with boosted HIV protease inhibitors can lower drug levels and potentially allow HIV or HCV rebound.
Again, most participants (about 70%) were men and the median age was 44 years; 65% had HCV genotype 1a, the rest 1b. Most had high baseline HCV RNA and about 5% had cirrhosis. The median CD4 count was about 580 cells/mm3.
Three months after completion of treatment, 61% of participants in the boceprevir arm achieved SVR12, compared with only 27% in the placebo arm – a difference of 34%. There were two relapses in the triple therapy group and one in the control group.
Three patients taking boceprevir and four taking pegylated interferon/ribavirin alone experienced HIV viral load rebound; again, absolute CD4 cell counts – but not CD4 cell percentages – fell in both groups.
This similarity raises a question about the clinical significance of the recently announced drug-drug interaction findings. However, in a press release describing the SVR12 findings, Merck said it "does not recommend the co-administration of [boceprevir] and ritonavir-boosted HIV protease inhibitors."
Seven people (21%) taking boceprevir and eleven (17%) taking pegylated interferon/ribavirin alone experienced serious adverse events. Boceprevir recipients were at least 10% more likely than placebo recipients to report anaemia (41% vs 26%), fever (36% vs 21%), weakness (34% vs 24%), loss of appetite (34% vs 18%), diarrhoea (28% vs 18%), vomiting (28% vs 15%), dysgeusia or unusual taste sensations (28% vs 15%) and neutropenia (19% vs 6%); flu-like illness was more common in the control group.
"HCV-HIV coinfected patients who were previously untreated had higher rates of HCV response on boceprevir," the investigators concluded. "Preliminary safety data of boceprevir/pegylated interferon/ribavirin in coinfected patients is consistent with that observed in [HCV] monoinfected patients."
At a press conference to discuss the findings Sulkowski said the latest data, taken together, are "really very encouraging," suggesting that triple therapy with an HCV protease inhibitor may be an important option for coinfected patients.
Dieterich D et al. Telaprevir in Combination with Pegylated Interferon-a-2a+RBV in HCV/HIV-co-infected Patients: A 24-Week Treatment Interim Analysis. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 46, 2012. The abstract is available on the official conference website.
Sulkowski M et al. Boceprevir + Pegylated Interferon + Ribavirin for the Treatment of HCV/HIV-co-infected Patients: End of Treatment (Week-48) Interim Results. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 47, 2012. The abstract is available on the official conference website.