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03/06/2013

CROI 2013: Triple therapy for HCV-HIV coinfection with 2nd generation HCV protease inhibitors


For HCV mono-infected patients with genotype 1, triple drug therapy with pegylated interferon (peg-INF), ribavirin (RBV) and an HCV protease inhibitor (PI), improves the cure rates over dual therapy with peg-IFN/RBV. Pilot studies of triple therapy done with telaprevir or boceprevir suggest that co-infected patients can achieve sustained virologic response (SVR) rates similar to mono-infected patients, but with a large pill burden and substantial adverse effects added to the already burdensome effects of peg-IFN/RBV. Both telaprevir and boceprevir have extensive drug interactions with commonly used antiretrovirals (ARVs), limiting choice for concurrent antiretroviral therapy (ART). No studies have yet established that co-infected patients can utilize response-guided therapy (RGT), which allows a shorter course of treatment.

At CROI 2013, Dieterich et al [1] reported interim results of a trial of the investigational HCV PI simeprevir 150 mg once daily plus peg-IFN/RBV in HCV genotype 1 HIV co-infected patients. Because of drug-drug interactions between simeprevir and many ARVs, concurrent ART regimens were mostly limited to those anchored by raltegravir or rilpivirine. Treatment-naive, non-cirrhotic patients and prior dual therapy relapsers were enrolled in a response-guided therapy (RGT) arm, which allowed discontinuation at 24 weeks in those with a rapid virologic response (RVR), defined here as HCV RNA <25 IU/ml at week 4 and below the limit of detection at week 12. Another cohort of prior peg-IFN/RBV non-responders and cirrhotics were treated for 48 weeks. In both arms, triple therapy with simeprevir was given only during the first 12 weeks of treatment, followed by peg-IFN/RBV alone. A total of 106 patients were enrolled. Rates of HCV RNA <25 IU/ml at week 4 were high, ranging from 78 in prior null responders to 100% in prior relapsers. In the first cohort, 88% were eligible for RGT. Very early results showed 77% achieved SVR at 12 weeks after discontinuation (SVR12), the currently accepted surrogate for cure, but this was based on only 13 patients who had enough follow-up. Adverse events were similar to those typically seen with peg-IFN/RBV alone, except for a 5% rate of isolated hyperbilirubinemia, due to inhibition of the cellular transporters OATP1B1 and MRP-2 by simeprevir. No SVR data for the second cohort was available.

Interim results were reported from another co-infection treatment study using the investigational HCV PI faldaprevir (BI 201335) with peg-IFN/RBV [2]. Like simeprevir, faldaprevir also is dosed once daily but based on interactions studies, it can be used at full dose (240 mg) with efavirenz and at half dose with boosted darunavir [3]. Three hundred eight genotype 1-infected, treatment-naive or prior dual therapy relapsers were enrolled. The study design was complex, involving either randomization or assignment to one of two doses of faldaprevir based on the ART regimen used, and additional randomization to 24 or 48 weeks of treatment among those achieving a protocol-defined RVR. Eighty percent achieved an RVR. No unusual safety issues were reported beyond those typically seen with peg-IFN/RBV. No data on SVR was available.

References:

1. Dieterich D, Rockstroh J, Orkin C, et al. Simeprevir with pegylated interferon/ribavirin in patients co-infected with chronic hepatitis C virus and HIV-1: Week-24 interim analysis of the TMC435-C212 study. Presented March 6, 2013 at the 20th CROI, Atlanta Georgia. Oral Abstract 154LB; http://www.retroconference.org/2013b/Abstracts/47929.htm

2. Dieterich D, Soriano V, Nelson M, et al. STARTVerso 4: High rates of early virologic response in hepatitis C virus genotype 1/HIV co-infected patients treated with faldaprevir + pegylated interferon and ribavirin. Presented March 4, 2013 at the 20th CROI, Atlanta Georgia. Oral Abstract 40LB; http://www.retroconference.org/2013b/Abstracts/47927.htm

3. Sabo J, Kort J, Haschke M, et al. Pharmacokinetic interactions of darunavir/ritonavir, efavirenz, and tenofovir with the hepatitis C virus protease inhibitor faldaprevir in healthy volunteers. Presented March 4, 2013 at the 20th CROI, Atlanta Georgia. Oral Abstract 35; http://www.retroconference.org/2013b/Abstracts/46357.htm


Source: Reporting from Atlanta for PRN News: David H. Shepp, MD