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03/03/2014

2nd Gen HCV Protease Inhibitors Improve Tolerability & HCV Outcomes in HIV Coinfection: CROI 2014


Compared to dual therapy with pegylated interferon plus ribavirin (P/R), triple therapy adding either telaprevir or boceprevir increased the likelihood of cure in both HCV mono-infected and HIV/HCV co-infected patients. However, this improvement came with a large pill burden, troublesome drug-drug interactions and substantial adverse effects added to the already burdensome effects of P/R. At CROI 2014, further treatment progress for HIV-infected individuals co-infected with genotype 1 HCV was evident in new HCV co-infection treatment studies using triple therapy with the recently approved HCV protease inhibitor (PI) simeprevir or the investigational PI faldaprevir.

Simeprevir (SMV). The study reported by Dieterich, et al [1] used simeprevir 150 mg once daily plus P/R in HCV genotype 1 HIV co-infected patients. Enrollment was limited to those receiving a short list of antiretrovirals (ARVs) free from interaction with SMV. For treatment-naive and prior relapse patients, the study design used response-guided therapy (RGT) to determine treatment for 24 or 48 weeks based on the presence or absence of a rapid virologic response, defined as HCV RNA <25 IU/ml at week 4 and below the limit of detection at week 12. Prior partial or null responders and all patients with cirrhosis were treated for 48 weeks. In all arms, 12 weeks of triple therapy was followed by P/R for the duration of treatment. A total of 106 patients were enrolled. Most had genotype 1a infection. Eighty-nine percent in the RGT arm met criteria for RGT. Treatment-naives, relapsers, partial, and null responders achieved sustained virologic response after 12 weeks off therapy (SVR12) in 79%, 87%, 70% and 57%. The presence of IL28B CC genotype improved cure rates to 100% except in null responders who had an SVR12 of 80%. Surprisingly, the presence of the NS3 gene Q80K polymorphism at baseline did not appear to influence results, as it did in the larger studies of SMV in mono-infected patients. Safety and tolerability were similar to that observed in mono-infection trials.

Faldaprevir (FDV). Final results were reported for the STARTVerso-4 trial, using triple therapy with P/R plus FDV, an HCV PI in late stage clinical development [2]. Unlike SMV, FDV can be used at 240 mg daily with efavirenz and 120 mg daily with boosted darunavir. The study had a complex design that included both randomization and assignment to FDV dose, based on the absence or presence of concurrent interacting ARVs, and re-randomizations at week 12 to dual or triple therapy and at week 24 to stop therapy or continue to 48 weeks in those with early treatment success (ETS), defined by HCV RNA levels at 4 and 8 weeks. Only treatment-naive patients and prior relapsers were studied. SVR12 was achieved in 72% of 308 predominantly genotype 1a participants, with little difference between the two FDV doses. Eighty percent had an ETS and 86% of this subgroup achieved SVR12. Extending treatment to 48 weeks in those with an ETS did not appear to substantially improve the cure rate. Factors associated with better response were prior relapser status and IL28B CC genotype but not genotype 1 subtype, cirrhosis or Q80 polymorphism. No unusual safety issues were reported beyond those typically seen with peg-IFN/RBV.

Both SMV and FDV are dosed once daily and have improved safety profiles compared to older HCV PIs, and so represent a step forward in management of HIV/HCV co-infection. Both regimens still have important limitations. Both require at least 24 weeks of treatment. Adverse events typical of P/R are still seen, although hematologic and skin toxicities appear to be less than those seen when older HCV PIs were used with P/R. Both drugs may cause indirect hyperbilirubinemia due to inhibition of bilirubin transporters or conjugating enzymes. Concurrent ARV use is still quite limited with SMV, although FDV can be used with two additional commonly prescribed ARVs. New all oral interferon-free regimens may be an attractive alternative to interferon-based treatment of HCV, especially for HIV/HCV co-infected patients.

References:
1. Dieterich D, Tural C, Nelson M, et al. Faldaprevir Plus Pegylated Interferon Alfa-2a/ Ribavirin in HIV/HCV Co-infection: STARTVerso4. Abstract 23, CROI 2014, Boston, MA, March 3-6, 2014
2. Dieterich D, Rockstroh J, Orkin C, et al. Simeprevir (TMC435) Plus PegIFN/Ribavirin in HCV Genotype-1/HIV-1 Co-infection (Study C212). Abstract 24, CROI 2014, Boston, MA, March 3-6, 2014


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