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03/03/2014

HCV Treatment without Interferon, Gets Shorter and Better: CROI 2014


Interferon has been a required component of all treatment for hepatitis C (HCV). It is also a major obstacle to greater treatment success due to numerous adverse events (AEs), the need for injection and variable activity in patients with different genetic backgrounds or infected with different HCV genotypes. In HIV/HCV co-infection, interferon-based treatment is less effective and shorter treatment courses are not an option. In December 2013, the FDA approved the HCV nucleotide polymerase inhibitor sofosbuvir (SOF) plus ribavirin as the first interferon-free regimen for HCV genotype 2 or 3, with an option for use in genotype 1 patients ineligible for interferon. New studies presented at CROI 2014 show that short duration interferon-free regimens can produce cure in most HCV-infected patients, including those with HIV/HCV co-infection.

PHOTON-1 Trial. This trial used SOF plus ribavirin in 223 co-infected HCV treatment-naive genotype 1, 2 and 3 patients and HCV treatment-experienced genotype 2 and 3 patients [1]. Treatment duration was 12 weeks for naive genotype 2 and 3 and 24 weeks for all others. A sustained virologic response after 12 weeks off treatment (SVR12) was achieved in 76%, 88% and 67% of treatment-naive genotype 1, 2 and 3, respectively. For treatment-experienced patients, the longer treatment duration gave an SVR12 of 92% in those with genotype 2, similar to the 88% seen in treatment-naive patients, while those with genotype 3 did notably better than their naive counterparts (SVR12 94%). Most virologic failures were due to relapse. No drug resistance developed, confirming that SOF has a very high genetic barrier to resistance. The only 2 patients with viral breakthrough on treatment were non-adherent based on plasma drug levels. During 24 weeks of treatment, anemia due to ribavirin occurred in 17% and indirect hyperbilirubinemia was seen in 18%, mainly those receiving concurrent atazanavir. Symptomatic adverse events (AEs) like fatigue, insomnia, headache and nausea were fairly common. Discontinuation for AEs occurred in 3-4%, although no pattern suggesting causation by study drug was evident. Because SOF has few drug-drug interactions, this regimen is attractive for co-infected patients, many of whom would have to change regimens to receive HCV protease inhibitors. The study also suggests that 12 weeks of treatment should be reserved for genotype 2 patients and the FDA-approved duration of therapy of 24 weeks should be used for all genotype 3 infections, including co-infected patients. In this trial, genotype 1 co-infected patients received 24 weeks of treatment, twice the FDA-approved duration for this genotype. While this regimen cured a 76%, it still allowed a significant number to relapse. If they cannot receive interferon, such patients may do better with regimens combining directly-acting antivirals (DAAs).

Triple DAA Regimens for Genotype 1a or 1b Mono-infection. Replacing ribavirin with 1 or 2 DAAs may allow for high cure rates with even shorter durations of therapy. The SYNERGY trial [2] compared 12 weeks of 2 DAAs to 6 weeks of 3 DAAs in treatment-naive HCV mono-infected patients. SOF and the NS5A inhibitor ledipasvir were used in all regimens. The 6 week regimens added either the non-nucleoside polymerase inhibitor protease inhibitor GS-9669 or the protease inhibitor GS-9451. All drugs were dosed once-daily. The characteristics of the study population were fairly typical of HCV patients in the US, except that cirrhotics were not enrolled in the 6 week triple therapy arms. Seventy percent had genotype 1a. Only one patient (in the GS-9669 arm) relapsed. All others (59/60 or 98%) achieved SVR12. Viral kinetic studies showed 3 DAAs produced a more rapid second phase HCV RNA decline than 2 DAAs. All regimens were safe and well tolerated. Headache, fatigue, GI and URI symptoms were reported commonly but there were no serious AEs related to study drug and no discontinuations for AEs. The extraordinary results of this small study will need confirmation in larger trials that include patients with cirrhosis. Pilot studies of even shorter durations of triple drug therapy also are warranted.

Everson et al [3] reported another all oral triple DAA regimen consisting of daclatasvir (DCV), an NS5A inhibitor, asunaprevir, a 2nd generation HCV protease inhibitor and one of two doses of BMS 791325, a non-nucleoside NS5B inhibitor given for 12 weeks. Although daclatasvir has been dosed once daily, in this study it was dosed twice daily to support plans for co-formulation with the other two antivirals which are dosed twice daily. Treatment-naive, HCV mono-infected genotype 1 patients (n=166) were enrolled. Eighty-two percent had genotype 1a. SVR12 was achieved in 89% (92% if missing data at post-treatment week 12 is omitted) with no apparent differences between the two doses of 791325. Efficacy did not appear to differ according IL28B genotype, HCV genotype 1 subtype or the presence or absence of cirrhosis, although few cirrhotics were included. There were 5 viral breakthroughs and 6 relapses. All were genotype 1a and all had 2 or 3 class drug resistance mutations at the time of failure. Grade 3/4 laboratory abnormalities occurred in 1% and serious AEs leading to discontinuation occurred in 2 patients. This 3 DAA regimen produced high rates of SVR, but contains low genetic barrier drugs that permit multi-class resistance upon viral failure. Considering the results of the SYNERGY trial, it is possible even shorter durations would also have high efficacy.

A DAA Regimen Targeting Genotype 1b. Although HCV genotype 1a is most common in the US, genotype 1b is encountered most often worldwide. Previous studies have shown that genotype 1b is easier to treat than 1a, largely because it is less prone to develop resistance. The PEARL-III study was a large, international phase 3 trial in treatment-naive, genotype 1b, mono-infected, non-cirrhotic patients [5]. The triple DAA regimen consisted of ABT-450/r, an HCV protease inhibitor boosted with ritonavir, ABT-267, an NS5A inhibitor, and ABT-333, a non-nucleoside polymerase inhibitor. ABT-450, ritonavir and ABT-267 were co-formulated as a single tablet dosed once daily. ABT-333 was separately formulated and dosed 250 mg bid. All 419 study participants received this regimen for 12 weeks and were additionally randomized to add ribavirin or placebo. Only 3 participants failed to achieve an SVR12. One experienced viral rebound on therapy, associated with resistance to NS5A inhibitors and 2 were lost to follow-up while HCV RNA was undetectable. Symptomatic AEs and anemia were more common in the ribavirin arm, but serious AEs were rare and no patient discontinued for AEs. This study demonstrated exceptional treatment efficacy (SVR12 99%), safety and tolerability for genotype 1b infections using this regimen of 3 potent DAAs, even though individually they have a low genetic barrier to resistance. Inclusion of ribavirin added only toxicity. Given the results of the SYNERGY trial, it is likely even shorter durations of therapy would be similarly effective and should be explored. Studies in patients with cirrhosis are also needed.

Summary. Although co-infected patients respond less well to interferon-based HCV treatment than mono-infected patients, results from PHOTON-1 suggest they respond very well to interferon-free therapy. The first interferon-free regimen, SOF & ribavirin, is now in clinical use. For co-infected patients, it offers a new treatment option with few interactions with antiretrovirals, but with the AEs of ribavirin and 24 weeks of treatment for most. Investigational regimens combining 2 or 3 DAAs given for 6 to 12 weeks eliminate both interferon and ribavirin and may offer even greater treatment success with enhanced safety, tolerability and simplicity. Careful attention must be paid to drug-drug interactions between certain DAAs and antiretrovirals, but use of these very promising regimens should greatly improve treatment and health outcomes in HCV-infected individuals, including those with co-infection.

References:
1. Naggie S, Sulkowski M, Lalezari J, et al. Sofosbuvir Plus Ribavirin for HCV Genotype 1-3 Infection in HIV Co-infected Patients (PHOTON-1). Abstract 26, CROI 2014, Boston, MA, March 3-6, 2014
2. Kohli A, Sims Z, Nelson A, et al. Combination Oral Hepatitis C AntiviralTherapy for 6 or 12 Weeks: Final Results of the SYNERGY Trial. Abstract 27LB, CROI 2014, Boston, MA, March 3-6, 2014
3. Everson GT, Thuluvath PJ, Lawitz E, et al. All-Oral Combination of Daclatasvir, Asunaprevir, and BMS-791325 for HCV Genotype 1 Infection. Abstract 25, CROI 2014, Boston, MA, March 3-6, 2014
4. Ferenci P, Nyberg A Bernstein D, et al. PEARLIII:SVR≥99%After 12 Weeks of ABT- 450/r/267 + ABT-333 ± RBV in Treatment Naïve HCV GT1b Infection. Abstract 25, CROI 2014, Boston, MA, March 3-6, 2014


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