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03/06/2013

CROI 2013: Promising interferon-free regimens in HCV mono-infection


Standard treatment for chronic HCV infection requires interferon-containing combination therapy. Interferon is difficult to use because of numerous adverse effects and contraindications, the need for injections and the prolonged duration of therapy. Use of interferon for HIV/HCV coinfection is even more difficult, as it is less well tolerated. African-Americans, who are disproportionately affected by HIV, respond less well to interferon-based therapy, and many coinfected patients cannot be treated due to contraindications such as psychiatric conditions and cytopenias. Interferon-free regimens are needed and may be especially beneficial in coinfected patients.

At CROI 2013, very exciting but preliminary results of interferon-free treatment for HCV were reported. ABT450, a promising investigational HCV protease inhibitor (PI), was studied in four small, short-duration treatment cohorts [1]. Two once-daily doses of ABT450 boosted by low-dose ritonavir were given with one of two investigational non-nucleoside HCV polymerase inhibitors (ABT 072 or ABT 333) and ribavirin (RBV) for only 12 weeks. Patients with advanced fibrosis or HIV coinfection were excluded. Each cohort contained between 11 and 17 participants. Three cohorts enrolled genotype 1-infected, naive patients and the last enrolled prior dual therapy non-responders.

Sustained virologic response at 12 weeks after treatment discontinuation (SVR12) was achieved in 91-95% of naive patients, although one of these patients had a late relapse. Non-responders did less well with an SVR12 rate of 47%, although this result is better than what would be expected with current triple therapy. Viral failures were due to both on-treatment breakthrough and relapse after discontinuation. Indirect hyperbilirubinemia attributable to inhibition of the OATP1B1 transporter occurred in several patients and single grade 3 ALT elevation without bilirubin elevation resolved upon treatment discontinuation.

Sofosbuvir is an investigational nucleotide HCV polymerase inhibitor that is also being studied in interferon-free regimens. The COSMOS study [2] enrolled genotype 1 mono-infected prior dual therapy null responders without advanced fibrosis. Participants received sofosbuvir 400 mg plus the investigational HCV PI simeprevir 150 mg, both once daily, were randomized 2:1 to add RBV and randomized again to 12 or 24 weeks of treatment. In the 12-week treatment arms, SVR8 was achieved in 26/27 (96%) and 13/14 (93%) of those who did or did not receive RBV. The two treatment failures observed were due to post-treatment relapse. There were no breakthroughs on treatment. Follow-up in the 24-week arms was incomplete at the time of the presentation. No unusual safety problems were identified. There were a small number of bilirubin elevations, attributed to the effect of simeprevir on the cellular transporters OATP1B1 and MRP-2, and asymptomatic amylase/lipase elevations, mostly in the RBV arms. There was no anemia in the RBV-free arms.

The effects of 12 weeks of triple therapy with sofosbuvir, plus RBV plus another potent directly acting antiviral, the investigational HCV NS5a inhibitor ledipasvir (GS 5885), were also reported [3]. Mono-infected, HCV genotype 1 patients were enrolled. This potent combination achieved SVR12 in 100% of 25 treatment naive and 9 null responders enrolled. This result contrasts a previous study of sofosbuvir plus RBV where prior null responders had a very high rate of relapse after treatment. Anemia attributable to RBV occurred in 5 participants. One discontinued treatment at 8 weeks due to a perforated diverticulum but still achieved SVR12. Larger studies and studies to determine if RBV is an essential component of this regimen are planned.

References:

1. Lawitz E, Cohen D, Poordad F, et al. 12 Weeks of ABT-450/Ritonavir, Non-nucleoside Inhibitor and Ribavirin Achieved SVR24 in >90% of Treatment-naïve Hepatitis C Virus GT1 Patients and 47% of Prior Non-responders. Presented March 4, 2013 at the 20th CROI, Atlanta Georgia. Oral Abstract 38; http://www.retroconference.org/2013b/Abstracts/46137.htm

2. Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of Viral Load through 4 Weeks Post-Treatment Results of a Once-daily Regimen of Simeprevir + Sofosbuvir with or without Ribavirin in Hepatitis C Virus GT 1 Null Responders. Presented March 6, 2013 at the 20th CROI, Atlanta Georgia. Oral Abstract 154LB; http://www.retroconference.org/2013b/Abstracts/47930.htm

3. Gane E, Hyland R , Ding X, et al. ELECTRON: 100% Suppression of Viral Load through 4 Weeks’ Post-treatment for Sofosbuvir + Ledipasvir (GS-5885) + Ribavirin for 12 Weeks in Treatment-naïve and -experienced Hepatitis C Virus GT 1 Patients. Presented March 4, 2013 at the 20th CROI, Atlanta Georgia. Oral Abstract 40LB; http://www.retroconference.org/2013b/Abstracts/47869.htm


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