- Category: Experimental HCV Drugs
- Published on Tuesday, 27 August 2013 00:00
- Written by Liz Highleyman
Nearly two-thirds of genotype 1 chronic hepatitis C patients treated with a 2-drug interferon-free regimen of sofosbuvir plus ribavirin for 24 weeks achieved sustained viral suppression despite having characteristics associated with poor treatment response, researchers reported in the August 28, 2013, Journal of the American Medical Association.
The development of direct-acting antiviral agents (DAAs) active against hepatitis C virus (HCV) has ushered in a new era of treatment, but many patients and providers are awaiting all-oral regimens without interferon, which must be injected and often causes difficult side effects.
AnuoluwapoOsinusi and Shyamasundaran Kottilil from the National Institute of Allergy and Infectious Diseases (NIAID) and fellow investigators with the SPARE study tested a simple regimen of sofosbuvir plus either standard weight-based or low-dose ribavirin in a Phase 2 study of hard-to-treat patients with genotype 1 hepatitis C in inner-city neighborhoods of Washington, DC, an area with a high rate of poverty and limited access to health services. Preliminary results were previously reported at the 2012 AASLD Liver Meeting and at this year's Retroviruses Conference, and complete findings have now been peer-reviewed for publication.
Sofosbuvir (GS-7977), developed by Gilead Sciences and currently undergoing priority review by the U.S. Food and Drug Administration (FDA), is a nucleotide analog HCV polymerase inhibitor. Studies to date indicate that it is highly effective against genotype 1 HCV in combination with other DAAs including the NS5A inhibitors daclatasvir (BMS-790052) and ledipasvir (GS-5885), and the HCV protease inhibitor simeprevir (TMC435). Sofosbuvir plus ribavirin alone works well against HCV genotype 2, but the ELECTRON trial showed less impressive results against genotype 1, especially for patients who did not respond to earlier treatment.
The open-label SPARE study comprised 2 parts and included 60 previously untreated chronic hepatitis C patients enrolled at the National Institutes of Health between October 2011 and April 2012.
In Part 1, as proof of concept, 10 people with absent to moderate liver fibrosis (stage F0-F2) were treated with 400 mg once-daily oral sofosbuvir plus weight-based ribavirin dosed at 1000 mg/day if they weighed <75 kg or 1200 mg/day if >75 kg, divided into 2 daily doses. In Part 2, 50 people with all stages of liver disease were randomly assigned (1:1) to receive the same dose of sofosbuvir plus either weight-based ribavirin or a lower fixed dose of 600 mg/day regardless of weight, in an effort to reduce the risk of anemia. Everyone was treated for 24 weeks.
All participants had HCV genotype 1, including about 70% with the more difficult-to-treat subtype 1a. A majority (66%) were men and the median age was approximately 50 years. More than 80% were African-American, a group that does not respond as well as whites to interferon-based therapy. Genetic analysis revealed that a similar proportionhad the unfavorable IL28B CT or TT gene patterns associated with poor interferon response.
About 60% had high HCV RNA (>800,000 IU/mL) at baseline, approximately half were classified as obese, and in Part 2 nearly one-quarter had advanced liver fibrosis or compensated cirrhosis (stage F3 or F4) -- all factors associated with lower treatment response. People coinfected with hepatitis B or HIV were excluded, as were those with abnormally low blood cell counts or hemoglobin levels at baseline.
The primary study endpoint was sustained virological response, or continued undetectable viral load, at 24 weeks after completion of treatment (SVR24) -- considered to be a cure.
- Overall, participants experienced rapid viral decline after starting therapy and there were no cases of viral breakthrough while treatment was underway.
- In Part 1, 9 out of 10 participants completed the course of therapy and all (90%) achieved SVR at both week 12 and week24 post-treatment.
- In Part 2, all but 1 of the 25 people taking weight-based ribavirin (96%) had undetectable HCV at the end of treatment; in the low-dose arm, 3 people discontinued treatment early and all of the remaining 22 (88%) had undetectable HCV at the end of treatment.
- 7 participants (28%) receiving weight-based ribavirin and 10 (40%) receiving low-dose ribavirin relapsed after treatment completion.
- The SVR24 rate was 68% in the weight-based ribavirin arm, falling to 48% in the low-dose arm -- a difference that did not reach statistical significance difference.
- Independent risk factors for relapse included male sex (odds ratio [OR] 6.09), high baseline HCV viral load (OR 5.74), and advanced liver fibrosis (OR 4.27).
- Among 20 patients who participated in a pharmacokinetic and viral kinetic substudy, relapsers experienced significantly slower decline of infectious virus than those who achieved SVR (clearance in 3.57 vs 5.60 days, respectively).
- Sofosbuvir plus ribavirin was generally safe and well-tolerated, with no deaths or treatment discontinuations due to adverse events.
- The most common side effects were headache, anemia, fatigue, and nausea, mostly mild to moderate.
- 7 severe (grade 3) adverse events were observed, including anemia, neutropenia, nausea, elevated blood phosphate, gallstones, and pancreatitis.
Based on these findings, the researchers concluded, "In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively."
"This study demonstrates the efficacy of an interferon-free regimen in a traditionally difficult-to-treat population while exploring the reasons for treatment relapse," they elaborated. "In this study, treatment of chronic HCV infection with a single directly acting antiviral agent (sofosbuvir) and weight-based ribavirin resulted in a high SVR rate in a population with unfavorable traditional predictors of treatment response compared with reported rates with currently used interferon-based therapy in similar populations."
"Because treatment of HCV is evolving from an interferon-based combination therapy to an all-oral, interferon-free directly acting antiviral agent regimen, these results are encouraging and provide important information regarding the expected treatment responses in a population representative of the U.S. epidemic," they added. "As new direct-acting antiviral agent regimens are being evaluated, it is important that these studies involve populations most affected by the disease."
"There is a pressing need for hepatitis C virus treatments that are less burdensome to the patient, have fewer side effects, and take less time to complete," NIAID director and study co-author Anthony Fauci said in a press release issued by NIAID. "Building on previous work, this trial provides compelling evidence that interferon-free regimens can be safe and effective."
A Osinusi, EG Meissner, Y-J Lee, S Kottilil, et al. Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics: A Randomized Clinical Trial. Journal of the American Medical Association 310(8):804-811. August 28, 2013.
National Institutes of Health. Investigational oral regimen for hepatitis C shows promise in NIH trial. Press release. August 27, 2013.
JAMA. Combination Drug Regimen Appears Beneficial for Patients With Hepatitis C and Unfavorable Treatment Characteristics. Media advisory for August 27, 2013.