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AASLD 2015: Sofosbuvir Plus Ribavirin Shows Suboptimal Efficacy for Acute Hepatitis C

A combination of sofosbuvir (Sovaldi) and ribavirin cured more than 90% of HIV-positive people with acute hepatitis C virus (HCV) in a small study, but a similar trial of the same regimen saw a much higher relapse rate, according to a pair of presentations at the AASLD Liver Meeting this past November.

Research done in the era of interferon-based therapy showed that treating people during the acute stage of HCV infection led to higher response rates and required a shorter duration than treatment started during chronic infection.

The advent of direct-acting antivirals used in interferon-free regimens has made treatment for chronic infection shorter, better tolerated, and more effective, and the same may be true for acute infection. Researcherspreviously showed that the first-generation HCV protease inhibitor telaprevir (Incivek) plus pegylated interferon and ribavirin produced a high cure rate for acute hepatitis C, but this triple combination was poorly tolerated.

SWIFT-C

Susanna Naggie from Duke University Medical Center presented findings from the ACTG A5327 SWIFT-C trial, which tested a combination of the HCV polymerase inhibitor sofosbuvir plus ribavirin for 12 weeks in HIV/HCV coinfected people with acute HCV infection. (Not to be confused with the C-SWIFT trial evaluating sofosbuvir plus grazoprevir/elbasvir.)

This multicenter trial enrolled 17 participants with acute HCV, defined as HCV antibody seroconversion or newly detectable HCV RNA in the prior 6 months, or a new liver enzyme elevation with detectable HCV RNA in people without a recent HCV test. Participants were enrolled within 12 to 24 weeks from the first evidence of HCV infection.

All 17 participants were men, 65% were Latino/Hispanic, the median age was 45 years, and 76% reported having never injected drugs (suggesting the possibility of sexually transmitted HCV). Most (88%) had HCV genotype 1, with a single person having genotype 2b and another undetermined. Median baseline HCV RNA was 2,280,000 IU/mL. Participants were all on antiretroviral therapy (ART) with undetectable HIV viral load and the median CD4 T-cell count was approximately 500 cells/mm³.

All participants in this single-arm open-label trial received 400 mg once-daily sofosbuvir plus 1000-1200 mg/day weight-based ribavirin for 12 weeks.

The primary endpoint was sustained virological response, or continued undetectable HCV viral load at 12 weeks after completion of treatment (SVR12). Results were compared against the historical SVR12 rate of 60% using pegylated interferon plus ribavirin for 24-48 weeks.

Results

• All 17 participants completed the study with no treatment discontinuations or dose adjustments.
• All participants had undetectable HCV RNA at the end of treatment.
• 10 of 17 patients (59%) achieved SVR12, which did not meet the criteria for non-inferiority to pegylated interferon plus ribavirin.
• 7 participants experienced HCV relapse or reinfection.
• No serious adverse events occurred, but about half of participants experienced grade 2 (moderate) or higher adverse events.

"A 12-week course of sofosbuvir and ribavirin achieved suppression of HCV in all participating HIV-infected men with acute HCV infection, but the relapse rate was high," the investigators concluded. "The mechanism(s) for the high relapse observed is unclear, but other treatment options are needed for this population."

New York Study

In the second study, Daniel Fierer from Mount Sinai School of Medicine and colleagues tested sofosbuvir plus ribavirin in HIV-positive people with acute hepatitis C who were ineligible for or unable to enroll in SWIFT-C.

This single-center study enrolled 13 men with recent HCV infection -- 11 with primary (first-time) infection and 2 with reinfection after previous HCV clearance. Reinfection was defined as detectable HCV after being undetectable for the prior 12 weeks.

About half of participants were white, 2 were black, 2 were Hispanic, and 1 was Asian; the median age was 43 years. All had HCV genotype 1 (10 with harder-to-treat subtype 1a and 2 with 1b). Median HCV RNA was approximately 32,000 copies IU/mL, but 2 had a very high viral load greater than 10,000,000. All but 2 were on ART with undetectable or low HIV viral load and the median CD4 count was 545 cells/mm³.

Participants were observed for 12 weeks before starting treatment to see if they spontaneously cleared HCV, and 1 man did so. The rest began treatment at a median 22 weeks after acute HCV was detected. Again, everyone was treated with 400 mg once-daily sofosbuvir plus weight-based ribavirin for 12 weeks.

Results

• All 12 treated participants completed 12 weeks of therapy.
• 11 patients (92%) achieved SVR 12.
• 1 participant experienced HCV relapse between weeks 4 and 9 post-treatment.
• This man with HCV reinfection had a low peak ALT and baseline HCV RNA >1,000,000 IU/mL before starting treatment and had previously failed interferon/ribavirin during primary infection.
• The most common adverse events were irritability and insomnia, but these did not limit treatment.

"Sofosbuvir + ribavirin for 12 weeks was highly effective in the treatment of acute genotype 1 HCV in HIV-infected men in this 'real-world' setting using broad enrollment and treatment criteria," the researchers concluded. "The reasons for the different outcome between this study and ACTG A5327 are not known."

Given the availability of newer direct-acting antivirals, they suggested that rather than confirming this regimen in larger studies, it would be better to test other regimens without ribavirin. The ACTG A5327 trial is now evaluating sofosbuvir/ledipasvir (Harvoni) for acute hepatitis C.

2/18/16

References

S Naggie, KM Marks, M Hughes, et al. Sofosbuvir Plus Ribavirin without Interferon For Treatment of Acute Hepatitis C Virus Infection in HIV-1 infected Individuals (SWIFT-C). AASLD Liver Meeting 2015. San Francisco, November 13-17, 2015. Abstract 1094.

DS Fierer, Z Barbati, D Dieterich, et al. Sofosbuvir in the Treatment of Acute HCV Infection in HIV-infected Men. AASLD Liver Meeting 2015. San Francisco, November 13-17, 2015. Abstract 1090.