- Category: Experimental HCV Drugs
- Published on Tuesday, 04 March 2014 00:00
- Written by Liz Highleyman
An interferon-free regimen of sofosbuvir plus ribavirin for 24 weeks led to sustained response in three-quarters of previously untreated genotype 1 HIV/HCV coinfected patients in the PHOTON-1 study, but a shorter 12-week regimen did not work as well for people with hepatitis C virus genotype 3, according to a report at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) this week in Boston.
People with HIV/HCV coinfection experience more rapid liver disease progression, on average, and do not respond as well to interferon-based therapy as people with hepatitis C alone. Direct-acting antivirals that target different steps of the HCV lifecycle offer the prospect of shorter treatment, fewer side effects, and higher cure rates for both HCV monoinfected and HIV/HCV coinfected patients.
As described by Susanna Naggie from Duke Clinical Research Institute, the open-label Phase 3 PHOTON-1 trial evaluated the safety and efficacy of Gilead Sciences' recently approved HCV NS5B polymerase inhibitor sofosbuvir (Sovaldi, formerly GS-7977) plus ribavirin for coinfected individuals with HCV genotypes 1, 2, or 3.
Sofosbuvir's FDA label indication -- the same for both HCV monoinfected and HIV/HCV coinfected patients -- is sofosbuvir plus ribavirin dual therapy for 12 weeks for genotype 2 and 24 weeks for genotype 3, while people with genotypes 1 or 4 are advised to use sofosbuvir with pegylated interferon and ribavirin for 12 weeks.
PHOTON-1 enrolled 114 treatment-naive genotype 1 coinfected patients. They received 400 mg once-daily sofosbuvir plus 1000-1200 mg weight-based ribavirin for 24 weeks. In addition, the study also included 68 treatment-naive and 41 treatment-experienced people with genotypes 2 or 3. Previously untreated patients received sofosbuvir/ribavirin for 12 weeks while prior non-responders were treated for 24 weeks.
Across all study arms most participants (about 85%) were men and the mean age was about 50 years. One-third of genotype 1 patients and about 15% of genotype 2 or 3 patients were black. 30% of treatment-naive patients and half of treatment-experienced participants had the favorable IL28B CC gene variant associated with good interferon responsiveness. Most genotype 1 patients (79%) had harder-to-treat subtype 1a. Rates of liver cirrhosis ranged from 4% among naive genotype 1 patients to 24% in the experienced genotype 2/3 group.
Participants had well-controlled HIV disease. More than 90% were on antiretroviral therapy (ART) and the mean CD4 T-cell count was above 600 cells/mm3. Unlike some HCV protease inhibitors, sofosbuvir does not affect CYP3A4 drug metabolism and it has no significant interactions with many widely used antiretrovirals. More than one-third of patients used efavirenz (Sustiva), nearly 20% used boosted atazanavir (Reyataz) or darunavir (Prezista), and about 15% used the integrase inhibitor raltegravir (Isentress); most also took tenofovir/emtricitabine (the drugs in Truvada).
Naggie reported final data from the study, including sustained virological response rates, or continued undetectable HCV RNA, at weeks 12 and 24 post-treatment (SVR12 and SVR24).
- Looking at the treatment-naive genotype 1 patients, 76% achieved SVR12.
- 1 person had detectable HCV again after completing treatment, giving an SVR24 rate of 75%, but this may have been a case of reinfection rather than relapse.
- Among treatment-naive genotype 2 patients treated for 12 weeks, the SVR12 and SVR24 rates were 88%.
- Among treatment-naive genotype 3 patients treated for the same duration, however, the SVR12 and SVR24 rates fell to 67%.
- Among treatment-experienced people treated for 24 weeks, SVR24 rates were 92% for genotype 2 and 94% for genotype 3.
- The 2 patients with HCV viral breakthrough while on treatment were found to have undetectable sofosbuvir levels, indicating probable non-adherence.
- No resistance mutations (including S282T) were detected on deep sequencing in patients with virological failure.
- Sofosbuvir plus ribavirin was generally safe and well-tolerated.
- 7 people treated for 12 weeks and 6 treated for 24 weeks experienced serious adverse events, and 4 and 3 patients, respectively, discontinued treatment for this reason.
- The most common side effects were fatigue, insomnia, headache, and nausea.
- Among the 11 coinfected patients who were not on ART, there were no clinically significant changes in HIV viral load.
- There were 2 cases of transiently increased HIV RNA, both associated with antiretroviral non-adherence.
- Absolute CD4 cell counts decreased -- a known effect of ribavirin -- but CD4 percentages remained the same.
- HCV subtype 1a vs 1b and IL28B status were not significant predictors of treatment response in a multivariate analysis.
- People with liver cirrhosis appeared to have somewhat lower response rates, but the number was small and the difference was not statistically significant..
"The interferon-free regimen of sofosbuvir + ribavirin resulted in high SVR12 and SVR24 rates in HIV-infected patients with HCV genotype 1, 2 and 3 coinfection," the researchers concluded.
Use of direct-acting antivirals appears to overcome the disadvantage in treatment response for people with HIV that was seen with interferon. At a hepatitis C press overview on the opening day of the conference, PHOTON-1 co-author Douglas Dieterich from Mt. Sinai noted that "overall SVR rates were very similar" between the coinfected patients in this study and HCV monoinfected people in other trials, and "adverse event profiles are the same."
"I believe HIV is no longer a player," Naggie stated.
These finding also support the growing awareness that HCV genotypes 2 and 3 should not be classified together as "easier to treat." In this study people with genotype 2 had high sustained response rates with either 12 or 24 weeks of dual therapy, but many genotype 3 patients appeared to need the extra 12 weeks.
Other recent studies have shown that adding other direct-acting antivirals to sofosbuvir can raise cure rates for harder-to-treat patients and may eliminate the need for ribavirin. Gilead has requested approval of a coformulation containing sofosbuvir and its HCV NS5A inhibitor ledipasvir (formerly GS-5885), and this combination is being tested in HIV/HCV coinfected people.
S Naggie, MS Sulkowski, J Lalezari, et al. Sofosbuvir Plus Ribavirin for HCV Genotype 1-3 Infection in HIV Coinfected Patients (PHOTON-1). 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 26.