- Category: Experimental HCV Drugs
- Published on Thursday, 10 April 2014 00:00
- Written by Liz Highleyman
Treatment for 12 weeks with a coformulation of sofosbuvir plus ledipasvir led to sustained response for all HIV/HCV coinfected individuals with genotype 1 hepatitis C followed for 12 weeks post-treatment, according to interim findings from the ERADICATE study presented at the 49thEASL International Liver Congress (EASL 2014) this week in London.
Anu Osinusi from the National Institute of Allergy and Infectious Diseases and colleagues tested a once-daily fixed-dose combination pill containing the recently approved HCV polymerase inhibitor sofosbuvir (Sovaldi) plus the NS5A inhibitor ledipasvir (400/90 mg) in patients coinfected with HIV and hepatitis C virus.
Historically, HIV/HCV coinfected people have not responded as well to interferon-based therapy as HIV negative people with HCV alone, but recent data suggest that interferon-free direct-acting antiviral regimens may be equally effective in people with HIV. The PHOTON-1 study, testing sofosbuvir plus ribavirin, found that coinfected people had sustained virological response rates at 12 weeks post-treatment (SVR12) similar to those seen in HCV monoinfected patients.
The NIAID ERADICATE trial was an investigator-initiated study that included 50 HIV positive people with genotype 1 HCV coinfection; about 80% had harder-to-treat subtype 1a. A majority were men, most were African-American, and the median age was approximately 58 years. About one-quarter had advanced liver fibrosis (stage F3), but none had cirrhosis.
Participants were divided into 2 groups according to HIV treatment status. The ARV-untreated group included 13 patients who were not on antiretroviral therapy (ART) and had either a stable CD4 T-cell count and HIV RNA <500 copies/mL or a CD4 count >500 cells/mm3 (above the threshold for starting ART in previous HIV treatment guidelines). The median CD4 count was 687 cells/mm3.
The ARV-treated group included 37 patients who had been on current ART for at least 8 weeks, had undetectable HIV RNA (<40 copies/mL), and had a CD4 count >100 cells/mm3 (median 576 cells/mm3). Treated participants used antiretrovirals that do not have clinically relevant interactions with sofosbuvir or ledipasvir. Everyone was on tenofovir/emtricitabine (the drugs in Truvada); in addition, 41% used efavirenz (Sustiva), 27% used raltegravir (Isentress), and 21% used rilpivirine (Edurant).
All participants were treated with the sofosbuvir/ledipasvir coformulation for 12 weeks. The ARV-untreated group, which started sooner, had long enough follow-up to determine SVR12, which is considered a cure. The ARV-treated group was still being followed, but a majority had SVR4 data available. SVR4 cannot yet be considered a cure as some people still relapse after this point.
- All participants reached undetectable HCV RNA by week 4 and had continued virological response at the end of treatment.
- In the ARV-untreated group, all 10 participants (100%) followed through 12 weeks post-treatment achieved SVR12 in an observed analysis.
- In the ARV-treated group, 100% of the 22 patients followed through post-treatment week 4 achieved SVR4.
- Among 10 ARV-treated participants who reached post-treatment week 12, the SVR12 rate remained at 100%.
- Looking at HIV outcomes, in the ARV-untreated group there were no clinically significant changes in HIV RNA during hepatitis C treatment.
- 1 person in the ARV-treated group experienced a transient HIV RNA increase after missing antiretrovirals for 4 days, but resumed HIV suppression on the same regimen.
- CD4 T-cell counts and percentages remained stable in both groups throughout hepatitis C treatment.
- Sofosbuvir/ledipasvir was generally safe and well-tolerated.
- There were no serious adverse events or early discontinuations for this reason in either group.
- The most common side effects were headache, fatigue, pain, nausea, diarrhea, and constipation.
- There were no notable changes in serum creatinine or estimated GFR (measures of kidney function) over time in either group.
The researchers concluded that the interferon- and ribavirin-free regimen of sofosbuvir plus ledipasvir led to SVR12 in 100% of ARV-untreated patients and SVR4 in 100% of ARV-treated patients, with data collection ongoing. Sofosbuvir/ledipasvir was safely administered in combination with several antiretroviral regimens.
In light of these promising results, an audience member asked about the prospect of reducing sofosbuvir/ledipasvir treatment duration to 8 weeks. Osinusi replied that many interferon-free studies have now suggested that HIV is not a risk factor for poorer response. "If an 8-week duration works in [HCV] monoinfected patients, I don’t see why it shouldn’t in coinfected [patients] as well," she said.
A Osinusi, K Townsend, A Nelson, et al (NIAID ERADICATE Study Team). Use of sofosbuvir/ledipasvir fixed dose combination for treatment of HCV genotype-1 in patients coinfected with HIV. 49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O14.