Coinfection

EASL 2016: Sofosbuvir/ Velpatasvir Cures 95% of HIV/HCV Coinfected People

A dual regimen of sofosbuvir plus velpatasvir was well-tolerated and highly effective against hepatitis C virus (HCV) genotypes 1 through 4 in HIV-positive people with chronic hepatitis C coinfection, according to results from the Phase 3 ASTRAL-5 trial presented at the 2016 EASL International Liver Congress last week in Barcelona.

The advent of direct-acting antiviral agents (DAAs) has enabled shorter, better tolerated, and much more effective hepatitis C treatment compared to interferon-based therapy. Studies have shown that HIV-positive people with HCV genotype 1 have a high likelihood of being cured with interferon-free DAA therapy, which is particularly beneficial because they experience more rapid liver disease progression.

Yet there is still room to optimize therapy for people with HCV genotypes other than 1. Genotype 3 is now considered the most difficult to treat, while genotypes 4, 5, and 6 do not have as much data. Ideally, combination DAA regimens will be pangenotypic -- or active against all genotypes -- meaning they could be prescribed without the need for genotype testing.

David Wyles from the University of California at San Diego presented findings from the ASTRAL-5 trial, evaluating a pangenotypic combination consisting of Gilead Sciences' HCV NS5B polymerase inhibitor sofosbuvir (marketed as Sovaldi) and the second-generation NS5A inhibitor velpatasvir (formerly GS-5816) for HIV/HCV coinfected patients.

The sofosbuvir/velpatasvir coformulation is currently under review by the U.S. Food and Drug Administration and European regulatory authorities. As reported at last year's AASLD Liver Meeting, the combination demonstrated high sustained response rates in the prior Phase 3 ASTRAL trials: ASTRAL for genotypes 1, 2, 4, 5, and 6; ASTRAL-2 for genotype 2; ASTRAL-3 for genotype 3; andASTRAL-4 forpatients with all genotypes had who decompensated liver disease.

The multicenter ASTRAL-5 trial enrolled 106 HIV-positive chronic hepatitis C patients in the U.S. with any HCV genotype. Most (86%) were men, 45% were black, and the mean age was 54 years. A majority (62%) had HCV genotype 1a, followed by 1b (11%), 2 (10%), 3 (11%), and 4 (5%); no one had genotypes 5 or 6, which are uncommon in the U.S. About a third had previously been treated for hepatitis C, the mean HCV RNA level was 6.3 log, and 18% had compensated cirrhosis.

With regard to HIV status, participants were on stable antiretroviral therapy (ART) with undetectable HIV viral load and a mean CD4 T-cell count of approximately 600 cells/mm³. They were taking a variety of ART regimens, most often including the HIV protease inhibitors atazanavir (Reyataz), darunavir (Prezista), or lopinavir/ritonavir (Kaletra) (47% on a PI); the integrase inhibitors raltegravir (Isentress) or elvitegravir (Vitekta) (34% taking this class); or the NNRTI rilpivirine (Edurant; 12%).

NRTI backbones included tenofovir (Viread, or with emtricitabine in Truvada) in a boosted regimen (53%), tenofovir in an unboosted regimen (33%), or abacavir/lamivudine (Epzicom; 14%). This breakdown enabled researchers to see whether boosted tenofovir was associated with kidney toxicity when combined with the hepatitis C drugs.

All participants in this open-label study received 400 mg sofosbuvir plus 100 mg velpatasvir taken as a once-daily coformulation for 12 weeks. They were followed for 12 weeks after completing treatment to assess sustained virological response (SVR12), or continued undetectable HCV RNA.

Results

• The overall SVR12 rate was 95%, or 99 out of 104 participants (with 2 still undergoing post-treatment follow-up) -- similar to rates seen in studies of HIV-negative hepatitis C patients.
• Non-responders included 2 relapsers, 1 loss to follow-up, and 1 withdrawal of consent.
• Response rates ranged from 92% for genotypes 1b and 3 (reflecting a single drop-out in each arm), to 95% for genotype 1a (reflecting the 2 relapses and 1 drop-out), to 100% for genotypes 2 and 4.
• SVR12 rates were similar regardless of the presence or absence of cirrhosis (100% and 94%, respectively).
• Cure rates were also similar for hepatitis C treatment-naive and treatment-experienced patients (93% and 97%, respectively).
• The 12% of participants with NS5A resistance-associated variants at baseline all achieved SVR12.
• Sofosbuvir/velpatasvir was generally safe and well-tolerated.
• There were 2 serious adverse events and 2 treatment discontinuations due to adverse events (1 of whom achieved SVR12).
• The most frequently reported side effects were fatigue (25%) and headache (13%), and the most common laboratory abnormality was elevated bilirubin in people taking boosted atazanavir.
• Creatinine clearance -- a marker of kidney function -- was lower among people taking boosted versus unboosted tenofovir, and lowest among people not taking tenofovir (who may have had existing kidney problems), but it remained relatively stable over time in all groups.
• No one experienced HIV viral rebound while on hepatitis C treatment.

"Sofosbuvir/velpatasvir for 12 weeks provides a simple, safe, and highly effective treatment for patients coinfected with HIV-1 and HCV," the researchers concluded.

No one in this study stopped or changed their antiretrovirals due to kidney concerns, Wyles noted.

4/18/16

Reference

D Wyles, N Brau, S Kottilil, et al.
Sofosbuvir/velpatasvir fixed dose combination for 12 weeks in patients co-infected with HCV and HIV-1: the Phase 3 ASTRAL-5 study. EASL International Liver Congress 2016. Barcelona, April 13-17, 2016. Abstract PS104.