Sofosbuvir + daclatasvir demonstrates high cure rates for people with HIV and HCV co-infection

Nearly all people with HIV and genotype 1-4 HCV co-infection treated for 12 weeks with an interferon-free regimen of sofosbuvir (Sovaldi) plus daclatasvir (Daklinza) achieved sustained virological response in the ALLY-2 trial, but 8 weeks did not work as well, according to a recent report in the New England Journal of Medicine. Sub-studies presented this month at IDWeek 2015 showed that this regimen is highly effective regardless of race or specific antiretroviral regimen.

The advent of direct-acting antiviral agents (DAAs) that can be used in all-oral regimens has revolutionised hepatitis C treatment, offering options that are shorter, better tolerated and more effective than interferon-based therapy. This is particularly beneficial for HIV-positive people co-infected with hepatitis C virus (HCV), who tend to have more rapid liver disease progression and do not respond as well to interferon.

David Wyles of the University of California at San Diego and fellow investigators with the ALLY-2 trial evaluated a combination of Gilead Sciences' HCV NS5B polymerase inhibitor sofosbuvir and Bristol-Myers Squibb's NS5A inhibitor daclatasvir without interferon or ribavirin. Results were previously presented in part at this year's Conference on Retroviruses and Opportunistic Infections (CROI).

This open-label study included 151 HIV/HCV co-infected participants who had not received prior hepatitis C treatment and 52 treatment-experienced patients. Nearly 90% were men, about 60% were white, about 35% were black and the median age was approximately 55 years; 14% had compensated liver cirrhosis. More than 80% had HCV genotype 1 (68% with harder-to-treat subtype 1a), while about 15% had genotypes 2 or 3 and a small number had genotype 4.

Almost all participants were on antiretroviral therapy (ART), mostly with undetectable HIV viral load, and the median CD4 count was above 500 cells/mm³. Those on ART were permitted to use a wide variety of antiretrovirals. About half were taking HIV protease inhibitors with most of the rest on NNRTIs or integrase inhibitors.

Previously untreated participants were randomly assigned to receive 400mg sofosbuvir plus 60 mg daclatasvir once-daily for either 8 or 12 weeks, while treatment-experienced patients were all treated for 12 weeks. Daclatasvir doses were adjusted when administered with specific antiretroviral medications based on prior drug interaction studies (down to 30mg when used with ritonavir-boosted HIV protease inhibitors or up to 90mg when used with most NNRTIs).

The primary study endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12).

Overall SVR12 rates were 97% for previously untreated people treated for 12 weeks, 76% for those treated for 8 weeks and 98% for treatment-experienced people treated for 12 weeks. Most relapses occurred in the 8-week treatment arm.

Looking at genotype 1 alone, cure rates were about the same: 96.4%, 75.6% and 97.7%, respectively. Everyone with genotypes 2, 3 or 4 achieved sustained response. People with cirrhosis had somewhat lower SVR12 rates in all treatment arms.

Sofosbuvir plus daclatasvir was generally safe and well-tolerated. Serious adverse events were uncommon (< 3% across treatment arms) and there were no adverse events leading to treatment discontinuation. The most common side-effects were fatigue, nausea and headache. Participants maintained HIV viral suppression and stable CD4 counts.

These findings show that sofosbuvir plus daclatasvir taken for 12 weeks is safe and effective for HIV/HCV co-infected people, the study authors concluded. These results support current hepatitis C treatment guidelines recommending that HIV-positive and HIV-negative people should be treated the same for hepatitis C after taking into account interactions with antiretrovirals.

As described in another study presented at CROI, Gilead's combination of sofosbuvir and its NS5A inhibitor ledipasvir (the drugs in Harvoni) was also highly effective for HIV/HCV co-infected people with genotype 1 in the ION-4 trial. Daclatasvir, however, is active against other HCV genotypes that are more common outside the U.S. (known as 'pangenotypic').

Response by race

As described in a poster presented at IDWeek, researchers performed a sub-analysis comparing response rates in ALLY-2 according to race.

All-oral DAA regimens may be particularly beneficial for the black population, which is disproportionately affected by hepatitis C, more likely to be medically ineligible for interferon-based therapy and less likely to respond to interferon, the researchers noted as background.

This analysis looked at 50 black ALLY-2 participants treated with sofosbuvir plus daclatasvir for 12 weeks (the 8-week arm was not considered). Again, most (84%) were men and the median age was 56 years. Black patients were equally likely to have HCV subtype 1a, more likely to have 1b and less likely to have genotypes 2 or 3. As expected, blacks were more likely than whites to have unfavourable non-CC IL28B gene patterns, which predicts poorer interferon response (84% vs 68%).

The overall SVR12 rate for black patients was 98% (100% for treatment-naive and 95% for treatment-experienced) compared to 97% for white patients. Response did not differ significantly according to HCV genotype or IL28B status, but was a bit lower for black patients with cirrhosis (88%). Here too, treatment was generally well-tolerated and black and white patients had similar overall rates of adverse events.

The researchers concluded that sofosbuvir plus daclatasvir led to high SVR12 rates for black people with HIV/HCV co-infection regardless of disease characteristics or concomitant antiretroviral therapy.

These findings are in accord with those from most other interferon-free DAA studies, which showed that black and white patients are equally likely to be cured. However, the ION-4 sofosbuvir/ledipasvir study saw a disparity in outcomes according to race, with all relapses occurring among black patients. This disparity – which was not seen in trials of HCV monoinfected patients – is unexplained and still under study.

Response by ART regimen

In a related poster Annie Luetkemeyer of the University of California at San Francisco and colleagues looked at the effect of different antiretroviral regimens in response to sofosbuvir plus daclatasvir.

At CROI Wyles reported SVR12 rates varied by ART regimen in the 8-week treatment-naive arm, with people taking ritonavir-boosted darunavir (Prezista) doing somewhat worse; there was no significant difference, however, in the 12-week arms. Luetkemeyer's analysis provided more detail about responses by ART regimen in the 12-week arms only; the 8-week arm was not considered.

SVR12 rates were high across nucleoside/nucleotide reverse transcriptase inhibitor 'backbones' (98% using tenofovir and 100% using abacavir) and 'anchor' drug classes (97% using HIV protease inhibitors, 100% using NNRTIs and 95% using integrase inhibitors). This was consistent regardless of prior treatment status, race, HCV genotype or presence of cirrhosis. Safety did not vary across antiretroviral regimens and HIV control was maintained.

Looking at specific drugs, SVR12 rates were 100% for people taking boosted atazanavir (Reyataz), lopinavir/ritonavir (Kaletra), efavirenz (Sustiva), nevirapine (Viramune), rilpivirine (Edurant) or dolutegravir (Tivicay). Two of 30 people taking boosted darunavir and two of 32 taking raltegravir were not cured (SVR12 rates of 93% and 94%, respectively).

The researchers concluded that HIV/HCV co-infected patients can be treated with sofosbuvir plus daclatasvir once-daily for 12 weeks "without the need to alter most current antiretroviral regimens."

However, they noted that recent data suggest that the dose of daclatasvir should stay at 60mg when used with ritonavir-boosted darunavir or lopinavir/ritonavir, not lowered to 30mg as was done in ALLY-2.