Coinfection

CROI 2015: Interferon-Free Regimens Show High Cure Rates for HIV/HCV Coinfected

A pair of 2-drug, 12-week regimens containing neither interferon nor ribavirin -- sofosbuvir (Sovaldi) plus either ledipasvir (the Harvoni coformulation) or daclatasvir (Daklinza) -- cured 96% of HIV/HCV coinfected people with various hepatitis C genotypes, according to presentations at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI) this week in Seattle. These findings confirm that hepatitis C patients with HIV can be treated the same as those with HCV alone.

The advent of oral direct-acting antiviral agents (DAAs) that target different steps of the hepatitis C virus (HCV) lifecycle has revolutionized treatment, offering therapy that is shorter, better tolerated and more effective than interferon-based treatment. This is particularly beneficial for HIV/HCV coinfected people who tend to have more rapid liver disease progression and do not respond as well to interferon.

Sofosbuvir/Ledipasvir

Susanna Naggie from Duke Clinical Research Institute in North Carolina presented results from ION-4, a Phase 3 trial evaluating the safety and efficacy of Gilead Science's nucleotide HCV NS5B polymerase inhibitor sofosbuvir plus NS5A inhibitor ledipasvir in HIV/HCV coinfected patients.

Results from ION-1 (genotype 1 treatment-naive, 12 vs 24 weeks), ION-2 (genotype 1 prior non-responders, 12 vs 24 weeks) and ION-3 (genotype 1 treatment naive, 8 vs 12 weeks) were presented previously, showing that sofosbuvir/ledipasvir cured 95% or more of HCV monoinfected people.

ION-4 study enrolled 335 coinfected participants in the U.S., Canada, and New Zealand. The trial had broad inclusion criteria and included more difficult-to-treat groups such as prior non-responders and people with liver cirrhosis.

Most participants (82%) were men, 34% were black -- far more than in most DAA trials to date -- and the mean age was 52 years. Almost all (98%) had HCV genotype 1, with a small number of genotype 4s. More than half (55%) were treatment-experienced, three-quarters had unfavorable IL28B gene variants, and 20% had compensated cirrhosis.

With regard to HIV, the participants were on antiretroviral therapy (ART) and most had undetectable HIV viral load. They could be taking either efavirenz (Sustiva, 48%), raltegravir (Isentress, 44%), or rilpivirine (Edurant, 9%), all with tenofovir/emtricitabine (Truvada).

All participants in this open-label study received 400 mg sofosbuvir plus 90 mg ledipasvir, taken as a once-daily coformulation, for 12 weeks. They were followed for an additional 12 weeks after completing treatment to assess sustained virological response (SVR12), or continued undetectable HCV RNA.

Results

• The overall SVR12 rate in this study was 96%, similar to rates seen in the ION HCV monoinfection studies.
• Rates were very similar for treatment naive and treatment-experienced patients (95% and 97%), and for people with and without cirrhosis (94% and 96%).
• The 20% of patients who were found to have NS5A resistance-associated variants at baseline had a 94% cure rate (no NS5B resistant variants were detected).
• 10 people relapsed after the end of treatment, 2 experienced treatment failure due to poor adherence, 1 was lost to follow-up, and 1 died of a presumed unrelated cause.
• In a multivariate analysis the only factor that significantly predicted relapse was black race/ethnicity -- in fact, all 10 relapsers were black.
• Sofosbuvir/ledipasvir was generally safe and well-tolerated.
• There were 2 serious adverse events due to advanced liver disease and 1 death, but no treatment discontinuations due to adverse events.
• The most common side effects were headache (25%), fatigue (21%), diarrhea (11%), and nausea (10%).
• Participants maintained stable CD4 counts and none had confirmed HIV rebound.
• Because they were taking tenofovir, their kidney function was carefully monitored; 4 patients (1%) had small creatinine increases, of whom 2 completed HCV treatment with no regimen change, 1 reduced their tenofovir dose, and 1 stopped tenofovir.

Naggie noted that the racial disparity in treatment failure rates was not seen in the ION monoinfection trials, in which 99% of black patients were cured, but their numbers may have been too small to see an effect. The researchers have not determined why this was the case, but further analysis including genetic sequencing and genome-wide association studies are underway.

Sofosbuvir + Daclatasvir

David Wyles from the University of California at San Diego presented results from the ALLY-2 trial looking at sofosbuvir in combination with a different NS5A inhibitor, Bristol-Myers Squibb's daclatasvir. Daclatasvir is available in Europe and Japan, and is currently awaiting U.S. Food and Drug Administration approval.

The sofosbuvir plus daclatasvir combination performed well in early studies, but Gilead decided to halt development of this regimen in order to focus on its own NS5A drug, ledipasvir. Once sofosbuvir was approved and on the market, however, Bristol-Myers was able to move forward with Phase 3 clinical trials.

ALLY-1 tested the sofosbuvir plus daclatasvir regimen with ribavirin for 12 weeks in patients with cirrhosis or liver transplant recipients with HCV genotypes 1-6, ALLY-2 tested sofosbuvir plus daclatasvir without ribavirin for 8 or 12 weeks in HIV/HCV coinfected people with HCV genotypes 1-6, and ALLY-3 tested the combination for 12 weeks in patients with genotype 3.

An advantage of daclatasvir is that it is active against multiple HCV genotypes (known as "pangenotypic") while ledipasvir is primarily active against genotype 1. This is important because while genotype 1 is most common in the U.S. and Europe, different genotypes predominate in other countries with high hepatitis C burdens.

All participants in ALLY-2 received once-daily 400 mg sofosbuvir plus daclatasvir. ALLY-2 enrolled 2 cohorts: 151 previously untreated patients (including prior use of sofosbuvir) who received the regimen for 8 or 12 weeks, and 52 treatment-experienced patients all of whom received the 12-week course.

Overall, nearly 90% were men, about 60% were white, about 35% were black, and the median age was approximately 55 years. A majority (63%-70% across treatment arms) had harder-to-treat HCV subtype 1a, 12%-21% had subtype 1b, 4%-12% had genotype 2, 6%-8% had genotype 3, and 0%-4% had genotype 4. About 10% of treatment-naive patients had cirrhosis, rising to 29% for the treatment-experienced group.

Participants could either be on ART with undetectable HIV RNA and a CD4 count of at least 100 cells/mm³, or not yet on ART with at least 350 cells/mm³. Median CD4 counts were in the 500-600 cells/mm³ range. Those on ART were permitted to take a wide range of antiretrovirals. The standard 60 mg daclatasvir dose was adjusted down to 30 mg with ritonavir-boosted HIV protease inhibitors or up to 90 mg with most NNRTIs to account for drug interactions (all doses were combined in the analysis).

Results

• SVR12 rates were high in the 12-week arms: 96% for treatment-naive patients and 98% for treatment-experienced.
• The cure rate fell to just 76%, however, for treatment-naive people who took only 8 weeks.
• These rates were nearly the same whether looking at just genotype 1 patients or all genotypes together.
• There was 1 relapse in both of the 12-week arms, but 10 in the 8-week arm.
• Both relapsers treated for 12 weeks had HCV 1a; everyone with genotypes 2, 3 or 4 treated for this duration were cured. 
• People with cirrhosis had lower cure rates than non-cirrhotics in both the 8-week arm (60% vs 77%) and in the naive (89% vs 99%) and experienced (93% vs 100%) 12-week arms.
• In the 8-week arm SVR12 rates also varied by ART regimen, with those taking darunavir/ritonavir (Prezista) doing worse; there was no difference, however, in the 12-week arms. Wyles suggested this might be due to sub-therapeutic drug levels, as ritonavir did not boost daclatasvir as much as expected.
• Here too, treatment was generally safe and well-tolerated.
• There were no deaths or adverse events leading to treatment discontinuation, and serious adverse events were uncommon (0%-3%).
• Most patients maintained HIV viral suppression and stable CD4 counts.

Speaking at a CROI press conference, both Naggie and Wyles noted that their studies saw response rates in these HIV/HCV coinfected patients as high as those for HCV monoinfected people in prior trials. This supports recent hepatitis C treatment guidelines recommending that HIV positive and negative people should be treated the same for hepatitis C, with the exception of taking into account interactions with antiretrovirals.

"These are really exceptional cure rates and they are very safe regimens," Naggie said. "ION-4 and ALLY-2 offer great options for people who are coinfected."

It remains unclear how sofosbuvir plus daclatasvir will be used in clinical practice, given the availability of Harvoni. The difference between the full (non-discounted) U.S. cost of sofosbuvir alone and Harvoni for 12 weeks is about US$10,500 -- likely less than the eventual price of daclatasvir. However, the relative cost and availability of specific drugs varies from country to country. Wyles suggested that it may be beneficial, especially for coinfected patients, to use 2 separate pills rather than a coformulation so that drug doses can be adjusted independently.

Daclatasvir appears to be active against a wider range of HCV genotypes than ledipasvir, though press conference moderator David Thomas from Johns Hopkins suggested that there have been too few patients with other genotypes in clinical trials to get definitive answers. Genotype 3 patients with cirrhosis remain a difficult-to-treat population. Gilead is working on a new coformulation of sofosbuvir and a next-generation NS5A inhibitor with pangenotypic activity (GS-5816).

2/27/15

References

D Wyles, P Ruane, M Sulkowski, et al. Daclatasvir in Combination With Sofosbuvir for HIV/HCV Coinfection: ALLY-2 Study
. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 151LB.

S Naggie, C Cooper, MS Saag, et al. Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected With HCV and HIV-1. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 152LB.