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AASLD 2014: AbbVie 3D Regimen and Sofosbuvir/ Ribavirin Show High Cure Rates for HIV/HCV Coinfection

AbbVie's 3D regimen (paritaprevir/ombitasvir/ritonavir plus dasabuvir) with ribavirin for 12 weeks and Gilead Science's sofosbuvir (Sovaldi) plus ribavirin for 24 weeks both produced good sustained virological response rates for most patients with HIV and hepatitis C virus (HCV) coinfection, according to studies presented at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting last week in Boston.

HIV/HCV coinfected people tend to experience more rapid liver disease progression and traditionally were considered more difficult to treat using interferon-based therapy. With the advent of all-oral direct-acting antiviral regimens, however, a growing body of evidence indicates that coinfected patients respond as well as people with hepatitis C alone.

TURQUOISE-I: 3D + Ribavirin

David Wyles from the University of California at San Diego and fellow investigators presented a poster outlining results from the Phase 2 portion of AbbVie's combined Phase 2/3 TURQUOISE-I trial. This study tested the all-oral 3D regimen -- expected to be approved soon in the U.S. and Europe -- for previously untreated and treatment-experienced HIV/HCV genotype 1 coinfected patients with and without compensated liver cirrhosis.

3D consists of the HCV NS3/4A protease inhibitor paritaprevir (ABT-450), NS5A inhibitor ombitasvir (ABT-267), and a ritonavir booster in a once-daily coformulation, taken with the twice-daily non-nucleoside HCV NS5B polymerase inhibitor dasabuvir (ABT-333). In this open-label trial, 63 participants were randomly assigned to receive 3D plus weight-based ribavirin for either 12 or 24 weeks.

TURQUOISE-I was conducted in the U.S. including Puerto Rico. Most study participants were men, three-quarters were white, and the average age was 51 years. Two-thirds were treatment-naive and one-third had previously tried interferon-based therapy, including prior relapsers (about 6%), partial responders (about 11%), and null responders (about 16%). More than 90% had harder-to-treat HCV subtype 1a, about 80% had unfavorable IL28B gene variants, and 19% had cirrhosis. People triply infected with hepatitis B virus were excluded.

Participants had a high mean CD4 T-cell count of approximately 630 cells/mm³. They were taking stable suppressive antiretroviral therapy (ART) containing tenofovir/emtricitabine (the drugs in Truvada) plus either atazanavir (Reyataz) or raltegravir (Isentress), which were found to have no clinically relevant interactions with the AbbVie HCV drugs. People taking atazanavir stopped taking stand-alone ritonavir, as it is included in the paritaprevir/ombitasvir coformulation.

Results

• At 12 weeks post-treatment, 94% of participants in the 12-week treatment arm and 91% in the 24-week arm achieved sustained virological response (SVR12), or continued undetectable HCV viral load.
• In both arms combined, SVR12 rates were 91% among patients with HCV subtype 1a and 100% among those with subtype 1b.
• In the 12-week arm, 1 patient relapsed at post-treatment week 4 and 1 person withdrew consent before finishing treatment; in the 24-week arm, 1 person experienced viral breakthrough during treatment and 2 appeared to be reinfected with different HCV strains.
• Both the relapser and the patient with viral breakthrough were prior null responders with cirrhosis, and both had treatment-emergent NS3/4A, NS5A and NS5B resistance-associated viral variants.
• The 3D regimen plus ribavirin was generally safe and well-tolerated, with no serious adverse events and no treatment discontinuations for this reason.
• The most common side effects were fatigue, insomnia, nausea, and headache.
• Two-thirds of patients experienced elevated bilirubin levels and about 11% developed moderate anemia; 6 people reduced their ribavirin doses due to anemia, but all went on to achieve SVR12.

"The high rates of virologic response and low rates of treatment discontinuation in the broadly representative cohort of HIV/HCV coinfected patients are consistent with results reported for the 3D + ribavirin combination in patients with HCV genotype 1 infection alone," the researchers concluded.

They added that the lower frequency of anemia seen in this study compared to prior studies of interferon-based therapy for coinfected patients "is likely due to the absence of the bone marrow suppressant effect of interferon."

The Phase 2 portion of TURQUOISE-I is ongoing with coinfected patients receiving the HIV protease inhibitor darunavir (Prezista). The international Phase 3 portion is currently recruiting participants.

PHOTON-1 and -2: Sofosbuvir + Ribavirin

Jürgen Rockstroh from the University of Bonn presented final combined results from the Phase 3 PHOTON trials, which evaluated a dual oral regimen of the nucleotide HCV polymerase sofosbuvir plus ribavirin. Sofosbuvir's FDA-approved indication is the same for HIV/HCV coinfected patients and those with HCV alone.

PHOTON-1 was conducted in the U.S. and PHOTON-2 took place in Europe and Australia. The 2 studies combined included a total of 497 participants. About 80% were men, most were white, and the average age was 48 years. Just under half (46%) had HCV genotype 1, 15% had genotype 2, 33% had genotype 3, and 6% had genotype 4. Most (81%) were previously untreated for hepatitis C, about 60% had unfavorable IL28B variants, and 15% had compensated cirrhosis.

The mean CD4 count was again high (605 cells/mm³) and almost all were on suppressive ART containing tenofovir/emtricitabine plus efavirenz (Sustiva; 30%), raltegravir (20%), boosted darunavir (19%), boosted atazanavir (17%), rilpivirine (Edurant; 5%), or other drugs (8%).

All participants received once-daily sofosbuvir plus ribavirin, with treatment duration determined by genotype:

• Genotype 1: treatment-naive 24 weeks (n=226);
• Genotype 2: treatment-naive 12 weeks (n=45); treatment-experienced 24 weeks (n=30);
• Genotype 3: treatment-naive 12 weeks (n=42) or 24 weeks (n=57); treatment-experienced 24 weeks (n=66);
• Genotype 4: treatment-naive 24 weeks (n=31).

Results

• SVR12 rates were as follows:

o   81% for treatment-naive genotype 1 patients treated for 24 weeks;

o   89% for treatment-naive genotype 2 patients treated for 12 weeks;

o   90% for treatment-experienced genotype 2 patients treated for 24 weeks;

o   67% for treatment-naive genotype 3 patients treated for 12 weeks;

o   91% for treatment-naive genotype 3 patients treated for 24 weeks;

o   88% for treatment-experienced genotype 3 patients treated for 24 weeks;

o   84% for treatment-naive genotype 4 patients treated for 24 weeks.

• Among people with genotype 1, SVR12 rates were 65% and 85% for subtype 1a patients with and without cirrhosis, respectively, compared to 60% and 67% for subtype 1b patients; this is contrary to most studies, which find higher cure rates for people with subtype 1b, but numbers here were small.
• Among people with genotype 2, SVR12 rates were 100% for patients with and 88% for those without cirrhosis in both the treatment-naive 12-week and treatment-experienced 24-week arms.
• Among people with genotype 3, SVR12 rates were 67% for treatment-naive people both with and without cirrhosis treated for 12-weeks; among those treated for 24 weeks, cure rates were 100% and 91%, respectively, for treatment-naive people with and without cirrhosis, and 79% and 95% for treatment-experienced people.
• Among people with genotype 4, SVR12 rates were 88% for those with and 83% for those without cirrhosis.
• Genotype 1 patients with cirrhosis had lower SVR12 rates, as expected; in some comparisons of the other genotypes, people with cirrhosis had numerically higher cure rates -- again contrary to previous studies -- but numbers of cirrhotics were too small to draw statistically valid conclusions.
• Genotype 2 patients had the same SVR12 rates whether they were treated for 12 or 24 weeks.
• Among genotype 3 patients, however, those treated for 24 weeks did better than those treated for the shorter duration.
• Among participants with treatment failure, 70 were due to post-treatment relapse, 3 were due to viral breakthrough during treatment, 6 withdrew consent, and 5 were lost to follow-up.
• The sofosbuvir plus ribavirin regimen was also generally safe and well-tolerated. In both the 12-week and 24-week arms, 6% experienced serious adverse events and 3% discontinued therapy for this reason.
• The most commonly reported side effects were fatigue, insomnia, nausea, and headache.
• About 10% developed moderate anemia, but fewer than 1% had severe anemia. 6 people experienced HIV breakthrough during hepatitis C treatment (2 of whom were non-adherent), but none required ART modification.
• CD4 counts dropped temporarily -- a known effect of ribavirin -- but CD4 percentages remained stable.

"Sofosbuvir + ribavirin resulted in high SVR12 rates in HIV patients coinfected with HCV genotype 1, 2, 3, or 4," the researchers concluded. "Rates were similar to those in HCV monoinfected patients."

Rockstroh noted that adverse event rates in this study were "much lower than anything we saw previously in coinfected patients in the interferon era," which gives support to hepatitis C treatment guidelines that no longer separate HCV monoinfected and HIV/HCV coinfected patients.

Session moderator Anna Lok pointed out that while these results "would have been very exciting a couple years ago," the field has moved on. A sofosbuvir/ledipasvir coformulation (Harvoni) is now available that has shown higher cure rates -- including for coinfected patients -- and eliminates ribavirin and its side effects.

Rockstroh suggested that sofosbuvir plus ribavirin "is likely to remain the standard of care for genotype 2," but for people with other genotypes, "adding another direct-acting antiviral is the way to go," as this may allow shorter treatment which would have a cost benefit.

11/19/14

References

DL Wyles, MS Sulkowski, JJ Eron, et al. TURQUOISE-I: 94% SVR12 in HCV/HIV-1 Coinfected Patients Treated with ABT-450/r/Ombitasvir, Dasabuvir and Ribavirin. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract 1939.

JK Rockstroh, M Puoti, M Rodriguez-Torres, et al. Sofosbuvir and Ribavirin Therapy for the Treatment of HIV/HCV Coinfected Patients with HCV GT1-4 Infection: The PHOTON-1 and -2 Trials. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract 195.

Other Source

AbbVie to Present Rsults from Studies in Chronic Hepatitis C patients with HIV-1 Co-infection (TURQUOISE-I) and Liver Transplant Recipients (CORAL-I) at the Liver Meeting. Press release. November 11, 2014.