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ICAAC 2012: HCV Polymerase Inhibitor Sofosbuvir Appears Safe and Effective for HIV/HCV Coinfected People

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HIV/HCV coinfected people taking the experimental hepatitis C virus (HCV) polymerase inhibitor sofosbuvir (formerly GS-7977) experienced a rapid decline in HCV viral load similar to that seen in HIV negative patients, researchers reported this week at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) in San Francisco. Side effects were also similar, and there was no sign of interactions with antiretroviral drugs in this 14-day study

HIV positive people with hepatitis C tend to experience more rapid liver disease progression than HIV negative individuals and do not respond as well to interferon-based treatment. Adding new direct-acting anti-HCV drugs can improve response, but raises concerns about worse toxicity and interactions with HIV drugs that could potentially compromise their effectiveness. Furthermore, many coinfected people are considered ineligible for interferon-based therapy or cannot tolerate its side effects and are eagerly awaiting more effective interferon-free regimens.

Sofosbuvir is a once-daily nucleotide analog HCV NS5B polymerase inhibitor active against multiple HCV genotypes. Studies of HIV negative people with hepatitis C have shown that sofosbuvir alone or in combination with ribavirin, pegylated interferon, or other direct-acting HCV drugs is well tolerated and has a high cure rate.

It ICAAC, Stephen Rossi, PharmD, from Gilead Sciences presented the first data on sofosbuvir in HIV/HCV coinfected people. This Phase 1b trial looked hepatitis C viral kinetics (speed and slope of viral decline) while taking 400 mg sofosbuvir once-daily for 7 days. Researchers also assessed tolerability, effect on HIV control, and drug-drug interactions with antiretrovirals.

The study included 30 HIV/HCV coinfected patients in Puerto Rico. About 80% were men, 57% were white, 43% were black, and the average age was 53 years. Half had difficult-to-treat HCV genotype 1a, 7 had genotype 1b, 4 had genotype 2, 3 had genotype 3, and 1 had genotype 4.

Participants were on stable antiretroviral therapy for at least 4 weeks and all but 1 had undetectable HIV viral load. They had well-preserved immune function with a median CD4 T-cell count of 600 cells/mm3, a median CD4 cell percentage of 31%, and no opportunistic infections or other HIV complications during the past 6 months.

The most common antiretroviral regimen, taken by one-third of participants, was efavirenz/tenofovir/emtricitabine (the drugs in the Atripla coformulation). In addition, 8 were taking ritonavir-boosted atazanavir (Reyataz) plus tenofovir/emtricitabine (the drugs in Truvada), 3 were taking raltegravir (Isentress) plus tenofovir/emtricitabine, and the rest were on other regimens.

Results

  • HCV viral load declined rapidly after starting sofosbuvir, falling by more than 2 logIU/mL during the first 24 hours.
  • The median decline was more than 4 logIU/mL at the end of the 7-day dosing period.
  • HCV RNA continued to drop for 2 more days after stopping sofosbuvir and then began to increase, but did not return to the baseline level by the end of follow-up at 14 days.
  • On the last day of dosing, approximately 40% of participants had undetectable HCV viral load.
  • This proportion approached 60% at 2 days after stopping the drug and remained at about 15% on the last day of follow-up.
  • This pattern of decline was similar for all HCV genotypes and was generally consistent regardless of antiretroviral regimen.
  • Viral kinetics also matched those seen in prior studies of HIV negative patients with hepatitis C alone.
  • Black patients, who do not do as well on interferon-based therapy, responded as well as white patients to sofosbuvir.
  • Responses according to IL28B status was not presented, but Rossi said a large proportion of people in Puerto Rico have the unfavorable C/C gene pattern.
  • Sofosbuvir was generally well-tolerated in this short study, with a safety profile similar to that of HCV monoinfected patients.
  • All adverse events were mild-to-moderate, and no single side effect was seen in more than 1 participant.
  • There were no treatment-emergent grade 3-4 laboratory abnormalities and no significant change in hematological parameters (an important consideration as some HCV drugs can cause anemia or neutropenia).
  • No evidence of HIV breakthrough was observed, and all participants who started with undetectable HIV RNA maintained viral suppression.
  • 4 people experienced HIV blips, but these subsequently fell below the level of detection.
  • There were also no clinically significant changes in absolute CD4 cell count or CD4 percentage. 

"Comparable HCV early viral kinetics was observed in HIV/HCV-  and HCV- infected patients and support further study of sofosbuvir in HIV/HCV co-infected patients," the researchers concluded.

Analysis of sofosbuvir interactions with antiretroviral therapy is underway, but the modest side effects and lack of changes in HIV parameters in this study suggests that major concerns are unlikely.

Rossi noted that a Phase 3 trial of sofosbuvir for HIV/HCV coinfected patients is currently enrolling in the U.S. and will start in Europe later this year. The sofosbuvir development program is among the first to test an HCV drug for coinfected people in parallel with HCV monoinfected people. Rossi projected that Gilead may file for FDA approval of sofosbuvir by mid-2013.

9/12/12

Reference

M Rodriguez-Torres, M Gonzalez, S Rossi, et al. HIV/HCV Coinfected and HCV Monoinfected Patients Have Similar Early HCV Viral Kinetics with the Potent HCV Nucleotide Polymerase Inhibitor Sofosbuvir (SOF). 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H1921a.