Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study

Background. There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)–containing ART

Ombitasvir, paritaprevir, and ritonavir plus ribavirin in adults with hepatitis C virus genotype 4 infection and cirrhosis (AGATE-I): a multicentre, phase 3, randomised open-label trial

Background Hepatitis C virus (HCV) genotype 4 infection is most commonly reported in sub-Saharan Africa and the Middle East; however, prevalence is increasing worldwide through immigration. HCV genotype 4 accounts for 20% of all infections, but clinical trial data for treatment remain limited. We assessed the combination of two direct-acting antivirals, ombitasvir (NS5A inhibitor) and paritaprevir (NS3/4A protease inhibitor; co-dosed with ritonavir) plus ribavirin in patients with HCV genotype 4 infection and compensated cirrhosis. Methods In this multicentre, randomised, open-label phase 3 trial (AGATE-I), treatment-naive and interferon or pegylated interferon and ribavirin treatment-experienced patients with HCV genotype 4 infection and compensated cirrhosis were recruited from academic, public, and private hospitals in Austria, Belgium, Canada, France, Germany, Greece, Italy, and the USA. Key eligibility criteria were age 18 years or older, with chronic HCV infection assessed by the presence of anti-HCV antibodies or HCV RNA. Patients were randomly assigned (1:1) to receive 25 mg ombitasvir, 150 mg paritaprevir, and 100 mg ritonavir once daily, with weight-based ribavirin dosed twice daily for either 12 weeks or 16 weeks. Randomisation was stratified by HCV treatment history (treatment-experienced vs treatment-naive patients) and further stratified by type of non-response to previous HCV treatment (null responders, partial responders, or relapsers) for treatment-experienced patients. Treatments were assigned by an interactive response technology system with computer-generated randomisation lists prepared by personnel from the study's funding sponsor who were not involved with the conduct of the study or with data analysis. The primary outcome was the proportion of patients with a sustained virological response (HCV RNA <25 IU/mL) at post-treatment week 12 (SVR12) in the intention-to-treat population, with the lower 97·5% CI compared with a clinically relevant threshold (67%; based on SVR reported for pegylated interferon and ribavirin) to achieve superiority. The safety population included all patients who received at least one dose of study drug, and safety analyses were done by the treatment duration received (12 weeks or 16 weeks). Data presented are from the planned primary interim analysis of part one of the study when all patients enrolled in part one had reached post-treatment week 12 or prematurely discontinued from the study. This trial is registered with ClinicalTrials.gov, number NCT02265237, and part two of the trial is ongoing but closed to new participants. Findings Between Nov 18, 2014, and May 19, 2015, we enrolled 120 eligible patients, with 59 patients assigned to receive 12 weeks of treatment and 61 patients assigned to receive 16 weeks of treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. One patient in the 12-week group experienced virological breakthrough and one discontinued prematurely after the first day of treatment. One patient missed the post-treatment week 12 visit in the 16-week group. SVR12 was achieved in 57 (97%; 97·5% CI 86·7–99·2) of 59 patients in the 12-week group and 60 (98%; 89·6–99·8) of 61 in the 16-week group. Adverse events in more than 10% of all patients were asthenia (11 [18%] of 60 in the 12-week group; 19 [32%] of 60 in the 16-week group), fatigue (ten [17%] in the 12-week group; 20 [33%] in the 16-week group), headache (14 [23%] in the 12-week group; 14 [23%] in the 16-week group), anaemia (nine [15%] in the 12-week group; 12 [20%] in the 16-week group), pruritus (five [8%] in the 12-week group; 14 [23%] in the 16-week group), nausea (six [10%] in the 12-week group; eight [13%] in the 16-week group), and dizziness (four [7%] in the 12-week group; nine [15%] in the 16-week group). Interpretation With SVR12 achieved in a high proportion of patients, no post-treatment relapses, and a similar adverse event profile for the 12-week and 16-week treatment groups, extending treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin beyond 12 weeks seems to have no additional benefit for patients with HCV genotype 4 infection and compensated cirrhosis and might not be necessary for this patient group. Funding AbbVie.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Ombitasvir/paritaprevir/ritonavir plus ribavirin for 24 weeks in patients with HCV GT4 and compensated cirrhosis (AGATE-I Part II)

Background and Aims: AGATE-I Part I previously reported high sustained virologic response rates in hepatitis C genotype 4 patients with cirrhosis, with 12 and 16 weeks' treatment with a combination of two direct-acting antivirals, ombitasvir and paritaprevir (codosed with ritonavir), plus ribavirin. Part II, reported here, extended the trial to include a 24-week treatment arm to fully assess treatment duration in patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis. Methods: Enrollment took place between June and November of 2015. Treatment-naive and interferon-experienced patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis were enrolled into Arm C; patients previously treated with a sofosbuvir-based regimen were enrolled into Arm D. All patients received a 24-week treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. The primary outcome was the proportion of patients with a sustained virologic response (hepatitis C virus RNA < 25 IU/mL) at posttreatment week 12 in the intention-to-treat population. The safety population included all patients who received at least one dose of study drug. Results: In total, 64 patients were enrolled into AGATE-I Part II. Sustained virologic response at posttreatment week 12 was achieved in 57 of 61 patients (93.4%; 97.5% confidence interval, 92.6-97.7) in Arm C and 3 of 3 patients (100%) in Arm D. Two patients were missing SVR12 data, and two prematurely discontinued treatment. The most common adverse events for Arm C were fatigue (16 [26%]) and asthenia (15 [25%]). Results were comparable with those reported in Part I. Conclusions: AGATE-I Part II indicates that extending treatment beyond 12 weeks in genotype 4–infected patients with compensated cirrhosis does not offer additional benefit.SCOPUS: ar.jinfo:eu-repo/semantics/publishe