Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study.

BACKGROUND: For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings. METHODS: A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715. FINDINGS: Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10·3% (95% CI 6·5-14·0) in the raltegravir group and 12·4% (8·3-16·5) in the NRTI group, with a weighted difference of -3·4% (-8·4 to 1·5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes. INTERPRETATION: In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity. FUNDING: National Institutes of Health.

Prevalence of hepatitis B and C seropositivity in a Nigerian cohort of HIV-infected patients.

INTRODUCTION: The clinical and public health implications of the convergence of the human immunodeficiency virus (HIV) epidemic and chronic viral hepatitis in sub-Saharan Africa are poorly understood. This study was designed to determine the seroprevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV), and the impact of co-infection on baseline serum alanine transaminase (ALT), CD4+ T lymphocyte (CD4) count, and plasma HIV-RNA (viral load) in a cohort of HIV-infected Nigerians. METHODS: A retrospective study was conducted, on eligible treatment-naive patients who presented between August 2004 and February 2007 to the University College Hospital (UCH), Ibadan, Nigeria. Demographic data and pre-treatment laboratory results (hepatitis B surface antigen (HBsAg), HCV antibodies (anti-HCV), ALT, CD4 count and viral load) were retrieved from the medical records. Fisher's exact, two sample t-tests, and the Wilcoxon rank sum tests were used to compare groups. A logistic regression model was fitted to explore characteristics associated with co-infection status. RESULTS: A total of 1779 HIV-infected patients (male: female ratio, 1:2) met inclusion criteria. HBsAg was present in 11.9%, anti-HCV in 4.8% and both markers in 1%. HBsAg was more common among males than females (15.4% vs 10.1%, respectively p = 0.001) while anti-HCV was detected in a similar proportion of males and females (5.3% versus 4.6%, respectively p = 0.559). HIV-infected patients with anti-HCV alone had a lower mean baseline CD4 count compared to those without anti-HCV or HBsAg (197 cells/mm3 vs 247 cells/mm3, respectively p = 0.008). Serum ALT was higher among patients with HBsAg compared to those without HBsAg or anti-HCV (43 International Units (IU) vs. 39 IU, respectively p = 0.015). Male gender was associated with HBV co-infection on logistic regression (OR1.786; 95% CI, 1.306-2.443; p < 0.005). CONCLUSION: More HIV-infected females than males presented for care in this cohort. We identified a relatively high prevalence of HBV and HCV co-infection in general, and a higher rate of HBV co-infection among males than females. Pre-treatment CD4 count was significantly lower among those with HCV co-infection, while ALT was slightly higher among those with HBV co-infection. Triple infection with HIV, HBV and HCV was present in a small but significant proportion of patients. These findings underscore the importance of testing for HBV and HCV in all HIV-infected persons in our setting.