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.

Building capacity for the assessment of HIV drug resistance: experiences from the PharmAccess African Studies to Evaluate Resistance network.

The PharmAccess African Studies to Evaluate Resistance (PASER) network was established as a collaborative partnership of clinical sites, laboratories, and research groups in 6 African countries; its purpose is to build research and laboratory capacity in support of a coordinated effort to assess population-level acquired and transmitted human immunodeficiency virus type-1 drug resistance (HIVDR), thus contributing to the goals of the World Health Organization Global HIV Drug Resistance Network. PASER disseminates information to medical professionals and policy makers and conducts observational research related to HIVDR. The sustainability of the network is challenged by funding limitations, constraints in human resources, a vulnerable general health infrastructure, and high cost and complexity of molecular diagnostic testing. This report highlights experiences and challenges in the PASER network from 2006 to 2010.

Genotype assays and third-line ART in resource-limited settings: a simulation and cost-effectiveness analysis of a planned clinical trial.

OBJECTIVES: To project the clinical and economic outcomes of a genotype assay for selection of third-line antiretroviral therapy (ART) in resource-limited settings, as per the planned international A5288 trial (MULTI-OCTAVE). METHODS: We used the Cost-effectiveness of Preventing AIDS Complications (CEPAC)-International Model to compare three strategies for patients who have failed second-line ART in South Africa: sustained second-line: no genotype assay, all patients remain on second-line ART; A5288: genotype to determine the resistance profile and assign an appropriate regimen; or population-based third-line: no genotype, all patients switch to a potent third-line regimen. Model inputs are from published data in South Africa. Resistance profiles, ART regimens, and efficacy data were those used for trial planning. RESULTS: Projected life expectancy for sustained second-line, A5288, and population-based third-line are 61.1, 103.8, and 104.2 months. Compared to sustained second-line ($12 ,460), per person lifetime costs increase for the A5288 ($39, 250) and population-based ($44, 120) strategies. The incremental cost-effectiveness ratio of A5288, compared to sustained second-line, is $7500/year of life saved (YLS), and for population-based third-line, compared to A5288, is $154 ,500/YLS. In the A5288 strategy, very late presentation to care, coupled with lengthy delays to obtain the genotype, dramatically reduces 5-year survival, making the population-based third-line strategy more attractive. CONCLUSIONS: We project that, whereas the public health approach to third-line therapy is unaffordable, genotype assays and third-line ART in resource-limited settings will increase survival and be cost-effective compared to the population-based approach, supporting the value of an efficacy study.