Resistance at virological failure using boosted protease inhibitors versus nonnucleoside reverse transcriptase inhibitors as first-line antiretroviral therapy--implications for sustained efficacy of ART in resource-limited settings.

BACKGROUND: Increases in the prevalence of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been observed among previously untreated individuals in all areas of sub-Saharan Africa. We aimed to examine whether first-line use of 2 NRTIs plus a boosted protease inhibitor (bPI) could protect against emergence of NRTI resistance mutations, compared to the use of 2 NRTIs plus 1 NNRTI. METHODS: We carried out a weighted meta-analysis of randomized clinical trials comparing bPI- with NNRTI-based first-line antiretroviral therapy regimens using random effects modeling. RESULTS: In intention to treat analyses, there was no difference in the risk of viral failure at week 48 between NNRTI and bPI (P = .19). At week 48, the overall difference between NNRTI- and PI-based regimens in selection of any major NRTI resistance mutation (crude unweighted prevalence 3.3% vs 1.6%) was 1.7% (95% confidence interval [CI], .4-3.0; P = .00927). There was a statistically significant difference in prevalence of K65R when comparing NNRTI (1.3%) with PI (0.67%); absolute weighted difference 1.0% (95% CI, .3-1.7; P = .00447). There was also a significant difference in prevalence of M184V/I between NNRTI and PI (crude unweighted prevalence 3.2% vs 1.4%); difference 1.6% (95% CI 0.1-3.1; P = .0368). CONCLUSIONS: Despite the equivalent efficacy and more favorable resistance implications of PI- versus NNRTI-based first line therapy, widespread use of PI-based first-line therapy is not warranted at this time, due to resource limitations and predicted increased risk of resistance-related failure of NNRTI/NRTI second-line regimens. PI-based first-line therapy could be reconsidered when antiretroviral agents from other classes become available for second-line regimens in resource-limited settings.

Background morbidity in HIV vaccine trial participants from various geographic regions as assessed by unsolicited adverse events.

BACKGROUND: Recently, more clinical trials are being conducted in Africa and Asia, therefore, background morbidity in the respective populations is of interest. Between 2000 and 2007, the International AIDS Vaccine Initiative sponsored 19 Phase 1 or 2A preventive HIV vaccine trials in the US, Europe, Sub-Saharan Africa and India, enrolling 900 healthy HIV-1 uninfected volunteers. OBJECTIVE: To assess background morbidity as reflected by unsolicited adverse events (AEs), unrelated to study vaccine, reported in clinical trials from four continents. METHODS: All but three clinical trials were double-blind, randomized, and placebo-controlled. Study procedures and data collection methods were standardized. The frequency and severity of AEs reported during the first year of the trials were analyzed. To avoid confounding by vaccine-related events, solicited reactogenicity and other AEs occurring within 28 d after any vaccination were excluded. RESULTS: In total, 2134 AEs were reported by 76% of all participants; 73% of all events were mild. The rate of AEs did not differ between placebo and vaccine recipients. Overall, the percentage of participants with any AE was higher in Africa (83%) compared with Europe (71%), US (74%) and India (65%), while the percentage of participants with AEs of moderate or greater severity was similar in all regions except India. In all regions, the most frequently reported AEs were infectious diseases, followed by gastrointestinal disorders. CONCLUSIONS: Despite some regional differences, in these healthy participants selected for low risk of HIV infection, background morbidity posed no obstacle to clinical trial conduct and interpretation. Data from controlled clinical trials of preventive interventions can offer valuable insights into the health of the eligible population.

Does less frequent routine monitoring of patients on a stable, fully suppressed cART regimen lead to an increased risk of treatment failure?

OBJECTIVE: To investigate whether HIV-infected patients on a stable and fully suppressive combination antiretroviral therapy (cART) regimen could safely be monitored less often than the current recommendations of every 3 months. DESIGN: Two thousand two hundred and forty patients from the EuroSIDA study who maintained a stable and fully suppressed cART regimen for 1 year were included in the analysis. METHODS: Risk of treatment failure, defined by viral rebound, fall in CD4 cell count, development of new AIDS-defining illness, serious opportunistic infection or death, in the 12 months following a year of a stable and fully suppressed regimen was assessed. RESULTS: One hundred thirty-one (6%) patients experienced treatment failure in the 12 months following a year of stable therapy, viral rebound occurred in 99 (4.6%) patients. After 3, 6 and 12 months, patients had a 0.3% [95% confidence interval (CI) 0.1-0.5], 2.2% (95% CI 1.6-2.8) and 6.0% (95% CI 5.0-7.0) risk of treatment failure, respectively. Patients who spent more than 80% of their time on cART with fully suppressed viraemia prior to baseline had a 38% reduced risk of treatment failure, hazard ratio 0.62 (95% CI 0.42-0.90, P = 0.01). CONCLUSION: Patients who have responded well to cART and are on a well tolerated and durably fully suppressive cART regimen have a low chance of experiencing treatment failure in the next 3-6 months. Therefore, in this subgroup of otherwise healthy patients, it maybe reasonable to extend visit intervals to 6 months, with cost and time savings to both the treating clinics and the patients.