48-week efficacy and safety of dolutegravir relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis.

BACKGROUND: A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the relative efficacy and safety of dolutegravir (DTG) versus third agents currently recommended by guidelines, including ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV), cobicistat-boosted elvitegravir (EVG/c), ritonavir-boosted lopinavir (LPV/r), raltegravir (RAL), and rilpivirine (RPV), in treatment-naive HIV-1-infected patients. METHODS: A systematic review of published literature was conducted to identify phase 3/4 randomized controlled clinical trials (up to August 2013) including at least one third agent of interest in combination with a backbone nucleoside reverse transcriptase inhibitor (NRTI) regimen. Bayesian fixed-effect network meta-analysis models adjusting for the type of nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate/emtricitabine [TDF/FTC] or abacavir/lamivudine [ABC/3TC]) were used to evaluate week 48 efficacy (HIV-RNA suppression to <50 copies/mL and change in CD4+ cells/µL) and safety (lipid changes, adverse events, and discontinuations due to adverse events) of DTG relative to all other treatments. Sensitivity analyses assessing the impact of NRTI treatment adjustment and random-effects models were performed. RESULTS: Thirty-one studies including 17,000 patients were combined in the analysis. Adjusting for the effect of NRTI backbone, treatment with DTG resulted in significantly higher odds of virologic suppression (HIV RNA<50 copies/mL) and increase in CD4+ cells/µL versus ATV/r, DRV/r, EFV, LPV/r, and RPV. Dolutegravir had better or equivalent changes in total cholesterol, LDL, triglycerides, and lower odds of adverse events and discontinuation due to adverse events compared to all treatments. Random-effects and unadjusted models resulted in similar conclusions. CONCLUSION: Three clinical trials of DTG have demonstrated comparable or superior efficacy and safety to DRV, RAL, and EFV in HIV-1-infected treatment-naive patients. This network meta-analysis suggests DTG is also favorable or comparable to other commonly used third agents (ATV/r, LPV/r, RPV, and EVG/c).

Evaluating effects of method of administration on Walking Impairment Questionnaire.

BACKGROUND: Intermittent claudication resulting from peripheral arterial disease (PAD) can substantially impair walking function. The Walking Impairment Questionnaire (WIQ) assesses patient self-reported difficulty in walking. Currently this questionnaire is validated for interviewer administration only. Since this can be burdensome in a large clinical trial, we examined the effects of alternative methods of administration on patient responses on the WIQ. METHODS: The WIQ, which consists of four subscales (pain severity, distance, speed, stairs), was modified to be self-administered or interviewer-administered by telephone. Patients with PAD were recruited from two sites and randomized into two groups: in group 1 the WIQ was self-administered, then telephone-administered; in group 2 the WIQ was telephone-administered, then self-administered. The two administrations occurred 4 to 7 days apart. Additional measures (SF-36, EQ-5D, and PAD symptom scale) and clinical data were included to further assess the validity of the WIQ and symptoms in patients with claudication. Telephone interviews were conducted by trained interviewers using standardized scripts. Two-week test-retest reliability was assessed for both the self-administered WIQ (group 1) and the telephone-administered WIQ (group 2). RESULTS: Sixty patients were recruited at two sites (n = 30 per group). Seventy-eight percent were men; mean patient age was 67.1 years; and 83% of patients were white. Mean duration of PAD symptoms was 6.8 years. No significant differences were observed in WIQ subscale scores between self administration and telephone administration. No interaction effects between order and method of administration were detected. Cronbach alpha for distance, speed, and stair-climbing subscales ranged from 0.82 to 0.94. Correlations among WIQ subscales and the symptom scale were good (r = -0.34 to -0.57). Correlations of WIQ subscales with physical health subscales of the SF-36 (r = 0.24-0.59) were higher than for mental health-related subscales (r = 0.08-0.26). CONCLUSIONS: The modified WIQ demonstrated good reliability and validity with both methods of administration. These results suggest that the self-administered and telephone-administered versions of the WIQ can be used reliably and efficiently in clinical trials.