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Per-protocol analysis of the ZINC trial for HIV disease among alcohol users
Sara Lodi1, Matthew Freiberg2, Natalia Gnatienko3
1Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA, 02118, USA. slodi@bu.edu.
Background:
The Zinc for INflammation and Chronic disease in HIV (ZINC) trial randomized person who live with HIV (PLWH) who engage in heavy drinking to either daily zinc supplementation or placebo. The primary outcome was change in the Veterans Aging Cohort Study (VACS) index, a predictor of mortality, between baseline and 18 months. Because adherence and follow-up were suboptimal, the intention-to-treat analysis, which was not statistically significant, may have underestimated the effect of the zinc supplementation.
Objective:
We estimated the per-protocol effect of zinc versus placebo in the ZINC trial (i.e., the effect that would have been observed if all participants had had high adherence and none was lost to follow-up).
Methods:
Adherence was measured as the self-reported percentage of pills taken in the previous 6 weeks and assessed at all post-baseline visits. We used inverse probability weighting to estimate and compare the change in the VACS index at 18 months in the zinc and placebo groups, had all the trial participants had high adherence (i.e., cumulative adherence ≥80% at 18 months). To examine trends by level of adherence, we rerun the analyses using thresholds for high adherence of 70% and 90% of average self-reported pill coverage.
Results:
The estimated (95% confidence interval) change in the VACS index was - 2.16 (- 8.07, 3.59) and 5.84 (0.73, 11.80) under high adherence and no loss to follow-up in the zinc and placebo groups, respectively. The per-protocol effect estimate of the mean difference in the change between the zinc and placebo groups was - 8.01 (- 16.42, 0.01), somewhat larger than the intention-to-treat effect difference in change (- 4.68 (- 9.62, 0.25)), but it was still not statistically significant. The mean difference in the change between individuals in the zinc and placebo groups was - 4.07 (- 11.5, 2.75) and -12.34 (- 20.14, -4.14) for high adherence defined as 70% and 90% of pill coverage, respectively.
Conclusions:
Overall, high adherence to zinc was associated with a lower VACS score, but confidence intervals were wide and crossed 0. Further studies with a larger sample size are needed to quantify the benefits of zinc supplementation in this population.
Trial Registration:
ClinicalTrials.gov NCT01934803 . Registered on August 30, 2013.
