Article
Using a network-based approach and targeted maximum likelihood estimation to evaluate the effect of adding pre-exposure prophylaxis to an ongoing Test-and-Treat trial
Clinical Trials
(2017)
Abstract
Background: Several cluster randomized trials are underway to investigate the implementation and effectiveness of a universal test-and-treat strategy on the HIV epidemic in sub-Saharan Africa. We consider nesting studies of pre-exposure prophylaxis (PrEP) within these trials. PrEP is a general strategy where high risk HIV- persons take antiretrovirals daily to reduce their risk of infection from exposure to HIV. We address how to target PrEP to high risk groups and how to maximize power to detect the individual and combined effects of universal test-and-treat and PrEP strategies.
Methods: We simulated 1000 trials, each consisting of 32 villages with 200 individuals per village. At baseline we randomized the universal test-and-treat strategy. Then after three years of follow-up, we considered four strategies for targeting PrEP: (i) all HIV- individuals who self-identify as high risk, (ii) all HIV- individuals who are identified by their HIV+ partner (serodiscordant couples), (iii) highly connected HIV- individuals, and (iv) the HIV- contacts of a newly diagnosed HIV+ individual (a ring-based strategy). We explored two possible trial designs, and all villages were followed for a total of seven years. For each village in a trial, we used a stochastic block model to generate bipartite (male-female) networks and simulated an agent-based epidemic process on these networks. We estimated the individual and combined intervention effects with a novel targeted maximum likelihood estimator, which used cross-validation to data-adaptively select from a pre-specified library the candidate estimator that maximized the efficiency of the analysis.
Results: The universal test-and-treat strategy reduced the three-year cumulative HIV incidence by 4.0% on average. The impact of each PrEP strategy on the four-year cumulative HIV incidence varied by the coverage of the universal test-and-treat strategy with lower coverage resulting in a larger impact of PrEP. Offering PrEP to serodiscordant couples resulted in the largest reductions in HIV incidence (2% reduction), and the ring-based strategy had little impact (0% reduction). The joint effect was larger than either individual effect with reductions in the seven-year incidence ranging from 4.5% to 8.8%. Targeted maximum likelihood estimation, data-adaptively adjusting for baseline covariates, substantially improved power over the unadjusted analysis, while maintaining nominal confidence interval coverage.
Conclusions: Our simulation study suggests that nesting a PrEP study within an ongoing trial can lead to combined intervention effects greater than those of universal test-and-treat alone and can provide information about the efficacy of PrEP in the presence of high coverage of treatment for HIV+ persons.Â
Keywords
- Adaptive pre-specification,
- cluster randomized trials,
- HIV,
- networks,
- pre-exposure prophylaxis (PrEP),
- targeted maximum likelihood estimation (TMLE)
Disciplines
Publication Date
January 3, 2017
Citation Information
Laura Balzer, Patrick Staples, Jukka-Pekka Onnela and Victor De Gruttola. "Using a network-based approach and targeted maximum likelihood estimation to evaluate the effect of adding pre-exposure prophylaxis to an ongoing Test-and-Treat trial" Clinical Trials (2017) Available at: http://works.bepress.com/laura_balzer/38/