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

Clin Trials. 2017 Apr;14(2):201-210. doi: 10.1177/1740774516679666. Epub 2017 Jan 26.


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 within these trials. Pre-exposure prophylaxis 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 pre-exposure prophylaxis to high-risk groups and how to maximize power to detect the individual and combined effects of universal test-and-treat and pre-exposure prophylaxis 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 3 years of follow-up, we considered four strategies for targeting pre-exposure prophylaxis: (1) all HIV- individuals who self-identify as high risk, (2) all HIV- individuals who are identified by their HIV+ partner (serodiscordant couples), (3) highly connected HIV- individuals, and (4) 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 7 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 3-year cumulative HIV incidence by 4.0% on average. The impact of each pre-exposure prophylaxis strategy on the 4-year cumulative HIV incidence varied by the coverage of the universal test-and-treat strategy with lower coverage resulting in a larger impact of pre-exposure prophylaxis. Offering pre-exposure prophylaxis 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 7-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.

Conclusion: Our simulation study suggests that nesting a pre-exposure prophylaxis 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 pre-exposure prophylaxis in the presence of high coverage of treatment for HIV+ persons.

Keywords: Adaptive pre-specification; HIV; cluster-randomized trials; networks; pre-exposure prophylaxis; targeted maximum likelihood estimation.

MeSH terms

  • Africa South of the Sahara
  • Anti-HIV Agents / therapeutic use*
  • Computer Simulation
  • Female
  • HIV Infections / diagnosis
  • HIV Infections / drug therapy
  • HIV Infections / prevention & control*
  • Humans
  • Likelihood Functions
  • Male
  • Mass Screening
  • Pre-Exposure Prophylaxis*
  • Randomized Controlled Trials as Topic
  • Research Design
  • Risk Assessment


  • Anti-HIV Agents