HPTN 071 (PopART): a cluster-randomized trial of the population impact of an HIV combination prevention intervention including universal testing and treatment: mathematical model

Abstract

Background: The HPTN 052 trial confirmed that antiretroviral therapy (ART) can nearly eliminate HIV transmission from successfully treated HIV-infected individuals within couples. Here, we present the mathematical modeling used to inform the design and monitoring of a new trial aiming to test whether widespread provision of ART is feasible and can substantially reduce population-level HIV incidence.

Methods and findings: The HPTN 071 (PopART) trial is a three-arm cluster-randomized trial of 21 large population clusters in Zambia and South Africa, starting in 2013. A combination prevention package including home-based voluntary testing and counseling, and ART for HIV positive individuals, will be delivered in arms A and B, with ART offered universally in arm A and according to national guidelines in arm B. Arm C will be the control arm. The primary endpoint is the cumulative three-year HIV incidence. We developed a mathematical model of heterosexual HIV transmission, informed by recent data on HIV-1 natural history. We focused on realistically modeling the intervention package. Parameters were calibrated to data previously collected in these communities and national surveillance data. We predict that, if targets are reached, HIV incidence over three years will drop by >60% in arm A and >25% in arm B, relative to arm C. The considerable uncertainty in the predicted reduction in incidence justifies the need for a trial. The main drivers of this uncertainty are possible community-level behavioral changes associated with the intervention, uptake of testing and treatment, as well as ART retention and adherence.

Conclusions: The HPTN 071 (PopART) trial intervention could reduce HIV population-level incidence by >60% over three years. This intervention could serve as a paradigm for national or supra-national implementation. Our analysis highlights the role mathematical modeling can play in trial development and monitoring, and more widely in evaluating the impact of treatment as prevention.

Figure 1. Model structure for susceptible men.

A. Flow diagram of the model. Arrows depict the different flow rates between compartments. Men can be circumcised during childhood (i.e., before the age of 15). If they are not, they can be circumcised following a negative HIV test. Upon testing, some HIV negative men decide to get circumcised. They then enter a “waiting” stage, which encompasses the time from testing to them actually visiting the clinic for circumcision. After circumcision, they go through a healing period, before being circumcised and healed. B. Relative susceptibility and infectivity in the different stages, relative to an uncircumcised man. Relative susceptibility and infectivity of circumcised men in healing period incorporate both biological increases in susceptibility and infectivity and reduction in sexual activity during the healing period (see main text).

Figure 2. Model structure for infected individuals.

A. Flow diagram of the model. The model describes progression through different stages of natural history and treatment. Arrows depict the different flow rates between compartments. Once infected, individuals enter an early/acute infection stage and then progress to death through 4 stages of infection shown in b. At any stage after acute infection, individuals can get HIV tested, following which a proportion of individuals will decide to seek care. Those individuals then enter the “treatment pending” stage, during which they visit the clinic and get assessed towards ART eligibility. Once assessed, all those eligible initiate treatment. Once on treatment, individuals go through a first phase during which viral load is not fully suppressed, before becoming successfully treated, that is, having a negligible viral load. Individuals on ART can drop out of or fail treatment; they then go back to the pre-test stages. B. Flow diagram of the four stages of infection following acute infection and leading to death. Those stages are defined by the level of CD4 in cells/mm3. Individuals can only move from a higher to a lower CD4 count. The rate of progressing through those stages is different for treated and untreated individuals (see File S1). C. Relative infectivity (on the log scale) of the different stages, compared to an undiagnosed individual with CD4≥350, not in acute infection. Individuals in acute infection and stage 4 (CD4<200) have an increased infectivity. Individuals on ART have a decreased infectivity.

Figure 3. Model fit and projections under central target scenario for Zambia (top row) and South Africa (bottom row).

Left panels show HIV prevalence and right panels show annualized HIV incidence over time. The red, blue and black lines correspond to arms A, B and C respectively. The grey dots and error bars are the UNAIDS HIV prevalence estimates .

Figure 4. Uncertainty on the trial outcome in Zambia (top panels) and South Africa (bottom panels).

The red and blue histograms show the relative reduction in 3-year cumulative incidence in arms A and B respectively when parameters vary within ranges shown in Table 1. The left panels show results obtained when all parameters are varied, and the right panels when assuming no population-level behavioural changes associated with the intervention.