High Incidence Is Not High Exposure: What Proportion of Prevention Trial Participants Are Exposed to HIV?

<div><p>Objective</p><p>Randomized clinical trials of HIV prevention in high-risk populations of women often assume that all participants have similar exposure to HIV. However, a substantial fraction of women enrolled in the trial may have no or low exposure to HIV. Our objective was to estimate the proportion of women exposed to HIV throughout a hypothetical high-risk study population.</p><p>Methods</p><p>A stochastic individual-based model was developed to simulate the sexual behavior and the risk of HIV acquisition for a cohort of sexually active HIV-uninfected women in high HIV prevalence settings. Key behavior and epidemic assumptions in the model were based on published studies on HIV transmission in South Africa. The prevalence of exposure, defined as the proportion of women who have sex with HIV-infected partner, and HIV incidence were evaluated.</p><p>Results</p><p>Our model projects that in communities with HIV incidence rate of 1 per 100 person years, only 5-6% of women are exposed to HIV annually while in communities with an HIV incidence of 5 per 100 person years 20-25% of women are exposed to HIV. Approximately 70% of the new infections are acquired from partners with asymptomatic HIV.</p><p>Conclusions</p><p>Mathematical models suggest that a high proportion of women enrolled in HIV prevention trials may be unexposed to HIV even when incidence rates are high. The relationship between HIV exposure and other risk factors should be carefully analyzed when future clinical trials are planned.</p></div

Characteristics of the simulated female cohort based on the last month of sexual activity.

<p>Characteristics of the simulated female cohort based on the last month of sexual activity.</p

Results from each of the simulations conducted under the assumptions in Table 1 are plotted, illustrating A) prevalence of exposure (PoE) and B) HIV incidence among 2000 originally uninfected women (blue), high-risk group (red) and low-risk group (black) over 1-year period for different values of HIV prevalence among male partners in 10 simulations (dots) per male prevalence level and averaged (thick lines); C) Distribution of female HIV acquisitions over 1-year period by the stage of HIV infection of the transmitting male partner; D) Scatter plot of the infected vs. exposed fractions over 1-year period.

<p>All simulations assume assortative mixing between different risk groups when partnerships are formed, i.e. high risk women have greater chance to partner with high risk men and similarly low-risk women partner more often with low-risk men.</p

Parameters values used in the main analysis.

<p>Parameters values used in the main analysis.</p

Sensitivity analysis—ART dropouts reinitiate ART only at CD4<200 cells/μl.

<p><b>A)</b> The fraction of HIV infections averted and <b>B)</b> The fraction of HIV-related deaths averted over the 10 year period when ART initiation rate is increased or ART dropout rate is decreased to achieve a final ART coverage of 55% or 62%. HIV-attributable mortality and disease progression rates in assumption A reduced by 50% on ART vs. off ART instead of 90%: <b>C)</b> The fraction of HIV infections averted and <b>D)</b> The fraction of HIV-related deaths averted over the 10 year period when ART initiation rate is increased or ART dropout rate is decreased to achieve a final ART coverage of 55% or 90%.</p

Projections from progression assumptions A-D.

<p><b>A)</b> The fraction of HIV infections averted and <b>B)</b> The fraction of HIV-related deaths averted over the 10 year period when increasing ART uptake rate (<i>ε</i>, solid lines) or decreasing ART dropout rate (<b><i>θ</i></b>, dashed lines) to obtain final ART coverage shown.</p

Model fitting data: Baseline values, sensitivity analysis ranges, and sources.

<p>Model fitting data: Baseline values, sensitivity analysis ranges, and sources.</p

Assumption-specific parameter symbols, definitions, baseline values, and sources.

<p>Assumption-specific parameter symbols, definitions, baseline values, and sources.</p

General parameter symbols, definitions, baseline values, sensitivity analysis ranges, and sources.

<p>General parameter symbols, definitions, baseline values, sensitivity analysis ranges, and sources.</p

Model diagrams.

<p><b>X)</b> General model structure showing only what is consistent across all progression assumptions, A, B, C, and D. The following model diagrams show only the ART compartments (A_i) and ART dropout compartments (D_i) and do not show mortality. Key differences are highlighted in red. <b>A)</b> <i>Progression assumption A</i>: ART reduces disease progression rate (<i>σ</i>_i) by a factor <b><i>τ</i></b> while ART dropouts progress at the same rate as ART-naive individuals (<i>δ</i> = 1). <b>B)</b> <i>Progression assumption B</i>: There is no movement between ART compartments; prognosis depends on CD4 at ART initiation. <b>C)</b> <i>Progression assumption C</i>: ART patients progress to higher CD4 categories over time at a per-capita rate <i>ψ</i>_i and the rest is as in progression assumption A. <b>D)</b> <i>Progression assumption D</i>: As in assumption B, there is no movement between ART compartments. However, upon dropping out of ART, individuals move to a higher CD4 category (reflecting improvement in CD4 count on ART) but then progress at an increased rate compared to ART-naive individuals (<i>δ</i>>1; reflecting the rapid CD4 decline which occurs after dropping out of ART).</p