Model assumptions of efficacy and uptake for HIV testing, risk behaviour reduction, circumcision and ART in the current standard and the combination interventions.

§<p>Representative values <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone.0054575-Cremin1" target="_blank">[83]</a>, Baseline values of condom use are listed in Table S3 in Supplementary Material.</p>**<p>Treatment initiation at HIV stages with CD4>100 cells/mm³ is immediate when the individual is aware of status and meeting the guideline and is delayed when unaware of status by an average duration that is calibrated to reflect current treatment programs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone.0054575-Mutevedzi1" target="_blank">[37]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone.0054575-Keiser1" target="_blank">[38]</a>.</p

Understanding the Potential Impact of a Combination HIV Prevention Intervention in a Hyper-Endemic Community

<div><h3>Objectives</h3><p>Despite demonstrating only partial efficacy in preventing new infections, available HIV prevention interventions could offer a powerful strategy when combined. In anticipation of combination HIV prevention programs and research studies we estimated the population-level impact of combining effective scalable interventions at high population coverage, determined the factors that influence this impact, and estimated the synergy between the components.</p> <h3>Methods</h3><p>We used a mathematical model to investigate the effect on HIV incidence of a combination HIV prevention intervention comprised of high coverage of HIV testing and counselling, risk reduction following HIV diagnosis, male circumcision for HIV-uninfected men, and antiretroviral therapy (ART) for HIV-infected persons. The model was calibrated to data for KwaZulu-Natal, South Africa, where adult HIV prevalence is approximately 23%.</p> <h3>Results</h3><p>Compared to current levels of HIV testing, circumcision, and ART, the combined intervention with ART initiation according to current guidelines could reduce HIV incidence by 47%, from 2.3 new infections per 100 person-years (pyar) to 1.2 per 100 pyar within 4 years and by almost 60%, to 1 per 100 pyar, after 25 years. Short-term impact is driven primarily by uptake of testing and reductions in risk behaviour following testing while long-term effects are driven by periodic HIV testing and retention in ART programs. If the combination prevention program incorporated HIV treatment upon diagnosis, incidence could be reduced by 63% after 4 years and by 76% (to about 0.5 per 100 pyar) after 15 years. The full impact of the combination interventions accrues over 10–15 years. Synergy is demonstrated between the intervention components.</p> <h3>Conclusion</h3><p>High coverage combination of evidence-based strategies could generate substantial reductions in population HIV incidence in an African generalized HIV epidemic setting. The full impact could be underestimated by the short assessment duration of typical evaluations.</p> </div

Projections of the impact of Combination I intervention on HIV incidence.

<p>(<b>A</b>) A 15-year incidence projections with the continuation of the intervention (arrows indicate the rounds of community HIV testing which are every four years) compared to incidence projections under individual intervention components (<b>B</b>) Projected incidence rate ratio (IRR) (colour coded) in year 4 with respect to current practice incidence at different assumptions of risk behaviour reduction following HIV diagnosis in the community testing relative to the risk behaviour reduction in the current standard and average duration of sustainability of this behaviour change. A ratio of risk behaviour reduction of 1 indicates equal behaviour change among newly HIV-diagnosed adults in community and in venue (current standard) testing. Incidence reductions of more than 50% (IRR<0.5) are delineated and the star marks IRR value with risk behaviour change assumptions as in (A) and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone-0054575-t002" target="_blank">Table 2</a>, (<b>C</b>) Projections of percentage reduction in incidence of the Combination I intervention with respect to current standard incidence projection of 2.1 (1.9–2.3) per 100 pyar at year 15 with various assumptions of failure to achieve the uptake levels of the interventions in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone-0054575-t002" target="_blank">Table 2:</a> (Ia) decreasing testing uptake to 60% in community testing rounds, (Ib) doubling the drop out rate on treatment to 28% per year, (Ic) halving the uptake of circumcision to 35% of uncircumcised men, and (Id) assuming no risk behaviour change following HIV diagnosis generated by testing.</p

Calculated values of the synergy measure (‘<i>Synergy’, </i><b><i>Equation 1</i></b><i>)</i> indicating the interaction between circumcision, ART, and risk behaviour reduction following HIV diagnosis in Combination I and Combination II.

<p>To show the synergy between ART and circumcision, the effects of risk behaviour reduction following HIV diagnosis (RBR) are ignored in calculating the dotted lines. <i>Synergy</i> values that are larger than zero (shaded region) indicate positive interaction between the interventions and that they are complementing each other in preventing HIV transmission, while less than zero values indicate that the interventions have redundancy in prevention.</p

Projections of HIV incidence under implementations of single intervention components after one round of community HIV testing.

<p>(A) The individual impacts of risk reduction following HIV diagnosis (behaviour change), ART, and circumcision acting alone as single intervention components. ‘ART only’ designates initiating treatment at CD4 threshold of 350. (B) HIV incidence after implementation of ART initiation at CD4 count threshold of 200, 350, and at any CD4 count for all individuals that have been tested. All Interventions are assumed to commence in 2014. In this figure we assume counterfactually that individuals newly diagnosed with HIV do not reduce risk behaviour except in panel (A) in which the individual impact of risk reduction following HIV diagnosis is studied. Projections at year 15 are also displayed for comparison.</p

Main model assumptions.

<p>Main model assumptions.</p

Calibration of model baseline projections by data from Kwazulu-Natal, South Africa.

<p>Sources of data used to calibrate the baseline model were in A) HIV prevalence among women attending prenatal clinics <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone.0054575-Department3" target="_blank">[46]</a> (dashed lines); HIV prevalence measurement in household-based surveys (crosses) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone.0054575-Shisana1" target="_blank">[36]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone.0054575-Welz1" target="_blank">[47]</a>; estimates of HIV incidence in household-based surveys <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone.0054575-Barnighausen1" target="_blank">[48]</a> (dot). In B) district-wide ART coverage statistics <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone.0054575-Rehle1" target="_blank">[49]</a> were used to calibrate baseline trends of ART recruitment. Multiple sets of parameters that were consistent with these data were identified <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone.0054575-Poole1" target="_blank">[72]</a> and generated model trajectories of baseline prevalence (red lines) and baseline incidence (grey lines) a sample of which is shown here (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054575#pone.0054575.s001" target="_blank">Supplementary Material S1</a>).</p

Cohort demographics and clinical data.

<p>Demographic, clinical and virologic data obtained from 20 MSM providing rectal swabs over 18 weeks. “Positive swabs” indicate swabs in which adenovirus was detected by real-time PCR. Baseline HIV viral load provided as log₁₀ copies/ml plasma on day 1.</p

Baseline serum neutralizing antibody titers by subject.

<p>Serum neutralizing antibody titers to HAdV-35, −5, −26 and −48 in each subject at beginning of study.</p

Adenoviral shedding by study day.

<p>Pattern of HAdV shedding from the lower gastrointestinal tract by study day. Y axis: Log₁₀ HAdV titers from rectal swab material. X-axis: study day. Outlined bars: no typing attempted. Black bars: sequence-based HAdV typing performed. Gray bars: serotyping unsuccessful.</p