UNAIDS established fast-track targets of 73% and 86% viral suppression among human immunodeficiency virus (HIV)-positive individuals by 2020 and 2030, respectively. The epidemiologic impact of achieving these goals is unknown. The HIV-Calibrated Dynamic Model, a calibrated agent-based model of HIV transmission, is used to examine scenarios of incremental improvements to the testing and antiretroviral therapy (ART) continuum in South Africa in 2015. The speed of intervention availability is explored, comparing policies for their predicted effects on incidence, prevalence and achievement of fast-track targets in 2020 and 2030. Moderate (30%) improvements in the continuum will not achieve 2020 or 2030 targets and have modest impacts on incidence and prevalence. Improving the continuum by 80% and increasing availability reduces incidence from 2.54 to 0.80 per 100 person-years (−1.73, interquartile range (IQR): −1.42, −2.13) and prevalence from 26.0 to 24.6% (−1.4 percentage points, IQR: −0.88, −1.92) from 2015 to 2030 and achieves fast track targets in 2020 and 2030. Achieving 90-90-90 in South Africa is possible with large improvements to the testing and treatment continuum. The epidemiologic impact of these improvements depends on the balance between survival and transmission benefits of ART with the potential for incidence to remain high.

For encapsulated bacteria such as Streptococcus pneumoniae, asymptomatic carriage is more common and longer in duration than disease, and hence is often a more convenient endpoint for clinical trials of vaccines against these bacteria. However, using a carriage endpoint entails specific challenges. Carriage is almost always measured as prevalence, whereas the vaccine may act by reducing incidence or duration. Thus, to determine sample size requirements, its impact on prevalence must first be estimated. The relationship between incidence and prevalence (or duration and prevalence) is convex, saturating at 100% prevalence. For this reason, the proportional effect of a vaccine on prevalence is typically less than its proportional effect on incidence or duration. This relationship is further complicated in the presence of multiple pathogen strains. In addition, host immunity to carriage accumulates rapidly with frequent exposures in early years of life, creating potentially complex interactions with the vaccine’s effect. We conducted a simulation study to predict the impact of an inactivated whole cell pneumococcal vaccine—believed to reduce carriage duration—on carriage prevalence in different age groups and trial settings. We used an individual-based model of pneumococcal carriage that incorporates relevant immunological processes, both vaccine-induced and naturally acquired. Our simulations showed that for a wide range of vaccine efficacies, sampling time and age at vaccination are important determinants of sample size. There is a window of favorable sampling times during which the required sample size is relatively low, and this window is prolonged with a younger age at vaccination, and in a trial setting with lower transmission intensity. These results illustrate the ability of simulation studies to inform the planning of vaccine trials with carriage endpoints, and the methods we present here can be applied to trials evaluating other pneumococcal vaccine candidates or comparing alternative dosing schedules for the existing conjugate vaccines.

Little is known about how combining efficacious interventions for human immunodeficiency virus (HIV) prevention could lead to HIV elimination. We used an agent-based simulation model, the HIV calibrated dynamic model, to assess the potential for HIV elimination in South Africa. We examined several scenarios (from continuation of the current status quo to perfect achievement of targets) with differing combinations of male condom use, adult male circumcision, HIV testing, and early antiretroviral therapy (ART). We varied numerous parameters, including the proportion of adult males circumcised, the frequency of condom use during sex acts, acceptance of HIV testing, linkage to health care, criteria for ART initiation, ART viral suppression rates, and loss to follow-up. Maintaining current levels of combination prevention would lead to increasing HIV incidence and prevalence in South Africa, while the perfect combination scenario was projected to eliminate HIV on a 50-year time scale from 2013 to 2063. Perfecting testing and treatment, without changing condom use or circumcision rates, resulted in an 89% reduction in HIV incidence but not elimination. Universal adult male circumcision alone resulted in a 21% incidence reduction within 20 years. Substantial decreases in HIV incidence are possible from sufficient uptake of both primary prevention and ART, but with continuation of the status quo, HIV elimination in South Africa is unlikely within a 50-year time scale.

12For encapsulated bacteria such as Streptococcus pneumoniae, asymptomatic carriage is 13 more common and longer in duration than disease, and hence is often a more convenient 14 endpoint for clinical trials of vaccines against these bacteria. However, using a carriage 15 endpoint entails specific challenges. Carriage is almost always measured as prevalence, 16 whereas the vaccine may act by reducing incidence or duration. Thus, to determine sample 17 size requirements, its impact on prevalence must first be estimated. The relationship between 18 incidence and prevalence (or duration and prevalence) is convex, saturating at 100% 19 prevalence. For this reason, the proportional effect of a vaccine on prevalence is typically less 20 than its proportional effect on incidence or duration. This relationship is further complicated in 21 the presence of multiple pathogen strains. In addition, host immunity to carriage accumulates 22 rapidly with frequent exposures in early years of life, creating potentially complex interactions 23 with the vaccine's effect. We conducted a simulation study to predict the impact of an 24 inactivated whole cell pneumococcal vaccine-believed to reduce carriage duration-on 25 carriage prevalence in different age groups and trial settings. We used an individual-based 26 model of pneumococcal carriage that incorporates relevant immunological processes, both 27 vaccine-induced and naturally acquired. Our simulations showed that for a wide range of 28 vaccine efficacies, sampling time and age at vaccination are important determinants of 29 sample size. There is a window of favorable sampling times during which the required sample 30 size is relatively low, and this window is prolonged with a younger age at vaccination, and in a 31 trial setting with lower transmission intensity. These results illustrate the ability of simulation 32 studies to inform the planning of vaccine trials with carriage endpoints, and the methods we 33

We investigated the impact of the displacement of sexual activity from adherent recipients of an intervention to others within or outside a trial population on the results from hypothetical trials of different sexual behavior interventions. A short-term model of HIV-prevention interventions that lead to female rejection of male partnership requests showed the impact of displacement expected at the start of a trial. An agent-based model, with sexual mixing and other South African specific demographics, evaluated consequences of displacement for sexual behavior interventions targeting young females in South Africa. This model measured the cumulative incidence among adherent, non-adherent, control and non-enrolled females in a hypothetical trial of HIV prevention. When males made more than one attempt to seek a partnership, interventions reduced short-term HIV infection risk among adherent females, but increased it among non-adherent females as well as controls, non-enrolled (females eligible for the trial but not chosen to participate) and ineligible females (females that did not qualify for the trial due to age). The impact of displacement depends on the intervention and the adherence. In both models, the risk to individuals who are not members of the adherent intervention group will increase with displacement leading to a biased calculation for the effect estimates for the trial. Likewise, intent-to-treat effect estimates become nonlinear functions of the proportion adherent.