Publications

Background
The rapid scale-up of antiretroviral therapy (ART) towards the UNAIDS 90-90-90 goals over the last decade has sparked considerable debate as to whether universal test and treat can end the HIV-1 epidemic in sub-Saharan Africa. We aimed to develop a network transmission model, calibrated to capture age-specific and sex-specific gaps in the scale-up of ART, to estimate the historical and future effect of attaining and surpassing the UNAIDS 90-90-90 treatment targets on HIV-1 incidence and mortality, and to assess whether these interventions will be enough to achieve epidemic control (incidence of 1 infection per 1000 person-years) by 2030.

Methods
We used eSwatini (formerly Swaziland) as a case study to develop our model. We used data on HIV prevalence by 5-year age bins, sex, and year from the 2007 Swaziland Demographic Health Survey (SDHS), the 2011 Swaziland HIV Incidence Measurement Survey, and the 2016 Swaziland Population Health Impact Assessment (PHIA) survey. We estimated the point prevalence of ART coverage among all HIV-infected individuals by age, sex, and year. Age-specific data on the prevalence of male circumcision from the SDHS and PHIA surveys were used as model inputs for traditional male circumcision and scale-up of voluntary medical male circumcision (VMMC). We calibrated our model using publicly available data on demographics; HIV prevalence by 5-year age bins, sex, and year; and ART coverage by age, sex, and year. We modelled the effects of five scenarios (historical scale-up of ART and VMMC [status quo], no ART or VMMC, no ART, age-targeted 90-90-90, and 100% ART initiation) to quantify the contribution of ART scale-up to declines in HIV incidence and mortality in individuals aged 15–49 by 2016, 2030, and 2050.

Findings
Between 2010 and 2016, status-quo ART scale-up among adults (aged 15–49 years) in eSwatini (from 34·0% in 2010 to 74·1% in 2016) reduced HIV incidence by 43·57% (95% credible interval 39·71 to 46·36) and HIV mortality by 56·17% (54·06 to 58·92) among individuals aged 15–49 years, with larger reductions in incidence among men and mortality among women. Holding 2016 ART coverage levels by age and sex into the future, by 2030 adult HIV incidence would fall to 1·09 (0·87 to 1·29) per 100 person-years, 1·42 (1·13 to 1·71) per 100 person-years among women and 0·79 (0·63 to 0·94) per 100 person-years among men. Achieving the 90-90-90 targets evenly by age and sex would further reduce incidence beyond status-quo ART, primarily among individuals aged 15–24 years (an additional 17·37% [7·33 to 26·12] reduction between 2016 and 2030), with only modest additional incidence reductions in adults aged 35–49 years (1·99% [–5·09 to 7·74]). Achieving 100% ART initiation among all people living with HIV within an average of 6 months from infection—an upper bound of plausible treatment effect—would reduce adult HIV incidence to 0·73 infections (0·55 to 0·92) per 100 person-years by 2030 and 0·46 (0·33 to 0·59) per 100 person-years by 2050.

Interpretation
Scale-up of ART over the last decade has already contributed to substantial reductions in HIV-1 incidence and mortality in eSwatini. Focused ART targeting would further reduce incidence, especially in younger individuals, but even the most aggressive treatment campaigns would be insufficient to end the epidemic in high-burden settings without a renewed focus on expanding preventive measures.

Introduction
Over one hundred implementation studies of HIV pre-exposure prophylaxis (PrEP) are completed, underway or planned. We synthesized evidence from these studies to inform mathematical modelling of the prevention cascade for oral and long-acting PrEP in the setting of western Kenya, one of the world’s most heavily HIV-affected regions.

Methods
We incorporated steps of the PrEP prevention cascade – uptake, adherence, retention and re-engagement after discontinuation – into EMOD-HIV, an open-source transmission model calibrated to the demography and HIV epidemic patterns of western Kenya. Early PrEP implementation research from East Africa was used to parameterize prevention cascades for oral PrEP as currently implemented, delivery innovations for oral PrEP, and future long-acting PrEP. We compared infections averted by PrEP at the population level for different cascade assumptions and sub-populations on PrEP. Analyses were conducted over the 2020 to 2040 time horizon, with additional sensitivity analyses for the time horizon of analysis and the time when long-acting PrEP becomes available.

Results
The maximum impact of oral PrEP diminished by over 98% across all prevention cascades, with the exception of long-acting PrEP under optimistic assumptions about uptake and re-engagement after discontinuation. Long-acting PrEP had the highest population-level impact, even after accounting for possible delays in product availability, primarily because its effectiveness does not depend on drug adherence. Retention was the most significant cascade step reducing the potential impact of long-acting PrEP. These results were robust to assumptions about the sub-populations receiving PrEP, but were highly influenced by assumptions about re-initiation of PrEP after discontinuation, about which evidence was sparse.

Conclusions
Implementation challenges along the prevention cascade compound to diminish the population-level impact of oral PrEP. Long-acting PrEP is expected to be less impacted by user uptake and adherence, but it is instead dependent on product availability in the short term and retention in the long term. To maximize the impact of long-acting PrEP, ensuring timely product approval and rollout is critical. Research is needed on strategies to improve retention and patterns of PrEP re-initiation.

Background

The number of people on antiretroviral therapy (ART) requiring treatment monitoring in low-resource settings is rapidly increasing. Point-of-care (POC) testing for ART monitoring might alleviate burden on centralised laboratories and improve clinical outcomes, but its cost-effectiveness is unknown.

Methods

We used cost and effectiveness data from the STREAM trial in South Africa (February, 2017–October, 2018), which evaluated POC testing for viral load, CD4 count, and creatinine, with task shifting from professional to lower-cadre registered nurses compared with laboratory-based testing without task shifting (standard of care). We parameterised an agent-based network model, EMOD-HIV, to project the impact of implementing this intervention in South Africa over 20 years, simulating approximately 175 000 individuals per run. We assumed POC monitoring increased viral suppression by 9 percentage points, enrolment into community-based ART delivery by 25 percentage points, and switching to second-line ART by 1 percentage point compared with standard of care, as reported in the STREAM trial. We evaluated POC implementation in varying clinic sizes (10–50 patient initiating ART per month). We calculated incremental cost-effectiveness ratios (ICERs) and report the mean and 90% model variability of 250 runs, using a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted for our main analysis.

Findings

POC testing at 70% coverage of patients on ART was projected to reduce HIV infections by 4·5% (90% model variability 1·6 to 7·6) and HIV-related deaths by 3·9% (2·0 to 6·0). In clinics with 30 ART initiations per month, the intervention had an ICER of $197 (90% model variability –27 to 863) per DALY averted; results remained cost-effective when varying background viral suppression, ART dropout, intervention effectiveness, and reduction in HIV transmissibility. At higher clinic volumes (‰¥40 ART initiations per month), POC testing was cost-saving and at lower clinic volumes (20 ART initiations per month) the ICER was $734 (93 to 2569). A scenario that assumed POC testing did not increase enrolment into community ART delivery produced ICERs that exceeded the cost-effectiveness threshold for all clinic volumes.

Interpretation

POC testing is a promising strategy to cost-effectively improve patient outcomes in moderately sized clinics in South Africa. Results are most sensitive to changes in intervention impact on enrolment into community-based ART delivery.

Funding

National Institutes of Health.

Background

Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV and has the potential to significantly impact the HIV epidemic. Given limited resources for HIV prevention, identifying PrEP provision strategies that maximize impact is critical.

Methods

We used a stochastic individual-based network model to evaluate the direct (infections prevented among PrEP users) and indirect (infections prevented among non-PrEP users as a result of PrEP) benefits of PrEP, the person-years of PrEP required to prevent one HIV infection, and the community-level impact of providing PrEP to populations defined by gender and age in western Kenya and South Africa. We examined sensitivity of results to scale-up of antiretroviral therapy (ART) and voluntary medical male circumcision (VMMC) by comparing two scenarios: maintaining current coverage (“status quo”) and rapid scale-up to meet programmatic targets (“fast-track”).

Results

The community-level impact of PrEP was greatest among women aged 15–24 due to high incidence, while PrEP use among men aged 15–24 yielded the highest proportion of indirect infections prevented in the community. These indirect infections prevented continue to increase over time (western Kenya: 0.4–5.5 (status quo); 0.4–4.9 (fast-track); South Africa: 0.5–1.8 (status quo); 0.5–3.0 (fast-track)) relative to direct infections prevented among PrEP users. The number of person-years of PrEP needed to prevent one HIV infection was lower (59 western Kenya and 69 in South Africa in the status quo scenario; 201 western Kenya and 87 in South Africa in the fast-track scenario) when PrEP was provided only to women compared with only to men over time horizons of up to 5 years, as the indirect benefits of providing PrEP to men accrue in later years.

Conclusions

Providing PrEP to women aged 15–24 prevents the greatest number of HIV infections per person-year of PrEP, but PrEP provision for young men also provides indirect benefits to women and to the community overall. This finding supports existing policies that prioritize PrEP use for young women, while also illuminating the community-level benefits of PrEP availability for men when resources permit.

Western Kenya suffers a highly endemic and also very heterogeneous epidemic of human immunodeficiency virus (HIV). Although female sex workers (FSW) and their male clients are known to be at high risk for HIV, HIV prevalence across regions in Western Kenya is not strongly correlated with the fraction of women engaged in commercial sex. An agent-based network model of HIV transmission, geographically stratified at the county level, was fit to the HIV epidemic, scale-up of interventions, and populations of FSW in Western Kenya under two assumptions about the potential mobility of FSW clients. In the first, all clients were assumed to be resident in the same geographies as their interactions with FSW. In the second, some clients were considered non-resident and engaged only in interactions with FSW, but not in longer-term non-FSW partnerships in these geographies. Under both assumptions, the model successfully reconciled disparate geographic patterns of FSW and HIV prevalence. Transmission patterns in the model suggest a greater role for FSW in local transmission when clients were resident to the counties, with 30.0% of local HIV transmissions attributable to current and former FSW and clients, compared to 21.9% when mobility of clients was included. Nonetheless, the overall epidemic drivers remained similar, with risky behavior in the general population dominating transmission in high-prevalence counties. Our modeling suggests that co-location of high-risk populations and generalized epidemics can further amplify the spread of HIV, but that large numbers of formal FSW and clients are not required to observe or mechanistically explain high HIV prevalence in the general population.

Background
Generalized HIV epidemics propagate to future generations according to the age patterns of transmission. We hypothesized that future generations could be protected from infection using age-targeted prevention, analogous to the ring-fencing strategies used to control the spread of smallpox.

Methods
We modeled age-targeted or cohort-targeted outreach with HIV treatment and/or prevention using EMOD-HIV v0·8, an individual-based network model of HIV transmission in South Africa.

Results
Targeting ages 20 to 30 with intensified outreach, linkage, and eligibility for antiretroviral therapy (ART) averted 45% as many infections as universal outreach for approximately one-fifth the cost beyond existing HIV services. Though cost-effective, targeting failed to eliminate all infections to those under 20 due to vertical and inter-generational transmission. Cost-effectiveness of optimal prevention strategies included US$6238 per infection averted targeting ages 10–30, US$5031 targeting 20–30, US$4279 targeting 22–27, and US$3967 targeting 25–27, compared to US$10 812 for full-population test-and-treat. Minimizing burden (disability-adjusted life years [DALYs]) rather than infections resulted in older target age ranges because older adults were more likely to receive a direct health benefit from treatment.

Conclusions
Age-targeted treatment for HIV prevention is unlikely to eliminate HIV epidemics, but is an efficient strategy for reducing new infections in generalized epidemics settings.

Background
Migrant populations such as mine workers contributed to the spread of HIV in sub-Saharan Africa. We used a mathematical model to estimate the community-wide impact of targeting treatment and prevention to male migrants.

Methods
We augmented an individual-based network model, EMOD-HIV v0.8, to include an age-dependent propensity for males to migrate. Migrants were exposed to HIV outside their home community, but continued to participate in HIV transmission in the community during periodic visits.

Results
Migrant-targeted interventions would have been transformative in the 1980s to 1990s, but post-2015 impacts were more modest. When targetable migrants comprised 2% of adult males, workplace HIV prevention averted 3.5% of community-wide infections over 20 years. Targeted treatment averted 8.5% of all-cause deaths among migrants. When migrants comprised 10% of males, workplace prevention averted 16.2% of infections in the community, one-quarter of which were among migrants. Workplace prevention and treatment acted synergistically, averting 17.1% of community infections and 11.6% of deaths among migrants. These estimates do not include prevention of secondary spread of HIV or tuberculosis at the workplace.

Conclusions
Though cost-effective, targeting migrants cannot collapse generalized epidemics in their home communities. Such a strategy would only have been possible prior to the early 1990s. However, migrant-targeted interventions synergize with general-population expansion of HIV services.

To study the effects of malaria-control interventions on parasite population genomics, we examined a set of 1,007 samples of the malaria parasite Plasmodium falciparum collected in Thiès, Senegal between 2006 and 2013. The parasite samples were genotyped using a molecular barcode of 24 SNPs. About 35% of the samples grouped into subsets with identical barcodes, varying in size by year and sometimes persisting across years. The barcodes also formed networks of related groups. Analysis of 164 completely sequenced parasites revealed extensive sharing of genomic regions. In at least two cases we found first-generation recombinant offspring of parents whose genomes are similar or identical to genomes also present in the sample. An epidemiological model that tracks parasite genotypes can reproduce the observed pattern of barcode subsets. Quantification of likelihoods in the model strongly suggests a reduction of transmission from 2006–2010 with a significant rebound in 2012–2013. The reduced transmission and rebound were confirmed directly by incidence data from Thiès. These findings imply that intensive intervention to control malaria results in rapid and dramatic changes in parasite population genomics. The results also suggest that genomics combined with epidemiological modeling may afford prompt, continuous, and cost-effective tracking of progress toward malaria elimination.

Our results do establish a foundational link between observations of parasite population genomics and epidemiological models that incorporate genetic mechanisms. Combining genomic observations with epidemiological modeling provides a powerful and complementary tool for elucidating population-level details of transmission in low-prevalence settings from a small sample of parasite genomes. In particular, modeling parasite genetics allows one to take a collection of many different types of measurement—effective population size, multilocus linkage disequilibrium, heterozygosity of mixed infections, complexity of infection—and from these measurements form a quantitative assessment of the transmission dynamics most consistent with the full information available.

Background
Mathematical models are widely used to simulate the effects of interventions to control HIV and to project future epidemiological trends and resource needs. We aimed to validate past model projections against data from a large household survey done in South Africa in 2012.
Methods
We compared ten model projections of HIV prevalence, HIV incidence, and antiretroviral therapy (ART) coverage for South Africa with estimates from national household survey data from 2012. Model projections for 2012 were made before the publication of the 2012 household survey. We compared adult (age 15–49 years) HIV prevalence in 2012, the change in prevalence between 2008 and 2012, and prevalence, incidence, and ART coverage by sex and by age groups between model projections and the 2012 household survey.
Findings
All models projected lower prevalence estimates for 2012 than the survey estimate (18·8%), with eight models’ central projections being below the survey 95% CI (17·5–20·3). Eight models projected that HIV prevalence would remain unchanged (n=5) or decline (n=3) between 2008 and 2012, whereas prevalence estimates from the household surveys increased from 16·9% in 2008 to 18·8% in 2012 (difference 1·9, 95% CI −0·1 to 3·9). Model projections accurately predicted the 1·6 percentage point prevalence decline (95% CI −0·3 to 3·5) in young adults aged 15–24 years, and the 2·2 percentage point (0·5 to 3·9) increase in those aged 50 years and older. Models accurately represented the number of adults on ART in 2012; six of ten models were within the survey 95% CI of 1·54–2·12 million. However, the differential ART coverage between women and men was not fully captured; all model projections of the sex ratio of women to men on ART were lower than the survey estimate of 2·22 (95% CI 1·73–2·71).
Interpretation
Projections for overall declines in HIV epidemics during the ART era might have been optimistic. Future treatment and HIV prevention needs might be greater than previously forecasted. Additional data about service provision for HIV care could help inform more accurate projections.
Funding
Bill & Melinda Gates Foundation.

Objective

EMOD-HIV v0.8 has been used to estimate the potential impact of expanding treatment guidelines to allow earlier initiation of antiretroviral therapy (ART) in sub-Saharan Africa with current or improved treatment coverage. In generating these results, a model must additionally make assumptions about the rates of dropout and re-initiation into ART programs before and after the program change, about which little is known. The objective of this work is to rigorously analyze modeling assumptions and the sensitivity of model results with respect to relevant mechanisms and parameters.

Methods

We varied key model assumptions pertaining to ART dropout and re-enrollment to analyze their effect on the cost, impact, and cost-effectiveness of expanding treatment guidelines, and of expanding coverage via improved testing and linkage to care. Additionally, we performed a sensitivity analysis of 17 relevant model parameters.

Setting

South Africa.

Results

Allowing re-initiation of ART irrespective of prior treatment doubled the cost and impact of expanding treatment guidelines, as compared with a scenario in which re-initiation could only be triggered by a health event (AIDS symptoms, diagnosis of a partner, or an antenatal care visit). Increasing the probability of ‘voluntary’ re-initiation (not triggered by a health event) was the most cost-effective way to improve the treatment program, especially in the short term because it provided immediate benefits to those who would otherwise have delayed re-initiation until the onset of AIDS symptoms. However, the maximum impact of this change was limited compared with expanding coverage through improvements in testing and linkage to care. Beyond improvements in coverage and re-initiation, further gains could be made by improving retention in care. Only with optimal retention in care was expansion of guidelines cost-saving after 20 years due to reductions in transmission. Re-initiation did not reduce transmission sufficiently to make a guideline change cost-effective due to transmission that occurred while patients were away from care. Sensitivity analysis suggested that enormous health benefits could be attained by improving treatment regimens to have higher efficacy at preventing transmission, increasing the proportion of the population with access to improved healthcare, and reducing ‘leaks’ in the ‘cascade of care.’ Increasing the proportion of individuals who receive CD4+ cell results was particularly cost-effective at baseline levels of coverage, and increasing retention on ART was particularly cost-effective with expanded coverage.

Conclusion

This analysis provides a sense of the magnitude of uncertainty in program cost and impact that policy-makers could anticipate in the face of uncertain future programmatic changes. Our findings suggest that increasing re-initiation is the most cost-effective means of initial program improvement, especially in the short term, but that improvements in retention are necessary in order to reap the full transmission-blocking benefits of a test-and-treat program in the long term.