Consortium papers
Evaluating strategies to improve HIV care outcomes in Kenya: a modelling study
Abstract:10.1016/S2352-3018(16)30120-5BACKGROUND: With expanded access to antiretroviral therapy (ART) in sub-Saharan Africa, HIV mortality has decreased, yet life-years are still lost to AIDS. Strengthening of treatment programmes is a priority. We examined the state of an HIV care programme in Kenya and assessed interventions to improve the impact of ART programmes on population health.
METHODS: We created an individual-based mathematical model to describe the HIV epidemic and the experiences of care among adults infected with HIV in Kenya. We calibrated the model to a longitudinal dataset from the Academic Model Providing Access To Healthcare (known as AMPATH) programme describing the routes into care, losses from care, and clinical outcomes. We simulated the cost and effect of interventions at different stages of HIV care, including improvements to diagnosis, linkage to care, retention and adherence of ART, immediate ART eligibility, and a universal test-and-treat strategy.
FINDINGS: We estimate that, of people dying from AIDS between 2010 and 2030, most will have initiated treatment (61%), but many will never have been diagnosed (25%) or will have been diagnosed but never started ART (14%). Many interventions targeting a single stage of the health-care cascade were likely to be cost-effective, but any individual intervention averted only a small percentage of deaths because the effect is attenuated by other weaknesses in care. However, a combination of five interventions (including improved linkage, point-of-care CD4 testing, voluntary counselling and testing with point-of-care CD4, and outreach to improve retention in pre-ART care and on-ART) would have a much larger impact, averting 1·10 million disability-adjusted life-years (DALYs) and 25% of expected new infections and would probably be cost-effective (US$571 per DALY averted). This strategy would improve health more efficiently than a universal test-and-treat intervention if there were no accompanying improvements to care ($1760 per DALY averted).
INTERPRETATION: When resources are limited, combinations of interventions to improve care should be prioritised over high-cost strategies such as universal test-and-treat strategy, especially if this is not accompanied by improvements to the care cascade. International guidance on ART should reflect alternative routes to programme strengthening and encourage country programmes to evaluate the costs and population-health impact in addition to the clinical benefits of immediate initiation.
FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development, National Institutes of Health.
The Incidence Patterns Model to Estimate the Distribution of New HIV Infections in Sub-Saharan Africa: Development and Validation of a Mathematical Model.
Abstract:10.1371/journal.pmed.1002121BACKGROUND: Programmatic planning in HIV requires estimates of the distribution of new HIV infections according to identifiable characteristics of individuals. In sub-Saharan Africa, robust routine data sources and historical epidemiological observations are available to inform and validate such estimates.
METHODS AND FINDINGS: We developed a predictive model, the Incidence Patterns Model (IPM), representing populations according to factors that have been demonstrated to be strongly associated with HIV acquisition risk: gender, marital/sexual activity status, geographic location, "key populations" based on risk behaviours (sex work, injecting drug use, and male-to-male sex), HIV and ART status within married or cohabiting unions, and circumcision status. The IPM estimates the distribution of new infections acquired by group based on these factors within a Bayesian framework accounting for regional prior information on demographic and epidemiological characteristics from trials or observational studies. We validated and trained the model against direct observations of HIV incidence by group in seven rounds of cohort data from four studies ("sites") conducted in Manicaland, Zimbabwe; Rakai, Uganda; Karonga, Malawi; and Kisesa, Tanzania. The IPM performed well, with the projections' credible intervals for the proportion of new infections per group overlapping the data's confidence intervals for all groups in all rounds of data. In terms of geographical distribution, the projections' credible intervals overlapped the confidence intervals for four out of seven rounds, which were used as proxies for administrative divisions in a country. We assessed model performance after internal training (within one site) and external training (between sites) by comparing mean posterior log-likelihoods and used the best model to estimate the distribution of HIV incidence in six countries (Gabon, Kenya, Malawi, Rwanda, Swaziland, and Zambia) in the region. We subsequently inferred the potential contribution of each group to transmission using a simple model that builds on the results from the IPM and makes further assumptions about sexual mixing patterns and transmission rates. In all countries except Swaziland, individuals in unions were the single group contributing to the largest proportion of new infections acquired (39%-77%), followed by never married women and men. Female sex workers accounted for a large proportion of new infections (5%-16%) compared to their population size. Individuals in unions were also the single largest contributor to the proportion of infections transmitted (35%-62%), followed by key populations and previously married men and women. Swaziland exhibited different incidence patterns, with never married men and women accounting for over 65% of new infections acquired and also contributing to a large proportion of infections transmitted (up to 56%). Between- and within-country variations indicated different incidence patterns in specific settings.
CONCLUSIONS: It is possible to reliably predict the distribution of new HIV infections acquired using data routinely available in many countries in the sub-Saharan African region with a single relatively simple mathematical model. This tool would complement more specific analyses to guide resource allocation, data collection, and programme planning.
Optimum resource allocation to reduce HIV incidence across sub-Saharan Africa: a mathematical modelling study.
Abstract:10.1016/S2352-3018(16)30051-0BACKGROUND: Advances in HIV prevention methods offer promise to accelerate declines in incidence, but how these methods can be deployed to have the best effect on the heterogeneous landscape and drivers of the pandemic remains unclear. We postulated that use of epidemic heterogeneity to inform the allocation of resources for combination HIV prevention could enhance the impact of HIV funding across sub-Saharan Africa.
METHODS: We developed a compartmental mathematical model of HIV transmission and disease progression by risk group to subnational resolution in 18 countries, capturing 80% of the adult HIV burden in sub-Saharan Africa. Adults aged 15-49 years were grouped by risk of HIV acquisition and transmission, and those older than 50 years were assumed to have negligible risk. For each top-level administrative division, we calibrated the model to historical data for HIV prevalence, sexual behaviours, treatment scale-up, and demographics. We then evaluated four strategies for allocation of prevention funding over a 15 year period from 2016 to 2030, which exploited epidemic differences between subnational regions to varying degrees.
FINDINGS: For a $US20 billion representative expenditure over the 15 year period, scale-up of prevention along present funding channels could avert 5·3 million infections relative to no scale-up. Prioritisation of key populations could avert 3·7 million more infections than present funding channels, and additional prioritisation by within-country geography could avert 400 000 more infections. Removal of national constraints could avert a further 600 000 infections. Risk prioritisation has greater marginal impact than geographical prioritisation across multiple expenditure levels. However, targeting by both risk and geography is best for total impact and could achieve gains of up to three times more than present channels. A shift from the present pattern to the optimum pattern would rebalance resources towards more cost-effective interventions and emerging epidemics.
INTERPRETATION: If domestic and international funders were to align strategically to build an aggregate funding pattern that is guided by the epidemiology of HIV, and particularly by the emerging understanding of local dynamics and epidemic drivers, more cost-effective and impactful HIV prevention investments could be achieved across sub-Saharan Africa.
FUNDING: The Bill & Melinda Gates Foundation.
How Much Do We Know about Drug Resistance Due to PrEP Use? Analysis of Experts' Opinion and Its Influence on the Projected Public Health Impact.
Abstract:10.1371/journal.pone.0158620BACKGROUND: Randomized controlled trials reported that pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine rarely selects for drug resistance. However, drug resistance due to PrEP is not completely understood. In daily practice, PrEP will not be used under the well-controlled conditions available in the trials, suggesting that widespread use of PrEP can result in increased drug resistance.
METHODS: We surveyed expert virologists with questions about biological assumptions regarding drug resistance due to PrEP use. The influence of these assumptions on the prevalence of drug resistance and the fraction of HIV transmitted resistance was studied with a mathematical model. For comparability, 50% PrEP-coverage of and 90% per-act efficacy of PrEP in preventing HIV acquisition are assumed in all simulations.
RESULTS: Virologists disagreed on the following: the time until resistance emergence (range: 20-180 days) in infected PrEP users with breakthrough HIV infections; the efficacy of PrEP against drug-resistant HIV (25%-90%); and the likelihood of resistance acquisition upon transmission (10%-75%). These differences translate into projections of 0.6%- 1% and 3.5%-6% infected individuals with detectable resistance 10 years after introducing PrEP, assuming 100% and 50% adherence, respectively. The rate of resistance emergence following breakthrough HIV infection and the rate of resistance reversion after PrEP use is discontinued, were the factors identified as most influential on the expected resistance associated with PrEP. Importantly, 17-23% infected individuals could virologically fail treatment as a result of past PrEP use or transmitted resistance to PrEP with moderate adherence.
CONCLUSIONS: There is no broad consensus on quantification of key biological processes that underpin the emergence of PrEP-associated drug resistance. Despite this, the contribution of PrEP use to the prevalence of the detectable drug resistance is expected to be small. However, individuals who become infected despite the use of PrEP should be closely monitored due to higher risk of virological failure when initiating antiretroviral treatment in the future.
Identifying key drivers of the impact of an HIV cure intervention in sub-Saharan Africa.
Abstract:10.1093/infdis/jiw120BACKGROUND: The properties required of an intervention that results in eradication or control of HIV in absence of antiretroviral therapy (ART-free viral suppression) to make it cost-effective in low income settings are unknown.
METHODS: We used a model of HIV and ART to investigate the effect of introducing an ART-free viral suppression intervention in 2022 in an example country of Zimbabwe. We assumed that the intervention (cost: $500) would be accessible for 90% of the population, be given to those on effective ART, have sufficient efficacy to allow ART interruption in 95%, with a rate of viral rebound 5% per year in the first three months, and a 50% decline in rate with each successive year.
RESULTS: An ART-free viral suppression intervention with these properties would result in over 0.53 million disability-adjusted-life-years averted over 2022-2042, with a reduction in HIV programme costs of $300 million (8.7% saving). An intervention of this efficacy costing anything up to $1400 is likely to be cost-effective in this setting.
CONCLUSION: Interventions aimed at curing HIV have the potential to improve overall disease burden and to reduce costs. Given the effectiveness and cost of ART, such interventions would have to be inexpensive and highly effective.
Evaluation of geospatial methods to generate subnational HIV prevalence estimates for local level planning.
Abstract:10.1097/QAD.0000000000001075OBJECTIVE: There is evidence of substantial subnational variation in the HIV epidemic. However, robust spatial HIV data are often only available at high levels of geographic aggregation and not at the finer resolution needed for decision making. Therefore, spatial analysis methods that leverage available data to provide local estimates of HIV prevalence may be useful. Such methods exist but have not been formally compared when applied to HIV.
DESIGN/METHODS: Six candidate methods - including those used by UNAIDS to generate maps and a Bayesian geostatistical approach applied to other diseases- were used to generate maps and subnational estimates of HIV prevalence across three countries using cluster level data from household surveys. Two approaches were used to assess the accuracy of predictions: (1) internal validation, whereby a proportion of input data is held back (test dataset) to challenge predictions, (2) comparison with location specific data from household surveys in earlier years.
RESULTS: Each of the methods can generate usefully accurate predictions of prevalence at unsampled locations, with the magnitude of the error in predictions similar across approaches. However, the Bayesian geostatistical approach consistently gave marginally the strongest statistical performance across countries and validation procedures.
CONCLUSIONS: Available methods may be able to furnish estimates of HIV prevalence at finer spatial scales than the data currently allow. The subnational variation revealed can be integrated into planning to ensure responsiveness to the spatial features of the epidemic. The Bayesian geostatistical approach is a promising strategy for integrating HIV data to generate robust local estimates.
Sustainable HIV treatment in Africa through viral-load-informed differentiated care.
Abstract:10.1038/nature16046There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.
Assessment of epidemic projections using recent HIV survey data in South Africa: a validation analysis of ten mathematical models of HIV epidemiology in the antiretroviral therapy era.
Abstract:Download PDF: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.
PIIS2214109X15000807.pdf
Estimating PMTCT's Impact on Heterosexual HIV Transmission: A Mathematical Modeling Analysis.
Abstract:10.1371/journal.pone.0134271INTRODUCTION: Prevention of mother-to-child HIV transmission (PMTCT) strategies include combined short-course antiretrovirals during pregnancy (Option A), triple-drug antiretroviral treament (ART) during pregnancy and breastfeeding (Option B), or lifelong ART (Option B+). The WHO also recommends ART for HIV treatment and prevention of sexual transmission of HIV. The impact of PMTCT strategies on prevention of sexual HIV transmission of HIV is not known. We estimated the population-level impact of PMTCT interventions on heterosexual HIV transmission in southwestern Uganda and KwaZulu-Natal, South Africa, two regions with different HIV prevalence and fertility rates.
MATERIALS AND METHODS: We constructed and validated dynamic, stochastic, network-based HIV transmission models for each region. PMTCT Options A, B, and B+ were simulated over ten years under three scenarios: 1) current ART and PMTCT coverage, 2) current ART and high PMTCT coverage, and 3) high ART and PMTCT coverage. We compared adult HIV incidence after ten years of each intervention to Option A (and current ART) at current coverage.
RESULTS: At current coverage, Options B and B+ reduced heterosexual HIV incidence by about 5% and 15%, respectively, in both countries. With current ART and high PMTCT coverage, Option B+ reduced HIV incidence by 35% in Uganda and 19% in South Africa, while Option B had smaller, but meaningful, reductions. The greatest reductions in HIV incidence were achieved with high ART and PMTCT coverage. In this scenario, all PMTCT strategies yielded similar results.
DISCUSSION: Implementation of Options B/B+ reduces adult HIV incidence, with greater effect (relative to Option A at current levels) in Uganda than South Africa. These results are likely driven by Uganda's higher fertility rates.
Recent HIV prevalence trends among pregnant women and all women in sub-Saharan Africa: implications for HIV estimates.
Abstract:Download PDF:OBJECTIVES:: National population-wide HIV prevalence and incidence trends in sub-Saharan Africa (SSA) are indirectly estimated using HIV prevalence measured among pregnant women attending antenatal clinics (ANC), among other data. We evaluated whether recent HIV prevalence trends among pregnant women are representative of general population trends.
DESIGN:: Serial population-based household surveys in 13 SSA countries.
METHODS:: We calculated HIV prevalence trends among all women aged 15-49 years and currently pregnant women between surveys conducted from 2003 to 2008 (period 1) and 2009 to 2012 (period 2). Log-binomial regression was used to test for a difference in prevalence trend between the two groups. Prevalence among pregnant women was age-standardized to represent the age distribution of all women.
RESULTS:: Pooling data for all countries, HIV prevalence declined among pregnant women from 6.5 [95% confidence interval (CI) 5.3-7.9%] to 5.3% (95% CI 4.2-6.6%) between periods 1 and 2, whereas it remained unchanged among all women at 8.4% (95% CI 8.0-8.9%) in period 1 and 8.3% (95% CI 7.9-8.8%) in period 2. Prevalence declined by 18% (95% CI -9-38%) more in pregnant women than nonpregnant women. Estimates were similar in Western, Eastern, and Southern regions of SSA; none were statistically significant (P > 0.05). HIV prevalence decreased significantly among women aged 15-24 years while increasing significantly among women 35-49 years, who represented 29% of women but only 15% of pregnant women. Age-standardization of prevalence in pregnant women did not reconcile the discrepant trends because at older ages prevalence was lower among pregnant women than nonpregnant women.
CONCLUSION:: As HIV prevalence in SSA has shifted toward older, less-fertile women, HIV prevalence among pregnant women has declined more rapidly than prevalence in women overall. Interpretation of ANC prevalence data to inform national HIV estimates should account for both age-specific fertility patterns and HIV-related sub-fertility.
Recent_HIV_prevalence_trends_among_pregnant_women.12.pdf
