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Introduction: The human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection presents significant challenges due to the complex interplay between these diseases, leading to exacerbated metabolic disturbances. Understanding these metabolic profiles is crucial for improving diagnostic and therapeutic approaches., Objective: This study aimed to characterise the urinary acylcarnitine and amino acid profiles, including 5-hydroxyindoleacetic acid (5-HIAA), in patients co-infected with HIV and TB using targeted liquid chromatography mass spectrometry (LC-MS) metabolomics., Methods: Urine samples, categorised into HIV, TB, HIV/TB co-infected, and healthy controls, were analysed using HPLC-MS/MS. Statistical analyses included one-way ANOVA and a Kruskal-Wallis test to determine significant differences in the acylcarnitine and amino acid profiles between groups., Results: The study revealed significant metabolic alterations, especially in TB and co-infected groups. Elevated levels of medium-chain acylcarnitines indicated increased fatty acid oxidation, commonly associated with cachexia in TB. Altered amino acid profiles suggested disruptions in protein and glucose metabolism, indicating a shift towards diabetes-like metabolic states. Notably, TB was identified as a primary driver of these changes, affecting protein turnover, and impacting energy metabolism in co-infected patients., Conclusion: The metabolic profiling of HIV/TB co-infection highlights the profound impact of TB on metabolic pathways, which may exacerbate the clinical complexities of co-infection. Understanding these metabolic disruptions can guide the development of targeted treatments and improve management strategies, ultimately enhancing the clinical outcomes for these patients. Further research is required to validate these findings and explore their implications in larger, diverse populations., (© 2024. The Author(s).)

Tuberculosis (TB) killed more people globally than any other single pathogen over the past decade. Where surveillance is weak, estimating TB burden estimates uses modeling. In many African countries, increases in HIV prevalence and antiretroviral therapy have driven dynamic TB epidemics, complicating estimation of burden, trends, and potential intervention impact. We therefore develop a novel age-structured TB transmission model incorporating evolving demographic, HIV and antiretroviral therapy effects, and calibrate to TB prevalence and notification data from 12 African countries. We use Bayesian methods to include uncertainty for all TB model parameters, and estimate age-specific annual risks of TB infection, finding up to 16.0%/year in adults, and the proportion of TB incidence from recent (re)infection, finding a mean across countries of 34%. Rapid reduction of the unacceptably high burden of TB in high HIV prevalence settings will require interventions addressing progression as well as transmission., (© 2023. The Author(s).)

Introduction: Despite antiretroviral therapy (ART) scale-up among people living with HIV (PLHIV), those with advanced HIV disease (AHD) (defined in adults as CD4 count <200 cells/mm 3 or clinical stage 3 or 4), remain at high risk of death from opportunistic infections. The shift from routine baseline CD4 testing towards viral load testing in conjunction with "Test and Treat" has limited AHD identification., Methods: We used official estimates and existing epidemiological data to project deaths from tuberculosis (TB) and cryptococcal meningitis (CM) among PLHIV-initiating ART with CD4 <200 cells/mm 3 , in the absence of select World Health Organization recommended diagnostic or therapeutic protocols for patients with AHD. We modelled the reduction in deaths, based on the performance of screening/diagnostic testing and the coverage and efficacy of treatment/preventive therapies for TB and CM. We compared projected TB and CM deaths in the first year of ART from 2019 to 2024, with and without CD4 testing. The analysis was performed for nine countries: South Africa, Kenya, Lesotho, Mozambique, Nigeria, Uganda, Zambia, Zimbabwe and the Democratic Republic of Congo., Results: The effect of CD4 testing comes through increased identification of AHD and consequent eligibility for protocols for AHD prevention, diagnosis and management; algorithms for CD4 testing avert between 31% and 38% of deaths from TB and CM in the first year of ART. The number of CD4 tests required per death averted varies widely by country from approximately 101 for South Africa to 917 for Kenya., Conclusions: This analysis supports retaining baseline CD4 testing to avert deaths from TB and CM, the two most deadly opportunistic infections among patients with AHD. However, national programmes will need to weigh the cost of increasing CD4 access against other HIV-related priorities and allocate resources accordingly., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: This paper forms part of an update of the World Health Organization Choosing Interventions that are Cost-Effective (WHO-CHOICE) programmes. It provides an assessment of global health system performance during the first decade of the 21st century (2000-2010) with respect to allocative efficiency in HIV, tuberculosis (TB) and malaria control, thereby shining a spotlight on programme development and scale up in these Millennium Development Goal (MDG) priority areas; and examining the cost-effectiveness of selected best-practice interventions and intervention packages commonly in use during that period., Methods: Generalized cost-effectiveness analysis (GCEA) was used to determine the cost-effectiveness of the selected interventions. Impact modelling was performed using the OpenMalaria platform for malaria and using the Goals and TIME (TB Impact Model and Estimates) models in Spectrum for HIV and TB. All health system costs, regardless of payer, were included and reported in international dollars. Health outcomes are estimated and reported as the gain in healthy life years (HLYs) due to the specific intervention or combination. Analysis was restricted to eastern sub-Saharan Africa and Southeast Asia., Results: At the reference year of 2010, commonly used interventions for HIV, TB and malaria were cost-effective, with cost-effectiveness ratios less than I$ 100/HLY saved for virtually all interventions included. HIV, TB and malaria prevention and treatment interventions are highly cost-effective and can be implemented through a phased approach to full coverage to achieve maximum health benefits and contribute to the progressive elimination of these diseases., Conclusion: During the first decade of the 21st century (2000-2010), the global community has done well overall for HIV, TB, and malaria programmes as regards both economic efficiency and programmatic selection criteria. The role of international assistance, financial and technical, arguably was critical to these successes. As the global community now tackles the challenge of universal health coverage, this analysis can reinforce commitment to Sustainable Development Goal targets but also the importance of continued focus on these critical programme areas., (© 2021 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Background: In addition to providing millions of men with lifelong lower risk for HIV infection, voluntary medical male circumcision (VMMC) also provides female partners with health benefits including decreased risk for human papillomavirus (HPV) and resultant cervical cancer (CC)., Setting: We modeled potential impacts of VMMC on CC incidence and mortality in Uganda as an additional benefit beyond HIV prevention., Methods: HPV and CC outcomes were modeled using the CC model from the Spectrum policy tool suite, calibrated for Uganda, to estimate HPV infection incidence and progression to CC, using a 50-year (2018-2067) time horizon. 2016 Demographic Health Survey data provided baseline VMMC coverage. The baseline (no VMMC scale-up beyond current coverage, minimal HPV vaccination coverage) was compared with multiple scenarios to assess the varying impact of VMMC according to different implementations of HPV vaccination and HPV screening programs., Results: Without further intervention, annual CC incidence was projected to rise from 16.9 to 31.2 per 100,000 women in 2067. VMMC scale-up alone decreased 2067 annual CC incidence to 25.3, averting 13,000 deaths between 2018 and 2067. With rapidly-achieved 90% HPV9 vaccination coverage for adolescent girls and young women, 2067 incidence dropped below 10 per 100,000 with or without a VMMC program. With 45% vaccine coverage, the addition of VMMC scaleup decreased incidence by 2.9 per 100,000 and averted 8000 additional deaths. Similarly, with HPV screen-and-treat without vaccination, the addition of VMMC scaleup decreased incidence by 5.1 per 100,000 and averted 10,000 additional deaths., Conclusions: Planned VMMC scale-up to 90% coverage from current levels could prevent a substantial number of CC cases and deaths in the absence of rapid scale-up of HPV vaccination to 90% coverage., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Introduction: Oral pre-exposure prophylaxis (PrEP) provision is a priority intervention for high HIV prevalence settings and populations at substantial risk of HIV acquisition. This mathematical modelling analysis estimated the impact, cost and cost-effectiveness of scaling up oral PrEP in 13 countries., Methods: We projected the impact and cost-effectiveness of oral PrEP between 2018 and 2030 using a combination of the Incidence Patterns Model and the Goals model. We created four PrEP rollout scenarios involving three priority populations-female sex workers (FSWs), serodiscordant couples (SDCs) and adolescent girls and young women (AGYW)-both with and without geographic prioritization. We applied the model to 13 countries (Eswatini, Ethiopia, Haiti, Kenya, Lesotho, Mozambique, Namibia, Nigeria, Tanzania, Uganda, Zambia and Zimbabwe). The base case assumed achievement of the Joint United Nations Programme on HIV/AIDS 90-90-90 antiretroviral therapy targets, 90% male circumcision coverage by 2020 and 90% efficacy and adherence levels for oral PrEP., Results: In the scenarios we examined, oral PrEP averted 3% to 8% of HIV infections across the 13 countries between 2018 and 2030. For all but three countries, more than 50% of the HIV infections averted by oral PrEP in the scenarios we examined could be obtained by rollout to FSWs and SDCs alone. For several countries, expanding oral PrEP to include medium-risk AGYW in all regions greatly increased the impact. The efficiency and impact benefits of geographic prioritization of rollout to AGYW varied across countries. Variations in cost-effectiveness across countries reflected differences in HIV incidence and expected variations in unit cost. For most countries, rolling out oral PrEP to FSWs, SDCs and geographically prioritized AGYW was not projected to have a substantial impact on the supply chain for antiretroviral drugs., Conclusions: These modelling results can inform prioritization, target-setting and other decisions related to oral PrEP scale-up within combination prevention programmes. We caution against extensive use given limitations in cost data and implementation approaches. This analysis highlights some of the immediate challenges facing countries-for example, trade-offs between overall impact and cost-effectiveness-and emphasizes the need to improve data availability and risk assessment tools to help countries make informed decisions., (© 2020 Avenir Health. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: Expanded HIV prevention options are needed to increase uptake of HIV prevention among women, especially in generalized epidemics. As the dapivirine vaginal ring moves forward through regulatory review and open-label extension studies, the potential public health impact and cost-effectiveness of this new prevention method are not fully known. We used mathematical modeling to explore the impact and cost-effectiveness of the ring in different implementation scenarios alongside scale-up of other HIV prevention interventions. Given the knowledge gaps about key factors influencing the ring's implementation, including potential uptake and delivery costs, we engaged in a stakeholder consultation process to elicit plausible parameter ranges and explored scenarios to identify the possible range of impact, cost, and cost-effectiveness., Methods and Findings: We used the Goals model to simulate scenarios of oral and ring pre-exposure prophylaxis (PrEP) implementation among female sex workers and among other women ≤21 years or >21 years with multiple male partners, in Kenya, South Africa, Uganda, and Zimbabwe. In these scenarios, we varied antiretroviral therapy (ART) coverage, dapivirine ring coverage and ring effectiveness (encompassing efficacy and adherence) by risk group. Following discussions with stakeholders, the maximum level of PrEP coverage (oral and/or ring) considered in each country was equal to modern contraception use minus condom use in the two age groups. We assessed results for 18 years, from 2018 to 2035. In South Africa, for example, the HIV infections averted by PrEP (ring plus oral PrEP) ranged from 310,000 under the highest-impact scenario (including ART held constant at 2017 levels, high ring coverage, and 85% ring effectiveness) to 55,000 under the lowest-impact scenario (including ART reaching the UNAIDS 90-90-90 targets by 2020, low ring coverage, and 30% ring effectiveness). This represented a range of 6.4% to 2.2% of new HIV infections averted. Given our assumptions, the addition of the ring results in 11% to 132% more impact than oral PrEP alone. The cost per HIV infection averted for the ring ranged from US$13,000 to US$121,000., Conclusions: This analysis offers a wide range of scenarios given the considerable uncertainty over ring uptake, consistency of use, and effectiveness, as well as HIV testing, prevention, and treatment use over the next two decades. This could help inform donors and implementers as they decide where to allocate resources in order to maximize the impact of the dapivirine ring in light of funding and implementation constraints. Better understanding of the cost and potential uptake of the intervention would improve our ability to estimate its cost-effectiveness and assess where it can have the most impact., Competing Interests: MR, CP, RG, and KK are employed by Avenir Health. EG is employed by AVAC. KT is employed by FHI 360. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

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., (Copyright © 2015 Eaton et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by Elsevier Ltd.. All rights reserved.)

HIV has fuelled increasing tuberculosis (TB) incidence in sub-Saharan Africa. Better control of TB in this region may be achieved directly through TB programme improvements and indirectly through expanded use of antiretroviral therapy (ART) among those with HIV. We used a mathematical model of TB and HIV in South Africa to examine the potential epidemiological impact in scenarios involving improvements in three dimensions of TB programmes: coverage, diagnosis and treatment effectiveness, as well as expanded ART use through broadened eligibility. We projected the effect of alternative scenarios on TB prevalence, incidence and TB-related mortality over 20 years. Of the three dimensions of TB programme improvement, expanding coverage would produce the greatest reduction in TB burden. Compared with current performance, combined TB programme improvements were projected to decrease TB incidence by 30% over 5 years and 46% over 20 years, and decrease TB-related mortality by 45% over 5 years and 69% over 20 years. Expanded ART eligibility was projected to decrease TB incidence by 22% over 5 years and 45% over 20 years, and TB-related mortality by 22% over 5 years and 50% over 20 years. We found that over a 20-year horizon, TB-specific and HIV-specific programme changes contribute equally to incidence reductions, whereas the TB-specific changes produce a majority of the mortality benefits. An aggressive expansion of ART alongside traditional TB-specific control measures has the potential to greatly reduce TB burden, with the different elements of a combined approach having a synergistic effect in reducing long-term TB incidence and mortality.

Background: In 2011 an Investment Framework was proposed that described how the scale-up of key HIV interventions could dramatically reduce new HIV infections and deaths in low and middle income countries by 2015. This framework included ambitious coverage goals for prevention and treatment services resulting in a reduction of new HIV infections by more than half. However, it also estimated a leveling in the number of new infections at about 1 million annually after 2015., Methods: We modeled how the response to AIDS can be further expanded by scaling up antiretroviral treatment (ART) within the framework provided by the 2013 WHO treatment guidelines. We further explored the potential contributions of new prevention technologies: 'Test and Treat', pre-exposure prophylaxis and an HIV vaccine., Findings: Immediate aggressive scale up of existing approaches including the 2013 WHO guidelines could reduce new infections by 80%. A 'Test and Treat' approach could further reduce new infections. This could be further enhanced by a future highly effective pre-exposure prophylaxis and an HIV vaccine, so that a combination of all four approaches could reduce new infections to as low as 80,000 per year by 2050 and annual AIDS deaths to 260,000., Interpretation: In a set of ambitious scenarios, we find that immediate implementation of the 2013 WHO antiretroviral therapy guidelines could reduce new HIV infections by 80%. Further reductions may be achieved by moving to a 'Test and Treat' approach, and eventually by adding a highly effective pre-exposure prophylaxis and an HIV vaccine, if they become available.

Objectives: Reliable estimates of the joint burden of HIV and tuberculosis epidemics are crucial to planning strategic global and national tuberculosis responses. Prior to the Global Tuberculosis Report 2013, the Global Tuberculosis Programme (GTB) released estimates for tuberculosis-HIV incidence at the global level only. Neither GTB nor United Nations Programme on HIV/AIDS (UNAIDS) published country specific estimates for tuberculosis-HIV mortality. We used a regression approach that combined all available data from GTB and UNAIDS in order to estimate tuberculosis-HIV incidence and mortality at country level., Methods: A regression method was devised to relate CD4 dynamics (based on national Spectrum files) to an increased relative risk (RR) of tuberculosis disease. The objective function is based on least squares and incorporates all available country-level estimates of tuberculosis-HIV incidence. Global regression parameters, obtained from averaging results over countries with population survey estimates for tuberculosis-HIV burden, were applied to countries with no survey tuberculosis-HIV incidence estimates., Results: The method produced results that are in reasonably close agreement with existing GTB estimates for global tuberculosis-HIV burden. It estimated that tuberculosis-HIV accounts for 12.6% of global tuberculosis incidence, 21.3% of all tuberculosis deaths, and 20% of all HIV deaths as estimated by the Spectrum AIDS Impact Module (AIM). Regional estimates show the highest absolute incidence burden in East and Southeast Asia, and the highest per capita burden in sub-Saharan Africa, where between 12.5% (Central sub-Saharan Africa) and 60.6% (Southern sub-Saharan Africa) of all tuberculosis disease occurs in people living with HIV (PLWH). Tuberculosis mortality follows a similar pattern, except that a disproportionate percentage of global tuberculosis deaths (12.1%) relative to global incidence (8.7%) occurred in Southern sub-Saharan Africa., Conclusion: The disaggregation of tuberculosis incidence using a regression method on RR of tuberculosis disease and all available data on HIV burden (from UNAIDS) and tuberculosis-HIV testing (survey, sentinel and routine surveillance data) produces results that closely match GTB estimates for 2011. The tuberculosis-HIV incidence and mortality results were published in the Global Tuberculosis Report 2013. Several limitations of and potential improvements to the process are suggested.

Introduction: Sex workers have endured a high burden of HIV infection in and across HIV epidemics. A comprehensive, community empowerment-based HIV prevention intervention emphasizes sex worker organization and mobilization to address HIV risk and often includes community-led peer education, condom distribution, and other activities. Meta-analysis of such interventions suggests a potential 51% reduction in inconsistent condom use. Mathematical modeling exercises provide theoretical insight into potential impacts of the intervention on HIV incidence and burden in settings where interventions have not yet been implemented., Methods: We used a deterministic model, Goals, to project the impact on HIV infections when the community empowerment interventions were scaled up among female sex workers in Kenya, Thailand, Brazil, and Ukraine. Modeling scenarios included expansion of the comprehensive community empowerment-based HIV prevention intervention from baseline coverage over a 5-year period (5-65% in Kenya and Ukraine; 10-70% in Thailand and Brazil), while other interventions were held at baseline levels. A second exercise increased the intervention coverage simultaneously with equitable access to ART for sex workers. Impacts on HIV outcomes among sex workers and adults are observed from 2012-2016 and, compared to status quo when all interventions are held constant., Results: Optimistic but feasible coverage (65%-70%) of the intervention demonstrated a range of impacts on HIV: 220 infections averted over 5 yrs. among sex workers in Thailand, 1,830 in Brazil, 2,220 in Ukraine, and 10,800 infections in Kenya. Impacts of the intervention for female sex workers extend to the adult population, cumulatively averting 730 infections in Thailand to 20,700 adult infections in Kenya. Impacts vary by country, influenced by HIV prevalence in risk groups, risk behaviors, intervention use, and population size., Discussion: A community empowerment approach to HIV prevention and access to universal ART for female sex workers is a promising human rights-based solution to overcoming the persistent burden of HIV among female sex workers across epidemic settings.

Introduction: Spectrum epidemiological models are used by UNAIDS to provide global, regional and national HIV estimates and projections, which are then used for evidence-based health planning for HIV services. However, there are no validations of the Spectrum model against empirical serological and mortality data from populations in sub-Saharan Africa., Methods: Serologic, demographic and verbal autopsy data have been regularly collected among over 30,000 residents in north-western Tanzania since 1994. Five-year age-specific mortality rates (ASMRs) per 1,000 person years and the probability of dying between 15 and 60 years of age (45Q15,) were calculated and compared with the Spectrum model outputs. Mortality trends by HIV status are shown for periods before the introduction of antiretroviral therapy (1994-1999, 2000-2005) and the first 5 years afterwards (2005-2009)., Results: Among 30-34 year olds of both sexes, observed ASMRs per 1,000 person years were 13.33 (95% CI: 10.75-16.52) in the period 1994-1999, 11.03 (95% CI: 8.84-13.77) in 2000-2004, and 6.22 (95% CI; 4.75-8.15) in 2005-2009. Among the same age group, the ASMRs estimated by the Spectrum model were 10.55, 11.13 and 8.15 for the periods 1994-1999, 2000-2004 and 2005-2009, respectively. The cohort data, for both sexes combined, showed that the 45Q15 declined from 39% (95% CI: 27-55%) in 1994 to 22% (95% CI: 17-29%) in 2009, whereas the Spectrum model predicted a decline from 43% in 1994 to 37% in 2009., Conclusion: From 1994 to 2009, the observed decrease in ASMRs was steeper in younger age groups than that predicted by the Spectrum model, perhaps because the Spectrum model under-estimated the ASMRs in 30-34 year olds in 1994-99. However, the Spectrum model predicted greater 45Q15 mortality than observed in the cohort,although the reasons for this over-estimate are unclear [corrected].

Objective(s): Many countries are considering expanding HIV treatment following recent findings emphasizing the effects of antiretroviral therapy (ART) on reducing HIV transmission in addition to already established survival benefits. Given the close interaction of tuberculosis (TB) and HIV epidemics, ART expansion could have important ramifications for TB burden. Previous studies suggest a wide range of possible TB impacts following ART expansion. We used three independently developed TB-HIV models to estimate the TB-related impact of expanding ART in South Africa., Design: We considered two dimensions of ART expansion--improving coverage of pre-ART and ART services, and expanding CD4-based ART eligibility criteria (from CD4 <350 to CD4 <500 or all HIV-positive)., Methods: Three independent mathematical models were calibrated to the same data pertaining to the South African HIV-TB epidemic, and used to assess standardized ART policy changes. Key TB impact indicators were projected from 2014 to 2033., Results: Compared with current eligibility and coverage, cumulative TB incidence was projected to decline by 6-30% over the period 2014-2033 if ART eligibility were expanded to all HIV positive individuals, and by 28-37% if effective ART coverage were additionally increased to 80%. Overall, expanding ART was estimated to avert one TB case for each 10-13 additional person-years of ART. All models showed that TB incidence and mortality reductions would grow over time, but would stabilize towards the end of the projection period., Conclusion: ART expansion could substantially reduce TB incidence and mortality in South Africa and could provide a platform for collaborative HIV-TB programs to effectively halt HIV-associated TB.

Background: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per μL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage., Methods: We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per μL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per μL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP., Findings: In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per μL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per μL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per μL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective., Interpretation: Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets., Funding: Bill & Melinda Gates Foundation, WHO., (Copyright © 2014 Eaton et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by .. All rights reserved.)

Problem: Female sex workers (FSWs) worldwide suffer disproportionate burdens of HIV and gender-based violence. Despite evidence linking these threats, little is known about the potential HIV epidemic impact of reducing abuse., Method of Study: The Goals model approximated the impact of reducing violence against FSWs on HIV epidemics in Ukraine and Kenya, measured by reductions in new infections among FSWs and adults. Cumulative infections averted over a 5-year period, in which violence declined was calculated, relative to a status quo with no reduction. Projections held HIV interventions constant at baseline levels; subsequently, scenarios adjusted for planned expansion of antiretroviral therapy (ART) coverage., Results: An approximate 25% reduction in incident HIV infections among FSWs was observed when physical or sexual violence was reduced; cumulative infections averted were 21,200 and 4700 in Kenya and Ukraine, respectively. Similar percent reductions were observed assuming ART coverage expansion, with approximately 18,200 and 4400 infections averted among FSWs in Kenya and Ukraine. New infections were also averted in the general population., Conclusion: Reducing violence against FSWs appears to impart significant reductions in new infections among FSWs and in the general adult population in both generalized and concentrated epidemics. Limitations provide direction to improve the precision of future estimates., (© 2013 John Wiley & Sons A/S.)

Circumstantial evidence from laboratory studies, mathematical models, ecological studies and bio behavioural surveys, suggests that injection-related HIV epidemics may be averted or reversed if people who inject drugs (PWID) switch from using high dead-space to using low dead-space syringes. In laboratory experiments that simulated the injection process and rinsing with water, low dead space syringes retained 1000 times less blood than high dead space syringes. In mathematical models, switching PWID from high dead space to low dead space syringes prevents or reverses injection-related HIV epidemics. No one knows if such an intervention is feasible or what effect it would have on HIV transmission among PWID. Feasibility studies and randomized controlled trials (RCTs) will be needed to answer these questions definitively, but these studies will be very expensive and take years to complete. Rather than waiting for them to be completed, we argue for an approach similar to that used with needle and syringe programs (NSP), which were promoted and implemented before being tested more rigorously. Before implementation, rapid assessments that involve PWID will need to be conducted to ensure buy-in from PWID and other local stakeholders. This commentary summarizes the existing evidence regarding the protective effects of low dead space syringes and estimates potential impacts on HIV transmission; it describes potential barriers to transitioning PWID from high dead space to low dead space needles and syringes; and it presents strategies for overcoming these barriers., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The occurrence of chronic myeloid leukaemia (CML) in patients infected with the human immunodeficiency virus (HIV) has rarely been reported in the literature. In this report, we describe the experience of a single centre in the management of 10 such patients, including demographic information, disease characteristics and response to therapy. We had a black female predominance in our series, with only a minority of patients achieving a complete cytogenetic response. The main reason for this appears to be compliance, which was influenced by distance to the treating centre. The side-effect profile was similar to that expected, with the exception of one patient who developed a drug rash with eosinophilia and systemic symptoms. Although CML patients co-morbid for HIV face certain unique challenges when compared to non-infected patients, their long-term outcome can be positive when appropriately managed.

Background: Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART., Methods and Findings: Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results., Conclusions: Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact.

Background: Randomized controlled trials (RCTs) for the prevention of HIV heterosexual acquisition are usually conducted among adult African populations with high heterogeneity in individual risk of infection., Purpose: The objectives were to (a) review how this heterogeneity has been considered when designing and interpreting such RCTs, (b) evaluate its effect on the findings and the statistical power of these trials, and (c) assess the potential advantages of using the crossover design with single failure-time endpoint., Methods: Individual-level HIV prevention RCTs conducted in Africa and published in the period 1998-2008 were reviewed. Using Monte Carlo simulations and statistical calculations, we assessed the effect of heterogeneity on the findings and the statistical power of HIV prevention RCTs., Results: All reviewed RCTs used the parallel design. The heterogeneity in individual risk of infection within study sites was not used for stratification nor generally considered in the design and interpretation of RCTs. Simulations showed that in the context of high HIV incidence, high heterogeneity can lead to a substantial underestimation of the impact of an intervention and reduced statistical power. Calculations demonstrated that the crossover design allowed for similar or better estimation and statistical power. The crossover design has the ethical advantage of sharing the potential benefits and risks of the intervention between participants., Limitations: Only trials with two treatment arms and two follow-up periods were modeled. The baseline risk of infection of each participant was assumed to be constant over time and HIV status was assessed at the end of each follow-up period., Conclusions: The heterogeneity in individual risk of HIV infection is an underestimated problem which should be taken into account when designing and interpreting RCTs that test prevention methods of HIV heterosexual acquisition in adult African populations with high HIV incidence. When the effects of tested interventions are rapidly reversible, the use of the crossover design should be considered.

Continuous differential equations are often applied to small populations with little time spent on understanding uncertainty brought about by small-population effects. Despite large numbers of individuals being latently infected with Mycobacterium tuberculosis (TB), progression from latent infection to observable disease is a relatively rare event. For small communities, this means case counts are subject to stochasticity, and deterministic models may not be appropriate tools for interpreting transmission trends. Furthermore, the nonlinear nature of the underlying dynamics means that fluctuations are autocorrelated, which can invalidate standard statistical analyses which assume independent fluctuations. Here we extend recent work using a system of differential equations to study the HIV-TB epidemic in Masiphumelele, a community near Cape Town in South Africa [Bacaër, et al., J. Mol. Biol. 57(4), 557-593] by studying the statistical properties of active TB events. We apply van Kampen's system-size (or population-size) expansion technique to obtain an approximation to a master equation describing the dynamics. We use the resulting Fokker-Planck equation and point-process theory to derive two-time correlation functions for active TB events. This method can be used to gain insight into the temporal aspect of cluster identification, which currently relies on DNA classification only., (Copyright © 2010. Published by Elsevier Ltd.)

Background: Mathematical modelers have given little attention to the question of how pre-exposure prophylaxis (PrEP) may impact on a generalized national HIV epidemic and its cost-effectiveness, in the context of control strategies such as condom use promotion and expanding ART programs., Methodology/principal Findings: We use an age- and gender-structured model of the generalized HIV epidemic in South Africa to investigate the potential impact of PrEP in averting new infections. The model utilizes age-structured mortality, fertility, partnership and condom use data to model the spread of HIV and the shift of peak prevalence to older age groups. The model shows that universal PrEP coverage would have to be impractically high to have a significant effect on incidence reduction while ART coverage expands. PrEP targeted to 15-35-year-old women would avert 10%-25% (resp. 13%-28%) of infections in this group and 5%-12% (resp. 7%-16%) of all infections in the period 2014-2025 if baseline incidence is 0.5% per year at 2025 (resp. 0.8% per year at 2025). The cost would be $12,500-$20,000 per infection averted, depending on the level of ART coverage and baseline incidence. An optimistic scenario of 30%-60% PrEP coverage, efficacy of at least 90%, no behavior change among PrEP users and ART coverage less than three times its 2010 levels is required to achieve this result. Targeting PrEP to 25-35-year-old women (at highest risk of infection) improves impact and cost-effectiveness marginally. Relatively low levels of condom substitution (e.g., 30%) do not nullify the efficacy of PrEP, but reduces cost-effectiveness by 35%-40%., Conclusions/significance: PrEP can avert as many as 30% of new infections in targeted age groups of women at highest risk of infection. The cost-effectiveness of PrEP relative to ART decreases rapidly as ART coverage increases beyond three times its coverage in 2010, after which the ART program would provide coverage to more than 65% of HIV(+) individuals. To have a high relative cost-effective impact on reducing infections in generalized epidemics, PrEP must utilize a window of opportunity until ART has been scaled up beyond this level.

A simple mathematical model (Granich et al., Lancet 373:48-57, 2009) suggested recently that annual HIV testing of the population, with all detected HIV(+) individuals immediately treated with antiretrovirals, could lead to the long-term decline of HIV in South Africa and could save millions of lives in the next few years. However, the model suggested that the long-term decline of HIV could not be achieved with less frequent HIV testing. Many observers argued that an annual testing rate was very difficult in practice. Small scale trials are nevertheless in preparation. In this paper, we use a more realistic age-structured model, which suggests that the recent high levels of reported condom use could already lead to a long-term decline of HIV in South Africa. The model therefore suggests that trials with for example 20% of the population tested each year would also be interesting. They would have similar (though smaller) advantages in terms of reduction of mortality and incidence, would be much easier to generalize to larger populations, and would not lead to long term persistence of HIV. Our model simulations also suggest that the age distribution of incidence has changed considerably over the past 20 years in South Africa. This raises some concern about an assumption presently used in EPP/Spectrum, the software used by UNAIDS for its estimates.

We present a simple mathematical model with six compartments for the interaction between HIV and TB epidemics. Using data from a township near Cape Town, South Africa, where the prevalence of HIV is above 20% and where the TB notification rate is close to 2,000 per 100,000 per year, we estimate some of the model parameters and study how various control measures might change the course of these epidemics. Condom promotion, increased TB detection and TB preventive therapy have a clear positive effect. The impact of antiretroviral therapy on the incidence of HIV is unclear and depends on the extent to which it reduces sexual transmission. However, our analysis suggests that it will greatly reduce the TB notification rate.

We develop a model of HIV infection with two viral strains, a cytotoxic T-lymphocyte (CTL) response and structured treatment interruptions. We derive new analytical relations characterizing the dynamics between drug-sensitive and drug-resistant variants of the virus, and the strength of the CTL response. [ABSTRACT FROM AUTHOR]