Maximising the effect of combination HIV prevention through prioritisation of the people and places in greatest need: a modelling study.

BACKGROUND: Epidemiological data show substantial variation in the risk of HIV infection between communities within African countries. We hypothesised that focusing appropriate interventions on geographies and key populations at high risk of HIV infection could improve the effect of investments in the HIV response. METHODS: With use of Kenya as a case study, we developed a mathematical model that described the spatiotemporal evolution of the HIV epidemic and that incorporated the demographic, behavioural, and programmatic differences across subnational units. Modelled interventions (male circumcision, behaviour change communication, early antiretoviral therapy, and pre-exposure prophylaxis) could be provided to different population groups according to their risk behaviours or their location. For a given national budget, we compared the effect of a uniform intervention strategy, in which the same complement of interventions is provided across the country, with a focused strategy that tailors the set of interventions and amount of resources allocated to the local epidemiological conditions. FINDINGS: A uniformly distributed combination of HIV prevention interventions could reduce the total number of new HIV infections by 40% during a 15-year period. With no additional spending, this effect could be increased by 14% during the 15 years-almost 100,000 extra infections, and result in 33% fewer new HIV infections occurring every year by the end of the period if the focused approach is used to tailor resource allocation to reflect patterns in local epidemiology. The cumulative difference in new infections during the 15-year projection period depends on total budget and costs of interventions, and could be as great as 150,000 (a cumulative difference as great as 22%) under different assumptions about the unit costs of intervention. INTERPRETATION: The focused approach achieves greater effect than the uniform approach despite exactly the same investment. Through prioritisation of the people and locations at greatest risk of infection, and adaption of the interventions to reflect the local epidemiological context, the focused approach could substantially increase the efficiency and effectiveness of investments in HIV prevention. FUNDING: The Bill & Melinda Gates Foundation and UNAIDS.

Transformation of HIV from pandemic to low-endemic levels: a public health approach to combination prevention.

Large declines in HIV incidence have been reported since 2001, and scientific advances in HIV prevention provide strong hope to reduce incidence further. Now is the time to replace the quest for so-called silver bullets with a public health approach to combination prevention that understands that risk is not evenly distributed and that effective interventions can vary by risk profile. Different countries have different microepidemics, with very different levels of transmission and risk groups, changing over time. Therefore, focus should be on high-transmission geographies, people at highest risk for HIV, and the package of interventions that are most likely to have the largest effect in each different microepidemic. Building on the backbone of behaviour change, condom use, and medical male circumcision, as well as expanded use of antiretroviral drugs for infected people and pre-exposure prophylaxis for uninfected people at high risk of infection, it is now possible to consider the prospect of what would be one of the most remarkable achievements in the history of public health: reduction of HIV transmission from a pandemic to low-level endemicity.

Distinct HIV discordancy patterns by epidemic size in stable sexual partnerships in sub-Saharan Africa.

OBJECTIVE: To describe patterns of HIV infection among stable sexual partnerships across sub-Saharan Africa (SSA). METHODS: The authors defined measures of HIV discordancy and conducted a comprehensive quantitative assessment of discordancy among stable partnerships in 20 countries in SSA through an analysis of the Demographic and Health Survey data. RESULTS: HIV prevalence explained at least 50% of the variation in HIV discordancy, with two distinct patterns of discordancy emerging based on HIV prevalence being roughly smaller or larger than 10%. In low-prevalence countries, approximately 75% of partnerships affected by HIV are discordant, while only about half of these are discordant in high-prevalence countries. Out of each 10 HIV infected persons, two to five are engaged in discordant partnerships in low-prevalence countries compared with one to three in high-prevalence countries. Among every 100 partnerships in the population, one to nine are affected by HIV and zero to six are discordant in low-prevalence countries compared with 16-45 and 9-17, respectively, in high-prevalence countries. Finally, zero to four of every 100 sexually active adults are engaged in a discordant partnership in low-prevalence countries compared with six to eight in high-prevalence countries. CONCLUSIONS: In high-prevalence countries, a large fraction of stable partnerships were affected by HIV and half were discordant, whereas in low-prevalence countries, fewer stable partnerships were affected by HIV but a higher proportion of them were discordant. The findings provide a global view of HIV infection among stable partnerships in SSA but imply complex considerations for rolling out prevention interventions targeting discordant partnerships.

Patterns of uptake of HIV testing in sub-Saharan Africa in the pre-treatment era.

OBJECTIVES: To compare nationally representative trends in self-reported uptake of HIV testing and receipt of results in selected countries prior to treatment scale-up. METHODS: Demographic and Health Survey (DHS) data from 13 countries in sub-Saharan Africa were used to describe the pattern of uptake of testing for HIV among sexually active participants. Univariate and multivariate logistic regression were used to analyse the associations between socio-demographic and behavioural characteristics and the uptake of testing. RESULTS: Knowledge of serostatus ranged from 2.2% among women in Guinea (2005) to 27.4% among women in Rwanda (2005). Despite varied levels of testing, univariate analysis showed the profile of testers to be remarkably similar across countries, with respect to socio-demographic characteristics such as area of residence and socio-economic status. HIV-positive participants were more likely to have tested and received their results than HIV-negative participants, with the exception of women in Senegal and men in Guinea. Adjusted analyses indicate that a secondary or higher level of education was a key determinant of testing, and awareness that treatment exists was independently positively associated with testing, once other characteristics were taken into account. CONCLUSION: This work provides a baseline for monitoring trends in testing and exploring changes in the profile of those who get tested after the introduction and scale-up of treatment.

Optimal uses of antiretrovirals for prevention in HIV-1 serodiscordant heterosexual couples in South Africa: a modelling study.

BACKGROUND: Antiretrovirals have substantial promise for HIV-1 prevention, either as antiretroviral treatment (ART) for HIV-1-infected persons to reduce infectiousness, or as pre-exposure prophylaxis (PrEP) for HIV-1-uninfected persons to reduce the possibility of infection with HIV-1. HIV-1 serodiscordant couples in long-term partnerships (one member is infected and the other is uninfected) are a priority for prevention interventions. Earlier ART and PrEP might both reduce HIV-1 transmission in this group, but the merits and synergies of these different approaches have not been analyzed. METHODS AND FINDINGS: We constructed a mathematical model to examine the impact and cost-effectiveness of different strategies, including earlier initiation of ART and/or PrEP, for HIV-1 prevention for serodiscordant couples. Although the cost of PrEP is high, the cost per infection averted is significantly offset by future savings in lifelong treatment, especially among couples with multiple partners, low condom use, and a high risk of transmission. In some situations, highly effective PrEP could be cost-saving overall. To keep couples alive and without a new infection, providing PrEP to the uninfected partner could be at least as cost-effective as initiating ART earlier in the infected partner, if the annual cost of PrEP is <40% of the annual cost of ART and PrEP is >70% effective. CONCLUSIONS: Strategic use of PrEP and ART could substantially and cost-effectively reduce HIV-1 transmission in HIV-1 serodiscordant couples. New and forthcoming data on the efficacy of PrEP, the cost of delivery of ART and PrEP, and couples behaviours and preferences will be critical for optimizing the use of antiretrovirals for HIV-1 prevention. Please see later in the article for the Editors' Summary.

Patterns of self-reported behaviour change associated with receiving voluntary counselling and testing in a longitudinal study from Manicaland, Zimbabwe.

Voluntary counselling and testing (VCT) is promoted as a potential HIV prevention measure. We describe trends in uptake of VCT for HIV, and patterns of subsequent behaviour change associated with receiving VCT in a population-based open cohort in Manicaland, Zimbabwe. The relationship between receipt of VCT and subsequent reported behaviour was analysed using generalized linear models with random effects. At the third survey, 8.6% of participants (1,079/12,533), had previously received VCT. Women who received VCT, both those positive and negative, reduced their reported number of new partners. Among those testing positive, this risk reduction was enhanced with time since testing. Among men, no behavioural risk reduction associated with VCT was observed. Significant increases in consistent condom use, with regular or non-regular partners, following VCT, were not observed. This study suggests that, among women, particularly those who are infected, behavioural risk reduction does occur following VCT.

An infectious way to teach students about outbreaks.

The study of infectious disease outbreaks is required to train today's epidemiologists. A typical way to introduce and explain key epidemiological concepts is through the analysis of a historical outbreak. There are, however, few training options that explicitly utilise real-time simulated stochastic outbreaks where the participants themselves comprise the dataset they subsequently analyse. In this paper, we present a teaching exercise in which an infectious disease outbreak is simulated over a five-day period and subsequently analysed. We iteratively developed the teaching exercise to offer additional insight into analysing an outbreak. An R package for visualisation, analysis and simulation of the outbreak data was developed to accompany the practical to reinforce learning outcomes. Computer simulations of the outbreak revealed deviations from observed dynamics, highlighting how simplifying assumptions conventionally made in mathematical models often differ from reality. Here we provide a pedagogical tool for others to use and adapt in their own settings.

Voluntary counselling and testing: uptake, impact on sexual behaviour, and HIV incidence in a rural Zimbabwean cohort.

OBJECTIVES: To examine the determinants of uptake of voluntary counselling and testing (VCT) services, to assess changes in sexual risk behaviour following VCT, and to compare HIV incidence amongst testers and non-testers. METHODS: Prospective population-based cohort study of adult men and women in the Manicaland province of eastern Zimbabwe. Demographic, socioeconomic, sexual behaviour and VCT utilization data were collected at baseline (1998-2000) and follow-up (3 years later). HIV status was determined by HIV-1 antibody detection. In addition to services provided by the government and non-governmental organizations, a mobile VCT clinic was available at study sites. RESULTS: Lifetime uptake of VCT increased from under 6% to 11% at follow-up. Age, increasing education and knowledge of HIV were associated with VCT uptake. Women who took a test were more likely to be HIV positive and to have greater HIV knowledge and fewer total lifetime partners. After controlling for demographic characteristics, sexual behaviour was not independently associated with VCT uptake. Women who tested positive reported increased consistent condom use in their regular partnerships. However, individuals who tested negative were more likely to adopt more risky behaviours in terms of numbers of partnerships in the last month, the last year and in concurrent partnerships. HIV incidence during follow-up did not differ between testers and non-testers. CONCLUSION: Motivation for VCT uptake was driven by knowledge and education rather than sexual risk. Increased sexual risk following receipt of a negative result may be a serious unintended consequence of VCT. It should be minimized with appropriate pre- and post-test counselling.

PrEP for key populations in combination HIV prevention in Nairobi: a mathematical modelling study.

BACKGROUND: The HIV epidemic in the population of Nairobi as a whole is in decline, but a concentrated sub-epidemic persists in key populations. We aimed to identify an optimal portfolio of interventions to reduce HIV incidence for a given budget and to identify the circumstances in which pre-exposure prophylaxis (PrEP) could be used in Nairobi, Kenya. METHODS: A mathematical model was developed to represent HIV transmission in specific key populations (female sex workers, male sex workers, and men who have sex with men [MSM]) and among the wider population of Nairobi. The scale-up of existing interventions (condom promotion, antiretroviral therapy, and male circumcision) for key populations and the wider population as have occurred in Nairobi is represented. The model includes a detailed representation of a PrEP intervention and is calibrated to prevalence and incidence estimates specific to key populations and the wider population. FINDINGS: In the context of a declining epidemic overall but with a large sub-epidemic in MSM and male sex workers, an optimal prevention portfolio for Nairobi should focus on condom promotion for male sex workers and MSM in particular, followed by improved antiretroviral therapy retention, earlier antiretroviral therapy, and male circumcision as the budget allows. PrEP for male sex workers could enter an optimal portfolio at similar levels of spending to when earlier antiretroviral therapy is included; however, PrEP for MSM and female sex workers would be included only at much higher budgets. If PrEP for male sex workers cost as much as US$500, average annual spending on the interventions modelled would need to be less than $3·27 million for PrEP for male sex workers to be excluded from an optimal portfolio. Estimated costs per infection averted when providing PrEP to all female sex workers regardless of their risk of infection, and to high-risk female sex workers only, are $65 160 (95% credible interval [CrI] $43 520-$90 250) and $10 920 (95% CrI $4700-$51 560), respectively. INTERPRETATION: PrEP could be a useful contribution to combination prevention, especially for under-served key populations in Nairobi. An ongoing demonstration project will provide important information regarding practical aspects of implementing PrEP for key populations in this setting. FUNDING: The Bill & Melinda Gates Foundation.

Estimating the range of potential epidemiological impact of pre-exposure prophylaxis: run-away success or run-away failure?

OBJECTIVE: To investigate the influence of potential interactions between key aspects of a pre-exposure prophylaxis (PrEP) intervention on projections of epidemiological impact and cost-effectiveness. METHODS: A mathematical model representing the HIV epidemic and intervention context in Nyanza province in Kenya was developed. We consider a scenario whereby a fixed annual budget is allocated to a PrEP intervention. A standard projection of impact is generated, assuming that the unit cost of PrEP, adherence to PrEP and the ability of the programme to direct PrEP to those at high risk, all stay constant. The influence of dynamic assumptions and possible interactions between PrEP intervention assumptions is then assessed in comparison. RESULTS: The cumulative impact of a PrEP intervention could be increased approximately two-fold, relative to the standard projection, if positive interactions (between coverage and cost, coverage and adherence, prioritization and time) are assumed, whereas negative interactions between these factors could almost entirely negate the preventive benefit of the PrEP intervention. The corresponding estimates of cost per infection averted span a wide range from $2060 to $36360. CONCLUSIONS: Multiple potentially interacting factors will determine the impact of PrEP. Model forecasts should reflect that uncertainty and programmes should focus on these factors and measure them, to maximize the impact of programmes.

Seasonal PrEP for partners of migrant miners in southern Mozambique: a highly focused PrEP intervention.

INTRODUCTION: To be used most effectively, pre-exposure prophylaxis (PrEP) should be prioritized to those at high risk of acquisition and would ideally be aligned with time periods of increased exposure. Identifying such time periods is not always straightforward, however. Gaza Province in southern Mozambique is characterized by high levels of HIV transmission and circular labour migration to mines in South Africa. A strong seasonal pattern in births is observable, reflecting an increase in conception in December. Given the potential for increased HIV transmission between miners returning in December and their partners in Gaza Province, PrEP use by the latter would be a useful means of HIV prevention, especially for couples who wish to conceive. METHODS: A mathematical model was used to represent population-level adult heterosexual HIV transmission in Gaza Province. Increased HIV acquisition among partners of miners in December, coinciding with the miners' return from South Africa, is represented. In addition to a PrEP intervention, the scale-up of treatment and recent scale-up of male circumcision that have occurred in Gaza are represented. RESULTS: Providing time-limited PrEP to the partners of migrant miners, as opposed to providing PrEP all year, would improve the cost per infection averted by 7.5-fold. For the cost per infection averted to be below US$3000, at least 85% of PrEP users would need to be good adherers and PrEP would need to be cheaper than US$115 per person per year. Uncertainty regarding incidence of HIV transmission among partners of miners each year in December has a strong influence on estimates of cost per infection averted. CONCLUSIONS: Providing time-limited PrEP to partners of migrant miners in Gaza Province during periods of increased exposure would be a novel strategy for providing PrEP. This strategy would allow for a better prioritized intervention, with the potential to improve the efficiency of a PrEP intervention considerably, as well as providing important reproductive health benefits.

Estimating the cost-effectiveness of pre-exposure prophylaxis to reduce HIV-1 and HSV-2 incidence in HIV-serodiscordant couples in South Africa.

OBJECTIVE: To estimate the cost-effectiveness of daily oral tenofovir-based PrEP, with a protective effect against HSV-2 as well as HIV-1, among HIV-1 serodiscordant couples in South Africa. METHODS: We incorporated HSV-2 acquisition, transmission, and interaction with HIV-1 into a microsimulation model of heterosexual HIV-1 serodiscordant couples in South Africa, with use of PrEP for the HIV-1 uninfected partner prior to ART initiation for the HIV-1 1infected partner, and for one year thereafter. RESULTS: We estimate the cost per disability-adjusted life-year (DALY) averted for two scenarios, one in which PrEP has no effect on reducing HSV-2 acquisition, and one in which there is a 33% reduction. After a twenty-year intervention, the cost per DALY averted is estimated to be $10,383 and $9,757, respectively--a 6% reduction, given the additional benefit of reduced HSV-2 acquisition. If all couples are discordant for both HIV-1 and HSV-2, the cost per DALY averted falls to $1,445, which shows that the impact is limited by HSV-2 concordance in couples. CONCLUSION: After a 20-year PrEP intervention, the cost per DALY averted with a reduction in HSV-2 is estimated to be modestly lower than without any effect, providing an increase of health benefits in addition to HIV-1 prevention at no extra cost. The small degree of the effect is in part due to a high prevalence of HSV-2 infection in HIV-1 serodiscordant couples in South Africa.

The new role of antiretrovirals in combination HIV prevention: a mathematical modelling analysis.

BACKGROUND AND OBJECTIVES: Antiretroviral drugs can reduce HIV acquisition among uninfected individuals (as pre-exposure prophylaxis: PrEP) and reduce onward transmission among infected individuals (as antiretroviral treatment: ART). We estimate the potential impact and cost-effectiveness of antiretroviral-based HIV prevention strategies. DESIGN AND METHODS: We developed and analysed a mathematical model of a hyperendemic setting with relatively low levels of condom use. We estimated the prevention impact and cost of various PrEP interventions, assuming a fixed amount of spending on PrEP; investigated the optimal role of PrEP and earlier ART in terms of epidemiological impact and cost; and systematically explored the impact of earlier ART and PrEP, in combination with medical male circumcision services; on HIV transmission. RESULTS: A PrEP intervention is unlikely to generate a large reduction in HIV incidence, unless the cost is substantially reduced. In terms of infections averted and quality adjusted life years gained, at a population-level maximal cost-effectiveness is achieved by providing ART to more infected individuals earlier rather than providing PrEP to uninfected individuals. However, early ART alone cannot reduce HIV incidence to very low levels and PrEP can be used cost-effectively in addition to earlier ART to reduce incidence further. If implemented in combination and at ambitious coverage levels, medical male circumcision, earlier ART and PrEP could produce dramatic declines in HIV incidence, but not stop transmission completely. CONCLUSION: A combination prevention approach based on proven-efficacy interventions provides the best opportunity for achieving the much hoped for prevention advance and curbing the spread of HIV.

Could better tolerated HIV drug regimens improve patient outcome?

OBJECTIVES: To quantify the performance of existing first-line and second-line combination antiretroviral therapy (cART) regimens on patient's clinical outcomes in the Netherlands using ATHENA data and to evaluate the potential for new drug regimens to improve patient's clinical outcomes using a data-based mathematical model. DESIGN AND METHODS: We analysed data from 3995 patients from the Dutch ATHENA national observational cohort between 2000 and 2010. We quantified the main drug-related reasons for switching from first-line and second-line cART, classified as toxicity, simplification/new medication becoming available, virological failure, or other reasons. We developed a deterministic model describing HIV infection and treatment in the Netherlands parameterized on the basis of these data. The model simulated how a new drug regimen, with either improved toxicity or virological failure profile, could impact on patient's clinical outcomes. RESULTS: The main reason for switching current first-line and second-line regimens was toxicity, accounting for around 50% of switching from first-line and from second-line cART. The model found that a new drug regimen with increased tolerability profile could have the highest potential impact on patient's outcomes, especially as a first-line treatment. A new first-line drug regimen with improved tolerability could increase the time patients spend on first-line cART, decrease their risk of switching from first-line cART and thus simplify patient management. CONCLUSION: New drug regimens with improved toxicity profiles could have the greatest impact on patient outcomes and simplify patient management in the Netherlands.