Optimum resource allocation to reduce HIV incidence across sub-Saharan Africa: a mathematical modelling study.

BACKGROUND: 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.

Are Thai MSM willing to take PrEP for HIV prevention? An analysis of attitudes, preferences and acceptance.

OBJECTIVE: We aimed to understand the attitudes, preferences and acceptance of oral and parenteral PrEP among men who have sex with men (MSM) in Thailand. BACKGROUND: Pre-exposure prophylaxis (PrEP), the use of antiretrovirals to prevent HIV acquisition, has shown promising results in recent trials. To assess the potential impact of this new HIV prevention method, in addition to efficacy data, we need to understand which psychosocial factors are likely to determine its uptake among members of potential user groups. METHODS AND FINDINGS: Surveys of willingness to use PrEP products were administered to MSM. Spearman's rank tests were used to uncover associations between questionnaire items. Mann-Whitney tests were performed to ascertain differences between groups. Conjoint analysis was used to examine the attitudes and preferences of MSM towards PrEP attributes. Most participants were willing to consider taking PrEP (39.2% "yes, definitely" and 49.2% "yes, probably") and perceived PrEP as giving them new possibilities in their lives (38.5% "a lot of hope" and 55.8% "some hope"), even after being instructed of potential side effects and costs. HIV testing was considered the most important attribute and a daily pill and longer lasting injection in the arm were the preferred routes of administration. CONCLUSIONS: Despite its multiple challenges, MSM in Thailand would be willing to take PrEP, even if they had to experience inconvenience and expense. If PrEP were to be implemented in Thailand, our findings show that its uptake could be considerable.

The promise of pre-exposure prophylaxis with antiretroviral drugs to prevent HIV transmission: a review.

PURPOSE OF REVIEW: Public health experts are wrestling with how to translate recent scientific findings from pre-exposure prophylaxis (PrEP) effectiveness trials into real-world programmes. This review summarizes clinical trial findings on oral and topical PrEP, discusses how decision-makers can evaluate the place of PrEP within combination prevention and highlights anticipated developments that could be important in future HIV-prevention strategies. RECENT FINDINGS: PrEP taken daily as oral tablets to create systemic protection has been found to be effective in the Pre-Exposure Prophylaxis Initiative (iPrEx), Partners' PrEP and TDF2 trials, but not in Fem-PrEP or the Vaginal and Oral Interventions to Control the Epidemic (VOICE) tenofovir arm. Tenofovir gel for topical protection was effective in CAPRISA 004 when used peri-coitally but not in VOICE with daily use. These findings underscore the importance of adherence to achieve adequate drug levels and the potential additive role of PrEP within combination prevention. Pivotal phase III trials are underway of the dapivirine ring, whereas phase I trials of injectable formulations show promise. SUMMARY: Antiretroviral-based HIV-prevention programmes should be tailored to those most likely to be adherent, providing them with state-of-the-art counselling and support to achieve high adherence during the time period of use. Long-acting products, if found well tolerated and effective, could be ideal for overcoming adherence challenges.

Views of policymakers, healthcare workers and NGOs on HIV pre-exposure prophylaxis (PrEP): a multinational qualitative study.

OBJECTIVES: To examine policymakers and providers' views on pre-exposure prophylaxis (PrEP) and their willingness to support its introduction, to inform policy and practice in this emerging field. DESIGN: Semistructured qualitative interview study. SETTING: Peru, Ukraine, India, Kenya, Uganda, Botswana and South Africa. PARTICIPANTS: 35 policymakers, 35 healthcare workers and 21 non-governmental organisation representatives involved in HIV prevention. RESULTS: Six themes emerged from the data: (1) perceived HIV prevention landscape: prevention initiatives needed to be improved and expanded; (2) PrEP awareness: 50 of 91 participants had heard of PrEP; (3) benefits of PrEP: one component of the combination prevention arsenal that could help prioritise HIV prevention, empower key populations and result in economic gains; (4) challenges of PrEP: regimen complexity, cost and cost-effectiveness, risk compensation, efficacy and effectiveness, stigmatisation and criminalisation, information and training and healthcare system capacity; (5) programmatic considerations: user eligibility, communication strategy, cost, distribution, medication and HIV testing compliance and (6) early versus late implementation: participants were divided as to whether they would support an early introduction of PrEP in their country or would prefer to wait until it has been successfully implemented in other countries, with around half of those we spoke to supporting each option. Very few said they would not support PrEP at all. CONCLUSIONS: Despite the multiple challenges identified, there was general willingness to support the introduction of PrEP. Yet, strengthening existing HIV prevention efforts was also deemed necessary. Our results suggest that an effective PrEP programme would be delivered in healthcare facilities and involve non-governmental organisations and the community and consider the needs of mobile populations. Comprehensive information packages and training for users and providers would be critical. The cost of PrEP would be affordable and possibly segmented. Extensive counselling and innovative monitoring measures ought to be considered.

Attitudes and acceptance of oral and parenteral HIV preexposure prophylaxis among potential user groups: a multinational study.

BACKGROUND: The use of antiviral medications by HIV negative people to prevent acquisition of HIV or pre-exposure prophylaxis (PrEP) has shown promising results in recent trials. To understand the potential impact of PrEP for HIV prevention, in addition to efficacy data, we need to understand both the acceptability of PrEP among members of potential user groups and the factors likely to determine uptake. METHODS AND FINDINGS: Surveys of willingness to use PrEP products were conducted with 1,790 members of potential user groups (FSWs, MSM, IDUs, SDCs and young women) in seven countries: Peru, Ukraine, India, Kenya, Botswana, Uganda and South Africa. Analyses of variance were used to assess levels of acceptance across different user groups and countries. Conjoint analysis was used to examine the attitudes and preferences towards hypothetical and known attributes of PrEP programs and medications. Overall, members of potential user groups were willing to consider taking PrEP (61% reported that they would definitely use PrEP). Current results demonstrate that key user groups in different countries perceived PrEP as giving them new possibilities in their lives and would consider using it as soon as it becomes available. These results were maintained when subjects were reminded of potential side effects, the need to combine condom use with PrEP, and for regular HIV testing. Across populations, route of administration was considered the most important attribute of the presented alternatives. CONCLUSIONS: Despite multiple conceivable barriers, there was a general willingness to adopt PrEP in key populations, which suggests that if efficacious and affordable, it could be a useful tool in HIV prevention. There would be a willingness to experience inconvenience and expense at the levels included in the survey. The results suggest that delivery in a long lasting injection would be a good target in drug development.

Planning for pre-exposure prophylaxis to prevent HIV transmission: challenges and opportunities.

There are currently several ongoing or planned trials evaluating the efficacy of pre-exposure prophylaxis (PrEP) as a preventative approach to reducing the transmission of HIV. PrEP may prove ineffective, demonstrate partial efficacy, or show high efficacy and have the potential to reduce HIV infection in a significant way. However, in addition to the trial results, it is important that issues related to delivery, implementation and further research are also discussed. As a part of the ongoing discussion, in June 2009, the Bill & Melinda Gates Foundation sponsored a Planning for PrEP conference with stakeholders to review expected trial results, outline responsible educational approaches, and develop potential delivery and implementation strategies. The conference reinforced the need for continued and sustained dialogue to identify where PrEP implementation may fit best within an integrated HIV prevention package. This paper identifies the key action points that emerged from the Planning for PrEP meeting.

A randomized, controlled, trial of short cycle intermittent compared to continuous antiretroviral therapy for the treatment of HIV infection in Uganda.

BACKGROUND: Short cycle treatment interruption could reduce toxicity and drug costs and contribute to further expansion of antiretroviral therapy (ART) programs. METHODS: A 72 week, non-inferiority trial enrolled one hundred forty six HIV positive persons receiving ART (CD4+ cell count > or =125 cells/mm(3) and HIV RNA plasma levels <50 copies/ml) in one of three arms: continuous, 7 days on/7 days off and 5 days on/2 days off treatment. Primary endpoint was ART treatment failure determined by plasma HIV RNA level, CD4+ cell count decrease, death attributed to study participation, or opportunistic infection. RESULTS: Following enrollment of 32 participants, the 7 days on/7 days off arm was closed because of a failure rate of 31%. Six of 52 (11.5%) participants in the 5 days on/2 days off arm failed. Five had virologic failure and one participant had immunologic failure. Eleven of 51 (21.6%) participants in the continuous treatment arm failed. Nine had virologic failure with 1 death (lactic acidosis) and 1 clinical failure (extra-pulmonary TB). The upper 97.5% confidence boundary for the difference between the percent of non-failures in the 5 days on/2 days off arm (88.5% non-failure) compared to continuous treatment (78.4% non failure) was 4.8% which is well within the preset non-inferiority margin of 15%. No significant difference was found in time to failure in the 2 study arms (p = 0.39). CONCLUSIONS: Short cycle 5 days on/2 days off intermittent ART was at least as effective as continuous therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00339456.

Virological outcome after structured interruption of antiretroviral therapy for human immunodeficiency virus infection is associated with the functional profile of virus-specific CD8+ T cells.

A clear understanding of the antiviral effects of CD8(+) T cells in the context of chronic human immunodeficiency virus (HIV) infection is critical for the development of prophylactic vaccines and therapeutics designed to support T-cell-mediated immunity. However, defining the potential correlates of effective CD8(+) T-cell immunity has proven difficult; notably, comprehensive analyses have demonstrated that the size and shape of the CD8(+) T-cell response are not necessarily indicative of efficacy determined by measures of plasma viral load. Here, we conducted a detailed quantitative and qualitative analysis of CD8(+) T-cell responses to autologous virus in a cohort of six HIV-infected individuals with a history of structured interruption of antiretroviral therapy (ART) (SIT). The magnitude and breadth of the HIV-specific response did not, by themselves, explain the changes observed in plasma virus levels after the cessation of ART. Furthermore, mutational escape from targeted epitopes could not account for the differential virological outcomes in this cohort. However, the functionality of HIV-specific CD8(+) T-cell populations upon antigen encounter, determined by the simultaneous and independent measurement of five CD8(+) T-cell functions (degranulation and gamma interferon, macrophage inflammatory protein 1beta, tumor necrosis factor alpha, and interleukin-2 levels) reflected the emergent level of plasma virus, with multiple functions being elicited in those individuals with lower levels of viremia after SIT. These data show that the quality of the HIV-specific CD8(+) T-cell response, rather than the quantity, is associated with the dynamics of viral replication in the absence of ART and suggest that the effects of SIT can be assessed by measuring the functional profile of HIV-specific CD8(+) T cells.

Effect of long-cycle structured intermittent versus continuous HAART on quality of life in patients with chronic HIV infection.

OBJECTIVE: To examine the effect of repeated, long-cycle structured intermittent versus continuous HAART on health-related quality of life (HRQL) and symptom distress in patients with chronic HIV infection and plasma HIV RNA of less than 50 copies/ml. DESIGN: Prospective survey of adult patients (n = 46) enrolled in a randomized clinical trial evaluating intermittent versus continuous HAART on immunological and virologic parameters. Patients (n = 23) randomized to structured intermittent therapy received serial cycles of 4 weeks on/8 weeks off HAART. OUTCOME MEASURES: HRQL was measured by the physical and mental health summary scores of the Medical Outcomes Study HIV Health Survey (MOS-HIV). Symptom distress was measured by the Symptom Distress Scale. Patients completed initial questionnaires prior to randomization and at weeks 4, 12, and 40 of the trial via a touch screen computer in an outpatient clinic. RESULTS: Baseline demographic and clinical characteristics were equivalent in both treatment groups. Although the mental health summary score declined significantly over time for the structured intermittent group, linear mixed modeling ANOVA indicated no significant difference across time for MOS-HIV summary and Symptom Distress Scale scores between the two treatment arms. CONCLUSION: In this small sample, repeated long-cycle structured intermittent therapy may not provide HRQL or symptom distress advantage compared to continuous HAART in patients with chronic HIV infection over 10 months of treatment. Further research in a heterogenous chronic HIV population and longer follow-up period is warranted.