Health Economics Research on Non-surgical Biomedical HIV Prevention: Identifying Gaps and Proposing a Way Forward.

BACKGROUND AND OBJECTIVE: Although HIV prevention science has advanced over the last four decades, evidence suggests that prevention technologies do not always reach their full potential. Critical health economics evidence at appropriate decision-making junctures, particularly early in the development process, could help identify and address potential barriers to the eventual uptake of future HIV prevention products. This paper aims to identify key evidence gaps and propose health economics research priorities for the field of HIV non-surgical biomedical prevention. METHODS: We used a mixed-methods approach with three distinct components: (i) three systematic literature reviews (costs and cost effectiveness, HIV transmission modelling and quantitative preference elicitation) to understand health economics evidence and gaps in the peer-reviewed literature; (ii) an online survey with researchers working in this field to capture gaps in yet-to-be published research (recently completed, ongoing and future); and (iii) a stakeholder meeting with key global and national players in HIV prevention, including experts in product development, health economics research and policy uptake, to uncover further gaps, as well as to elicit views on priorities and recommendations based on (i) and (ii). RESULTS: Gaps in the scope of available health economics evidence were identified. Little research has been carried out on certain key populations (e.g. transgender people and people who inject drugs) and other vulnerable groups (e.g. pregnant people and people who breastfeed). Research is also lacking on preferences of community actors who often influence or enable access to health services among priority populations. Oral pre-exposure prophylaxis, which has been rolled out in many settings, has been studied in depth. However, research on newer promising technologies, such as long-acting pre-exposure prophylaxis formulations, broadly neutralising antibodies and multipurpose prevention technologies, is lacking. Interventions focussing on reducing intravenous and vertical transmission are also understudied. A disproportionate amount of evidence on low- and middle-income countries comes from two countries (South Africa and Kenya); evidence from other countries in sub-Saharan Africa as well as other low- and middle-income countries is needed. Further, data are needed on non-facility-based service delivery modalities, integrated service delivery and ancillary services. Key methodological gaps were also identified. An emphasis on equity and representation of heterogeneous populations was lacking. Research rarely acknowledged the complex and dynamic use of prevention technologies over time. Greater efforts are needed to collect primary data, quantify uncertainty, systematically compare the full range of prevention options available, and validate pilot and modelling data once interventions are scaled up. Clarity on appropriate cost-effectiveness outcome measures and thresholds is also lacking. Lastly, research often fails to reflect policy-relevant questions and approaches. CONCLUSIONS: Despite a large body of health economics evidence on non-surgical biomedical HIV prevention technologies, important gaps in the scope of evidence and methodology remain. To ensure that high-quality research influences key decision-making junctures and facilitates the delivery of prevention products in a way that maximises impact, we make five broad recommendations related to: improved study design, an increased focus on service delivery, greater community and stakeholder engagement, the fostering of an active network of partners across sectors and an enhanced application of research.

Cost-effectiveness of easy-access, risk-informed oral pre-exposure prophylaxis in HIV epidemics in sub-Saharan Africa: a modelling study.

BACKGROUND: Approaches that allow easy access to pre-exposure prophylaxis (PrEP), such as over-the-counter provision at pharmacies, could facilitate risk-informed PrEP use and lead to lower HIV incidence, but their cost-effectiveness is unknown. We aimed to evaluate conditions under which risk-informed PrEP use is cost-effective. METHODS: We applied a mathematical model of HIV transmission to simulate 3000 setting-scenarios reflecting a range of epidemiological characteristics of communities in sub-Saharan Africa. The prevalence of HIV viral load greater than 1000 copies per mL among all adults (HIV positive and negative) varied from 1·1% to 7·4% (90% range). We hypothesised that if PrEP was made easily available without restriction and with education regarding its use, women and men would use PrEP, with sufficient daily adherence, during so-called seasons of risk (ie, periods in which individuals are at risk of acquiring infection). We refer to this as risk-informed PrEP. For each setting-scenario, we considered the situation in mid-2021 and performed a pairwise comparison of the outcomes of two policies: immediate PrEP scale-up and then continuation for 50 years, and no PrEP. We estimated the relationship between epidemic and programme characteristics and cost-effectiveness of PrEP availability to all during seasons of risk. For our base-case analysis, we assumed a 3-monthly PrEP cost of US$29 (drug $11, HIV test $4, and $14 for additional costs necessary to facilitate education and access), a cost-effectiveness threshold of $500 per disability-adjusted life-year (DALY) averted, an annual discount rate of 3%, and a time horizon of 50 years. In sensitivity analyses, we considered a cost-effectiveness threshold of $100 per DALY averted, a discount rate of 7% per annum, the use of PrEP outside of seasons of risk, and reduced uptake of risk-informed PrEP. FINDINGS: In the context of PrEP scale-up such that 66% (90% range across setting-scenarios 46-81) of HIV-negative people with at least one non-primary condomless sex partner take PrEP in any given period, resulting in 2·6% (0·9-6·0) of all HIV negative adults taking PrEP at any given time, risk-informed PrEP was predicted to reduce HIV incidence by 49% (23-78) over 50 years compared with no PrEP. PrEP was cost-effective in 71% of all setting-scenarios, and cost-effective in 76% of setting-scenarios with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%. In sensitivity analyses with a $100 per DALY averted cost-effectiveness threshold, a 7% per year discount rate, or with PrEP use that was less well risk-informed than in our base case, PrEP was less likely to be cost-effective, but generally remained cost-effective if the prevalence of HIV viral load greater than 1000 copies per mL among all adults was higher than 3%. In sensitivity analyses based on additional setting-scenarios in which risk-informed PrEP was less extensively used, the HIV incidence reduction was smaller, but the cost-effectiveness of risk-informed PrEP was undiminished. INTERPRETATION: Under the assumption that making PrEP easily accessible for all adults in sub-Saharan Africa in the context of community education leads to risk-informed use, PrEP is likely to be cost-effective in settings with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%, suggesting the need for implementation of such approaches, with ongoing evaluation. FUNDING: US Agency for International Development, US President's Emergency Plan for AIDS Relief, and Bill & Melinda Gates Foundation.

Ending AIDS as a public health threat by 2030: Time to reset targets for 2025.

Paul De Lay and co-authors introduce a Collection on the design of targets for ending the AIDS epidemic.

Costs and Scale-Up Costs of Integrating HIV Self-Testing Into Civil Society Organisation-Led Programmes for Key Populations in Côte d'Ivoire, Senegal, and Mali.

Despite significant progress on the proportion of individuals who know their HIV status in 2020, Côte d'Ivoire (76%), Senegal (78%), and Mali (48%) remain far below, and key populations (KP) including female sex workers (FSW), men who have sex with men (MSM), and people who use drugs (PWUD) are the most vulnerable groups with a HIV prevalence at 5-30%. HIV self-testing (HIVST), a process where a person collects his/her own specimen, performs a test, and interprets the result, was introduced in 2019 as a new testing modality through the ATLAS project coordinated by the international partner organisation Solthis (IPO). We estimate the costs of implementing HIVST through 23 civil society organisations (CSO)-led models for KP in Côte d'Ivoire (N = 7), Senegal (N = 11), and Mali (N = 5). We modelled costs for programme transition (2021) and early scale-up (2022-2023). Between July 2019 and September 2020, a total of 51,028, 14,472, and 34,353 HIVST kits were distributed in Côte d'Ivoire, Senegal, and Mali, respectively. Across countries, 64-80% of HIVST kits were distributed to FSW, 20-31% to MSM, and 5-8% to PWUD. Average costs per HIVST kit distributed were $15 for FSW (Côte d'Ivoire: $13, Senegal: $17, Mali: $16), $23 for MSM (Côte d'Ivoire: $15, Senegal: $27, Mali: $28), and $80 for PWUD (Côte d'Ivoire: $16, Senegal: $144), driven by personnel costs (47-78% of total costs), and HIVST kits costs (2-20%). Average costs at scale-up were $11 for FSW (Côte d'Ivoire: $9, Senegal: $13, Mali: $10), $16 for MSM (Côte d'Ivoire: $9, Senegal: $23, Mali: $17), and $32 for PWUD (Côte d'Ivoire: $14, Senegal: $50). Cost reductions were mainly explained by the spreading of IPO costs over higher HIVST distribution volumes and progressive IPO withdrawal at scale-up. In all countries, CSO-led HIVST kit provision to KP showed relatively high costs during the study period related to the progressive integration of the programme to CSO activities and contextual challenges (COVID-19 pandemic, country safety concerns). In transition to scale-up and integration of the HIVST programme into CSO activities, this model shows large potential for substantial economies of scale. Further research will assess the overall cost-effectiveness of this model.

HIV immunoprophylaxis: preparing the pathway from proof of concept to policy decision and use.

Various long-awaited efficacy studies of vaccines and broadly neutralising antibodies for prevention of HIV are now well underway in highly endemic settings. One broadly neutralising monoclonal antibody is being assessed for proof of concept, and combinations are in the pipeline. Two multicomponent prime-and-boost vaccine regimens are being evaluated, one of which is designed for global coverage. These multicomponent vaccines present a new level of complexity that will challenge health delivery systems. We recommend that while awaiting the results, which will appear in 2020-22, the target product profiles and full public value proposition for both categories of products should be defined, and the regulatory, policy, and implementation pathways should be prepared. Economic and health benefits, cost of goods, administrative complexity, and user perspectives will be key considerations for the roll-out of effective products. Investments in manufacturing capacity and public-sector delivery systems will be needed to prepare for product introduction and scale-up. We propose a prioritisation of activities on the basis of a broad stakeholder consultation organised by WHO and UNAIDS.

Socio-economic gradients in prevalent tuberculosis in Zambia and the Western Cape of South Africa.

OBJECTIVE: To describe the associations between socio-economic position and prevalent tuberculosis in the 2010 ZAMSTAR Tuberculosis Prevalence Survey, one of the first large tuberculosis prevalence surveys in Southern Africa in the HIV era. METHODS: The main analyses used data on 34 446 individuals in Zambia and 30 017 individuals in South Africa with evaluable tuberculosis culture results. Logistic regression was used to estimate adjusted odds ratios for prevalent TB by two measures of socio-economic position: household wealth, derived from data on assets using principal components analysis, and individual educational attainment. Mediation analysis was used to evaluate potential mechanisms for the observed social gradients. RESULTS: The quartile with highest household wealth index in Zambia and South Africa had, respectively, 0.55 (95% CI 0.33-0.92) times and 0.70 (95% CI 0.54-0.93) times the adjusted odds of prevalent TB of the bottom quartile. College or university-educated individuals in Zambia and South Africa had, respectively, 0.25 (95% CI 0.12-0.54) and 0.42 (95% CI 0.25-0.70) times the adjusted odds of prevalent TB of individuals who had received only primary education. We found little evidence that these associations were mediated via several key proximal risk factors for TB, including HIV status. CONCLUSION: These data suggest that social determinants of TB remain important even in the context of generalised HIV epidemics.

Diabetes mellitus in Zambia and the Western Cape province of South Africa: Prevalence, risk factors, diagnosis and management.

AIMS: To determine the prevalence of and risk factors for diabetes mellitus and examine its diagnosis and management in the study communities. METHODS: This is a population-based cross-sectional study among adults in 24 communities from Zambia and the Western Cape (WC) province of South Africa. Diabetes is defined as a random blood glucose concentration (RBG)⩾11.1mmol/L, or RBG<11.1mmol/L but with a self-reported prior diabetes diagnosis. For individuals with a prior diagnosis of diabetes, RBG<7.8mmol/L was considered to be an acceptable level of glycaemia. RESULTS: Among 45,767 Zambian and 12,496 WC participants the age-standardised prevalence of diabetes was 3.5% and 7.2% respectively. The highest risk groups identified were those of older age and those with obesity. Of those identified to have diabetes, 34.5% in Zambia and 12.7% in WC were previously unaware of their diagnosis. Among Zambian participants with diabetes, this proportion was lower among individuals with better education or with higher household socio-economic position. Of all those with previously diagnosed diabetes, 66.0% in Zambia and 59.4% in WC were not on any diabetes treatment, and 34.4% in Zambia and 32.7% in WC had a RBG concentration beyond the recommended level, ⩾7.8mmol/L. CONCLUSIONS: The diabetes risk factor profile for our study communities is similar to that seen in high-income populations. A high proportion of individuals with diabetes are not on diabetes treatment and of those on treatment a high proportion have high glycaemic concentrations. Such data may assist in healthcare planning to ensure timely diagnosis and management of diabetes.

Effect of home-based interventions on virologic outcomes in adults receiving antiretroviral therapy in Africa: a meta-analysis.

BACKGROUND: The success of adherence to combination antiretroviral therapy (ART) in sub-Saharan Africa is hampered by factors that are unique to this setting. Home based interventions have been identified as possible strategies for decentralizing ART care and improving access and adherence to ART. There is need for evidence at individual- or community-level of the benefits of home-based interventions in improving HIV suppression in African patients receiving ART. METHODS: We conducted a systematic review and meta-analysis of the literature to assess the effect of home-based interventions on virologic outcomes in adults receiving ART in Africa. RESULTS: A total of 260 publications were identified by the search strategy, 249 were excluded on initial screening and 11 on full review, leaving 5 publications for analysis. The overall OR of virologic suppression at 12 months after starting ART of home-based interventions to standard of care was 1.13 (95% CI: 0.51-2.52). CONCLUSIONS: There was insufficient data to know whether there is a difference in HIV suppression at 12 months in the home-based arm compared with the standard of care arm in adults receiving ART in Africa. Given the few trials conducted from Africa, there is need for further research that measures the effects of home-based models on HIV suppression in African populations.

Evaluation of tuberculosis diagnostics: establishing an evidence base around the public health impact.

The limitations of existing tuberculosis diagnostic tools are significantly hampering tuberculosis control efforts, most noticeably in areas with high prevalence of human immunodeficiency virus (HIV) infection and antituberculosis drug resistance. However, renewed global interest in tuberculosis research has begun to bear fruit, with several new diagnostic technologies progressing through the development pipeline. There are significant challenges in building a sound evidence base to inform public health policies because most diagnostic research focuses on the accuracy of individual tests, with often significant limitations in the design, conduct, and reporting of diagnostic accuracy studies. Diagnostic accuracy studies may not be appropriate to guide public health policies, and clinical trials may increasingly be required to determine the incremental value and cost-effectiveness of new tools. The urgent need for new diagnostics should not distract from pursuing rigorous scientific evaluation focused on public health impact.

The association between household socioeconomic position and prevalent tuberculosis in Zambia: a case-control study.

BACKGROUND: Although historically tuberculosis (TB) has been associated with poverty, few analytical studies from developing countries have tried to: 1. assess the relative impact of poverty on TB after the emergence of HIV; 2. explore the causal mechanism underlying this association; and 3. estimate how many cases of TB could be prevented by improving household socioeconomic position (SEP). METHODS AND FINDINGS: We undertook a case-control study nested within a population-based TB and HIV prevalence survey conducted in 2005-2006 in two Zambian communities. Cases were defined as persons (15+ years of age) culture positive for M. tuberculosis. Controls were randomly drawn from the TB-free participants enrolled in the prevalence survey. We developed a composite index of household SEP combining variables accounting for four different domains of household SEP. The analysis of the mediation pathway between household SEP and TB was driven by a pre-defined conceptual framework. Adjusted Population Attributable Fractions (aPAF) were estimated. Prevalent TB was significantly associated with lower household SEP [aOR = 6.2, 95%CI: 2.0-19.2 and aOR = 3.4, 95%CI: 1.8-7.6 respectively for low and medium household SEP compared to high]. Other risk factors for prevalent TB included having a diet poor in proteins [aOR = 3.1, 95%CI: 1.1-8.7], being HIV positive [aOR = 3.1, 95%CI: 1.7-5.8], not BCG vaccinated [aOR = 7.7, 95%CI: 2.8-20.8], and having a history of migration [aOR = 5.2, 95%CI: 2.7-10.2]. These associations were not confounded by household SEP. The association between household SEP and TB appeared to be mediated by inadequate consumption of protein food. Approximately the same proportion of cases could be attributed to this variable and HIV infection (aPAF = 42% and 36%, respectively). CONCLUSIONS: While the fight against HIV remains central for TB control, interventions addressing low household SEP and, especially food availability, may contribute to strengthen our control efforts.

Evaluation of the Capilia TB assay for culture confirmation of Mycobacterium tuberculosis infections in Zambia and South Africa.

The performance and cost of the Capilia TB assay were evaluated for use in a resource-limited setting. The sensitivity and specificity were 99.6% and 99.5%, respectively. The incremental costs of the Capilia test were estimated to be $1.46 and $1.84 when the test was added to liquid and solid culture processes, respectively. These findings suggest that the Capilia TB assay represents a rapid, simple, and inexpensive Mycobacterium tuberculosis identification test that can be used in resource-limited settings.

Tuberculosis infection in Zambia: the association with relative wealth.

This study aimed to assess the association between household socioeconomic position and tuberculosis (TB) infection in two communities of Zambia. For this purpose we implemented a cross-sectional investigation, nested within a larger case control study. Infection was assessed using Quantiferon-TB Gold. A socioeconomic position index was constructed through principal component analysis combining data on human resources, food availability, housing quality, and access to services and infrastructures. In this study, higher socioeconomic position, rather than lower, was associated with significantly higher risk of TB infection. None of the traditional risk factors for TB infection mediated this association, suggesting that in these two communities TB transmission may occur through exposure to as yet undefined risk factors that are associated with higher socioeconomic position. Although further studies are needed, these results suggest emerging new patterns of TB transmission and a role of socioeconomic position on the risk of TB infection opposite to that expected.

Integrating tuberculosis and HIV services for people living with HIV: costs of the Zambian ProTEST Initiative.

BACKGROUND: In the face of the dual TB/HIV epidemic, the ProTEST Initiative was one of the first to demonstrate the feasibility of providing collaborative TB/HIV care for people living with HIV (PLWH) in poor settings. The ProTEST Initiative facilitated collaboration between service providers. Voluntary counselling and testing (VCT) acted as the entry point for services including TB screening and preventive therapy, clinical treatment for HIV-related disease, and home-based care (HBC), and a hospice. This paper estimates the costs of the ProTEST Initiative in two sites in urban Zambia, prior to the introduction of anti-retroviral therapy. METHODS: Annual financial and economic providers costs and output measures were collected in 2000-2001. Estimates are made of total costs for each component and average costs per: person reached by ProTEST; VCT pre-test counselled, tested and completed; isoniazid preventive therapy started and completed; clinic visit; HBC patient; and hospice admission and bednight. RESULTS: Annual core ProTEST costs were (in 2007 US dollars) $84,213 in Chawama and $31,053 in Matero. The cost of coordination was 4%-5% of total site costs ($1-$6 per person reached). The largest cost component in Chawama was voluntary counselling and testing (56%) and the clinic in Matero (50%), where VCT clients had higher HIV-prevalences and more advanced HIV. Average costs were lower for all components in the larger site. The cost per HBC patient was $149, and per hospice bednight was $24. CONCLUSION: This study shows that coordinating an integrated and comprehensive package of services for PLWH is relatively inexpensive. The lessons learnt in this study are still applicable today in the era of ART, as these services must still be provided as part of the continuum of care for people living with HIV.

Costs of measures to control tuberculosis/HIV in public primary care facilities in Cape Town, South Africa.

OBJECTIVE: To measure the costs and estimate the cost-effectiveness of the ProTEST package of tuberculosis/human immunodeficiency virus (TB/HIV) interventions in primary health care facilities in Cape Town, South Africa. METHODS: We collected annual cost data retrospectively using ingredients-based costing in three primary care facilities and estimated the cost per HIV infection averted and the cost per TB case prevented. FINDINGS: The range of costs per person for the ProTEST interventions in the three facilities were: US$ 7-11 for voluntary counselling and testing (VCT), US$ 81-166 for detecting a TB case, US$ 92-183 for completing isoniazid preventive therapy (IPT) and US$ 20-44 for completing six months of cotrimoxazole preventive therapy. The estimated cost per HIV infection averted by VCT was US$ 67-112. The cost per TB case prevented by VCT (through preventing HIV) was US$ 129-215, by intensified case finding was US$ 323-664 and by IPT was US$ 486-962. Sensitivity analysis showed that the use of chest X-rays for IPT screening decreases the cost-effectiveness of IPT in preventing TB cases by 36%. IPT screening with or without tuberculin purified protein derivative screening was almost equally cost-effective. CONCLUSION: We conclude that the ProTEST package is cost saving. Despite moderate adherence, linking prevention and care interventions for TB and HIV resulted in the estimated costs of preventing TB being less than previous estimates of costs of treating it. VCT was less expensive than previously reported in Africa.

Uptake of workplace HIV counselling and testing: a cluster-randomised trial in Zimbabwe.

BACKGROUND: HIV counselling and testing is a key component of both HIV care and HIV prevention, but uptake is currently low. We investigated the impact of rapid HIV testing at the workplace on uptake of voluntary counselling and testing (VCT). METHODS AND FINDINGS: The study was a cluster-randomised trial of two VCT strategies, with business occupational health clinics as the unit of randomisation. VCT was directly offered to all employees, followed by 2 y of open access to VCT and basic HIV care. Businesses were randomised to either on-site rapid HIV testing at their occupational clinic (11 businesses) or to vouchers for off-site VCT at a chain of free-standing centres also using rapid tests (11 businesses). Baseline anonymised HIV serology was requested from all employees. HIV prevalence was 19.8% and 18.4%, respectively, at businesses randomised to on-site and off-site VCT. In total, 1,957 of 3,950 employees at clinics randomised to on-site testing had VCT (mean uptake by site 51.1%) compared to 586 of 3,532 employees taking vouchers at clinics randomised to off-site testing (mean uptake by site 19.2%). The risk ratio for on-site VCT compared to voucher uptake was 2.8 (95% confidence interval 1.8 to 3.8) after adjustment for potential confounders. Only 125 employees (mean uptake by site 4.3%) reported using their voucher, so that the true adjusted risk ratio for on-site compared to off-site VCT may have been as high as 12.5 (95% confidence interval 8.2 to 16.8). CONCLUSIONS: High-impact VCT strategies are urgently needed to maximise HIV prevention and access to care in Africa. VCT at the workplace offers the potential for high uptake when offered on-site and linked to basic HIV care. Convenience and accessibility appear to have critical roles in the acceptability of community-based VCT.

The research agenda for improving health policy, systems performance, and service delivery for tuberculosis control: a WHO perspective.

The development of WHO's DOTS strategy for the control of tuberculosis (TB) in 1995 led to the expansion, adaptation and improvement of operational research in this area. From being a patchwork of small-scale studies concerned with aspects of service delivery, TB operational research shifted to larger-scale, often multicountry projects that were also concerned with health policy and the needs of health systems. The results are now being put into practice by national TB control programmes. In 1998 an ad hoc committee identified the chief factors inhibiting the expansion of DOTS: lack of political will and commitment, poor financial support for TB control, poor organization and management of health services, inadequate human resources, irregular drug supplies, the HIV epidemic, and the rise of multidrug resistance. An analysis of current operational research on TB is presented on the basis of these constraints, and examples of successful projects are outlined in the article. We discuss the prerequisites for success, the shortcomings of this WHO- supported programme, and future challenges and needs.