Unitaid

BACKGROUND: Indian manufacturers of generic antiretroviral (ARV) medicines facilitated the rapid scale up of HIV/AIDS treatment in developing countries though provision of low-priced, quality-assured medicines. The legal framework in India that facilitated such production, however, is changing with implementation of the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights, and intellectual property measures being discussed in regional and bilateral free trade agreement negotiations. Reliable quantitative estimates of the Indian role in generic global ARV supply are needed to understand potential impacts of such measures on HIV/AIDS treatment in developing countries. METHODS: We utilized transactional data containing 17,646 donor-funded purchases of ARV tablets made by 115 low- and middle-income countries from 2003 to 2008 to measure market share, purchase trends and prices of Indian-produced generic ARVs compared with those of non-Indian generic and brand ARVs. RESULTS: Indian generic manufacturers dominate the ARV market, accounting for more than 80% of annual purchase volumes. Among paediatric ARV and adult nucleoside and non-nucleoside reverse transcriptase inhibitor markets, Indian-produced generics accounted for 91% and 89% of 2008 global purchase volumes, respectively. From 2003 to 2008, the number of Indian generic manufactures supplying ARVs increased from four to 10 while the number of Indian-manufactured generic products increased from 14 to 53. Ninety-six of 100 countries purchased Indian generic ARVs in 2008, including high HIV-burden sub-Saharan African countries. Indian-produced generic ARVs used in first-line regimens were consistently and considerably less expensive than non-Indian generic and innovator ARVs. Key ARVs newly recommended by the World Health Organization are three to four times more expensive than older regimens. CONCLUSIONS: Indian generic producers supply the majority of ARVs in developing countries. Future scale up using newly recommended ARVs will likely be hampered until Indian generic producers can provide the dramatic price reductions and improved formulations observed in the past. Rather than agreeing to inappropriate intellectual property obligations through free trade agreements, India and its trade partners--plus international organizations, donors, civil society and pharmaceutical manufacturers--should ensure that there is sufficient policy space for Indian pharmaceutical manufacturers to continue their central role in supplying developing countries with low-priced, quality-assured generic medicines.

OBJECTIVE: An increasing number of countries have been estimating the distribution of new adult HIV infections by modes of transmission (MOT) to help prioritise prevention efforts. We compare results from studies conducted between 2008 and 2012 and discuss their use for planning and responding to the HIV epidemic. METHODS: The UNAIDS recommended MOT model helps countries to estimate the proportion of new HIV infections that occur through key transmission modes including sex work, injecting drug use (IDU), men having sex with men (MSM), multiple sexual partnerships, stable relationships and medical interventions. The model typically forms part of a country-led process that includes a comprehensive review of epidemiological data. Recent revisions to the model are described. RESULTS: Modelling results from 25 countries show large variation between and within regions. In sub-Saharan Africa, new infections occur largely in the general heterosexual population because of multiple partnerships or in stable discordant relationships, while sex work contributes significantly to new infections in West Africa. IDU and sex work are the main contributors to new infections in the Middle East and North Africa, with MSM the main contributor in Latin America. Patterns vary substantially between countries in Eastern Europe and Asia in terms of the relative contribution of sex work, MSM, IDU and spousal transmission. CONCLUSIONS: The MOT modelling results, comprehensive review and critical assessment of data in a country can contribute to a more strategically focused HIV response. To strengthen this type of research, improved epidemiological and behavioural data by risk population are needed.

BACKGROUND: Although gay, bisexual, and other cisgender men who have sex with men (MSM) and transgender women have the highest HIV burden in Latin America, pre-exposure prophylaxis (PrEP) implementation is poor. We aimed to assess the feasibility of same-day oral PrEP delivery in Brazil, Mexico, and Peru. METHODS: Implementation PrEP (ImPrEP) was a prospective, single-arm, open-label, multicentre PrEP implementation study conducted in Brazil (14 sites), Mexico (four sites), and Peru (ten sites). MSM and transgender women were eligible to participate if they were aged 18 years or older, HIV-negative, and reported one or more prespecified criteria. Enrolled participants received same-day initiation of daily oral PrEP (tenofovir disoproxil fumarate [300 mg] coformulated with emtricitabine [200 mg]). Follow-up visits were scheduled at week 4 and quarterly thereafter. We used logistic regression models to identify factors associated with early loss to follow-up (not returning after enrolment), PrEP adherence (medication possession ratio ≥0·6), and long-term PrEP engagement (attending three or more visits within 52 weeks). This study is registered at the Brazilian Registry of Clinical Trials, U1111-1217-6021. FINDINGS: From Feb 6, 2018, to June 30, 2021, 9979 participants were screened and 9509 were enrolled (Brazil n=3928, Mexico n=3288, and Peru n=2293). 543 (5·7%) participants were transgender women, 8966 (94·3%) were cisgender men, and 2481 (26·1%) were aged 18-24 years. There were 12 185·25 person-years of follow-up. 795 (8·4%) of 9509 participants had early loss to follow-up, 6477 (68·1%) of 9509 were adherent to PrEP, and 5783 (70·3%) of 8225 had long-term PrEP engagement. Transgender women (adjusted odds ratio 1·60, 95% CI 1·20-2·14), participants aged 18-24 years (1·80, 1·49-2·18), and participants with primary education (2·18, 1·29-3·68) had increased odds of early loss to follow-up. Transgender women (0·56, 0·46-0·70), participants aged 18-24 years (0·52, 0·46-0·58), and those with primary education (0·60, 0·40-0·91) had lower odds of PrEP adherence. Transgender women (0·56, 0·45-0·71), participants aged 18-24 years (0·56, 0·49-0·64), and those with secondary education (0·74, 0·68-0·86) had lower odds of long-term PrEP engagement. HIV incidence was 0·85 per 100 person-years (95% CI 0·70-1·03) and was higher for transgender women, participants from Peru, those aged 18-24 years, Black and mixed-race participants, and participants who were non-adherent to PrEP. INTERPRETATION: Same-day oral PrEP is feasible for MSM and transgender women in Latin America. Social and structural determinants of HIV vulnerability need to be addressed to fully achieve the benefits of PrEP. FUNDING: Unitaid, WHO, and Ministries of Health in Brazil, Mexico, and Peru. TRANSLATIONS: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

INTRODUCTION: HIV self-testing (HIVST) was first proposed as an additional option to standard HIV testing services in the 1980s. By 2015, two years after the first HIVST kit was approved for the American market and the year in which Unitaid invested in the "HIV Self-Testing AfRica (STAR) Initiative," HIVST remained unexplored with negligible access in low- and middle-income countries (LMIC). However, rapid progress had been made. This commentary outlines the interlinked market, regulatory and policy barriers that had inhibited product development and kept HIVST out of LMIC policy. We detail the components of STAR that enabled rapid HIVST scale-up, including critical investments in implementation, research, market forecasting, and engagement with manufacturers and regulators. DISCUSSION: The STAR Initiative has generated crucial information about how to distribute HIVST products effectively, ethically and efficiently. Service delivery models range from clinic-based distribution to workplace and partner-delivered approaches to reach first-time male testers, to community outreach to sex workers and general population "hotspots." These data directly informed supportive policy, notably the 2016 WHO guidelines strongly recommending HIVST as an additional testing approach, and regulatory change through support for WHO prequalification of the first HIVST kit in 2017. In July 2015, only two countries had national HIVST policies and were implementing HIVST. Three years later, 59 countries have policies, actively implemented in 28, with an additional 53 countries reporting policies under development. By end-November 2018 several quality-assured HIVST products had been registered, including two WHO prequalified tests. STAR Initiative countries have drafted regulations governing in vitro diagnostics, including HIVST products. With enabling policies, pre-qualification and regulations in place, donor procurement of kits has increased rapidly, to a forecasted estimate of 16 million HIVST kits procured by 2020. CONCLUSIONS: The STAR Initiative provided a strong foundation to introduce HIVST in LMICs and allow for rapid scale-up based on the wealth of multi-country evidence gathered. Together with sustained coordination and acceleration of market development work, HIVST can help address the testing gap and provide a focused and cost-effective means to expand access to treatment and prevention services.

The modes of transmission model has been widely used to help decision-makers target measures for preventing human immunodeficiency virus (HIV) infection. The model estimates the number of new HIV infections that will be acquired over the ensuing year by individuals in identified risk groups in a given population using data on the size of the groups, the aggregate risk behaviour in each group, the current prevalence of HIV infection among the sexual or injecting drug partners of individuals in each group, and the probability of HIV transmission associated with different risk behaviours. The strength of the model is its simplicity, which enables data from a variety of sources to be synthesized, resulting in better characterization of HIV epidemics in some settings. However, concerns have been raised about the assumptions underlying the model structure, about limitations in the data available for deriving input parameters and about interpretation and communication of the model results. The aim of this review was to improve the use of the model by reassessing its paradigm, structure and data requirements. We identified key questions to be asked when conducting an analysis and when interpreting the model results and make recommendations for strengthening the model's application in the future.

UNLABELLED: Rifampicin (R) and isoniazid (H) are key first-line anti-tuberculosis drugs. Failure to detect resistance to these two drugs early results in treatment failure and poor clinical outcomes. The study purpose was to validate the use of the GenoType MTBDRplus line probe assay (LPA) to detect resistance to R and H in Mycobacterium tuberculosis strains directly from smear-positive sputum samples in India. METHOD: Smear positive sputum specimens from 320 patients were subjected to LPA and results compared against those from conventional Lowenstein Jensen (LJ) culture and drug susceptibility testing (C&DST). All specimens with discordant R DST results were subjected to either sequencing of the rpoB gene and/or repeat DST on liquid culture (MGIT 960) at a National Reference Laboratory. RESULTS: Significantly higher proportion of interpretable results were observed with LPA compared to LJ C&DST (94% vs. 80%, p-value <0.01). A total of 248 patients had both LJ and LPA DST results available; 232 (93.5%) had concordant R DST results. Among the 16 discordant R DST results, 13 (81%) were resolved in agreement with LPA results. Final LPA performance characteristics were sensitivity 96% (CI: 90%-98%), specificity 99% (CI: 95%-99%), positive predictive value 99% (CI: 95%-99%), and negative predictive value 95% (CI: 89%-98%). The median turnaround testing time, including specimen transportation time, on LPA was 11 days as compared with 89 days for LJ C&DST. CONCLUSIONS: LPA proved highly accurate in the rapid detection of R resistance. The reduction in time to diagnosis may potentially enable earlier commencement of the appropriate drug therapy, leading to some reduction of transmission of drug-resistant strains.

In regard to tuberculosis (TB) and other major global epidemics, the use of new diagnostic tests is increasing dramatically, including in resource-limited countries. Although there has never been as much digital information generated, this data source has not been exploited to its full potential. In this opinion paper, we discuss lessons learned from the global scale-up of these laboratory devices and the pathway to tapping the potential of laboratory-generated information in the field of TB by using connectivity. Responding to the demand for connectivity, innovative third-party players have proposed solutions that have been widely adopted by field users of the Xpert(®) MTB/RIF assay. The experience associated with the utilisation of these systems, which facilitate the monitoring of wide laboratory networks, stressed the need for a more global and comprehensive approach to diagnostic connectivity. In addition to facilitating the reporting of test results, the mobility of digital information allows the sharing of information generated in programme settings. When they become easily accessible, these data can be used to improve patient care, disease surveillance and drug discovery. They should therefore be considered as a public health good. We list several examples of concrete initiatives that should allow data sources to be combined to improve the understanding of the epidemic, support the operational response and, finally, accelerate TB elimination. With the many opportunities that the pooling of data associated with the TB epidemic can provide, pooling of this information at an international level has become an absolute priority.

Antiretrovirals are a significant cost driver for HIV programmes. Current first-line regimens have performed well in real-life programmes, but have a low barrier to virological resistance and still carry toxicity that limits adherence. New drug developments may mean that we have access to safer, more robust and cheaper regimens, but only if the appropriate clinical trials are conducted. We briefly discuss these trials, and demonstrate the large cost savings to the South African HIV programme if these are successful.

Long-acting antiretroviral drugs have emerged as exciting treatment and preexposure prophylaxis (PrEP) options for people with HIV and at risk of HIV. Long-acting regimens may improve dosing convenience, tolerability and cost compared with current daily-based oral therapy. They can also circumvent stigma associated with oral therapy for both treatment and PrEP, thereby improving adherence and outcomes. Yet, multiple challenges remain, many specific to low-income and middle-income countries (LMICs), where the epidemic is most concentrated and HIV prevention and treatment options are limited. To optimize the use of long-acting formulations, key outstanding questions must be addressed. Uncertain costing, scale-up manufacturing, complex delivery systems and implementation challenges are potential barriers when considering the scalability of long-acting ARVs for global use.

Globally, we are at an inflection point in achieving UNAIDS’ 95-95-95 goals for 2030. A recent Lancet editorial observed that “the last big shared challenge remaining is testing—in every region the number of undiagnosed HIV infections remains a substantial barrier to achieving UNAIDS targets and ending AIDS by 2030” 1. While UNAIDS estimates we are at 75% diagnostic coverage globally, within this figure is great variation: between men and women, younger and older individuals, rural and urban populations, among key populations and between countries 2, 3. After 18 years of expansive programming in global health for HIV testing through a multitude of modalities in communities and facilities, reaching the remaining undiagnosed individuals with flat-lined donor funding will require new efforts 3. Many of the remaining undiagnosed individuals are presumably not engaging with HIV services, and novel avenues to HIV testing services (HTS) that overcome both stigma and structural barriers are needed: a new HIV testing paradigm is urgently needed to reach these remaining undiagnosed individuals and effectively link them to treatment. HIV self-testing (HIVST) has developed substantially in recent years and is now considered a new and critical HIV response strategy in controlling the epidemic. In 2012, the US FDA approved the OraQuick® HIV Self-Test Kit introducing the first HIV rapid test kit intended for use by the general population and available for purchase over-the-counter in the United States. Building on a history of public health interventions aimed at self-screening for health conditions that includes home pregnancy tests, breast self-examinations for cancer screening and blood-glucose monitoring, access to HIVST permits individuals perceiving themselves to be at-risk of infection to test independently and privately. Global attention to the potential of HIVST took root in 2013 following the OraQuick FDA approval, with UNAIDS and the World Health Organization (WHO) holding an initial consultation on the ethical and public health implications of HIVST. At that time, no HIVST kits were publicly available in low- and middle-income countries (LMIC) (outside a small number of studies and “grey market” test kits), no normative guidelines had been established and only a small body of LMIC-focused evidence around HIVST existed. Within a year, a full HIVST journal supplement had been published exploring early issues in HIVST introduction: regulation and policy, optimal product profiles, ethical considerations and both positive and negative potential impacts of rollout 4-6. This led, in 2015, to Unitaid's catalytic investment in the five-year HIV Self-Testing Africa (STAR) initiative. The first two-year phase, which included Malawi, Zambia and Zimbabwe, aimed to generate evidence on the feasibility and acceptability of HIVST as well as how to distribute self-test products effectively, ethically and efficiently, with adequate post-test support. Evidence from this phase supported country policy development, and studied impacts and cost-effectiveness of various delivery models, addressed structural barriers and assessed consumer demand. Findings from these and other studies led to the WHO guidance on HIVST in 2016 (also strategically paired with the HTS) Partner Notification guidelines 7. A separate but concurrent process resulted OraQuick being the first WHO prequalified HIVST kit. In 2017, the Bill and Melinda Gates Foundation provided financial support to bring the unit cost of the OraQuick self-test kit down to US$2 in selected sub-Saharan African and other low-income countries, removing a critical cost barrier to HIVST expansion 8. These initial supportive efforts established the foundation needed for HIVST expansion across countries. The second three-year phase of STAR added Lesotho, Eswatini and South Africa, and aimed to create a market for HIVST and evaluate optimal distribution models for increasing access to testing among those unwilling or unable to utilize traditional testing venues and ensuring linkage from a preliminary positive HIVST result to confirmatory testing and treatment. By the end of the programme, Unitaid, the STAR programme's commodities funder, will have provided five million HIVST kits to the six project countries. Building on STAR's momentum and their own smaller scale pilot programmes in 2016, PEPFAR expanded its HIVST programming and will have delivered 2.3 million HIVST kits across 11 countries in 2017 to 2018. Similarly, the Global Fund is expanding HIVST support across 18 countries, estimated to cover about 12% of the global HIVST volume 9. With 59 countries having, or developing, national HIVST policies, there is global acceleration towards the expansion of HIVST access and programmes and, with good linkage, increased diagnostic coverage 9. However, these numbers remain small relative to the overall number of people tested; PEPFAR alone accounted for roughly 85 million HIV tests in 2017 10. But HIVST deployed strategically within programmes, and made available through multiple avenues, is anticipated to amplify the impact of current HIV programming by reaching the critical remaining at-risk populations with needed testing and treatment. The articles collected for this Supplement present a diverse range of the key findings from the first phase of STAR, and provide a basis for needed programmatic action to accelerate expansion. Presently, in sub-Saharan Africa, there are 15 countries that have HIVST policies in place or under consideration and multiple products available with some type of certification 9, 11. However, products of unknown quality have been available on the unregulated market, posing risks and underscoring the need for further quality and consumer protection regulations 6, 11. Dacombe et al. explore the regulatory environment in Malawi, Zambia and Zimbabwe 12. Using key informant interviews which included laboratory staff and policymakers, they consulted 66 individuals from the three countries. Interviews showed that in these countries, there was a need for regulation of in vitro diagnostic tests in general, and HIVST kits were no exception. The authors call for a regional collaboration to spread the regulatory burden across countries and facilitate the passing of required legislation to support more codified regulation of diagnostics. WHO prequalified test kits have gone through quality assurance evaluations aimed at ensuring “global standards of quality, safety and efficacy” to support Ministries of Health and the introduction of quality diagnostics 13. However, product performance includes not just quality standards of the test kit itself, but also usability by the target population and the successful insertion of HIVST into the clinical cascade. Early studies showed some challenges in following instructions for use (IFU) 5, 14, but as kits have been refined, results have improved. A recent review demonstrated general agreement between results of HIVST kits and facility testing algorithms 15. However, challenges relating to literacy remain, underscoring the need for clear and simple language in package inserts 15-17 and IFUs that are adapted to local contexts. In this Supplement, Simwinga et al. present findings from Malawi and Zambia evaluating an IFU translated into the local language and evaluated for clarity and ease of use 18. Investigators used feedback from testers to optimize the IFU, concurring with previous findings that the educational level of the tester correlates to the ability to follow the IFU. In response, they suggest that in certain contexts community demonstrations of how to use HIVST kits could overcome this barrier. In another study, given that programmes have proposed late reading of returned kits to determine HIV positivity, Watson et al. evaluated the OraQuick HIV-1/2 antibody test kits for result stability post-testing. They showed that while strongly reactive HIVST remained stable, 29% of initially non-reactive kits converting to be weakly reactive false positive when read at least four days later, countering previous work which indicated OraQuick test kits were stable for up to a year 19, 20. Re-reading may be problematic and result in artificially inflated positivity rates; this finding led the WHO to recommend against any delayed readings of kits 21. Eaton et al. model how HIVST and other “test for triage” strategies might impact national algorithm performance 22. Considering modelled high- and low-prevalence scenarios, as well as using data from Malawi, a high-prevalence country with high rates of diagnosis 23, the authors show that the addition of triage testing before the national algorithm increases the positive predictive value and decreases the number of false-positive diagnoses, possibly eliminating the need for verification testing at initiation of antiretroviral therapy (ART). Methodologies for HIVST distribution will be a critical aspect of programme effectiveness. Various delivery modes have been considered: vending machines, over-the-counter at pharmacies, secondary distribution when an HIVST is distributed to one person for use by another, and facility- and community-based distribution 11, 15, 24-26. In this Supplement, Sibanda et al. began with the clients, investigating preferences for access to HIVST in rural Zimbabwe through discrete choice assessments, finding respondent preferences for door-to-door distribution, kits free-of-charge, access by telephone to help in using kits and linkage to confirmatory testing, and that programmes use patient reminders and outreach to enhance effectiveness 27. For confirmatory testing and ART initiation, respondents also preferred these to be free, located near their home and that ART could be initiated immediately 27. This study supports previous findings on user preferences emphasizing ease of access, usability and privacy 11. Also in this Supplement, Hatzold et al. reviewed STAR data from Malawi, Zambia and Zimbabwe that assessed the integration of HIVST tools into HIV programming 28. They found that by having clients perform HIVST in outpatient settings, they were able to decongest clinical testing facilities because healthcare workers could focus only on those that screened positive. They also demonstrated the ability to reach men through community distribution and in particular workplaces, and explored male attitudes to HIVST, noting that the briefer counselling messages, privacy and convenience appealed to them 28. Advantages of HIVST, such as the ability to test privately, may also be misused or abused and potential social harms should not be ignored. Previously in Kenya, low rates of physical and verbal abuse have been reported with the introduction of HIVST kits by women for their male partners to test themselves 29. In this Supplement, Kumwenda et al. provide new evidence on social harms from projects in Malawi, summarizing data from six HIVST projects from 2011 to 2017 where a combination of qualitative and quantitative methods were used 30. Coercion was reframed to have both negative and positive aspects, and the concept of compassionate coercion was introduced to describe instances when family members encourage a member who is ill to test. Overall, they report 25 serious adverse events through the active reporting systems from all six studies with a total of 178,833 self-tests distributed. The most common event was marriage breakdown in serodiscordant relationships though verbal abuse, and physical and economic intimate partner violence were infrequently also observed 30. The potential for social harms is not unique to HIVST, but the present work elucidates the need for intimate partner violence screening when considering HIVST secondary distribution and partner testing, and the need for ongoing monitoring of social harms within existing systems. In the context of HIVST, linkage to care refers not just to the initiation of ART, but first to confirmatory testing after a positive HIVST 31. Since using an HIVST kit in private is often preferred by testers, the onus to link to care is firmly placed in the hands of the tester. As such, linking testers to care and estimating linkage rates can be a challenge. Some HIVST research studies have estimated linkage rates to be between 36% and 78% with a variety of methodologies as there is no standard process to measure linkage 24, 29, 31, 32. In this Supplement, Neuman et al. reflect on the difficulties in estimating linkage as HIVST is brought to scale 33. They note the limited metrics available – HIVST kit distribution totals and self-reported data, neither of which is optimal to estimate linkage rates accurately 33. The investigators present a summary of study protocols estimating linkage from published STAR studies. These estimate HIVST linkage by using ecological indicators such as comparisons of ART initiation rates in areas with HIVST campaigns versus in areas without HIVST campaigns. Taken on its own, it is only correlative; however, when considered in addition to other information it can be used to create a body of evidence regarding linkage to care. Costing HTS is highly contextual with considerable variation, but important to programme planning and bringing HIVST to scale. In this Supplement, Mangenah et al. performed a cost analysis of community HIVST kit distribution in Malawi, Zambia and Zimbabwe as well as a sensitivity and scenario analysis to project future costs 34. The average cost per kit distributed (i.e. not only the commodity cost) ranged from US$ 7.23 to US$ 14.58 with variation by site location, but still comparable to previously published values 35. In a second article, Cambiano et al. use this data to present a modelling analysis comparing community distribution to three priority populations in Zimbabwe and Malawi: women having transactional sex (WTS), youth and adult men 36. The model showed that distribution to men averted the most deaths, but distribution to WTS was the most efficient as measured in number of tests per death averted. Cambiano et al. have added to cost-effectiveness research, considering the trade-offs between investing in HIVST and other HIV programmes, they estimate that HIVST is cost-effective when the mean cost per disability adjusted life year averted is below US$ 500. According to their models, this occurs when HIVST kits were distributed to WTS and men but not to youth. Offering commentary on the use of HIVST, Ingold et al. focus on the broader policy environment in LMIC, market development for HIVST kits, the STAR programme experience and its positioning for HIVST scale-up 37. As part of the intervention, the STAR programme engaged with manufactures and stakeholders at the country and multilateral levels to create demand, assess viability of HIVST as a route to diagnosis and research delivery methods. The overall goal being to pave the way for increased access to quality HIVST kits to mobilize more people living with HIV to know their status. The authors highlight the progress that has been made in addressing these barriers, including amassing a sufficient evidence base for WHO guidance and a more enabling policy environment in general, prequalification of two types of HIVST kits and a more robust product pipeline. Pilot studies have demonstrated the ability of HIVST to reach populations that have traditionally been refractory to other testing strategies and viability for priority populations. Ingold et al. also touch on outstanding challenges to be addressed and present a call to action to maintain momentum in bringing HIVST to scale 37. Since 2012, substantial progress has been made on HIVST programmes, policy and products – but few countries are implementing HIVST at scale, with many still conducting smaller volume pilot programmes. Recent HIV response framings have declared that “what got us here won't get us there” 38; for HIV testing, the rapid expansion of voluntary counselling and testing, provider-initiated approaches and community-based campaigns have achieved a global 75% diagnosis rate. The final reach to the remaining undiagnosed individuals, including early diagnosis of decreasing numbers of newly infected persons, will depend critically on an evolution of new approaches: HIVST, expansions of index testing and partner notification as a new minimum standard of care, and programmatic improvements of existing HTS access points. The evidence to date has demonstrated the potential of HIVST to reach both the unreached and those at high risk, which is key in achieving the 95-95-95 goals and controlling the epidemic. However, operational questions remain. Intentional misuse, accuracy and performance of secondary distribution, more effective leveraging of public–private sector collaborations to reach high-risk populations, programmatic use of blood-based HIVST kits, use of HIVST as a demand generation tool for Pre-exposure prophylaxis (PrEP), volume procurement approaches to reduce unit pricing and the use of mobile technology and other methods to estimate linkage post-HIVST, could all benefit from more operations research to guide programming. The body of evidence produced in this Supplement adds significantly to the field of HTS, exemplifying the potential public health role of this new technology to critically increase coverage. Still, HIVST access will not reach the scale needed to impact the epidemic without both leveraging existing health programmes and developing new and innovative avenues of access. The integration of HIVST should work to amplify existing HIV programming to achieve multiple purposes that serve public health goals: reaching unreached and high-risk individuals at an early disease stage, reducing testing burdens on taxed health systems, and critically identifying the most effective avenues to linking persons screening positive to onward testing and treating or linking persons screening negative to prevention services. All are outcomes of critical importance to controlling the HIV epidemic. And novel avenues such as private sector delivery will continue to need to be explored. While we find ourselves at the “last big shared challenge” of HIV testing, in the race towards control of the HIV epidemic, this Supplement strongly illustrates that a new testing paradigm based in part on HIVST is key to the next decade of the HIV response and achieving 95% diagnosis rates everywhere. VW, EJ, NF and HI declare no competing interests. VW and EJ drafted the initial manuscript. All authors critically reviewed the manuscript, suggested revisions and editorial changes, and approved the final version. VW is a member of the Unitaid HIVSTAR Technical Advisory Group. The authors thank Dr. Kawango Agot for providing comments to the manuscript. The STAR Initiative is made possible thanks to Unitaid's funding and support. Unitaid accelerates access to innovative health products and lays the foundations for their scale-up by countries and partners. Unitaid is a hosted partnership of the World Health Organization. The contents in this article are those of the authors and do not necessarily reflect the view of the U.S. President's Emergency Plan for AIDS Relief, the U.S. Agency for International Development or the U.S. Government.

OBJECTIVE: We estimate facility-level average annual costs per client along the HIV testing and counselling (HTC) and prevention of mother-to-child transmission (PMTCT) service cascades. DESIGN: Data collected covered the period 2011-2012 in 230 HTC and 212 PMTCT facilities in Kenya, Rwanda, South Africa, and Zambia. METHODS: Input quantities and unit prices were collected, as were output data. Annual economic costs were estimated from the service providers' perspective using micro-costing. Average annual costs per client in 2013 United States dollars (US$) were estimated along the service cascades. RESULTS: For HTC, average cost per client tested ranged from US$5 (SD US$7) in Rwanda to US$31 (SD US$24) in South Africa, whereas average cost per client diagnosed as HIV-positive ranged from US$122 (SD US$119) in Zambia to US$1367 (SD US$2093) in Rwanda. For PMTCT, average cost per client tested ranged from US$18 (SD US$20) in Rwanda to US$89 (SD US$56) in South Africa; average cost per client diagnosed as HIV-positive ranged from US$567 (SD US$417) in Zambia to US$2021 (SD US$3210) in Rwanda; average cost per client on antiretroviral prophylaxis ranged from US$704 (SD US$610) in South Africa to US$2314 (SD US$3204) in Rwanda; and average cost per infant on nevirapine ranged from US$888 (SD US$884) in South Africa to US$2359 (SD US$3257) in Rwanda. CONCLUSION: We found important differences in unit costs along the HTC and PMTCT service cascades within and between countries suggesting that more efficient delivery of these services is possible.

Globally, HIV testing services (HTS) have been scaled up resulting in 79% of all people with HIV aware of their status in 2018 [1]. However, 8.1 million people remain undiagnosed [1], many of whom are hard to reach through traditional HTS approaches. In 2016, the World Health Organization (WHO) strongly recommended HIV self-testing (HIVST) as an HTS approach, followed by an update in 2019 [2, 3]. Since 2016, the number of countries with supportive HIVST policies has grown rapidly to 77 with 38 countries implementing HIVST as of July 2019 [1]. HIVST has proved effective in reaching people with undiagnosed HIV and those at high ongoing risk [4-6], however, many countries are yet to implement or scale up HIVST. As with any HTS, HIVST needs to provide a pathway to appropriate HIV treatment, care and prevention services. Because no single test, including HIVST, can provide an HIV-positive diagnosis, all individuals with reactive HIVST results must receive further testing by a trained provider before initiating antiretroviral therapy (ART) [5]. Measuring linkage to ART is important to demonstrate programme effectiveness and impact, however, monitoring linkage after HIVST can be challenging because of its private nature. We highlight key challenges in measuring linkage to treatment and care following HIVST and suggest pragmatic approaches to addressing these in low-income settings that routinely offer HIVST. Evidence from randomized trials shows that the proportion of people linked to ART following HIVST is comparable to that of standard facility-based HTS [5]. However, outside a research or trial environment, it may be unclear whether routine programmatic HIVST implementation results in similar successes. The challenges to accurately measuring linkage following HIVST include: (i) not knowing the number of HIVST kits used out of the number distributed, particularly when distributed in the community or via secondary distribution to partners and/or social contacts; (ii) clients on ART using HIVST to “check” their HIV status without disclosing their HIV-positive status and/or ART use to the provider (kit distributor); (iii) clients using HIVST as a prompt for “re-engaging” in care or “restarting” ART without disclosing their HIV-positive status and/or ART use to the provider (kit distributor) [7]; (iv) clients with reactive HIVST results who are lost to follow-up; and (v) use of paper-based and unlinked clinic records, such as clinic registers or logbooks and the lack of case-based surveillance in many low-income settings, leading to duplicate or missing information, an issue affecting HTS monitoring broadly. No single method would give an accurate measure of linkage following HIVST due to the limitations of each of them. However, using data and information from diverse sources, such as survey and programme data, can increase confidence in linkage estimates and minimize missing information. WHO is developing guidance for countries to monitor and evaluate HIVST, including linkage. HIVST is an important testing approach for meeting the global goals of diagnosing 95% of all people with HIV by 2025. Effective linkage to appropriate services following HIVST is important. Given the privacy of HIVST, which allows autonomy, fosters empowerment and reaches people who may not otherwise test, a resource-intensive approach to monitor linkage is neither feasible nor desirable as programmes scale up HIVST. The need to collect in-depth linkage data should not delay the wider availability of HIVST. Programmes, donors and implementers should consider pragmatic and innovative ways to measure linkage. The authors declare no conflicts of interest. MSJ, CJ, ATC and PM conceived the idea. ATC wrote the first draft of manuscript. MSJ, PM, EC, EC, LC, HI, EBA, MdE, MDC, MM, TS, VW, RB and CJ reviewed, provided input and approved the final draft of manuscript. WHO HIV Self-testing Technical Working Group members who are not co-authors: Amy Medley, Anita Sands, Asha Hedge, Christine Kisia, Elena Vovc, Elkin Bermudez, Emmanuelle Bomo, Ena Oru, Euphemia Sibanda, Florence Anam, Francesca Merico, Fritz Fonkeng, Germina Mphoso, Giovanni Ravasi, Jean Njab, Jennifer Cohn, Karen Champenois, Karin Hatzold, Kimberly Green, Kristina Grabbe, Lelia Coppens, Maeve de Mello, Mark Lanigan, Morganne Ahmar, Muhammad Safdar Pasha, Naoko Ishikawa, Nayé Bah, Olga Denisiuk, Patricia Garcia, Peris Urassa, Philippe Girault, Simbarashe Mabaya, Sofia Furqan, Thato Chidarikire, Valdilea Veloso, Van Thi Thuy Nguyen and Wanjiru Mukoma. Bill and Melinda Gates Foundation OPP1177903 and Unitaid (PO# 10140–0-600 and PO# 8477–0-600). PM is funded by the Wellcome Trust (206575/Z/17/Z). EC is funded under a Wellcome Trust Senior Research Fellowship in Clinical Science (grant number: WT091769) and by Unitaid-STAR Initiative (NCT02718274). The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated including the World Health Organization, the U.S. President's Emergency Plan for AIDS Relief, the U.S. Agency for International Development and the U.S. Government. The corresponding author had final responsibility for the decision to submit for publication.

Antiretrovirals are a significant cost driver for HIV programmes. Current first-line regimens have performed well in real-life programmes, but have a low barrier to virological resistance and still carry toxicity that limits adherence. New drug developments may mean that we have access to safer, more robust and cheaper regimens, but only if the appropriate clinical trials are conducted. We briefly discuss these trials, and demonstrate the large cost savings to the South African HIV programme if these are successful.

For the first time since AIDS erupted as worldwide emergency, global leaders, the scientific community, activists and people living with HIV are venturing to speak about the end to the pandemic. Signs of hope abound: over 8 million people are receiving life-saving treatment, the number of new infections is on significant decline, the remarkable evidence of treatment's impact on preventing new infections and the aspiration of zero new HIV infections among children is firmly within grasp. This progress, won by people living with HIV and countries with support from partners such as the US programme PEPFAR, the Clinton Health Access Initiative and untold more, embodies global solidarity to bring about an AIDS-free generation. Shared responsibility and global solidarity represents a normative ideal to which both individual stakeholders and the global community must subscribe and embrace if our collective vision of an AIDS-free world is to be realised. The idea of shared responsibility and global solidarity needs to goes further than raising and investing resources and extend to the level of control countries take of their AIDS response. This editorial explores five areas that require further attention.

BACKGROUND: Guidelines and implementation of tuberculosis preventive treatment (TPT) vary by age and HIV status. Specifically, TPT is strongly recommended for people living with HIV/AIDS (PLWHA) and household contacts younger than 5 years but only conditionally recommended for older contacts. Cost remains a major barrier to implementation. The aim of this study was to evaluate the cost-effectiveness of TPT for household contacts and PLWHA. METHODS: We developed a state-transition model to simulate short-course TPT for household contacts and PLWHA in 29 high-incidence countries based on data from previous studies and public databases. Our primary outcome was the incremental cost-effectiveness ratio, expressed as incremental discounted costs (2020 US$, including contact investigation costs) per incremental discounted disability-adjusted life year (DALY) averted, compared with a scenario without any TPT or contact investigation. We propagated uncertainty in all model parameters using probabilistic sensitivity analysis and also evaluated the sensitivity of results to the screening algorithm used to rule out active disease, the choice of TPT regimen, the modelling time horizon, assumptions about TPT coverage, antiretroviral therapy discontinuation, and secondary transmission. FINDINGS: Between 2023 and 2035, scaling up TPT prevented 0·9 (95% uncertainty interval 0·4-1·6) people from developing tuberculosis and 0·13 (0·05-0·27) tuberculosis deaths per 100 PLWHA, at an incremental cost of $15 (9-21) per PLWHA. For household contacts, TPT (with contact investigation) averted 1·1 (0·5-2·0) cases and 0·7 (0·4-1·0) deaths per 100 contacts, at a cost of $21 (17-25) per contact. Cost-effectiveness was most favourable for household contacts younger than 5 years ($22 per DALY averted) and contacts aged 5-14 years ($104 per DALY averted) but also fell within conservative cost-effectiveness thresholds in many countries for PLWHA ($722 per DALY averted) and adult contacts ($309 per DALY averted). Costs per DALY averted tended to be lower when compared with a scenario with contact investigation but no TPT. The cost-effectiveness of TPT was not substantially altered in sensitivity analyses, except that TPT was more favourable in analysis that considered a longer time horizon or included secondary transmission benefits. INTERPRETATION: In many high-incidence countries, short-course TPT is likely to be cost-effective for PLWHA and household contacts of all ages, regardless of whether contact investigation is already in place. Failing to implement tuberculosis contact investigation and TPT will incur a large burden of avertable illness and mortality in the next decade. FUNDING: Unitaid.

Tuberculosis (TB) remains a challenge in Brazil, particularly among prison inmates.To assess TB prevalence by active case finding in a public prison in southern Brazil.Prison inmates were screened for TB using the presence of cough and chest X-ray (CXR) from October 2014 to August 2016. Presence of cough, irrespective of duration, and abnormal CXRs were further investigated using laboratory tests.Of 10 326 inmates screened, 196 had confirmed TB (1898/100 000 inmates screened). At the first screening, 1759 inmates presented with cough only, 16 of whom had TB; among those with only abnormal CXR (n = 1273), 92 had TB. Xpert was positive in 155 patients, and negative in 15; these results were confirmed using culture. The remaining 26 patients did not undergo Xpert testing and were confirmed using microscopy (27%), culture (42%) or both (31%).The combined use of symptom screening (cough) and CXR was much more effective in maximising TB yield than using either method alone. If patients presenting with cough alone had not been investigated, 10% of TB patients would have been missed; if those with abnormal CXR but no cough had not been investigated, 51% of TB patients would have been missed. We detected high TB prevalence in this prison by using active case finding.

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations.

### Summary box HIV self-testing (HIVST) has shifted the paradigm for HIV testing, the first step in the care continuum. Although HIVST, whereby the person performs the test and interprets the results, was conceived early in the HIV epidemic, wider access to HIVST in low-income and middle-income countries (LMICs) is a recent phenomenon. A decade ago, large-scale HIVST use was limited due to concerns about accuracy, feasibility and safety. Through coordination between the WHO and implementation projects, including the Unitaid-funded HIV Self-Testing Africa (STAR) Initiative, HIVST is now part of the approach to HIV diagnosis in a growing number of high burden settings, with lessons for HIV programmes, other disease control efforts and the wider universal health coverage agenda.1 This shift to HIVST was driven by a need for better HIV diagnostic strategies, particularly in sub-Saharan Africa where under 50% of people living with HIV (PLHIV) knew their status in 2013.2 Despite no precedent for self-testing, no registered commercial assays and several implementation barriers, researchers and funders, set out to inform guidelines, policy development and regulatory frameworks. This effort shed light on the feasibility and effectiveness of large-scale implementation of HIVST by establishing preferred distribution channels, thereby generating demand. We describe key lessons learnt from HIVST in LMICs to …

The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome. The target product profiles also cover tests of cure conducted at the end of treatment. The development of the target product profiles was informed by a stakeholder survey, a cost-effectiveness analysis and a patient-care pathway analysis. Additional feedback from stakeholders was obtained by means of a Delphi-like process, a technical consultation and a call for public comment on a draft document. A scientific development group agreed on the final targets in a consensus meeting. For characteristics rated of highest importance, the document lists: (i) high diagnostic accuracy (sensitivity and specificity); (ii) time to result of optimally ≤ 2 hours and no more than 1 day; (iii) required sample type to be minimally invasive, easily obtainable, such as urine, breath, or capillary blood, or a respiratory sample that goes beyond sputum; (iv) ideally the test could be placed at a peripheral-level health facility without a laboratory; and (v) the test should be affordable to low- and middle-income countries, and allow wide and equitable access and scale-up. Use of these target product profiles should facilitate the development of new tuberculosis treatment monitoring and optimization tests that are accurate and accessible for all people being treated for tuberculosis.

Diabetes mellitus (DM) has important implications for tuberculosis (TB), as it increases the risk for disease activation and is associated with unfavorable TB treatment outcomes. This study analyzed the association between TB and DM (TBDM) in Brazil from 2007 to 2014. This was a retrospective cohort study carried out in 709,429 new cases of TB reported to the national disease notification system of the Brazilian Ministry of Health. Sociodemographic and clinical data, test results, and treatment outcomes were analyzed. TBDM was found in 6.0% of TB cases, mostly in men aged 18-59 years. The lethality rate was 5.1% higher in all age groups with diabetes, except in those older than 60 years of age. The frequency of multi-drug-resistant tuberculosis (MDR-TB) in patients with DM was higher in those without DM, with a 1.6- to 3.8-fold increase in the odds of MDR-TB. The elderly showed an increase in the prevalence of TBDM from 14.3% to 18.2%. Women were more likely to have DM, and elderly women had 41.0% greater chance of having DM. Relapse was significant among patients younger than 17 years of age. TBDM was high in Brazil, affected all age groups, and was associated with unfavorable TB treatment outcomes. We emphasize the need for strategies for the clinical management of diabetic tuberculosis patients in Brazil aiming at minimizing relapses, deaths, and MDR-TB.