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Introduction: The World Health Organization recommends differentiated service delivery (DSD) to support resource-limited health systems in providing patient-centered HIV care. DSD offers alternative care models to clinic-based care for people living with HIV who are stable on antiretroviral therapy (ART). Despite good patient-related outcomes, there is limited evidence of their sustainability. Our review evaluated the reporting of sustainability indicators of DSD interventions conducted in sub-Saharan Africa (SSA)., Methods: We searched PubMed and EMBASE for studies conducted between 2000 and 2019 assessing DSD interventions targeting HIV-positive individuals who are established in ART in sub-Saharan Africa. We evaluated them through a comprehensive sustainability framework of constructs categorized into 6 domains (intervention design, process, external environment, resources, organizational setting, and people involvement). We scored each construct 1, 2, or 3 for no, partial, or sufficient level of evidence, respectively. Interventions with a calculated sustainability score (overall and domain-specific) of >90% or domain-specific median score >2.7 were considered likely to be sustainable., Results: Overall scores ranged from 69% to 98%. Top scoring intervention types included adherence clubs (98%) and community ART groups (95%) which comprised more than half of interventions. The highest scoring domains were design (2.9) and organizational setting (2.8). The domains of resources (2.4) and people involvement (2.3) scored lowest revealing potential areas for improvement to support DSD sustainability., Conclusions: With the right investment in stakeholder involvement and domestic funding, DSD models generally show potential for sustainability. Our results could guide informed decisions on which DSD intervention is likely to be sustainable per setting and highlight areas that could motivate further research., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The integrase inhibitor dolutegravir is being considered in several countries in sub-Saharan Africa instead of efavirenz for people initiating antiretroviral therapy (ART) because of superior tolerability and a lower risk of resistance emergence. WHO requested updated modelling results for its 2019 Antiretroviral Guidelines update, which was restricted to the choice of dolutegravir or efavirenz in new ART initiators. In response to this request, we modelled the risks and benefits of alternative policies for initial first-line ART regimens., Methods: We updated an existing individual-based model of HIV transmission and progression in adults to consider information on the risk of neural tube defects in women taking dolutegravir at time of conception, as well as the effects of dolutegravir on weight gain. The model accounted for drug resistance in determining viral suppression, with consequences for clinical outcomes and mother-to-child transmission. We sampled distributions of parameters to create various epidemic setting scenarios, which reflected the diversity of epidemic and programmatic situations in sub-Saharan Africa. For each setting scenario, we considered the situation in 2018 and compared ART initiation policies of an efavirenz-based regimen in women intending pregnancy, and a dolutegravir-based regimen in others, and a dolutegravir-based regimen, including in women intending pregnancy. We considered predicted outcomes over a 20-year period from 2019 to 2039, used a 3% discount rate, and a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted., Findings: Considering updated information on risks and benefits, a policy of ART initiation with a dolutegravir-based regimen rather than an efavirenz-based regimen, including in women intending pregnancy, is predicted to bring population health benefits (10 990 DALYs averted per year) and to be cost-saving (by $2·9 million per year), leading to a reduction in the overall population burden of disease of 16 735 net DALYs per year for a country with an adult population size of 10 million. The policy involving ART initiation with a dolutegravir-based regimen in women intending pregnancy was cost-effective in 87% of our setting scenarios and this finding was robust in various sensitivity analyses, including around the potential negative effects of weight gain., Interpretation: In the context of a range of modelled setting scenarios in sub-Saharan Africa, we found that a policy of ART initiation with a dolutegravir-based regimen, including in women intending pregnancy, was predicted to bring population health benefits and be cost-effective, supporting WHO's strong recommendation for dolutegravir as a preferred drug for ART initiators., Funding: Bill & Melinda Gates Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Most countries have formally adopted the World Health Organization's 2015 recommendation of universal HIV treatment ("treat all"). However, there are few rigorous assessments of the real-world impact of treat all policies on antiretroviral treatment (ART) uptake across different contexts., Methods and Findings: We used longitudinal data for 814,603 patients enrolling in HIV care between 1 January 2004 and 10 July 2018 in 6 countries participating in the global International epidemiology Databases to Evaluate AIDS (IeDEA) consortium: Burundi (N = 11,176), Kenya (N = 179,941), Malawi (N = 84,558), Rwanda (N = 17,396), Uganda (N = 96,286), and Zambia (N = 425,246). Using a quasi-experimental regression discontinuity design, we assessed the change in the proportion initiating ART within 30 days of enrollment in HIV care (rapid ART initiation) after country-level adoption of the treat all policy. A modified Poisson model was used to identify factors associated with failure to initiate ART rapidly under treat all. In each of the 6 countries, over 60% of included patients were female, and median age at enrollment ranged from 32 to 36 years. In all countries studied, national adoption of treat all was associated with large increases in rapid ART initiation. Significant increases in rapid ART initiation immediately after treat all policy adoption were observed in Rwanda, from 44.4% to 78.9% of patients (34.5 percentage points [pp], 95% CI 27.2 to 41.7; p < 0.001), Kenya (25.7 pp, 95% CI 21.8 to 29.5; p < 0.001), Burundi (17.7 pp, 95% CI 6.5 to 28.9; p = 0.002), and Malawi (12.5 pp, 95% CI 7.5 to 17.5; p < 0.001), while no immediate increase was observed in Zambia (0.4 pp, 95% CI -2.9 to 3.8; p = 0.804) and Uganda (-4.2 pp, 95% CI -9.0 to 0.7; p = 0.090). The rate of rapid ART initiation accelerated sharply following treat all policy adoption in Malawi, Uganda, and Zambia; slowed in Kenya; and did not change in Rwanda and Burundi. In post hoc analyses restricted to patients enrolling under treat all, young adults (16-24 years) and men were at increased risk of not rapidly initiating ART (compared to older patients and women, respectively). However, rapid ART initiation following enrollment increased for all groups as more time elapsed since treat all policy adoption. Study limitations include incomplete data on potential ART eligibility criteria, such as clinical status, pregnancy, and enrollment CD4 count, which precluded the assessment of rapid ART initiation specifically among patients known to be eligible for ART before treat all., Conclusions: Our analysis indicates that adoption of treat all policies had a strong effect on increasing rates of rapid ART initiation, and that these increases followed different trajectories across the 6 countries. Young adults and men still require additional attention to further improve rapid ART initiation., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The 90-90-90 target states that by 2020, 90% of people living with HIV should be diagnosed, 90% of those diagnosed treated, and 90% of those treated virally suppressed. We assessed the actions needed in each country of sub-Saharan Africa to achieve the 90-90-90 target., Methods: We developed a mathematical model to assess the number of patients needing to start antiretroviral therapy (ART) between 2017 and 2020 to achieve 81% coverage by 2020 in each country, and the proportion of treated patients who are virally suppressed in four scenarios, combining two scenarios of retention (current-level or perfect), and routine viral load monitoring (current or universal coverage). We performed two separate simulations, one using observed failure rates from cohort studies, and one with considerably lower failure rates to set a theoretical lower limit., Results: Our model projected that 2.9 million people started ART in 2017 in sub-Saharan Africa. If, depending on scenario, at least 2.2-2.7 million patients continue to start ART annually, 81% ART coverage will be reached in 2020 in sub-Saharan Africa on average. In 37% of the countries, a multiple-fold increase in annual number of patients starting ART is needed. Virological suppression >90% in 2020 could be reached only in the best-case scenario assuming low probability of treatment failure, elimination of treatment interruptions, and universal routine viral load monitoring., Conclusion: The 90-90-90 target is realistic in sub-Saharan Africa on average, but not necessarily in all individual countries. Each country should identify and focus on the specific gaps needing attention., (© 2018 John Wiley & Sons Ltd.)

Early mortality and morbidity remain high in children initiating antiretroviral therapy (ART), especially in sub-Saharan Africa. Many children still present with advanced human immunodeficiency virus (HIV) disease. Tuberculosis, pneumonia, and severe bacterial infections are the main causes of hospital admission in HIV-infected children. In contrast to adults with advanced HIV disease, cryptococcal disease is not common in childhood, although there is a peak in infancy and adolescence. Interventions such as TB screening in symptomatic children, and isoniazid and cotrimoxazole prophylaxis should be implemented. There is evidence suggesting that rapid initiation (within 1 week) of ART in children with severe malnutrition or those with advanced HIV disease admitted to hospital is not beneficial and should be delayed until their condition has been stabilized. Research informing the prevention of severe bacterial infections, the management of pediatric immune reconstitution inflammatory syndrome, and other potential strategies to decrease morbidity and mortality in HIV-infected children are urgently needed.

Introduction: By 2020, 90% of all people diagnosed with HIV should receive long-term combination antiretroviral therapy (ART). In sub-Saharan Africa, this target is threatened by loss to follow-up in ART programmes. The proportion of people retained on ART long-term cannot be easily determined, because individuals classified as lost to follow-up, may have self-transferred to another HIV treatment programme, or may have died. We describe retention on ART in sub-Saharan Africa, first based on observed data as recorded in the clinic databases, and second adjusted for undocumented deaths and self-transfers., Methods: We analysed data from HIV-infected adults and children initiating ART between 2009 and 2014 at a sub-Saharan African HIV treatment programme participating in the International epidemiology Databases to Evaluate AIDS (IeDEA). We used the Kaplan-Meier method to calculate the cumulative incidence of retention on ART and the Aalen-Johansen method to calculate the cumulative incidences of death, loss to follow-up, and stopping ART. We used inverse probability weighting to adjust clinic data for undocumented mortality and self-transfer, based on estimates from a recent systematic review and meta-analysis., Results: We included 505,634 patients: 12,848 (2.5%) from Central Africa, 109,233 (21.6%) from East Africa, 347,343 (68.7%) from Southern Africa and 36,210 (7.2%) from West Africa. In crude analyses of observed clinic data, 52.1% of patients were retained on ART, 41.8% were lost to follow-up and 6.0% had died 5 years after ART initiation. After accounting for undocumented deaths and self-transfers, we estimated that 66.6% of patients were retained on ART, 18.8% had stopped ART and 14.7% had died at 5 years., Conclusions: Improving long-term retention on ART will be crucial to attaining the 90% on ART target. Naïve analyses of HIV cohort studies, which do not account for undocumented mortality and self-transfer of patients, may severely underestimate both mortality and retention on ART., (© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)

Objective: To ascertain estimates of adult patients, recorded as lost to follow-up (LTFU) within antiretroviral treatment (ART) programmes, who have self-transferred care, died or truly stopped ART in low- and middle-income countries., Methods: PubMed, EMBASE, Web of Science, Science Direct, LILACS, IndMed and AIM databases (2003-2013) and IAS/AIDS conference abstracts (2011-2013) were searched for tracing studies reporting the proportion of traced patients found to have self-transferred, died or stopped ART. These estimates were then combined using random-effects meta-analysis. Risk of bias was assessed through subgroup and sensitivity analyses., Results: Twenty eight studies were eligible for inclusion, reporting true outcomes for 10,806 traced patients attending approximately 258 ART facilities. None were from outside sub-Saharan Africa. Twenty three studies reported 4.5-54.4% traced LTFU patients self-transferring care, providing a pooled estimate of 18.6% (95% CI 15.8-22.0%). A significant positive association was found between rates of self-transfer and LTFU in the ART cohort. The pooled estimates for unreported deaths were 38.8% (95% CI 30.8-46.8%; 27 studies) and 28.6% (95% CI 21.9-36.0%; 20 studies) for patients stopping ART. A significant decrease in unreported deaths from 50.0% (95% CI 41.5-58.4%) to 30.0% (95% CI 21.1-38.9%) was found comparing study periods before and after 31 December 2007., Conclusions: Substantial unaccounted for transfers and deaths amongst patients LTFU confirms that retention and mortality is underestimated where the true outcomes of LTFU patients are not ascertained., (© 2014 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Objectives: Further scale-up of antiretroviral therapy (ART) to those in need while supporting the growing patient cohort on ART requires continuous adaptation of healthcare delivery models. We describe several approaches to manage stable patients on ART developed by Médecins Sans Frontières together with Ministries of Health in four countries in sub-Saharan Africa., Methods: Using routine programme data, four approaches to simplify ART delivery for stable patients on ART were assessed from a patient and health system perspective: appointment spacing for clinical and drug refill visits in Malawi, peer educator-led ART refill groups in South Africa, community ART distribution points in DRC and patient-led community ART groups in Mozambique., Results: All four approaches lightened the burden for both patients (reduced travel and lost income) and health system (reduced clinic attendance). Retention in care is high: 94% at 36 months in Malawi, 89% at 12 months in DRC, 97% at 40 months in South Africa and 92% at 48 months in Mozambique. Where evaluable, service provider costs are reported to be lower., Conclusion: Separating ART delivery from clinical assessments was found to benefit patients and programmes in a range of settings. The success of community ART models depends on sufficient and reliable support and resources, including a flexible and reliable drug supply, access to quality clinical management, a reliable monitoring system and a supported lay workers cadre. Such models require ongoing evaluation and further adaptation to be able to reach out to more patients, including specific groups who may be challenged to meet the demands of frequent clinic visits and the integrated delivery of other essential chronic disease interventions., (© 2014 John Wiley & Sons Ltd.)

Timely linkage to antiretroviral therapy (ART) care is critical for reducing HIV-related morbidity, mortality and transmission. Studies investigating interventions to improve linkage to, and retention in, pre-ART care in sub-Saharan Africa were reviewed. Certain interventions used to overcome economic barriers for ART-patients (i.e. integration of services, medical and food incentives, intensified counselling and peer support) have also shown favourable results in the pre-ART period. A combined package of interventions found to be effective in the pre-ART and ART period might be effective for reducing attrition in both periods. Further operational research in this area is needed to identify local solutions.

Cryptococcal meningitis is the leading cause of adult meningitis in sub-Saharan Africa, and contributes up to 20% of AIDS-related mortality in low-income and middle-income countries every year. Antifungal treatment for cryptococcal meningitis relies on three old, off-patent antifungal drugs: amphotericin B deoxycholate, flucytosine, and fluconazole. Widely accepted treatment guidelines recommend amphotericin B and flucytosine as first-line induction treatment for cryptococcal meningitis. However, flucytosine is unavailable in Africa and most of Asia, and safe amphotericin B administration requires patient hospitalisation and careful laboratory monitoring to identify and treat common side-effects. Therefore, fluconazole monotherapy is widely used in low-income and middle-income countries for induction therapy, but treatment is associated with significantly increased rates of mortality. We review the antifungal drugs used to treat cryptococcal meningitis with respect to clinical effectiveness and access issues specific to low-income and middle-income countries. Each drug poses unique access challenges: amphotericin B through cost, toxic effects, and insufficiently coordinated distribution; flucytosine through cost and scarcity of registration; and fluconazole through challenges in maintenance of local stocks--eg, sustainability of donations or insufficient generic supplies. We advocate ten steps that need to be taken to improve access to safe and effective antifungal therapy for cryptococcal meningitis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Demographic changes and the increasing availability and coverage of antiretroviral therapy imply that the burden of HIV is shifting to older age groups in sub-Saharan Africa. However, very little is known about the burden of disease and the unique considerations required to adequately treat and retain older Africans. In this review, we summarize the epidemiological data on HIV prevalence among older Africans, and review progress and barriers to accessing treatment and care. The unique clinical considerations distinguishing the management of older HIV-infected Africans are summarized, with a focus on cardiovascular disease, neuropsychiatric conditions, oncologic illness, and musculoskeletal morbidity. The review concludes by suggesting opportunities for improving our knowledge about and management of HIV among older Africans, including prevention opportunities and potential technologies, including a polypill for reducing comorbidity in this under-recognized highly vulnerable group.

Context: Recent studies have highlighted the increased risk of adverse outcomes among older patients on antiretroviral therapy (ART). We report on the associations between older age and adverse outcomes in HIV/AIDS antiretroviral programmes across 17 programmes in sub-Saharan Africa., Methods: We included data from nine countries: Central African Republic, Côte d'Ivoire, Democratic Republic of Congo, Ethiopia, Nigeria, Republic of Congo, Uganda, Zambia and Zimbabwe. We describe survival probability for progression to death and loss to follow-up for patients initiating ART aged less than 50 years and at least 50 years. Multivariate Cox proportional hazards models were used to assess the association between age (15-39, 40-49, 50-59, 60-69 and 70-94 years) and adverse outcomes adjusting for confounders identified a priori., Results: Our analysis included 17,561 patients followed for a median of 12 months. The majority (65%) were female and 6672 (38%) were severely immunosuppressed at baseline. Median age at ART initiation was 36.0 years (interquartile range 30.1-42.8); 11.4% of patients were aged at least 50 years. Median gain in CD4 cell count at 6 and 12 months was significantly higher in patients less than 50 years old compared with those at least 50 years (134 vs. 112 cells/μl at 6 months; 170 vs. 139 cells/μl at 12 months; both P < 0.001). In multivariate analysis, there was a significant increased risk of mortality beyond 3 months after ART initiation in all age groups of at least 40 years of age compared with less than 40 years [40-49 years adjusted hazard ratios (aHRs) 1.59, P < 0.001; 50-59 years aHR 1.58, P = 0.002; 60-69 years aHR 2.63, P < 0.001; 70-94 years aHR 3.64, P = 0.004)., Conclusion: Older age groups represent an important proportion of the overall treatment cohort in these sub-Saharan Africa programmes, and risk of mortality increased as age increased. Future research should be directed at further understanding the reasons for higher mortality, and defining simple interventions that are feasible in highly under-resourced settings to allow for adapted follow-up and care approaches for older age groups.

Background: Vertical HIV programs have achieved good results but may not be feasible or appropriate in many resource-limited settings. Médecins sans Frontières has treated HIV in vertical programs since 2000 and over time integrated HIV treatment into general health care services using simplified protocols. We analyzed the survival probability among patients receiving antiretroviral therapy (ART) from 2003 to 2010 in integrated versus vertical programs in 9 countries in sub-Saharan Africa., Methods and Findings: Cox regression assessed mortality and program design association, adjusting for baseline age, body mass index, clinical WHO stage, tuberculosis, program age and setting. The analysis included 15,403 HIV-positive adults on ART in 7 vertical (14,124 patients) and 10 integrated (1279 patients) programs. Cox regression including 14,523 patients followed for up to 30 months ART showed similar outcomes for mortality (adjusted hazard ratio (aHR) 1.02; 95% confidence interval (CI): 0.83 to 1.24) and lower risk of loss to follow-up (aHR: 0.71; 95% CI: 0.61 to 0.83) in integrated compared with vertical programs. The greatest risk of death was from initiating ART at WHO stage 4 (aHR 1.99, 95% CI: 1.74 to 2.29), although greater program experience was protective (aHR: 0.77, 95% CI: 0.66 to 0.89). Risk of loss to follow-up was greater in experienced programs (aHR: 3.33; 95% CI: 2.92 to 3.79) and rural settings (aHR: 3.82; 95% CI: 3.49 to 4.20)., Conclusions: ART delivery in integrated general health care programs results in good outcomes. Compared with vertical HIV programs, patients initiated ART in integrated programs at more advanced stages of clinical immunosuppression yet had similar risk of death and lower risk of loss to follow-up.

Objective: To estimate the lost investment of domestically educated doctors migrating from sub-Saharan African countries to Australia, Canada, the United Kingdom, and the United States., Design: Human capital cost analysis using publicly accessible data., Settings: Sub-Saharan African countries., Participants: Nine sub-Saharan African countries with an HIV prevalence of 5% or greater or with more than one million people with HIV/AIDS and with at least one medical school (Ethiopia, Kenya, Malawi, Nigeria, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe), and data available on the number of doctors practising in destination countries., Main Outcome Measures: The financial cost of educating a doctor (through primary, secondary, and medical school), assuming that migration occurred after graduation, using current country specific interest rates for savings converted to US dollars; cost according to the number of source country doctors currently working in the destination countries; and savings to destination countries of receiving trained doctors., Results: In the nine source countries the estimated government subsidised cost of a doctor's education ranged from $21,000 (£13,000; €15,000) in Uganda to $58,700 in South Africa. The overall estimated loss of returns from investment for all doctors currently working in the destination countries was $2.17bn (95% confidence interval 2.13bn to 2.21bn), with costs for each country ranging from $2.16m (1.55m to 2.78m) for Malawi to $1.41bn (1.38bn to 1.44bn) for South Africa. The ratio of the estimated compounded lost investment over gross domestic product showed that Zimbabwe and South Africa had the largest losses. The benefit to destination countries of recruiting trained doctors was largest for the United Kingdom ($2.7bn) and United States ($846m)., Conclusions: Among sub-Saharan African countries most affected by HIV/AIDS, lost investment from the emigration of doctors is considerable. Destination countries should consider investing in measurable training for source countries and strengthening of their health systems.

There has been an historic expectation that delivering combination antiretroviral therapy (cART) to populations affected by violent conflict is untenable due to population movement and separation of drug supplies. There is now emerging evidence that cART provision can be successful in these populations. Using examples from Médecins Sans Frontières experience in a variety of African settings and also local nongovernmental organizations' experiences in northern Uganda, we examine novel approaches that have ensured retention in programs and adequate adherence. Emerging guidelines from United Nations bodies now support the expansion of cART in settings of conflict.

Sub-Saharan Africa is facing a crisis in human health resources due to a critical shortage of health workers. The shortage is compounded by a high burden of infectious diseases; emigration of trained professionals; difficult working conditions and low motivation. In particular, the burden of HIV/AIDS has led to the concept of task shifting being increasingly promoted as a way of rapidly expanding human resource capacity. This refers to the delegation of medical and health service responsibilities from higher to lower cadres of health staff, in some cases non-professionals. This paper, drawing on Médecins Sans Frontières' experience of scaling-up antiretroviral treatment in three sub-Saharan African countries (Malawi, South Africa and Lesotho) and supplemented by a review of the literature, highlights the main opportunities and challenges posed by task shifting and proposes specific actions to tackle the challenges. The opportunities include: increasing access to life-saving treatment; improving the workforce skills mix and health-system efficiency; enhancing the role of the community; cost advantages and reducing attrition and international 'brain drain'. The challenges include: maintaining quality and safety; addressing professional and institutional resistance; sustaining motivation and performance and preventing deaths of health workers from HIV/AIDS. Task shifting should not undermine the primary objective of improving patient benefits and public health outcomes.

There is a heavy burden of HIV-hepatitis B virus (HBV) and HIV-hepatitis C virus (HCV) co-infection in many regions of the developing world. An often unmentioned illness, issues of poverty, socio-economic status, nutrition, access to medical care, and mistrust of Western-style medicine conspire to reduce the opportunity to receive clinical work-up and treatment for chronic viral hepatitis. We discuss key issues specific to the treatment of viral hepatitis and obstacles to success with this endeavor in the context of HIV co-infection in Africa. We predict that provision of viral hepatitis antiviral therapy will become a more pressing issue as more HIV-infected patients receive lifesaving combination antiretroviral therapy only to succumb thereafter from viral hepatitis-induced liver disease. Given the lessons learned from combination antiretroviral rollout in sub-Saharan Africa, establishing expertise and infrastructure for viral hepatitis care and antiviral therapy is relevant. Failure to act now may diminish the milestones and the gains made with antiretroviral therapy in the developing world.