Primary health care preparedness to integrate diabetes care in Blantyre, Malawi: A mixed methods study.

BACKGROUND: There is limited access to diabetes care services at primary care facilities in Malawi. Assessing the capacity of facilities to provide diabetes care is an initial step to integrating services at primary care. AIM: To assess the preparedness for delivering diabetes services at primary care level within the Blantyre District Health Office (DHO) to support the response to NCD epidemic in Malawi. SETTING: Blantyre DHO primary care facilities. MATERIALS AND METHODS: A mixed methods approach nested in a national needs assessment for NCD response in Malawi was used. Fourteen primary healthcare facilities from Blantyre DHO were assessed. A tool adapted from the WHO rapid assessment questionnaire was used to identify human resource, equipment, supplies, and medication needed for comprehensive diabetes care. Descriptive statistics were done to analyze the quantitative data. Fisher's exact test was used to assess if there was a statistically significant difference between urban and rural facilities. Seventeen health care workers from the selected facilities participated in key informant interviews. Framework analysis method guided the qualitative data analysis. The quantitative and qualitative data were merged and displayed jointly. RESULTS: The quantitative assessment showed that none of the facilities assessed had capacity to provide all the interventions recommended by WHO for diabetes care at primary level. Eight (57%) of the facilities had the capacity to diagnose diabetes, monitor glucose, prevent limb amputations and manage hypoglycemia and hyperglycemia. Four themes emerged from the qualitative data: differences in level of preparedness and implementation of diabetes care; disparities in resources between urban and rural facilities; low utilization of diabetes services; and strategy and policy recommendations for improvement of diabetes care. CONCLUSION: Inadequate health financing resulted in significant disparities in the available resources between the rural and urban facilities to offer diabetes care services. There is need to develop national policies and guidelines for diabetes care to strengthen the capacity of primary care facilities to facilitate achievement of universal health coverage.

Implementation strategies to build mental health-care capacity in Malawi: a health-economic evaluation.

BACKGROUND: Depression is a major contributor to morbidity and mortality in sub-Saharan Africa. Due to low system capacity, three in four patients with depression in sub-Saharan Africa go untreated. Despite this, little attention has been paid to the cost-effectiveness of implementation strategies to scale up evidence-based depression treatment in the region. In this study, we investigate the cost-effectiveness of two different implementation strategies to integrate the Friendship Bench approach and measurement-based care in non-communicable disease clinics in Malawi. METHODS: The two implementation strategies tested in this study are part of a trial, in which ten clinics were randomly assigned (1:1) to a basic implementation package consisting of an internal coordinator acting as a champion (IC-only group) or to an enhanced package that complemented the basic package with quarterly external supervision, and audit and feedback of intervention delivery (IC + ES group). We included material costs, training costs, costs related to project-wide meetings, transportation and medication costs, time costs related to internal champion activities and depression screening or treatment, and costs of external supervision visits if applicable. Outcomes included the number of patients screened with the patient health questionnaire 2 (PHQ-2), cases of remitted depression at 3 and 12 months, and disability-adjusted life-years (DALYs) averted. We compared the cost-effectiveness of both packages to the status quo (ie, no intervention) using a micro-costing-informed decision-tree model. FINDINGS: Relative to the status quo, IC + ES would be on average US$10 387 ($1349-$17 365) more expensive than IC-only but more effective in achieving remission and averting DALYs. The cost per additional remission would also be lower with IC + ES than IC-only at 3 months ($119 vs $223) and 12 months ($210 for IC + ES; IC-only dominated by the status quo at 12 months). Neither package would be cost-effective under the willingness-to-pay threshold of $65 per DALY averted currently used by the Malawian Ministry of Health. However, the IC + ES package would be cost-effective in relation to the commonly used threshold of three times per-capita gross domestic product per DALY averted. INTERPRETATION: Investing in supporting champions might be an appropriate use of resources. Although not currently cost-effective by Malawian willingness-to-pay standards compared with the status quo, the IC + ES package would probably be a cost-effective way to build mental health-care capacity in resource-constrained settings in which decision makers use higher willingness-to-pay thresholds. FUNDING: National Institute of Mental Health.

Global implementation research capacity building to address cardiovascular disease: An assessment of efforts in eight countries.

Cardiovascular diseases are the leading causes of morbidity and mortality worldwide, but implementation of evidence-based interventions for risk factors such as hypertension is lacking, particularly in low and middle income countries (LMICs). Building implementation research capacity in LMICs is required to overcome this gap. Members of the Global Research on Implementation and Translation Science (GRIT) Consortium have been collaborating in recent years to establish a research and training infrastructure in dissemination and implementation to improve hypertension care. GRIT includes projects in Ghana, Guatemala, India, Kenya, Malawi, Nepal, Rwanda, and Vietnam. We collected data from each site on capacity building activities using the Potter and Brough (2004) model, mapping formal and informal activities to develop (a) structures, systems and roles, (b) staff and infrastructure, (c) skills, and (d) tools. We captured information about sites' needs assessments and metrics plus program adaptations due to the COVID-19 pandemic. All sites reported capacity building activities in each layer of the Capacity Pyramid, with the largest number of activities in the Skills and Tools categories, the more technical and easier to implement categories. All sites included formal and informal training to build Skills. All sites included a baseline needs assessment to guide capacity building activities or assess context and inform intervention design. Sites implementing evidence-based hypertension interventions used common implementation science frameworks to evaluate implementation outcomes. Although the COVID-19 pandemic affected timelines and in-person events, all projects were able to pivot and carry out planned activities. Although variability in the activities and methods used existed, GRIT programs used needs assessments to guide locally appropriate design and implementation of capacity building activities. COVID-19 related changes were necessary, but strong collaborations and relationships with health ministries were maintained. The GRIT Consortium is a model for planning capacity building in LMICs.

Assessing suicidality during the SARS-CoV-2 pandemic: Lessons learned from adaptation and implementation of a telephone-based suicide risk assessment and response protocol in Malawi.

The SARS-CoV-2 pandemic led to the rapid transition of many research studies from in-person to telephone follow-up globally. For mental health research in low-income settings, tele-follow-up raises unique safety concerns due to the potential of identifying suicide risk in participants who cannot be immediately referred to in-person care. We developed and iteratively adapted a telephone-delivered protocol designed to follow a positive suicide risk assessment (SRA) screening. We describe the development and implementation of this SRA protocol during follow-up of a cohort of adults with depression in Malawi enrolled in the Sub-Saharan Africa Regional Partnership for Mental Health Capacity Building (SHARP) randomized control trial during the COVID-19 era. We assess protocol feasibility and performance, describe challenges and lessons learned during protocol development, and discuss how this protocol may function as a model for use in other settings. Transition from in-person to telephone SRAs was feasible and identified participants with suicidal ideation (SI). Follow-up protocol monitoring indicated a 100% resolution rate of SI in cases following the SRA during this period, indicating that this was an effective strategy for monitoring SI virtually. Over 2% of participants monitored by phone screened positive for SI in the first six months of protocol implementation. Most were passive risk (73%). There were no suicides or suicide attempts during the study period. Barriers to implementation included use of a contact person for participants without personal phones, intermittent network problems, and pre-paid phone plans delaying follow-up. Delays in follow-up due to challenges with reaching contact persons, intermittent network problems, and pre-paid phone plans should be considered in future adaptations. Future directions include validation studies for use of this protocol in its existing context. This protocol was successful at identifying suicide risk levels and providing research assistants and participants with structured follow-up and referral plans. The protocol can serve as a model for virtual SRA development and is currently being adapted for use in other contexts.

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.

BACKGROUND: HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. METHODS: The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. FINDINGS: The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda. INTERPRETATION: The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. FUNDING: European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. TRANSLATIONS: For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.

Relative cost-effectiveness of long-acting injectable cabotegravir versus oral pre-exposure prophylaxis in South Africa based on the HPTN 083 and HPTN 084 trials: a modelled economic evaluation and threshold analysis.

BACKGROUND: Long-acting injectable cabotegravir, a drug taken every 2 months, has been shown to be more effective at preventing HIV infection than daily oral tenofovir disoproxil fumarate and emtricitabine, but its cost-effectiveness in a high-prevalence setting is not known. We aimed to estimate the incremental cost-effectiveness of long-acting injectable cabotegravir compared with tenofovir disoproxil fumarate and emtricitabine in South Africa, using methods standard to government planning, and to determine the threshold price at which long-acting injectable cabotegravir is as cost-effective as tenofovir disoproxil fumarate and emtricitabine. METHODS: In this modelled economic evaluation and threshold analysis, we updated a deterministic model of the South African HIV epidemic with data from the HPTN 083 and HPTN 084 trials to evaluate the effect of tenofovir disoproxil fumarate and emtricitabine and long-acting injectable cabotegravir provision to heterosexual adolescents and young women and men aged 15-24 years, female sex workers, and men who have sex with men. We estimated the average intervention cost, in 2021 US$, using ingredients-based costing, and modelled the cost-effectiveness of two coverage scenarios (medium or high, assuming higher uptake of long-acting injectable cabotegravir than tenofovir disoproxil fumarate and emtricitabine throughout) and, for long-acting injectable cabotegravir, two duration subscenarios (minimum: same pre-exposure prophylaxis duration as for tenofovir disoproxil fumarate and emtricitabine; maximum: longer duration than tenofovir disoproxil fumarate and emtricitabine) over 2022-41. FINDINGS: Across long-acting injectable cabotegravir scenarios, 15-28% more new HIV infections were averted compared with the baseline scenario (current tenofovir disoproxil fumarate and emtricitabine roll-out). In scenarios with increased coverage with oral tenofovir disoproxil fumarate and emtricitabine, 4-8% more new HIV infections were averted compared with the baseline scenario. If long-acting injectable cabotegravir drug costs were equal to those of tenofovir disoproxil fumarate and emtricitabine for the same 2-month period, the incremental cost of long-acting injectable cabotegravir to the HIV programme was higher than that of tenofovir disoproxil fumarate and emtricitabine (5-10% vs 2-4%) due to higher assumed uptake of long-acting injectable cabotegravir. The cost per infection averted was $6053-6610 (tenofovir disoproxil fumarate and emtricitabine) and $4471-6785 (long-acting injectable cabotegravir). The cost per long-acting cabotegravir injection needed to be less than twice that of a 2-month supply of tenofovir disoproxil fumarate and emtricitabine to remain as cost-effective, with threshold prices ranging between $9·03 per injection (high coverage; maximum duration) and $14·47 per injection (medium coverage; minimum duration). INTERPRETATION: Long-acting injectable cabotegravir could potentially substantially change HIV prevention. However, for its implementation to be financially feasible across low-income and middle-income countries with high HIV incidence, long-acting injectable cabotegravir must be reasonably priced. FUNDING: United States Agency for International Development, The Bill & Melinda Gates Foundation.

Costing and cost-effectiveness of Cepheid Xpert HIV -1 Qual Assay using whole blood protocol versus PCR by Abbott Systems in Malawi.

Background: Timely diagnosis of HIV in infants and children is an urgent priority. In Malawi, 40,000 infants annually are HIV exposed. However, gold standard polymerase-chain-reaction (PCR) based testing requires centralised laboratories, causing turn-around times (TAT) of 2 to 3 months and significant loss to follow-up. If feasible and acceptable, minimising diagnostic delays through HIV Point-of-care-testing (POCT) may be cost-effective. We assessed whether POCT Cepheid Xpert HIV-1 Qual assay whole blood (XpertHIV) was more cost-effective than PCR. Methods: From July-August 2018, 700 PCR Abbott tests using dried blood spots (DBS) were performed on 680 participants who enrolled on the feasibility, acceptability and performance of the XpertHIV study. Newly identified HIV-positive We conducted a cost-minimisation and cost-effectiveness analysis of XpertHIV against PCR, as the standard of care. A random sample of 200 caregivers from the 680 participants had semi-structured interviews to explore costs from a societal perspective of XpertHIV at Mulanje District Hospital, Malawi. Analysis used TAT as the primary outcome measure. Results were extrapolated from the study period (29 days) to a year (240 working days). Sensitivity analyses characterised individual and joint parameter uncertainty and estimated patient cost per test. Results: During the study period, XpertHIV was cost-minimising at $42.34 per test compared to $66.66 for PCR. Over a year, XpertHIV remained cost-minimising at $16.12 compared to PCR at $27.06. From the patient perspective (travel, food, lost productivity), the cost per test of XpertHIV was $2.45. XpertHIV had a mean TAT of 7.10 hours compared to 153.15 hours for PCR. Extrapolates accounting for equipment costs, lab consumables and losses to follow up estimated annual savings of $2,193,538.88 if XpertHIV is used nationally, as opposed to PCR. Conclusions: This preliminary evidence suggests that adopting POCT XpertHIV will save time, allowing HIV-exposed infants to receive prompt care and may improve outcomes. The Malawi government will pay less due to XpertHIV's cost savings and associated benefits.

Identifying Adolescent Girls and Young Women at High Risk for HIV Acquisition: A Risk Assessment Tool From the Girl Power-Malawi Study.

BACKGROUND: Prioritizing HIV prevention for adolescent girls and young women (AGYW) at high risk for HIV acquisition in sub-Saharan Africa (typically considered ≥3 per 100 person-years [PYs]) is urgently needed, but identifying these AGYW is challenging. We sought to assess and, if needed, enhance a risk assessment tool from the VOICE trial for identifying AGYW at high risk for HIV in Lilongwe, Malawi. METHODS: A multisite prospective cohort study was conducted among sexually active AGYW 15 to 24 years old at 4 health centers in 2016 to 2017. The VOICE tool was first applied and then updated by excluding variables that were not predictive and adding variables that were. Incidence rates (IRs), incidence rate ratios, 95% confidence intervals (CIs), area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were calculated. RESULTS: Seven hundred ninety-five participants experienced 14 seroconversions for 672 PYs (IR, 2.08 per 100 PYs; 95% CI, 1.23-3.52). The VOICE tool had moderate predictive ability (AUC, 0.64; 95% CI, 0.52-0.75). Maintaining 2 variables (genital ulcers and vaginal discharge), removing 5 sociodemographic variables, and adding 2 variables (ever pregnant and >5-year male-female age gap) enhanced performance (AUC, 0.79; 95% CI, 0.69-0.89). Thirty-five percent had a score of 0, 41% had a score of 1 to 2, and 24% had a score >3. A score >1 resulted in 100% sensitivity, 35.9% specificity, and an IR of 3.25 per 100 PYs. A score >3 resulted in 64.3% sensitivity, 76.8% specificity, and an IR of 5.89 per 100 PYs. CONCLUSIONS: A simple risk assessment tool identified a subset of AGYW in Malawi at high risk for HIV acquisition who may benefit from biomedical HIV prevention.

The impact of an integrated depression and HIV treatment program on mental health and HIV care outcomes among people newly initiating antiretroviral therapy in Malawi.

BACKGROUND: Depression is highly prevalent among patients newly starting antiretroviral treatment (ART) in Malawi and many other countries. Untreated depression at ART initiation can disrupt the HIV care continuum. Effective approaches for depression screening and treatment exist for low-resource settings, but they are rarely applied. Identifying effective implementation strategies are critical. METHODS: A pilot program integrated depression screening and treatment into routine HIV care using existing staff at two public health clinics in Malawi in two phases; a screening-only "control" phase and an active "intervention" phase. During the intervention phase, providers prescribed antidepressants or referred patients for Friendship Bench problem-solving therapy. We evaluated the program's impact on retention in HIV care, viral suppression, and depression remission at 6 months using tabular comparisons and log-binomial models to estimate adjusted risk ratios and mean differences among the intervention group relative to the control group. RESULTS: Nearly all consenting participants were screened for depression appropriately and 25% had mild to severe depressive symptoms. During the intervention phase, 86% of participants with mild depressive symptoms started Friendship Bench therapy and 96% of participants with moderate to severe depressive symptoms started antidepressants. Few participants in the intervention group received consistent depression treatment over their first 6 months in care. In the adjusted main analysis, program exposure did not demonstrably affect most HIV or mental health outcomes, though the probability of currently being on ART at 6 months was significantly lower among the intervention group than the control group [RR 0.6(95%CI: 0.4-0.9)]. CONCLUSIONS: While it is feasible to integrate depression screening and treatment initiation into ART initiation, providing ongoing depression treatment over time is challenging. Similar implementation science studies focused on maintaining depression management will be increasingly important as we strive to understand and test the best ways to implement evidence-based depression treatment within HIV care.

Addition of Flucytosine to Fluconazole for the Treatment of Cryptococcal Meningitis in Africa: A Multicountry Cost-effectiveness Analysis.

BACKGROUND: Mortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain. METHODS: The effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER. RESULTS: The mean costs per patient were US $847 (95% confidence interval [CI] $776-927) for FLU+5FC, and US $628 (95% CI $557-709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9-41.7%) with FLU+5FC and 53.8% (95% CI 43.1-64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28-208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved. CONCLUSIONS: The addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus-infected persons in Africa.

The effectiveness of depression management for improving HIV care outcomes in Malawi: protocol for a quasi-experimental study.

BACKGROUND: Depression, prevalent among people living with HIV (PLWH) in Malawi, is associated with negative HIV patient outcomes and likely affects HIV medical management. Despite the high prevalence of depression, its management has not been integrated into HIV care in Malawi or most low-income countries. METHODS: This study employs a pre-post design in two HIV clinics in Lilongwe, Malawi, to evaluate the effect of integrating depression management into routine HIV care on both mental health and HIV outcomes. Using a multiple baseline design, this study is examining mental health and HIV outcome data of adult (≥18 years) patients newly initiating ART who also have depression, comparing those entering care before and after the integration of depression screening and treatment into HIV care. The study is also collecting cost information to estimate the cost-effectiveness of the program in improving rates of depression remission and HIV treatment engagement and success. DISCUSSION: We anticipate that the study will generate evidence on the effect of depression management on HIV outcomes and the feasibility of integrating depression management into existing HIV care clinics. The results of the study will inform practice and policy decisions on integration of depression management in HIV care clinics in Malawi and related settings, and will help design a next-step strategy to scale-up integration to a larger scale. TRIAL REGISTRATION: ClinicalTrials.gov ID [ NCT03555669 ]. Retrospectively registered on 13 June 2018.

AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study.

INTRODUCTION: Cryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation. METHODS AND ANALYSIS: Country-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial. ETHICS AND DISSEMINATION: The AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings. TRIAL REGISTRATION: ISRCTN 7250 9687; Pre-results.

Healthcare Costs and Life-years Gained From Treatments Within the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) Trial on Cryptococcal Meningitis: A Comparison of Antifungal Induction Strategies in Sub-Saharan Africa.

BACKGROUND: Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses. METHODS: Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done. RESULTS: Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91-1210) per life-year saved. CLINICAL TRIALS REGISTRATION: ISRCTN45035509. CONCLUSIONS: Both 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments.

Global Health Mentoring Toolkits: A Scoping Review Relevant for Low- and Middle-Income Country Institutions.

Capacity building in low- and middle-income country (LMIC) institutions hinges on the delivery of effective mentorship. This study presents an overview of mentorship toolkits applicable to LMIC institutions identified through a scoping review. A scoping review approach was used to 1) map the extent, range, and nature of mentorship resources and tools available and 2) to identify knowledge gaps in the current literature. To identify toolkits, we collected and analyzed data provided online that met the following criteria: written in English and from organizations and individuals involved in global health mentoring. We searched electronic databases, including PubMed, Web of Science, and Google Scholar, and Google search engine. Once toolkits were identified, we extracted the available tools and mapped them to pre-identified global health competencies. Only three of the 18 identified toolkits were developed specifically for the LMIC context. Most toolkits focused on individual mentor-mentee relationships. Most focused on the domains of communication and professional development. Fewer toolkits focused on ethics, overcoming resource limitations, and fostering institutional change. No toolkits discussed strategies for group mentoring or how to adapt existing tools to a local context. There is a paucity of mentoring resources specifically designed for LMIC settings. We identified several toolkits that focus on aspects of individual mentor-mentee relationships that could be adapted to local contexts. Future work should focus on adaptation and the development of tools to support institutional change and capacity building for mentoring.

Infant and young child feeding learning sessions during savings groups are feasible and acceptable for HIV-positive and HIV-negative women in Malawi.

Based on formative research, HIV-positive women in Lilongwe District, Malawi receive little infant and young child feeding (IYCF) counselling postpartum and want more support for IYCF from their husbands. To address these gaps, we implemented a behaviour change communication intervention promoting IYCF in village savings and loan associations (VSLAs) that included HIV-positive and HIV-negative women. The intervention consisted of 15 IYCF learning sessions facilitated by VSLA volunteers during regular VSLA meetings and included four sessions to which husbands were invited. We assessed the feasibility and acceptability of the intervention through learning session participation logs, structured observations of learning sessions, and in-depth interviews with HIV-positive and HIV-negative VSLA members, husbands of members, and VSLA volunteers. Nine VSLA volunteers conducted learning sessions with approximately 300-400 women, about one quarter of whom were lactating, and 25-35 men. VSLA volunteers consistently communicated technical information correctly, followed the learning session steps, and used visual aids. Sessions averaged 46 min, with <20% of observed sessions completed within the recommended time (20-25 min). Key themes from interviews were the following: (a) learning sessions were useful; (b) including HIV-positive and HIV-negative women in the sessions was acceptable; (c) information learned during sessions encouraged families to change IYCF practices; (d) IYCF messages were shared with others in the community; and (e) male participation was low because men considered VSLAs and IYCF to be women's activities. In conclusion, integrating IYCF learning sessions into VLSAs was feasible and acceptable for mixed groups of HIV-positive and HIV-negative women. Future research should test other strategies for involving men in IYCF.

AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial.

BACKGROUND: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). METHODS: An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. DISCUSSION: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. TRIAL REGISTRATION: ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

Integrating depression management into HIV primary care in central Malawi: the implementation of a pilot capacity building program.

BACKGROUND: In Malawi, early retention in HIV care remains challenging. Depression is strongly associated with reduced anti-retroviral therapy (ART) adherence and viral suppression. Appropriate depression care for people initiating ART is likely to be supportive of early and continued engagement in the HIV care continuum. This paper aims to provide an overview of a task-shifting program that integrates depression screening and treatment into HIV care and the strategy used to evaluate this program, describes the implementation process, and discusses key challenges and lessons learned in the first phase of program implementation. METHODS: We are implementing a program integrating depression screening and treatment into HIV care initiation at two clinics in Lilongwe District, Malawi. The program's effect on patients' depression and HIV outcomes will be evaluated using a multiple baseline pre-post study. In this manuscript, we draw from our experiences as program implementers and some of the quantitative data to describe the process of implementation and key lessons learned. RESULTS: We successfully implemented the screening phase of this program at both clinics; 88.3 and 93.2% of newly diagnosed patients have been screened for depression at each clinic respectively. 25% of enrolled patients reported symptoms of mild-to-severe depression and only 6% reported symptoms of moderate-to-severe depression. Key lessons learned from the process show the importance of utilizing existing processes and infrastructure and focusing on iterative and collaborative learning. We continued to face challenges around establishing a sense of program ownership among providers, developing capacity to diagnose and manage depression, and ensuring the availability of appropriate medication. Our efforts to address these challenges provide insight into the technical and managerial support needed to prepare for, roll out, and sustain integrated models of mental health and HIV care. CONCLUSIONS: This activity demonstrates how a depression screening program can successfully be integrated into HIV care within the public health system in Malawi. While this program focuses on integrating depression management into HIV care, most of the lessons learned could apply to integration of mental health into any non-psychiatric specialist setting. TRIAL REGISTRATION: ClinicalTrials.gov ID [ NCT03555669 ]. Retrospectively registered on 13 June 2018.

Impact of Facility- and Community-Based Peer Support Models on Maternal Uptake and Retention in Malawi's Option B+ HIV Prevention of Mother-to-Child Transmission Program: A 3-Arm Cluster Randomized Controlled Trial (PURE Malawi).

BACKGROUND: Many sub-Saharan African countries have adopted Option B+, a prevention of mother-to-child transmission approach providing HIV-infected pregnant and lactating women with immediate lifelong antiretroviral therapy. High maternal attrition has been observed in Option B+. Peer-based support may improve retention. METHODS: A 3-arm stratified cluster randomized controlled trial was conducted in Malawi to assess whether facility- and community-based peer support would improve Option B+ uptake and retention compared with standard of care (SOC). In SOC, no enhancements were made (control). In facility-based and community-based models, peers provided patient education, support groups, and patient tracing. Uptake was defined as attending a second scheduled follow-up visit. Retention was defined as being alive and in-care at 2 years without defaulting. Attrition was defined as death, default, or stopping antiretroviral therapy. Generalized estimating equations were used to estimate risk differences (RDs) in uptake. Cox proportional hazards regression with shared frailties was used to estimate hazard of attrition. RESULTS: Twenty-one facilities were randomized and enrolled 1269 women: 447, 428, and 394 in facilities that implemented SOC, facility-based, and community-based peer support models, respectively. Mean age was 27 years. Uptake was higher in facility-based (86%; RD: 6%, confidence interval [CI]: -3% to 15%) and community-based (90%; RD: 9%, CI: 1% to 18%) models compared with SOC (81%). At 24 months, retention was higher in facility-based (80%; RD: 13%, CI: 1% to 26%) and community-based (83%; RD: 16%, CI: 3% to 30%) models compared with SOC (66%). CONCLUSIONS: Facility- and community-based peer support interventions can benefit maternal uptake and retention in Option B+.

Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study.

BACKGROUND: For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings. METHODS: A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715. FINDINGS: Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10·3% (95% CI 6·5-14·0) in the raltegravir group and 12·4% (8·3-16·5) in the NRTI group, with a weighted difference of -3·4% (-8·4 to 1·5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes. INTERPRETATION: In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity. FUNDING: National Institutes of Health.

The value of informal care in the context of option B+ in Malawi: a contingent valuation approach.

BACKGROUND: Informal care, the health care provided by the patient's social network is important in low income settings although its monetary value is rarely estimated. The lack of estimates of the value of informal care has led to its omission in economic evaluations but this can result in incorrect decisions about cost effectiveness of an intervention. We explore the use of contingent valuation methods of willingness to pay (WTP) and willingness to accept (WTA) to estimate the value of informal care provided to HIV infected women that are accessing antiretroviral therapy (ART) under the Option B+ approach to prevention of mother-to-child transmission (PMTCT) of HIV in Malawi. METHODS: We collected cross sectional data from 93 caregivers of women that received ART care from six health facilities in Malawi. Caregivers of women that reported for ART care on the survey day and consented to participate in the survey were included until the targeted sample size for the facility was reached. We estimated the value of informal care by using the willingness to accept (WTA) and willingness to pay (WTP) approaches. Medians were used to summarize the values and these were compared by the Wilcoxon signed-rank test. RESULTS: The median WTA to provide informal care in a month was US$30 and the median WTP for informal care was US$13 and the two were statistically different (p < 0.000). Median WTP was higher in the urban areas than in the rural areas (US$21 vs. US$13, p < 0.001) and for caregivers from households from higher wealth quintile than in the lower quintile (US$15 vs. US$13, p < 0.0462). CONCLUSION: Informal caregivers place substantial value on informal care giving. In low income settings where most caregivers are not formally employed, WTP and WTA approaches can be used to value informal care. CLINICAL TRIAL NUMBER: NCT02005835.