Examining barriers to antiretroviral therapy initiation in infants living with HIV in sub-Saharan Africa despite the availability of point-of-care diagnostic testing: a narrative systematic review.

INTRODUCTION: Antiretroviral therapy (ART) initiation in infants living with HIV before 12 weeks of age can reduce the risk of mortality by 75%. Point-of-care (POC) diagnostic testing is critical for prompt ART initiation; however, despite its availability, rates of ART initiation are still relatively low before 12 weeks of age. This systematic review describes the barriers to ART initiation in infants before 12 weeks of age, despite the availability of POC. METHODS: This systematic review used a narrative synthesis methodology. We searched PubMed and Scopus using search strategies that combined terms of multiple variants of the keywords "early infant initiation on antiretroviral therapy," "barriers" and "sub-Saharan Africa" (initial search 18th January 2023; final search 1st August 2023). We included qualitative, observational and mixed methods studies that reported the influences of early infant initiation on ART. We excluded studies that reported influences on other components of the Prevention of Mother to Child Transmission cascade. Using a deductive approach guided by the updated Consolidated Framework of Implementation Research, we developed descriptive codes and themes around barriers to early infant initiation on ART. We then developed recommendations for interventions for the identified barriers using the action, actor, target and time framework from the codes. RESULTS: Of the 266 abstracts reviewed, 52 full-text papers were examined, of which 12 papers were included. South Africa had most papers from a single country (n = 3) and the most reported study design was retrospective (n = 6). Delays in ART initiation beyond 12 weeks in infants 0-12 months were primarily associated with health facility and maternal factors. The most prominent barriers identified were inadequate resources for POC testing (including human resources, laboratory facilities and patient follow-up). Maternal-related factors, such as limited male involvement and maternal perceptions of treatment and care, were also influential. DISCUSSION: We identified structural barriers to ART initiation at the health system, social and cultural levels. Improvements in the timely allocation of resources for POC testing operations, coupled with interventions addressing social and behavioural barriers among both mothers and healthcare providers, hold a promise for enhancing timely ART initiation in infants. CONCLUSIONS: This paper identifies barriers and proposes strategies for timely ART initiation in infants.

Characterising HIV acquisition risk, treatment gaps and populations reached through venue-based outreach and clinical services in Blantyre, Malawi: findings from a district-wide CLOVE Study.

BACKGROUND: In 2017, Blantyre district had the highest adult HIV prevalence in Malawi (17.7%) and lowest viral suppression (60%). In response, the Ministry of Health expanded prevention and treatment services. We assessed whether outreach to social venues could identify individuals with increased HIV acquisition risk or with unsuppressed HIV not currently reached by clinic-based services. METHODS: We conducted a cross-sectional bio-behavioral survey in Blantyre, Malawi, from January to March 2022. We visited social venues where people meet new sexual partners and government clinics providing HIV testing or STI screening. Participants aged > 15 years were interviewed, and tested for HIV infection if not on ART. HIV recency tests were performed on those testing positive, and dried blood spots (DBS) was collected to quantify viral load and also to identify acute infection in those with HIV- results. RESULTS: HIV prevalence (18.5% vs 8.3%) and unsuppressed HIV infection (3.9% vs 1.7%) were higher among venue-recruited (n=1802) compared with clinic-recruited participants(n=2313). Among PLHIV at both clinics (n=199) and venues (n=289), 79% were virally suppressed. Few had acute(n=1) or recent infection(n=8). Among women, HIV prevalence was four times higher (38.9% venue vs 8.9% clinic). At clinics, PLHIV reporting visiting venues were less likely to be suppressed (54.6 vs 82.6%). More men at venues than at clinics reported paying for sex (49% vs 30%) or having multiple sex partners in the past 4 weeks (32% vs 16%). CONCLUSIONS: Enhanced venue-based prevention and testing for men and women could reduce treatment lapses, HIV treatment outcomes and reduce onward transmission.

Acceptability and feasibility of using a blended quality improvement strategy among health workers to monitor women engagement in Option B+ program in Lilongwe Malawi.

Option B + provides lifelong ART to pregnant and breastfeeding women with HIV to reduce mother-to-child transmission of HIV (eMTCT) and improve maternal health. The effectiveness of Option B + relies on continuous engagement, but suboptimal monitoring of HIV care hinders our measurements of engagement. Process mapping and quality improvement (PROMAQI) is a quality improvement strategy for healthcare workers (HCWs) to optimize complex processes such as monitoring HIV care. We assessed the acceptability and feasibility of the PROMAQI among HCWs and identified barriers and facilitators for PROMAQI implementation. A cross-sectional study using a mixed method approach was conducted from August 2021 to March 2022 across five urban health facilities participating in PROMAQI implementation n the Lilongwe district, Malawi. We assessed PROMAQI acceptability and feasibility at the end of the study. A 5-point Likert (1 = worst to 5 = best) scale tool was administered to 110 HCWs (n = 15-33 per facility) involved in PROMAQI implementationThese data were analysed using descriptive statistics Among the 110 HCWs, twenty-two (QI team (n = 11) and QI implementers (n = 11)) were purposively selected for in-depth interviews. Thematic analysis was conducted using deducted and inductive approaches. The theoretical framework for acceptability (TFA) was used to identify reasons for acceptability. The Consolidated Framework for Implementation Research (CFIR) was used to characterize the barriers and facilitators of PROMAQI implementation. HCWs recruited had a median age of 37 (32-43) years, 82.0% of whom were female. Most (42%) had completed secondary education, and 84% were nurses and community health workers. The median (IQR) acceptability and feasibility scores for the PROMAQI were 5 (IQR 4-5) and 4 (IQR 4-5), respectively. Reasons for high PROMAQI acceptability included addressing a relevant gap and improving performance. Perceived implementation barriers included poor work attitudes, time constraints, resource limitations, knowledge gaps, and workbook difficulties. The facilitators included communication, mentorship, training, and financial incentives. PROMAQI is a highly acceptable and feasible tool for monitoring engagement of women in Option B + . Addressing these barriers may optimize the implementation of PROMAQI. Scaling up PROMAQI may enhance retention in the Option B + program and facilitate eMTCT.

Impact of Low-Frequency Human Immunodeficiency Virus Type 1 Drug Resistance Mutations on Antiretroviral Therapy Outcomes.

BACKGROUND: The association between low-frequency human immunodeficiency virus type 1 (HIV-1) drug resistance mutations (DRMs) and treatment failure (TF) is controversial. We explore this association using next-generation sequencing (NGS) methods that accurately sample low-frequency DRMs. METHODS: We enrolled women with HIV-1 in Malawi who were either antiretroviral therapy (ART) naive (cohort A), had ART failure (cohort B), or had discontinued ART (cohort C). At entry, cohorts A and C began a nonnucleoside reverse transcriptase inhibitor-based regimen and cohort B started a protease inhibitor-based regimen. We used Primer ID MiSeq to identify regimen-relevant DRMs in entry and TF plasma samples, and a Cox proportional hazards model to calculate hazard ratios (HRs) for entry DRMs. Low-frequency DRMs were defined as ≤20%. RESULTS: We sequenced 360 participants. Cohort B and C participants were more likely to have TF than cohort A participants. The presence of K103N at entry significantly increased TF risk among A and C participants at both high and low frequency, with HRs of 3.12 (95% confidence interval [CI], 1.58-6.18) and 2.38 (95% CI, 1.00-5.67), respectively. At TF, 45% of participants showed selection of DRMs while in the remaining participants there was an apparent lack of selective pressure from ART. CONCLUSIONS: Using accurate NGS for DRM detection may benefit an additional 10% of patients by identifying low-frequency K103N mutations.

Safety and Immunogenicity of a DNA Vaccine With Subtype C gp120 Protein Adjuvanted With MF59 or AS01B: A Phase 1/2a HIV-1 Vaccine Trial.

BACKGROUND: An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.C glycoprotein 120) subtype C envelope protein combinations, adjuvanted with MF59 or AS01B. METHODS: HIV Vaccine Trials Network (HVTN)108 was a randomized, placebo-controlled, double-blind, phase 1/2a trial conducted in the United States and South Africa. HIV-negative adults were randomly assigned to 1 of 7 intervention arms or placebo to assess DNA prime with DNA/protein/adjuvant boosts, DNA/protein/adjuvant co-administration, and low-dose protein/adjuvant regimens. HVTN111 trial participants who received an identical regimen were also included. Outcomes included safety and immunogenicity 2 weeks and 6 months after final vaccination. RESULTS: From June 2016 to July 2018, 400 participants were enrolled (N = 334 HVTN108, N = 66 HVTN111); 370 received vaccine and 30 received placebo. There were 48 grade 3 and 3 grade 4 reactogenicity events among 39/400 (9.8%) participants, and 32 mild/moderate-related adverse events in 23/400 (5.8%) participants. All intervention groups demonstrated high IgG response rates (>89%) and high magnitudes to HIV-1 Env gp120 and gp140 proteins; response rates for AS01B-adjuvanted groups approached 100%. V1V2 IgG magnitude, Fc-mediated functions, IgG3 Env response rates, and CD4+ T-cell response magnitudes and rates were higher in the AS01B-adjuvanted groups. The AS01B-adjuvanted low-dose protein elicited greater IgG responses than the higher protein dose. CONCLUSIONS: The vaccine regimens were generally well tolerated. Co-administration of DNA with AS01B-adjuvanted bivalent Env gp120 elicited the strongest humoral responses; AS01B-adjuvanted regimens elicited stronger CD4+ T-cell responses, justifying further evaluation.ClinicalTrials.gov registration: NCT02915016, registered 26 September 2016.

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.

Correction: The cross-sectional association of stressful life events with depression severity among patients with hypertension and diabetes in Malawi.

[This corrects the article DOI: 10.1371/journal.pone.0279619.].

Effectiveness of double-dose dolutegravir in people receiving rifampin-based tuberculosis treatment: an observational, cohort study of people with HIV from six countries.

BACKGROUND: Tenofovir-lamivudine-dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen. An additional 50 mg dose of dolutegravir (TLD + 50) is required with rifampin-containing tuberculosis (TB) co-treatment. There are limited data on the effectiveness of TLD + 50 in individuals with TB/HIV. METHODS: Prospective, observational cohort study at 12 sites in Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe. Participants starting TLD and rifampin-containing TB treatment were eligible. Primary outcome was HIV-1 RNA ≤1000 copies/mL at end of TB treatment. FINDINGS: We enrolled 91 participants with TB/HIV: 75 (82%) ART-naïve participants starting TLD after a median 15 days on TB treatment, 10 (11%) ART-naïve participants starting TLD and TB treatment, 5 (5%) starting TB treatment after a median 3.3 years on TLD, and 1 (1%) starting TB treatment and TLD after changing from efavirenz/lamivudine/tenofovir. Median age was 37 years, 35% female, median CD4 count 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment. Among 89 surviving participants, 80 were followed to TB treatment completion, including 7 who had no HIV-1 RNA result due to missed visits. Primary virologic outcome was assessed in 73 participants, of whom 69 (95%, 95% CI 89-100%) had HIV-1 RNA ≤1000 copies/mL. No dolutegravir resistance mutations were detected among four participants with HIV-1 RNA >1000 copies/mL. INTERPRETATION: In routine programmatic settings, concurrent rifampin-containing TB treatment and TLD + 50 was feasible, well-tolerated, and achieved high rates of viral suppression in a cohort of predominantly ART-naïve people with TB/HIV.

Acceptability, feasibility and appropriateness of intensified health education, SMS/phone tracing and transport reimbursement for uptake of voluntary medical male circumcision in a sexually transmitted infections clinic in Malawi: a mixed methods study.

Introduction: Uptake of voluntary medical male circumcision (VMMC) remains a challenge in many settings. Innovative implementation strategies are required to scale-up VMMC uptake. Methodology: RITe was a multi-faceted intervention comprising transport reimbursement (R), intensified health education (IHE) and SMS/Telephone tracing (Te), which increased the uptake of VMMC among uncircumcised men with sexually transmitted infections (STIs) in Malawi. Using a concurrent exploratory mixed-method approach, we assessed the intervention's acceptability, feasibility and appropriateness among men with STIs and healthcare workers (HCWs) at Bwaila District Hospital. Participants completed Likert scale surveys and participated in-depth interviews (IDIs) and focus group discussions (FGDs). We calculated percentages of responses to survey items and summarized common themes using thematic analysis. Median scores and interquartile ranges (IQR) were calculated for acceptability, feasibility and appropriateness of each strategy at baseline and end-line and compared using the Wilcoxon signed rank test. Results: A total of 300 surveys, 17 IDIs and 4 FGDs were conducted with men and HCWs between baseline and end-line. The mean age for men in the survey was 29 years (SD ±8) and most were married/cohabiting (59.3%). Mean age for HCWs was 38.5 years (SD ±7), and most were female (59.1%). For acceptability, participants agreed that RITe was welcome, approvable, and likable. Despite participants agreeing that RITe was a good idea, culture and religion influenced appropriateness, particularly at baseline, which improved at end-line for Te and R. For feasibility, HCWs agreed that RITe was easy to implement, but expressed concerns that R (end-line median = 4, IQR: 2, 4) and Te (end-line median = 4, IQR: 4, 4), were resource intensive, hence unsustainable. Interviews corroborated the survey results. Participants reported that IHE provided important information, Te was a good reminder and R was attractive, but they reported barriers to R and Te such as electricity, limited access to phones and distrust in the government. Conclusions: The RITe intervention was acceptable, feasible and appropriate. However, culture/religion and structural barriers affected perceptions of appropriateness and feasibility, respectively. Continued awareness raising on VMMC and addressing setting-specific structural factors are required to overcome barriers that impede demand-creation interventions for VMMC. Study registration: ClinicalTrials.gov identifier: NCT04677374. Registered on December 18, 2020.

The longitudinal association of stressful life events with depression remission among SHARP trial participants with depression and hypertension or diabetes in Malawi.

Depressive disorders are leading contributors to morbidity in low- and middle-income countries and are particularly prevalent among people with non-communicable diseases (NCD). Stressful life events (SLEs) are risk factors for, and can help identify those at risk of, severe depressive illness requiring more aggressive treatment. Yet, research on the impact of SLEs on the trajectory of depressive symptoms among NCD patients indicated for depression treatment is lacking, especially in low resource settings. This study aims to estimate the longitudinal association of SLEs at baseline with depression remission achievement at three, six, and 12 months among adults with either hypertension or diabetes and comorbid depression identified as being eligible for depression treatment. Participants were recruited from 10 NCD clinics in Malawi from May 2019-December 2021. SLEs were measured by the Life Events Survey and depression remission was defined as achieving a Patient Health Questionaire-9 (PHQ-9) score <5 at follow-up. The study population (n = 737) consisted predominately of females aged 50 or higher with primary education and current employment. At baseline, participants reported a mean of 3.5 SLEs in the prior three months with 90% reporting ≥1 SLE. After adjustment, each additional SLE was associated with a lower probability of achieving depression remission at three months (cumulative incidence ratio (CIR) 0.94; 95% confidence interval: 0.90, 0.98, p = 0.002), six months (0.95; 0.92, 0.98, p = 0.002) and 12 months (0.96; 0.94, 0.99, p = 0.011). Re-expressed per 3-unit change, the probability of achieving depression remission at three, six, and 12 months was 0.82, 0.86, and 0.89 times lower per 3 SLEs (the median number of SLEs). Among NCD patients identified as eligible for depression treatment, recent SLEs at baseline were associated with lower probability of achieving depression remission at three, six, and 12 months. Findings suggest that interventions addressing SLEs during integrated NCD and depression care interventions (e.g., teaching and practicing SLE coping strategies) may improve success of depression treatment among adult patient populations in low-resource settings and may help identify those at risk of severe and treatment resistant depression.

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.

Two implementation strategies to support the integration of depression screening and treatment into hypertension and diabetes care in Malawi (SHARP): parallel, cluster-randomised, controlled, implementation trial.

BACKGROUND: Although evidence-based treatments for depression in low-resource settings are established, implementation strategies to scale up these treatments remain poorly defined. We aimed to compare two implementation strategies in achieving high-quality integration of depression care into chronic medical care and improving mental health outcomes in patients with hypertension and diabetes. METHODS: We conducted a parallel, cluster-randomised, controlled, implementation trial in ten health facilities across Malawi. Facilities were randomised (1:1) by covariate-constrained randomisation to either an internal champion alone (ie, basic strategy group) or an internal champion plus external supervision with audit and feedback (ie, enhanced strategy group). Champions integrated a three-element, evidence-based intervention into clinical care: universal depression screening; peer-delivered psychosocial counselling; and algorithm-guided, non-specialist antidepressant management. External supervision involved structured facility visits by Ministry officials and clinical experts to assess quality of care and provide supportive feedback approximately every 4 months. Eligible participants were adults (aged 18-65 years) seeking hypertension and diabetes care with signs of depression (Patient Health Questionnaire-9 score ≥5). Primary implementation outcomes were depression screening fidelity, treatment initiation fidelity, and follow-up treatment fidelity over the first 3 months of treatment, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03711786, and is complete. FINDINGS: Five (50%) facilities were randomised to the basic strategy and five (50%) to the enhanced strategy. Between Oct 1, 2019, and Nov 30, 2021, in the basic group, 587 patients were assessed for eligibility, of whom 301 were enrolled; in the enhanced group, 539 patients were assessed, of whom 288 were enrolled. All clinics integrated the evidence-based intervention and were included in the analyses. Of 60 774 screening-eligible visits, screening fidelity was moderate (58% in the enhanced group vs 53% in the basic group; probability difference 5% [95% CI -38% to 47%]; p=0·84) and treatment initiation fidelity was high (99% vs 98%; 0% [-3% to 3%]; p=0·89) in both groups. However, treatment follow-up fidelity was substantially higher in the enhanced group than in the basic group (82% vs 20%; 62% [36% to 89%]; p=0·0020). Depression remission was higher in the enhanced group than in the basic group (55% vs 36%; 19% [3% to 34%]; p=0·045). Serious adverse events were nine deaths (five in the basic group and four in the enhanced group) and 26 hospitalisations (20 in the basic group and six in the enhanced group); none were treatment-related. INTERPRETATION: The enhanced implementation strategy led to an increase in fidelity in providers' follow-up treatment actions and in rates of depression remission, consistent with the literature that follow-up decisions are crucial to improving depression outcomes in integrated care models. These findings suggest that external supervision combined with an internal champion could offer an important advance in integrating depression treatment into general medical care in low-resource settings. FUNDING: The National Institute of Mental Health.

Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Discontinuation of tenofovir disoproxil fumarate from initial ART regimens because of renal adverse events: An analysis of data from four multi-country clinical trials.

Tenofovir disoproxil fumarate (TDF), a potent and commonly used antiretroviral drug, is associated with renal tubular dysfunction and renal adverse events. We evaluated the frequency of, time to, and baseline risk factors for discontinuing TDF from initial antiretroviral therapy (ART) regimens because of renal adverse events from presumed tenofovir renal toxicity. We conducted an observational cohort study as a secondary analysis of data from four clinical trials conducted mainly in low- and middle-income countries. We included ART naïve participants living with HIV who started TDF-containing ART regimens in the trials. Participants had to have estimated creatinine clearance (eCrCl) equal to or greater than 60ml/min before starting ART. The primary outcome was the first instance of discontinuing TDF because of renal adverse events attributed to tenofovir renal toxicity during the first 48 weeks after starting ART. We evaluated the cumulative incidence of discontinuing TDF and associated risk factors using Fine and Gray competing risk regression models with a backward elimination variable selection strategy. There were 2802 ART-naïve participants who started TDF-containing ART from the four clinical trials were included in the analysis. Fifty-eight percent were female, the median age was 34 years, and 87% had CD4 cell counts less than 200 cells/µl. Sixty-four participants (2.4%, 95% CI 1.7%-2.8%) discontinued TDF due to renal adverse events. Among the 64 participants, the median time to discontinue TDF was 9.4 weeks (IQR: 3.4-20.7 weeks). From multivariable Fine and Gray regression models, risk factors for discontinuing TDF were older age, CD4 cell count <200 cells/µl, presence and severity of anemia, and eCrCl <90 ml/min. The risk of discontinuing TDF because of renal adverse events was low in participants initiating TDF-containing ART with advanced HIV and normal renal function, attesting to the tolerability of TDF in ART in low- and middle-income countries.

Improving integrated depression and non-communicable disease care in Malawi through engaged leadership and supportive implementation climate.

BACKGROUND: Low- and middle-income countries often lack access to mental health services, leading to calls for integration within other primary care systems. In sub-Saharan Africa, integration of depression treatment in non-communicable disease (NCD) settings is feasible, acceptable, and effective. However, leadership and implementation climate challenges often hinder effective integration and quality of services. The aim of this study was to identify discrete leadership strategies that facilitate overcoming barriers to the integration of depression care in NCD clinics in Malawi and to understand how clinic leadership shapes the implementation climate. METHODS: We conducted 39 in-depth interviews with the District Medical Officer, the NCD coordinator, one NCD provider, and the research assistant from each of the ten Malawian NCD clinics (note one District Medical Officer served two clinics). Based on semi-structured interview guides, participants were asked their perspectives on the impact of leadership and implementation climate on overcoming barriers to integrating depression care into existing NCD services. Thematic analysis used both inductive and deductive approaches to identify emerging themes and compare among participant type. RESULTS: The results revealed how engaged leadership can fuel a positive implementation climate where clinics had heightened capacity to overcome implementation barriers. Effective leaders were approachable and engaged in daily operations of the clinic and problem-solving. They held direct involvement with and mentorship during the intervention, providing assistance in patient screening and consultation with treatment plans. Different levels of leadership utilized their respective standings and power dynamics to influence provider attitudes and perceptions surrounding the intervention. Leaders acted by informing providers about the intervention source and educating them on the importance of mental healthcare, as it was often undervalued. Lastly, they prioritized teamwork and collective ownership for the intervention, increasing provider responsibility. CONCLUSION: Training that prioritizes leadership visibility and open communication will facilitate ongoing Malawi Ministry of Health efforts to scale up evidence-based depression treatment within NCD clinics. This proves useful where extensive and external monitoring may be limited. Ultimately, these results can inform successful strategies to close implementation gaps to achieve integration of mental health services in low-resource settings through improved leadership and implementation climate. TRIAL REGISTRATION: These findings are reported from ClinicalTrials.gov, NCT03711786. Registered on 18/10/2018. https://clinicaltrials.gov/ct2/show/NCT03711786 .

Virological Findings and Treatment Outcomes of Cases That Developed Dolutegravir Resistance in Malawi's National HIV Treatment Program.

Millions of Africans are on dolutegravir-based antiretroviral therapy (ART), but few detailed descriptions of dolutegravir resistance and its clinical management exist. We reviewed HIV drug resistance (HIVDR) testing application forms submitted between June 2019 and October 2022, data from the national HIVDR database, and genotypic test results. We obtained standardized ART outcomes and virological results of cases with dolutegravir resistance, and explored associations with dolutegravir resistance among individuals with successful integrase sequencing. All cases were on two nucleoside reverse transcriptase inhibitors (NRTIs)/dolutegravir, and had confirmed virological failure, generally with prolonged viremia. Among 89 samples with successful integrase sequencing, 24 showed dolutegravir resistance. Dolutegravir resistance-associated mutations included R263K (16/24), E138K (7/24), and G118R (6/24). In multivariable logistic regression analysis, older age and the presence of high-level NRTI resistance were significantly associated with dolutegravir resistance. After treatment modification recommendations, four individuals (17%) with dolutegravir resistance died, one self-discontinued ART, one defaulted, and one transferred out. Of the 17 remaining individuals, 12 had follow-up VL results, and 11 (92%) were <1000 copies/mL. Twenty-four cases with dolutegravir resistance among 89 individuals with confirmed virological failure suggests a considerable prevalence in the Malawi HIV program. Successful management of dolutegravir resistance was possible, but early mortality was high. More research on the management of treatment-experienced individuals with dolutegravir resistance is needed.

Training in eight low-and middle-income countries: lessons learned from a pilot study using the WHO-TDR dissemination and implementation massive open online course.

Introduction: Non-communicable diseases (NCDs) are a leading cause of morbidity and mortality in low-and middle- income countries (LMICs). Despite this, a lack of funding, training and mentorship for NCD investigators in LMICs exists. In an effort to gain knowledge and skills to address these gaps, participants from the Global Research on Implementation and Translation Science (GRIT), a consortium of studies in eight LMICs and their networks, attended the dissemination and implementation (D&I) massive open online course (MOOC) developed by the Special Programme for Research and Training in Tropical Diseases at the World Health Organization to strengthen D&I capacity building. Here, we report on the pilot of this MOOC, which was implemented during the SARS COVID-19 pandemic from April- November 2020. Methods: Participants completed pre-and post-training questionnaires to assess self-reported D&I competencies, general research skills, and research mentor access and quality. D&I competencies were measured by use of a scale developed for a US-based training program, with change in competency scores assessed by paired t test. We used univariate statistics to analyze the data for all other outcomes. Results: Of the 247 participants enrolled, 32 (13%) completed all course requirements, 21 (9%) completed the pre-and post-surveys and are included in the analysis. D&I competency scores suggest improvement for those who had complete pre- and post-assessments. Trainee's average score on the full competency scale improved 1.45 points (0-5 scale) from pre- to post-test; all four subscales also showed evidence of improvements. There were small but not significant increases in competencies for grant writing, proposal/ manuscript writing and presentations from pre- to post-test assessment. 40% of trainees reported access to a research mentor and 12% reported access to a D&I specific mentor. Participants reported barriers (e.g., unstable internet access and challenges due to COVID-19) and facilitators (e.g., topical interests, collaboration with colleagues) to completing the MOOC. Conclusions: Although COVID-19 affected program usage and completion, the MOOC was feasible. We also had signals of effectiveness, meaning among LMIC participants completing the course, there was improvement in self-report D&I competency scores. Recommendations for future D&I trainings in LMICs include (1) adding more topic specific modules (i.e., NCD research, general research skills) for scalability; (2) fostering more collaboration with participants across LMICs; and (3) establishing partnerships with D&I mentors for course participants.