Assessing the effect of health system resources on HIV and tuberculosis programmes in Malawi: a modelling study.

BACKGROUND: Malawi is progressing towards UNAIDS and WHO End TB Strategy targets to eliminate HIV/AIDS and tuberculosis. We aimed to assess the prospective effect of achieving these goals on the health and health system of the country and the influence of consumable constraints. METHODS: In this modelling study, we used the Thanzi la Onse (Health for All) model, which is an individual-based multi-disease simulation model that simulates HIV and tuberculosis transmission, alongside other diseases (eg, malaria, non-communicable diseases, and maternal diseases), and gates access to essential medicines according to empirical estimates of availability. The model integrates dynamic disease modelling with health system engagement behaviour, health system use, and capabilities (ie, personnel and consumables). We used 2018 data on the availability of HIV and tuberculosis consumables (for testing, treatment, and prevention) across all facility levels of the country to model three scenarios of HIV and tuberculosis programme scale-up from Jan 1, 2023, to Dec 31, 2033: a baseline scenario, when coverage remains static using existing consumable constraints; a constrained scenario, in which prioritised interventions are scaled up with fixed consumable constraints; and an unconstrained scenario, in which prioritised interventions are scaled up with maximum availability of all consumables related to HIV and tuberculosis care. FINDINGS: With uninterrupted medical supplies, in Malawi, we projected HIV and tuberculosis incidence to decrease to 26 (95% uncertainty interval [UI] 19-35) cases and 55 (23-74) cases per 100 000 person-years by 2033 (from 152 [98-195] cases and 123 [99-160] cases per 100 000 person-years in 2023), respectively, with programme scale-up, averting a total of 12·21 million (95% UI 11·39-14·16) disability-adjusted life-years. However, the effect was compromised by restricted access to key medicines, resulting in approximately 58 700 additional deaths (33 400 [95% UI 22 000-41 000] due to AIDS and 25 300 [19 300-30 400] due to tuberculosis) compared with the unconstrained scenario. Between 2023 and 2033, eliminating HIV treatment stockouts could avert an estimated 12 100 deaths compared with the baseline scenario, and improved access to tuberculosis prevention medications could prevent 5600 deaths in addition to those achieved through programme scale-up alone. With programme scale-up under the constrained scenario, consumable stockouts are projected to require an estimated 14·3 million extra patient-facing hours between 2023 and 2033, mostly from clinical or nursing staff, compared with the unconstrained scenario. In 2033, with enhanced screening, 188 000 (81%) of 232 900 individuals projected to present with active tuberculosis could start tuberculosis treatment within 2 weeks of initial presentation if all required consumables were available, but only 8600 (57%) of 15 100 presenting under the baseline scenario. INTERPRETATION: Ignoring frailties in the health-care system, in particular the potential non-availability of consumables, in projections of HIV and tuberculosis programme scale-up might risk overestimating potential health impacts and underestimating required health system resources. Simultaneous health system strengthening alongside programme scale-up is crucial, and should yield greater benefits to population health while mitigating the strain on a heavily constrained health-care system. FUNDING: Wellcome and UK Research and Innovation as part of the Global Challenges Research Fund.

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.

Burden and Trends of Symptomatic Sexually Transmitted Infections in Malawi From 2000 to 2021: Comparative Analysis of Survey and Case Report Data.

BACKGROUND: In settings without etiologic testing for sexually transmitted infections (STIs), programs rely on STI symptom data to inform priorities. To evaluate whether self-reported STI symptoms in household surveys consistently represent the STI burden, we compared symptomatic infection rates between survey self-reporting and health facility case reporting in Malawi. METHODS: We analyzed self-reported symptoms and treatment seeking in the past year among sexually active adults from 4 Malawi Demographic and Health Surveys between 2000 and 2015. Bayesian mixed-effects models were used to estimate temporal trends, spatial variation, and sociodemographic determinants. Survey reporting was compared with health facility syndromic diagnoses between 2014 and 2021. RESULTS: In surveys, 11.0% (95% confidence interval, 10.7%-11.4%) of adults reported STI or STI-related symptoms in the last year, of whom 54.2% (52.8%-55.7%) sought treatment. In facilities, the mean annual symptomatic case diagnosis rate was 3.3%. Survey-reported treatment in the last year was 3.8% (95% credible interval, 2.3%-6.1%) for genital ulcer, 3.8% (2.0%-6.7%) for vaginal discharge, and 2.6% (1.2%-4.7%) for urethral discharge. Mean annual diagnosis rates at facilities were 0.5% for genital ulcer, 2.2% for vaginal discharge, and 2.0% for urethral discharge. Both data sources indicated a higher burden of symptoms among women, individuals older than 25 years, and those in Southern Malawi. CONCLUSIONS: Survey and facility case reports indicated similar spatial and demographic patterns of STI symptom burden and care seeking, but implied large differences in the magnitude and relative burden of symptoms, particularly genital ulcer, which could affect program priorities. Targeted etiologic surveillance would improve interpretation of these data to enable more comprehensive STI surveillance.

Age-disparate and intergenerational sex partnerships and HIV: the role of gender norms among adolescent girls and young women in Malawi.

BACKGROUND: Age-mixing (age-disparate [5-9 years difference] and intergenerational [≥ 10 years difference]) partnerships are hypothesized drivers of HIV in adolescent girls and young women (AGYW; 15-24 years). These partnerships are often associated with increased gender inequities which undermine women's agency and assertiveness. We assessed whether age-mixing partnerships were associated with HIV in Malawi and if endorsement of inequitable gender norms modifies this relationship. METHODS: We analyzed data from the Malawi Population-based HIV Impact Assessment, a nationally representative household survey conducted in 2015-2016. Participants underwent HIV testing and completed questionnaires related to actively endorsed gender norms and sexual risk behavior. We used multivariate logistic regression and multiplicative interaction to assess associations among AGYW who reported the age of their primary sex partner from the last year. RESULTS: The analysis included 1,958 AGYW (mean age = 19.9 years, SD = 0.1), 459 (23.4%) and 131 (6.7%) of whom reported age-disparate and intergenerational partnerships, respectively. AGYW in age-mixing partnerships accounted for 13% of all AGYW and were older, more likely to reside in urban areas, to be married or cohabitating with a partner, and to have engaged in riskier sexual behavior compared with AGYW in age-concordant partnerships (p < 0.05). HIV prevalence among AGYW in age-disparate and intergenerational partnerships was 6.1% and 11.9%, respectively, compared with 3.2% in age-concordant partnerships (p < 0.001). After adjusting for residence, age, education, employment, wealth quintile, and ever been married or cohabitated as married, AGYW in age-disparate and intergenerational partnerships had 1.9 (95% CI: 1.1-3.5) and 3.4 (95% CI: 1.6-7.2) greater odds of HIV, respectively, compared with AGYW in age-concordant partnerships. Among the 614 (31% of the study group) who endorsed inequitable gender norms, AGYW in age-disparate and intergenerational partnerships had 3.5 (95% CI: 1.1-11.8) and 6.4 (95% CI: 1.5-27.8) greater odds of HIV, respectively, compared with AGYW in age-concordant partnerships. CONCLUSIONS: In this Malawi general population survey, age-mixing partnerships were associated with increased odds of HIV among AGYW. These findings highlight inequitable gender norms as a potential focus for HIV prevention and could inform interventions targeting structural, cultural, and social constraints of this key group.

Brief Report: Self-Reported HIV-Positive Status but Subsequent HIV-Negative Test Results in Population-Based HIV Impact Assessment Survey Participants-11 Sub-Saharan African Countries, 2015-2018.

BACKGROUND: HIV testing is a critical step to accessing antiretroviral therapy (ART) because early diagnosis can facilitate earlier initiation of ART. This study presents aggregated data of individuals who self-reported being HIV-positive but subsequently tested HIV-negative during nationally representative Population-Based HIV Impact Assessment surveys conducted in 11 countries from 2015 to 2018. METHOD: Survey participants aged 15 years or older were interviewed by trained personnel using a standard questionnaire to determine HIV testing history and self-reported HIV status. Home-based HIV testing and counseling using rapid diagnostic tests with return of results were performed by survey staff according to the respective national HIV testing services algorithms on venous blood samples. Laboratory-based confirmatory HIV testing for all participants identified as HIV-positives and self-reported positives, irrespective of HIV testing results, was conducted and included Geenius HIV-1/2 and DNA polymerase chain reaction if Geenius was negative or indeterminate. RESULTS: Of the 16,630 participants who self-reported as HIV-positive, 16,432 (98.6%) were confirmed as HIV-positive and 198 (1.4%) were HIV-negative by subsequent laboratory-based testing. Participants who self-reported as HIV-positive but tested HIV-negative were significantly younger than 30 years, less likely to have received ART, and less likely to have received a CD4 test compared with participants who self-reported as HIV-positive with laboratory-confirmed infection. CONCLUSIONS: A small proportion of self-reported HIV-positive individuals could not be confirmed as positive, which could be due to initial misdiagnosis, deliberate wrong self-report, or misunderstanding of the questionnaire. As universal ART access is expanding, it is increasingly important to ensure quality of HIV testing and confirmation of HIV diagnosis before ART initiation.

Awareness of and willingness to use oral pre-exposure prophylaxis (PrEP) for HIV prevention among sexually active adults in Malawi: results from the 2020 Malawi population-based HIV impact assessment.

BACKGROUND: The World Health Organization recommends Pre-Exposure Prophylaxis (PrEP) for all populations at substantial risk of HIV infection. Understanding PrEP awareness and interest is crucial for designing PrEP programs; however, data are lacking in sub-Saharan Africa. In Malawi, oral PrEP was introduced in 2018. We analyzed data from the 2020 Malawi Population-based HIV Impact Assessment (MPHIA) to assess PrEP awareness and factors associated with PrEP interest in Malawi. METHODS: MPHIA 2020 was a national cross-sectional household-based survey targeting adults aged 15 + years. Oral PrEP was first described to the survey participants as taking a daily pill to reduce the chance of getting HIV. To assess awareness, participants were asked if they had ever heard of PrEP and to assess interest, were asked if they would take PrEP to prevent HIV, regardless of previous PrEP knowledge. Only sexually active HIV-negative participants are included in this analysis. We used multivariable logistic regression to assess sociodemographic factors and behaviors associated with PrEP interest. All results were weighted. RESULTS: We included 13,995 HIV-negative sexually active participants; median age was 29 years old. Overall, 15.0%, 95% confidence interval (CI): 14.2-15.9% of participants were aware of PrEP. More males (adjusted odds ratio (aOR): 1.3, 95% CI: 1.2-1.5), those with secondary (aOR: 1.5, 95% CI: 1.2-2.0) or post-secondary (aOR: 3.4, 95% CI: 2.4-4.9) education and the wealthiest (aOR: 1.6, 95% CI: 1.2-2.0) were aware of PrEP than female, those without education and least wealthy participants, respectively. Overall, 73.0% (95% CI: 71.8-74.1%) of participants were willing to use PrEP. Being male (aOR: 1.2; 95% CI: 1.1-1.3) and having more than one sexual partner (aOR: 1.7 95% CI: 1.4-1.9), were associated higher willingness to use PrEP. CONCLUSIONS: In this survey, prior PrEP knowledge and use were low while PrEP interest was high. High risk sexual behavior was associated with willingness to use PrEP. Strategies to increase PrEP awareness and universal access, may reduce HIV transmission.

Trends in HIV prevalence, incidence, and progress towards the UNAIDS 95-95-95 targets in Malawi among individuals aged 15-64 years: population-based HIV impact assessments, 2015-16 and 2020-21.

BACKGROUND: In 2014, UNAIDS set the goal of ending the AIDS epidemic by 2030 through the achievement of testing and treatment cascade targets. To evaluate progress achieved and highlight persisting gaps in HIV epidemic control in Malawi, we aimed to compare key indicators (prevalence, incidence, viral load suppression, and UNAIDS 95-95-95 targets) from the 2015-16 and 2020-21 Malawi Population-based HIV Impact Assessment (PHIA) survey results. METHODS: The Malawi PHIAs were nationally representative, cross-sectional surveys with a two-stage cluster sampling design. The first survey was conducted between Nov 27, 2015, and Aug 26, 2016; the second survey was conducted between Jan 15, 2020, and April 26, 2021. Our analysis included survey participants aged 15-64 years. Participants were interviewed and a 14 mL blood sample was collected and tested for HIV infection using the national rapid testing algorithm. For each survey, we estimated key HIV epidemic indicators and achievement of 95-95-95 targets. The risk ratio (RR) of the indicators between surveys were computed and considered significant at a confidence level of 0·05. All results were weighted, and self-reported awareness and treatment status were adjusted to account for detection of antiretrovirals. FINDINGS: Our analysis included 17 187 participants aged 15-64 years in 2015-16 and 21 208 in 2020-21 who participated in the surveys and blood draw. In the 2020-21 survey, 88·4% (95% CI 86·7-90·0) of people living with HIV were aware of their HIV-positive status; of those aware, 97·8% (97·1-98·5) were on antiretroviral therapy; and of those on treatment, 96·9% (95·9-97·7) were virally suppressed. Between surveys, the national HIV prevalence decreased significantly from 10·6% (10·0-11·2) to 8·9% (8·4-9·5) with RR 0·85 (95% CI 0·78-0·92; p<0·0001). The annual HIV incidence decreased from 0·37% (0·20-0·53) to 0·22% (0·11-0·34) with RR 0·61 (95% CI 0·31-1·20; p=0·15). The population viral load suppression increased from 68·3% (66·0-70·7) in 2015-16 to 87·0% (85·3-88·5) in 2020-21 (RR 1·27 [95% CI 1·22-1·32]; p<0·0001). INTERPRETATION: These results suggest that Malawi had already surpassed the UNAIDS viral load suppression target for 2030 (85·7%) by 2020-21. Through strategies and evidence-informed interventions implemented in the last half decade, especially scale-up of effective HIV treatment, Malawi has made tremendous progress, including decreasing HIV prevalence and incidence and achieving both the second and third 95 targets ahead of 2030. To address the first 95, efforts in HIV diagnosis should focus on males and younger age groups. There is a continued need for effective linkage to care, retention on antiretroviral therapy, and adherence support to maintain and build on progress. FUNDING: US President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention.

Combination HIV prevention during pregnancy and the post-partum period in Malawi and Zambia: a mathematical modelling analysis.

INTRODUCTION: Despite widespread success in reducing vertical HIV transmission, most antenatal care (ANC) programmes in eastern and southern Africa have not emphasized primary prevention of maternal HIV acquisition during pregnancy and lactation/breastfeeding. We hypothesized that combination HIV prevention interventions initiated alongside ANC could substantially reduce maternal HIV incidence. METHODS: We constructed a multi-state model describing male-to-female HIV transmission in steady heterosexual partnerships during pregnancy and lactation/breastfeeding, with initial conditions based on population distribution estimates for Malawi and Zambia in 2020. We modelled individual and joint increases in three HIV prevention strategies at or soon after ANC initiation: (1) HIV testing of male partners, resulting in HIV diagnosis and less condomless sex among those with previously undiagnosed HIV; (2) initiation (or re-initiation) of suppressive antiretroviral therapy (ART) for male partners with diagnosed but unsuppressed HIV; and (3) adherent pre-exposure prophylaxis (PrEP) for HIV-negative female ANC patients with HIV-diagnosed or unknown-status male partners. We estimated the percentage of within-couple, male-to-female HIV transmissions that could be averted during pregnancy and lactation/breastfeeding with these strategies, relative to base-case conditions in which 45% of undiagnosed male partners become newly HIV diagnosed via testing, 75% of male partners with diagnosed but unsuppressed HIV initiate/re-initiate ART and 0% of female ANC patients start PrEP. RESULTS: Increasing uptake of any single strategy by 20 percentage points above base-case levels averted 10%-11% of maternal HIV acquisitions during pregnancy and lactation/breastfeeding in the model. Joint uptake increases of 20 percentage points in two interventions averted an estimated 19%-23% of transmissions, and with a 20-percentage-point increase in uptake of all three interventions, 29% were averted. Strategies achieving 95% male testing, 90% male ART initiation/re-initiation and 40% female PrEP use reduced incident infections by 45%. CONCLUSIONS: Combination HIV prevention strategies provided alongside ANC and sustained through the post-partum period could substantially reduce maternal HIV incidence during pregnancy and lactation/breastfeeding in eastern and southern Africa.

The epidemiology of HIV population viral load in twelve sub-Saharan African countries.

BACKGROUND: We examined the epidemiology and transmission potential of HIV population viral load (VL) in 12 sub-Saharan African countries. METHODS: We analyzed data from Population-based HIV Impact Assessments (PHIAs), large national household-based surveys conducted between 2015 and 2019 in Cameroon, Cote d'Ivoire, Eswatini, Kenya, Lesotho, Malawi, Namibia, Rwanda, Tanzania, Uganda, Zambia, and Zimbabwe. Blood-based biomarkers included HIV serology, recency of HIV infection, and VL. We estimated the number of people living with HIV (PLHIV) with suppressed viral load (<1,000 HIV-1 RNA copies/mL) and with unsuppressed viral load (viremic), the prevalence of unsuppressed HIV (population viremia), sex-specific HIV transmission ratios (number female incident HIV-1 infections/number unsuppressed male PLHIV per 100 persons-years [PY] and vice versa) and examined correlations between a variety of VL metrics and incident HIV. Country sample sizes ranged from 10,016 (Eswatini) to 30,637 (Rwanda); estimates were weighted and restricted to participants 15 years and older. RESULTS: The proportion of female PLHIV with viral suppression was higher than that among males in all countries, however, the number of unsuppressed females outnumbered that of unsuppressed males in all countries due to higher overall female HIV prevalence, with ratios ranging from 1.08 to 2.10 (median: 1.43). The spatial distribution of HIV seroprevalence, viremia prevalence, and number of unsuppressed adults often differed substantially within the same countries. The 1% and 5% of PLHIV with the highest VL on average accounted for 34% and 66%, respectively, of countries' total VL. HIV transmission ratios varied widely across countries and were higher for male-to-female (range: 2.3-28.3/100 PY) than for female-to-male transmission (range: 1.5-10.6/100 PY). In all countries mean log10 VL among unsuppressed males was higher than that among females. Correlations between VL measures and incident HIV varied, were weaker for VL metrics among females compared to males and were strongest for the number of unsuppressed PLHIV per 100 HIV-negative adults (R2 = 0.92). CONCLUSIONS: Despite higher proportions of viral suppression, female unsuppressed PLHIV outnumbered males in all countries examined. Unsuppressed male PLHIV have consistently higher VL and a higher risk of transmitting HIV than females. Just 5% of PLHIV account for almost two-thirds of countries' total VL. Population-level VL metrics help monitor the epidemic and highlight key programmatic gaps in these African countries.

Mesenchymal Stem Cells from COPD Patients Are Capable of Restoring Elastase-Induced Emphysema in a Murine Experimental Model.

COPD is a chronic lung disease that affects millions of people, declining their lung function and impairing their life quality. Despite years of research and drug approvals, we are still not capable of halting progression or restoring normal lung function. Mesenchymal stem cells (MSC) are cells with extraordinary repair capacity, and MSC-based therapy brings future hope for COPD treatment, although the best source and route of administration are unclear. MSC from adipose tissue (AD-MSC) represents an option for autologous treatment; however, they could be less effective than donor MSC. We compared in vitro behavior of AD-MSC from COPD and non-COPD individuals by migration/proliferation assay, and tested their therapeutic potential in an elastase mouse model. In addition, we tested intravenous versus intratracheal routes, inoculating umbilical cord (UC) MSC and analyzed molecular changes by protein array. Although COPD AD-MSC have impaired migratory response to VEGF and cigarette smoke, they were as efficient as non-COPD in reducing elastase-induced lung emphysema. UC-MSC reduced lung emphysema regardless of the administration route and modified the inflammatory profile in elastase-treated mice. Our data demonstrate equal therapeutic potential of AD-MSC from COPD and non-COPD subjects in the pre-clinical model, thus supporting their autologous use in disease.

Subnational HIV incidence trends in Malawi: large, heterogeneous declines across space.

The rate of new HIV infections globally has decreased substantially from its peak in the late 1990s, but the epidemic persists and remains highest in many countries in eastern and southern Africa. Previous research hypothesised that, as the epidemic recedes, it will become increasingly concentrated among sub-populations and geographic areas where transmission is the highest and that are least effectively reached by treatment and prevention services. However, empirical data on subnational HIV incidence trends is sparse, and the local transmission rates in the context of effective treatment scale-up are unknown. In this work, we developed a novel Bayesian spatio-temporal epidemic model to estimate adult HIV prevalence, incidence and treatment coverage at the district level in Malawi from 2010 through the end of 2021. We found that HIV incidence decreased in every district of Malawi between 2010 and 2021 but the rate of decline varied by area. National-level treatment coverage more than tripled between 2010 and 2021 and more than doubled in every district. Large increases in treatment coverage were associated with declines in HIV transmission, with 12 districts having incidence-prevalence ratios of 0.03 or less (a previously suggested threshold for epidemic control). Across districts, incidence varied more than HIV prevalence and ART coverage, suggesting that the epidemic is becoming increasingly spatially concentrated. Our results highlight the success of the Malawi HIV treatment programme over the past decade, with large improvements in treatment coverage leading to commensurate declines in incidence. More broadly, we demonstrate the utility of spatially resolved HIV modelling in generalized epidemic settings. By estimating temporal changes in key epidemic indicators at a relatively fine spatial resolution, we were able to directly assess, for the first time, whether the ART scaleup in Malawi resulted in spatial gaps or hotspots. Regular use of this type of analysis will allow HIV program managers to monitor the equity of their treatment and prevention programmes and their subnational progress towards epidemic control.

Cost-effectiveness of voluntary medical male circumcision for HIV prevention across sub-Saharan Africa: results from five independent models.

BACKGROUND: Voluntary medical male circumcision (VMMC) has been a recommended HIV prevention strategy in sub-Saharan Africa since 2007, particularly in countries with high HIV prevalence. However, given the scale-up of antiretroviral therapy programmes, it is not clear whether VMMC still represents a cost-effective use of scarce HIV programme resources. METHODS: Using five existing well described HIV mathematical models, we compared continuation of VMMC for 5 years in men aged 15 years and older to no further VMMC in South Africa, Malawi, and Zimbabwe and across a range of setting scenarios in sub-Saharan Africa. Outputs were based on a 50-year time horizon, VMMC cost was assumed to be US$90, and a cost-effectiveness threshold of US$500 was used. FINDINGS: In South Africa and Malawi, the continuation of VMMC for 5 years resulted in cost savings and health benefits (infections and disability-adjusted life-years averted) according to all models. Of the two models modelling Zimbabwe, the continuation of VMMC for 5 years resulted in cost savings and health benefits by one model but was not as cost-effective according to the other model. Continuation of VMMC was cost-effective in 68% of setting scenarios across sub-Saharan Africa. VMMC was more likely to be cost-effective in modelled settings with higher HIV incidence; VMMC was cost-effective in 62% of settings with HIV incidence of less than 0·1 per 100 person-years in men aged 15-49 years, increasing to 95% with HIV incidence greater than 1·0 per 100 person-years. INTERPRETATION: VMMC remains a cost-effective, often cost-saving, prevention intervention in sub-Saharan Africa for at least the next 5 years. FUNDING: Bill & Melinda Gates Foundation for the HIV Modelling Consortium.

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.

Toward elimination of mother-to-child transmission of HIV in Malawi: Findings from the Malawi Population-based HIV Impact Assessment (2015-2016).

BACKGROUND: Malawi spearheaded the development and implementation of Option B+ for prevention of mother-to-child transmission of HIV (PMTCT), providing life-long ART for all HIV-positive pregnant and breastfeeding women. We used data from the 2015-2016 Malawi Population-based HIV Impact Assessment (MPHIA) to estimate progress toward 90-90-90 targets (90% of those with HIV know their HIV-positive status; of these, 90% are receiving ART; and of these, 90% have viral load suppression [VLS]) for HIV-positive women reporting a live birth in the previous 3 years. METHODS: MPHIA was a nationally representative household survey; consenting eligible women aged 15-64 years were interviewed on pregnancies and outcomes, including HIV status during their most recent pregnancy, PMTCT uptake, and early infant diagnosis (EID) testing. Descriptive analyses were weighted to account for the complex survey design. Viral load (VL) results were categorized by VLS (<1,000 copies/mL) and undetectable VL (target not detected/below the limit of detection). RESULTS: Of the 3,153 women included in our analysis, 371 (10.1%, 95% confidence interval [CI]: 8.8%-11.3%) tested HIV positive in the survey. Most HIV-positive women (84.2%, 95% CI: 79.9%-88.6%) reported knowing their HIV-positive status; of these, 94.9% (95% CI: 91.7%-98.2%) were receiving ART; and of these, 91.2% (95% CI: 87.4%-95.0%) had VLS. Among the 371 HIV-positive women, 76.0% (95% CI: 70.4%-81.7%) had VLS and 66.5% (95% CI: 59.8%-73.2%) had undetectable VL. Among 262 HIV-exposed children, 50.8% (95% CI: 42.8%-58.8%) received EID testing within 2 months of birth, whereas 17.9% (95% CI: 11.9%-23.8%) did not receive EID testing. Of 190 HIV-exposed children with a reported HIV test result, 2.1% (95% CI: 0.0%-4.6%) had positive results. CONCLUSIONS: MPHIA data demonstrate high PMTCT uptake at a population level. However, our results identify some gaps in VLS in postpartum women and EID testing.

Analysis of AI-Based Single-View 3D Reconstruction Methods for an Industrial Application.

Machine learning (ML) is a key technology in smart manufacturing as it provides insights into complex processes without requiring deep domain expertise. This work deals with deep learning algorithms to determine a 3D reconstruction from a single 2D grayscale image. The potential of 3D reconstruction can be used for quality control because the height values contain relevant information that is not visible in 2D data. Instead of 3D scans, estimated depth maps based on a 2D input image can be used with the advantage of a simple setup and a short recording time. Determining a 3D reconstruction from a single input image is a difficult task for which many algorithms and methods have been proposed in the past decades. In this work, three deep learning methods, namely stacked autoencoder (SAE), generative adversarial networks (GANs) and U-Nets are investigated, evaluated and compared for 3D reconstruction from a 2D grayscale image of laser-welded components. In this work, different variants of GANs are tested, with the conclusion that Wasserstein GANs (WGANs) are the most robust approach among them. To the best of our knowledge, the present paper considers for the first time the U-Net, which achieves outstanding results in semantic segmentation, in the context of 3D reconstruction tasks. Unlike the U-Net, which uses standard convolutions, the stacked dilated U-Net (SDU-Net) applies stacked dilated convolutions. Of all the 3D reconstruction approaches considered in this work, the SDU-Net shows the best performance, not only in terms of evaluation metrics but also in terms of computation time. Due to the comparably small number of trainable parameters and the suitability of the architecture for strong data augmentation, a robust model can be generated with only a few training data.

Novel Graphene Adjustable-Barrier Transistor with Ultra-High Current Gain.

A graphene-based three-terminal barristor device was proposed to overcome the low on/off ratios and insufficient current saturation of conventional graphene field-effect transistors. In this study, we fabricated and analyzed a novel graphene-based transistor, which resembles the structure of the barristor but uses a different operating condition. This new device, termed graphene adjustable-barriers transistor (GABT), utilizes a semiconductor-based gate rather than a metal-insulator gate structure to modulate the device currents. The key feature of the device is the two graphene-semiconductor Schottky barriers with different heights that are controlled simultaneously by the gate voltage. Due to the asymmetry of the barriers, the drain current exceeds the gate current by several orders of magnitude. Thus, the GABT can be considered an amplifier with an alterable current gain. In this work, a silicon-graphene-germanium GABT with an ultra-high current gain (ID/IG up to 8 × 106) was fabricated, and the device functionality was demonstrated. Additionally, a capacitance model is applied to predict the theoretical device performance resulting in an on-off ratio above 106, a swing of 87 mV/dec, and a drive current of about 1 × 106 A/cm2.

Resistance levels to non-nucleoside reverse transcriptase inhibitors among pregnant women with recent HIV infection in Malawi.

BACKGROUND: Information on HIV drug resistance (HIVDR) prevalence in people newly diagnosed with HIV is limited. We implemented a cross-sectional study to estimate HIVDR prevalence among pregnant women recently infected with HIV in Malawi. METHODS: The HIVDR study was nested within a routine antenatal clinic (ANC) sentinel surveillance survey. Dried blood spot samples were tested for recent infection using a limiting antigen antibody assay together with HIV viral load testing. HIV-1 protease and reverse transcriptase were sequenced using Sanger sequencing. Drug susceptibility was predicted using Stanford HIVdb algorithm (version 8.9). Weighted analysis was performed in Stata 15.1. RESULTS: Of the 21,642 pregnant women enrolled in the ANC survey, 8.4% (1826/21,642) tested HIV positive. Of these, 5.0% (92/1826) had recent HIV infection, and 90.2% (83/92) were tested by PCR. The amplification and sequencing success rate was 57.8% (48/83). The prevalence of any HIVDR was 14.6% (5/45) (95% CI: 4.7-36.8%), all of which indicated HIVDR to nonnucleoside reverse transcriptase inhibitors (NNRTIs). HIVDR to nucleoside reverse transcriptase inhibitors was 7.9% (2/45) (95% CI: 1.4-34.6%). Resistance to protease inhibitors currently in use in Malawi was not observed. CONCLUSIONS: Despite the low number of cases with presumed TDR, our study hints that resistance to NNRTIs was high, above the 10% target for regimen change. Further investigation is needed to establish the exact magnitude of presumed TDR among women recently infected with HIV. These findings support the transition to an integrase inhibitor-based first-line regimen for patients initiating or on ART.

Viral suppression and HIV-1 drug resistance 1 year after pragmatic transitioning to dolutegravir first-line therapy in Malawi: a prospective cohort study.

BACKGROUND: Many countries are now replacing non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) with a regimen containing tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). Recognising laboratory limitations, Malawi opted to transition those on NNRTI-based first-line ART to TLD without viral load testing. We aimed to assess viral load and HIV drug resistance during 1 year following transition to TLD without previous viral load testing. METHODS: In this prospective cohort study, we monitored 1892 adults transitioning from NNRTI-based first-line ART to the TLD regimen in the Médecins Sans Frontières-supported decentralised HIV programme in Chiradzulu District, Malawi. Eligible adults were enrolled between Jan 17 and May 11, 2019, at Ndunde and Milepa health centres, and between March 8 and May 11, 2019, at the Boma clinic. Viral load at the start of the TLD regimen was assessed retrospectively and measured at month 3, 6, and 12, and additionally at month 18 for those ever viraemic (viral load ≥50 copies per mL). Dolutegravir minimal plasma concentrations (Cmin) were determined for individuals with viraemia. Drug-resistance testing was done at the start of TLD regimen and at viral failure (viral load ≥50 copies per mL, followed by viral load ≥500 copies per mL; resistance defined as Stanford score ≥15). FINDINGS: Of 1892 participants who transitioned to the TLD regimen, 101 (5·3%) were viraemic at TLD start. 89 of 101 had drug-resistance testing with 31 participants (34·8%) with Lys65Arg mutation, 48 (53·9%) with Met184Val/Ile, and 42 (40·4%) with lamivudine and tenofovir disoproxil fumerate dual resistance. At month 12 (in the per-protocol population), 1725 (97·9% [95% CI 97·1-98·5]) of 1762 had viral loads of less than 50 copies per mL, including 83 (88·3% [80·0-94·0]) of 94 of those who were viraemic at baseline. At month 18, 35 (97·2% [85·5-99·9]) of 36 who were viraemic at TLD start with lamivudine and tenofovir disoproxil fumarate resistance and 27 (81·8% [64·5-93·0]) of 33 of those viraemic at baseline without resistance had viral load suppression. 14 of 1838 with at least two viral load tests upon transitioning had viral failure (all with at least one dolutegravir Cmin value <640 ng/mL; active threshold), suggesting suboptimal adherence. High baseline viral load was associated with viral failure (adjusted odds ratio [aOR] 14·1 [2·3-87·4] for 1000 to <10 000 copies per mL; aOR 64·4 [19·3-215·4] for ≥10 000 copies per mL). Two people with viral failure had dolutegravir resistance at 6 months (Arg263Lys or Gly118Arg mutation), both were viraemic with lamivudine and tenofovir disoproxil fumarate resistance at baseline. INTERPRETATION: High viral load suppression 1 year after introduction of the TLD regimen supports the unconditional transition strategy in Malawi. However, high pre-transition viral load, ongoing adherence challenges, and possibly existing nucleoside reverse transcriptase inhibitor resistance can lead to rapid development of dolutegravir resistance in a few individuals. This finding highlights the importance of viral load monitoring and dolutegravir-resistance surveillance after mass transitioning to the TLD regimen. FUNDING: Médecins Sans Frontières. TRANSLATIONS: For the French and Portuguese translations of the abstract see Supplementary Materials section.

HIV suppression was maintained during the COVID-19 pandemic in Malawi: a program-level cohort study.

BACKGROUND AND OBJECTIVES: Measures introduced to reduce the spread of SARS-CoV-2 by the Malawi government and the national HIV care program might have compromised treatment outcomes of patients living with HIV on antiretroviral therapy (ART). We studied viral load (VL) outcomes before and during the COVID-19 epidemic in Malawi. METHODS: In this population-based cohort study, we included all routine VL measurements collected from July 2019 to December 2020 in about 650 ART clinics in Malawi. We examined differences between pandemic periods (before/during COVID-19) for i) VL monitoring, and ii) VL suppression (VLS: <1,000 copies/ml). For i) we studied the number of VL measurements over time and assessed predictors of missed measurements before and during COVID-19 in logistic regression models. For ii) we estimated the odds of VLS before and during the COVID-19 epidemic stratified by treatment regimen using generalized estimation equations adjusted for age, sex, time on ART, and type of biological sample. We imputed missing treatment regimens by population-calibrated multiple imputation. RESULTS: We included 607,894 routine VL samples from 556,281 patients. VL testing declined during COVID-19 (243,729; 40%) compared to before COVID-19 (365,265; 60%), but predictors of missing tests were similar in the two periods. VLS rates increased slightly from 93% before to 94% during COVID-19. Compared to before COVID-19, the odds of VLS increased during COVID-19 for patients on protease inhibitor-based (PI) regimens (adjusted odds ratio [aOR] 1.22, 95% CI: 0.99-1.49) and for patients on integrase strand transfer inhibitor-based (INSTI) regimens (aOR 1.10, 95% CI: 1.03-1.17). There was no difference in VLS between the two periods among patients on nonnucleoside reverse transcriptase inhibitor-based (NNRTI) regimens. VLS varied by age, sex, regimen, and duration on ART, ranging from 45.1% (95% CI 40.3-50.0%) to 97.2% (95% CI 96.9-97.4%). CONCLUSION: There was a significant decline in VL monitoring during COVID-19, but we did not find clear evidence that the pandemic reduced VL suppression rates. Routine scheduled VL monitoring, targeted adherence support, and timely regimen switches for patients with treatment failure remain critical to improving VLS.