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Background: Incident HIV during the perinatal period significantly impedes elimination of Mother-to-Child HIV Transmission (eMTCT) efforts. Pre-Exposure Prophylaxis (PrEP) effectively reduces HIV acquisition, and new agents like injectable Cabotegravir (CAB-LA) offer potential advantages for pregnant and breastfeeding women. The Pregnancy, Infant, and Maternal health Outcomes (PrIMO) study will compare rates of composite adverse pregnancy outcomes, and infant adverse events, growth and neurodevelopment between mother-infant dyads receiving CAB-LA and those receiving oral PrEP in Malawi., Methods: PrIMO is an observational cohort study involving: (1) the development of a PrEP Pregnancy Registry for longitudinal surveillance of pregnant women on PrEP in Malawi; and (2) the enrolment of a prospective safety cohort of 621 pregnant women initiating oral PrEP or CAB-LA and their subsequent infants. The registry will include all women continuing or initiating PrEP during pregnancy across targeted sites in Lilongwe and Blantyre districts. The safety cohort will enrol a subset of those women and their infants from Bwaila District Hospital in Lilongwe, Malawi. We hypothesize that CAB-LA's safety will be comparable to daily oral PrEP regarding adverse pregnancy outcomes, maternal/infant adverse events, and infant development. Participants in the cohort will choose either oral PrEP or CAB-LA and will be followed until 52 weeks post-delivery. Safety data will be collected from all mother-infant pairs and qualitative interviews will be conducted with a subset of purposively selected women (n = 50) to assess the acceptability of each PrEP modality., Discussion: The PrIMO study will provide critical data on the safety of CAB-LA in pregnant and breastfeeding women and their infants. Results will guide clinical recommendations as the Malawi Ministry of Health prepares for the rollout of CAB-LA to this population. Evaluation of Registry implementation will inform its expansion to a nationwide safety monitoring system for PrEP use during pregnancy, with implications for similar systems in the region., Trial Registration Number: NCT06158126. The study was prospectively registered (5 December 2023) in ClinicalTrials.gov., (© 2024. The Author(s).)

Background: Detection of acute (pre-seroconversion) HIV infection (AHI), the phase of highest transmission risk, requires resource-intensive RNA- or antigen-based detection methods that can be infeasible for routine use. Risk score algorithms can improve the efficiency of AHI detection by identifying persons at highest risk of AHI for prioritized RNA/antigen testing, but prior algorithms have not considered geospatial information, potential differences by sex, or current antibody testing paradigms., Methods: We used elastic net models to develop sex-stratified risk score algorithms in a case-control study of persons (136 with AHI, 250 without HIV) attending a sexually transmitted infections (STI) clinic in Lilongwe, Malawi from 2015 to 2019. We designed algorithms for varying clinical contexts according to three levels of data availability: 1) routine demographic and clinical information, 2) behavioral and occupational data obtainable through patient interview, and 3) geospatial variables requiring external datasets or field data collection. We calculated sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) to assess model performance and developed a web application to support implementation., Results: The highest-performing AHI risk score algorithm for men (AUC=0.74) contained five variables (condom use, body aches, fever, rash, genital sores/ulcers) from the first two levels of data availability. The highest-performing algorithm for women (AUC=0.81) contained fifteen variables from all three levels of data availability. A risk score cut-point of 0.26 had an AHI detection sensitivity of 93% and specificity of 27% for males, and a cut-point of 0.15 had 97% sensitivity and 44% specificity for females. Additional models are available in the web application., Conclusion: Risk score algorithms can facilitate efficient AHI detection in STI clinic settings, creating opportunities for HIV transmission prevention interventions during this critical period of elevated transmission risk., Competing Interests: The authors report no conflicts of interest related to this work., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The increase in syphilis rates worldwide necessitates development of a vaccine with global efficacy. We aimed to explore Treponema pallidum subspecies pallidum (TPA) molecular epidemiology essential for vaccine research by analysing clinical data and specimens from early syphilis patients using whole-genome sequencing (WGS) and publicly available WGS data., Methods: In this multicentre, cross-sectional, molecular epidemiology study, we enrolled patients with primary, secondary, or early latent syphilis from clinics in China, Colombia, Malawi, and the USA between Nov 28, 2019, and May 27, 2022. Participants aged 18 years or older with laboratory confirmation of syphilis by direct detection methods or serological testing, or both, were included. Patients were excluded from enrolment if they were unwilling or unable to give informed consent, did not understand the study purpose or nature of their participation, or received antibiotics active against syphilis in the past 30 days. TPA detection and WGS were conducted on lesion swabs, skin biopsies, skin scrapings, whole blood, or rabbit-passaged isolates. We compared our WGS data to publicly available genomes and analysed TPA populations to identify mutations associated with lineage and geography., Findings: We screened 2802 patients and enrolled 233 participants, of whom 77 (33%) had primary syphilis, 154 (66%) had secondary syphilis, and two (1%) had early latent syphilis. The median age of participants was 28 years (IQR 22-35); 154 (66%) participants were cisgender men, 77 (33%) were cisgender women, and two (1%) were transgender women. Of the cisgender men, 66 (43%) identified as gay, bisexual, or other sexuality. Among all participants, 56 (24%) had HIV co-infection. WGS data from 113 participants showed a predominance of SS14-lineage strains with geographical clustering. Phylogenomic analyses confirmed that Nichols-lineage strains were more genetically diverse than SS14-lineage strains and clustered into more distinct subclades. Differences in single nucleotide variants (SNVs) were evident by TPA lineage and geography. Mapping of highly differentiated SNVs to three-dimensional protein models showed population-specific substitutions, some in outer membrane proteins (OMPs) of interest., Interpretation: Our study substantiates the global diversity of TPA strains. Additional analyses to explore TPA OMP variability within strains is vital for vaccine development and understanding syphilis pathogenesis on a population level., Funding: US National Institutes of Health National Institute for Allergy and Infectious Disease, the Bill & Melinda Gates Foundation, Connecticut Children's, and the Czech Republic National Institute of Virology and Bacteriology., Competing Interests: Declaration of interests ACS reports royalties from UptoDate; honoraria from the University of Alabama at Birmingham; and support for meetings or travel from the American STD Association as a member of the Executive Board outside the scope of the current work. JAG-L reports honoraria from the Universidad de Antioquia; support for meetings or travel from Carnott Laboratories, Cantabria Labs, Epidermique, Pharmaderm, and Janssen; receipt of writing materials from Epidermique, Cantabria labs, Isdin, Pharmaderm, Skindrugs, Loreal, Galderma, Cetaphil, Cerave, Isispharma, Carnott, Janssen, Pharmalab, Novartis, Pfizer, and Lilly outside of the scope of work. JJJ reports membership in the Worldwide Antimalarial Resistance Network. KLH reports honoraria from the Eastern Virginia Medical School and the Lawrence Livermore National Laboratory. JDR receives royalties from Biokit, Chembio, and Span Diagnostics for syphilis serodiagnostic reagents; and support for meetings or travel from Indiana University outside the scope of the current work. JBP reports research support from Gilead Sciences; non-financial support from Abbott Diagnostics; and consulting for Zymeron Corporation, all outside the scope of the current work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (© 2024. The Author(s).)

Background: Designathons can be used to enhance public health training and spur innovation. A designathon is a 3-stage participatory activity that includes preparation, intensive collaboration, and follow-up activities. We organized a designathon focused on developing actionable sexually transmitted disease (STD) control strategies and examined the content of ideas resulting from an STD designathon., Methods: For this designathon, we created four groups: early career researchers, silver group (people with >10 years of experience), travelers (people from low- and middle-income countries and those who received a conference scholarship) and a community group. Each group developed its own plan to consult members, iteratively develop ideas, and aggregate insights. Each group developed STD control strategies that were presented. Cross-cutting themes across these ideas were identified., Results: Designathon participants included a subset of conference participants. Cross-cutting themes from final ideas included cocreating STD interventions with end-users, using sex-positive framing, enhancing open access digital STD resources, and reducing STD stigma. Early career researchers presented a call for community ideas focusing on ending STD epidemics by increasing accessibility to STD care services among all populations. The silver group proposed digital innovations, including an AI-powered tool for testing and treatment and a social game to promote sex positivity. The traveler group conceptualized an information hub to support implementation of STD programs. Community members underscored the importance of a more human-centered approach to STD control, which reduces stigma and normalizes sex and sexual pleasure., Conclusion: Sex positive campaigns and open access digital resources should be considered within STD programs. Implementation research studies are needed to evaluate these ideas., Competing Interests: Conflicts of Interest and Source of Funding: J.D.T. received support from NIAID K24AI143471 and R.G. received money from NIMH K23MH126794. For the remaining authors none were declared., (Copyright © 2024 American Sexually Transmitted Diseases Association. All rights reserved.)

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., (© 2024 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ngongondo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: To examine the time required to suppress HIV in the genital tract with antiretroviral therapy (ART) in men with urethritis., Design: An observational cohort study., Methods: Men with HIV and urethritis not on ART were enrolled at an STI clinic in Malawi and offered to initiate ART. Blood and semen samples were collected pretreatment and at 1, 2, 4, 8, 12 and 24 weeks posturethritis treatment. Median viral loads (VLs) were calculated by ART initiation groups: 'within 1 week', 'between 1 and 4 weeks' and 'no ART before 4 weeks', based on the men's choice about whether or not to initiate ART. The presence of ART at each visit was confirmed by bioanalytical methods., Findings: Between January 2017 and November 2018, 74 men presented with urethritis and HIV and were confirmed ART naive. The median age was 32 years. Forty-one (55% of men) initiated ART within 1 week; 12 (16%) between 1 and 4 weeks; and 21 (28%) did not initiate ART by week 4. Within the 1 week group, median VL was suppressed within 4 weeks in both semen and blood. Among the 1-4 weeks group, VL was suppressed within 4 weeks in semen and 5 weeks in blood. Among the no ART before 4 weeks group, VL in semen declined within the first 4 weeks but remained unsuppressed through week 24, and there was no significant decline in blood HIV., Conclusion: Treatment of urethritis and prompt initiation of ART with counseling for safer sex for at least one month is a critical measure to reduce transmission of HIV., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Understanding depression, alcohol use, and sexual behaviors according to HIV infection stage and diagnosis timing is important for HIV prevention efforts. We enrolled persons with recent infection and diagnosis (i.e., acute HIV infection (AHI) (n = 92) persons newly diagnosed seropositive (n = 360)) and persons previously diagnosed with HIV (n = 190) into a randomized controlled trial in Lilongwe, Malawi (N = 641) and estimated the prevalence of probable depression (Patient Health Questionnaire-9 ≥ 5), hazardous alcohol use (Alcohol Use Disorder Identification Test-C: men ≥ 4; women ≥ 3), and sexual behaviors (transactional sex, condomless sex). Compared with previously diagnosed participants, participants newly seropositive and those with AHI reported a higher proportion of probable depression (7%, 27%, 38%; AHI/Previous: Table Probability: 0.02, p < 0.01; AHI/New: Table Probability: <0.01, p < 0.01), hazardous alcohol use (8%, 18%, 29%; AHI/Previous and AHI/New: Table Probability: <0.01, p < 0.01), and transactional sex (5%, 14%, 20%; AHI/Previous: Table Probability: <0.01, p < 0.01; AHI/New: Table Probability: 0.06, p = 0.24), respectively. HIV prevention services addressing mental health and alcohol misuse may be particularly beneficial for persons with recent HIV infection and or diagnosis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Genital ulcer diseases (GUDs) are a common syndrome associated with sexually transmitted infections. Genital ulcer diseases increase the risk of HIV transmission, necessitating appropriate diagnosis and treatment. We provide an updated GUD etiology assessment in Malawi to guide diagnostic development and treatment algorithms., Methods: We enrolled patients 18 years or older presenting with GUD at a sexually transmitted infection clinic in Lilongwe, Malawi, between May and October 2021. We purposively sampled by HIV status. Swabs of ulcers were tested for Treponema pallidum, herpes simplex virus (HSV)-1 and HSV-2, Haemophilus ducreyi, and Chlamydia trachomatis using polymerase chain reaction. Blood was collected for syphilis and HSV-2 serologies and acute HIV testing. Participants were treated per Malawi guidelines. Ulcer resolution (size reduced by >50%) was evaluated 14 days later., Results: Fifty participants enrolled (30 without HIV, 2 with acute HIV infection, 18 with HIV seropositivity; 32 men, 18 women). Forty-six (92%) had an etiology identified. Syphilis was more common among those without HIV (22 of 30 [73%]) than participants with HIV (PWH; 8 of 20 [40%]; P = 0.04). Herpes simplex virus was more common among PWH (11 of 20 [55%]) than participants without (2 of 30 [7%]; P = 0.0002). One-fifth (9 of 50 [18%]) had H. ducreyi. Among those who returned for follow-up (n = 45), 9 (20%) had unresolved ulcers; persistent GUD was slightly more common in PWH (6 of 19 [32%]) than participants without (3 of 26 [12%]; P = 0.14)., Conclusions: We observed a dramatic increase in syphilis ulcer proportion in a population whose GUDs were previously HSV predominant. Observed differences in etiology and resolution by HIV status could play an important role in the ongoing transmission and treatment evaluation of GUD., Competing Interests: Conflict of Interest and Sources of Funding: None declared., (Copyright © 2023 American Sexually Transmitted Diseases Association. All rights reserved.)

Objective: To evaluate the effect a multistrategy demand-creation and linkage intervention on voluntary medical male circumcision (VMMC) uptake, time to VMMC and predictors of VMMC uptake among men with sexually transmitted infections (STIs)., Design: Pragmatic preinterventional and postinterventional quasi-experimental study combined with a prospective observational design., Setting: A public and specialised STI clinic in Lilongwe, Malawi., Population: Uncircumcised men who presented to the STI clinic., Methods and Intervention: The intervention consisted of transport reimbursement ('R'), intensified health education ('I') and short-messaging services/telephonic tracing ('Te'), abbreviated (RITe). A preintervention phase was conducted at baseline while RITe was rolled-out in the intervention phase in a sequential manner called implementation blocks: 'I' only-block 1; 'I+Te'-block 2 and RITe-block 3., Main Outcome Measures: Primary: VMMC uptake and time to VMMC for the full intervention and for each block. Secondary: predictors of VMMC uptake., Results: A total of 2230 uncircumcised men presented to the STI clinic. The mean age was 29 years (SD±9), 58% were married/cohabiting, HIV prevalence was 6.4% and 43% had urethral discharge. Compared with standard of care (8/514, 1.6%), uptake increased by 100% during the intervention period (55/1716, 3.2%) (p=0.048). 'I' (25/731, 113%, p=0.044) and RITe (17/477, 125%, p=0.044) significantly increased VMMC uptake. The median time to VMMC was shorter during the intervention period (6 days, IQR: 0, 13) compared with standard of care (15 days, IQR: 9, 18). There was no significant incremental effect on VMMC uptake and time to VMMC between blocks. Men with genital warts were 18 times more likely to receive VMMC (adjusted relative risk=18.74, 95% CI: 2.041 to 172.453)., Conclusions: Our intervention addressing barriers to VMMC improved VMMC uptake and time to VMMC among uncircumcised men with STIs, an important subpopulation for VMMC prioritisation., Trial Registration Number: NCT04677374., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Understanding heterogeneity across patients in effectiveness of network-based HIV testing interventions may optimize testing and contact tracing strategies, expediting linkage to therapy or prevention for contacts of persons with HIV (PWH)., Setting: We analyzed data from a randomized controlled trial of a combination intervention comprising acute HIV testing, contract partner notification (cPN), and social contact referral conducted among PWH at 2 STI clinics in Lilongwe, Malawi, between 2015 and 2019., Methods: We used binomial regression to estimate the effect of the combination intervention vs. passive PN (pPN) on having any (1) contact, (2) newly HIV-diagnosed contact, and (3) HIV-negative contact present to the clinic, overall and by referring participant characteristics. We repeated analyses comparing cPN alone with pPN., Results: The combination intervention effect on having any presenting contact was greater among referring women than men [prevalence difference (PD): 0.17 vs. 0.10] and among previously vs. newly HIV-diagnosed referring persons (PD: 0.20 vs. 0.11). Differences by sex and HIV diagnosis status were similar in cPN vs. pPN analyses. There were no notable differences in the intervention effect on newly HIV-diagnosed referrals by referring participant characteristics. Intervention impact on having HIV-negative presenting contacts was greater among younger vs. older referring persons and among those with >1 vs. ≤1 recent sex partner. Effect differences by age were similar for cPN vs. pPN., Conclusion: Our intervention package may be particularly efficacious in eliciting referrals from women and previously diagnosed persons. When the combination intervention is infeasible, cPN alone may be beneficial for these populations., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Alcohol use disorders (AUD) are a common cause of poor treatment outcomes among people with HIV (PWH). In Malawi, routine screening for AUD among PWH is unavailable. We piloted the utility of the Alcohol Use Disorders Identification Test (AUDIT) in screening for AUD among PWH and assessed its adoption, acceptability and fidelity in HIV clinics in Malawi., Methods: We implemented the AUDIT tool at Mchinji, Kapiri and Kochirira hospitals in Mchinji District between April and May 2021. AUD were defined and classified based on WHO classification as low-risk, harmful/hazardous alcohol use or alcohol dependence. We calculated the prevalence of AUD, the proportion of providers who conducted AUD screening (adoption) and the proportion of providers who conducted AUD screening as intended (fidelity) and compared between clinics. Lastly, we assessed acceptability through a survey among providers., Results: Out of 2036 PWH, 875 (43%) were screened for AUD and 51% were female, mean age was 41 years (SD±12) and 338 (39%) had AUD. Adoption was highest at Mchinji (58%) compared to Kapiri (31%) and Kochiria (29%) (P<0.001). Overall Fidelity was 96%, and it was highest at Kapiri (99%) compared to Mchinji (95%) and Kochirira (98%) (P=0.01). AUD screening with AUDIT was highly acceptable as most providers agreed or completely agreed that the AUDIT was important (100%), easy to use (96%), satisfactory (96%), agreed to continue use (61%) and recommended it for other facilities in the district (100%)., Conclusion: AUD were common among PWH. While the adoption of AUDIT for AUD screening was moderate, acceptability and fidelity were high. The impact of AUD on HIV treatment outcomes needs to be assessed to determine the role of routine AUD screening in HIV clinics in Malawi., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Global antimicrobial resistance (AMR) surveillance in Neisseria gonorrhoeae is essential. In 2017-18, only five (10.6%) countries in the WHO African Region reported to the WHO Global Gonococcal Antimicrobial Surveillance Programme (WHO GASP). Genomics enhances our understanding of gonococcal populations nationally and internationally, including AMR strain transmission; however, genomic studies from Africa are extremely scarce. We describe the gonococcal genomic lineages/sublineages, including AMR determinants, and baseline genomic diversity among strains in Uganda, Malawi and South Africa, 2015-20, and compare with sequences from Kenya and Burkina Faso., Methods: Gonococcal isolates cultured in Uganda (n = 433), Malawi (n = 154) and South Africa (n = 99) in 2015-20 were genome-sequenced. MICs were determined using ETEST. Sequences of isolates from Kenya (n = 159), Burkina Faso (n = 52) and the 2016 WHO reference strains (n = 14) were included in the analysis., Results: Resistance to ciprofloxacin was high in all countries (57.1%-100%). All isolates were susceptible to ceftriaxone, cefixime and spectinomycin, and 99.9% were susceptible to azithromycin. AMR determinants for ciprofloxacin, benzylpenicillin and tetracycline were common, but rare for cephalosporins and azithromycin. Most isolates belonged to the more antimicrobial-susceptible lineage B (n = 780) compared with the AMR lineage A (n = 141), and limited geographical phylogenomic signal was observed., Conclusions: We report the first multi-country gonococcal genomic comparison from Africa, which will support the WHO GASP and WHO enhanced GASP (EGASP). The high prevalence of resistance to ciprofloxacin (and empirical use continues), tetracycline and benzylpenicillin, and the emerging resistance determinants for azithromycin show it is imperative to strengthen the gonococcal AMR surveillance, ideally including genomics, in African countries., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Pre-exposure prophylaxis (PrEP) reduces HIV acquisition risk by >90% and is a critical lever to reduce HIV incidence. Identifying individuals most likely to benefit from PrEP and retaining them on PrEP throughout HIV risk is critical to realize PrEP's prevention potential. Individuals with sexually transmitted infections (STIs) are an obvious priority PrEP population, but there are no data from sub-Saharan Africa (SSA) confirming the effectiveness of integrating PrEP into STI clinics. Assisted partner notification may further enhance STI clinic-based PrEP programming by recruiting PrEP users from the pool of named sexual partners of individuals presenting with an incident STI. However, the acceptability, feasibility, and effectiveness of these integrated and enhanced strategies are unknown., Objective: This study aims to describe the implementation outcomes of acceptability, feasibility, and effectiveness (regarding PrEP uptake and persistence) of integrating an enhanced PrEP implementation strategy into an STI clinic in Malawi., Methods: The enhanced PrEP STI study is a prospective cohort study enrolling patients who are eligible for PrEP (aged ≥15 years) who are seeking STI services at a Lilongwe-based STI clinic. Data collection relies on a combination of in-depth interviews, patient and clinic staff surveys, and clinic record review. All enrolled PrEP users will be screened for acute HIV infection and receive quarterly testing for Neisseria gonorrhea, Chlamydia trachomatis, and syphilis. Participants will be asked to name recent sexual partners for assisted notification; returning partners will be screened for PrEP eligibility and, if interested, enrolled into the cohort of PrEP initiators. We will also enroll patients who are eligible for PrEP but choose not to initiate it, from the STI clinic. Patient participants will be followed for 6 months; we will assess self-reported PrEP use, PrEP refills, sexual behaviors, perceived HIV risk, and incident STIs. Clinic staff participants will be interviewed at baseline and at approximately 6 months and will complete surveys examining the perceived acceptability and feasibility of the integrated and enhanced PrEP strategy., Results: Enrollment began in March 2022 and is projected to continue until February 2023, with patient participant follow-up through August 2023. The results of this study are expected to be reported in 2024., Conclusions: This study will generate important evidence regarding the potential integration of PrEP services into STI clinics in SSA and preliminary data regarding the effectiveness of an enhanced intervention that includes assisted partner notification as a strategy to identify potential PrEP users. Furthermore, this trial will provide some of the first insights into STI incidence among PrEP users recruited from an STI clinic in SSA-critical data to inform the use of etiologic STI testing where syndromic management is the current standard. These findings will help to design future PrEP implementation strategies in SSA., Trial Registration: ClinicalTrials.gov NCT05307991; https://clinicaltrials.gov/ct2/show/NCT05307991., International Registered Report Identifier (irrid): DERR1-10.2196/37395., (©Sarah E Rutstein, Mitch Matoga, Jane S Chen, Esther Mathiya, Beatrice Ndalama, Naomi Nyirenda, Naomi Bonongwe, Shyreen Chithambo, Maganizo Chagomerana, Gerald Tegha, Mina C Hosseinipour, Michael E Herce, Edward Jere, Robert G Krysiak, Irving F Hoffman. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 05.12.2022.)

Sequencing of most Treponema pallidum genomes excludes repeat regions in tp0470 and the tp0433 gene, encoding the acidic repeat protein ( arp ). As a first step to understanding the evolution and function of these genes and the proteins they encode, we developed a protocol to nanopore sequence tp0470 and arp genes from 212 clinical samples collected from ten countries on six continents. Both tp0470 and arp repeat structures recapitulate the whole genome phylogeny, with subclade-specific patterns emerging. The number of tp0470 repeats is on average appears to be higher in Nichols-like clade strains than in SS14-like clade strains. Consistent with previous studies, we found that 14-repeat arp sequences predominate across both major clades, but the combination and order of repeat type varies among subclades, with many arp sequence variants limited to a single subclade. Although strains that were closely related by whole genome sequencing frequently had the same arp repeat length, this was not always the case. Structural modeling of TP0470 suggested that the eight residue repeats form an extended α-helix, predicted to be periplasmic. Modeling of the ARP revealed a C-terminal sporulation-related repeat (SPOR) domain, predicted to bind denuded peptidoglycan, with repeat regions possibly incorporated into a highly charged β-sheet. Outside of the repeats, all TP0470 and ARP amino acid sequences were identical. Together, our data, along with functional considerations, suggests that both TP0470 and ARP proteins may be involved in T. pallidum cell envelope remodeling and homeostasis, with their highly plastic repeat regions playing as-yet-undetermined roles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lieberman, Armstrong, Chung, Pfalmer, Hennelly, Haynes, Romeis, Wang, Zhang, Kou, Ciccarese, Conte, Cusini, Drago, Nakayama, Lee, Ohnishi, Konda, Vargas, Eguiluz, Caceres, Klausner, Mitja, Rompalo, Mulcahy, Hook, Hoffman, Matoga, Zheng, Yang, Lopez-Medina, Ramirez, Radolf, Hawley, Salazar, Lukehart, Seña, Parr, Giacani and Greninger.)

Background: People with human immunodeficiency virus (HIV) and advanced immunosuppression initiating antiretroviral therapy (ART) remain vulnerable to tuberculosis (TB) and early mortality. To improve early survival, isoniazid preventive therapy (IPT) or empiric TB treatment have been evaluated; however, their benefit on longer-term outcomes warrants investigation., Methods: We present a 96-week preplanned secondary analysis among 850 ART-naive outpatients (≥13 years) enrolled in a multicountry, randomized trial of efavirenz-containing ART plus either 6-month IPT ( n  = 426) or empiric 4-drug TB treatment ( n  = 424). Inclusion criteria were CD4 count <50 cells/mm 3 and no confirmed or probable TB. Death and incident TB were compared by strategy arm using the Kaplan-Meier method. The impact of self-reported adherence (calculated as the proportion of 100% adherence) was assessed using Cox-proportional hazards models., Results: By 96 weeks, 85 deaths and 63 TB events occurred. Kaplan-Meier estimated mortality (10.1% vs 10.5%; P  = .86) and time-to-death ( P  = .77) did not differ by arm. Empiric had higher TB risk (6.1% vs 2.7%; risk difference, -3.4% [95% confidence interval, -6.2% to -0.6%]; P  = .02) and shorter time to TB ( P  = .02) than IPT. Tuberculosis medication adherence lowered the hazards of death by ≥23% ( P  < .0001) in empiric and ≥20% ( P  < .035) in IPT and incident TB by ≥17% ( P  ≤ .0324) only in IPT., Conclusions: Empiric TB treatment offered no longer-term advantage over IPT in our population with advanced immunosuppression initiating ART. High IPT adherence significantly lowered death and TB incidence through 96 weeks, emphasizing the benefit of ART plus IPT initiation and completion, in persons with advanced HIV living in high TB-burden, resource-limited settings., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The continued emergence of Neisseria gonorrhoeae isolates which are resistant to first-line antibiotics has reinvigorated interest in alternative therapies such as expanded use of gentamicin (Gen). We hypothesized that expanded use of Gen promotes emergence of gonococci with clinical resistance to this aminoglycoside. To understand how decreased susceptibility of gonococci to Gen might develop, we selected spontaneous low-level Gen-resistant (Gen R ) mutants (Gen MIC = 32 μg/mL) of the Gen-susceptible strain FA19. Consequently, we identified a novel missense mutation in fusA , which encodes elongation factor G (EF-G), causing an alanine (A) to valine (V) substitution at amino acid position 563 in domain IV of EF-G; the mutant allele was termed fusA2 . Transformation analysis showed that fusA2 could increase the Gen MIC by 4-fold. While possession of fusA2 did not impair either in vitro gonococcal growth or protein synthesis, it did result in a fitness defect during experimental infection of the lower genital tract in female mice. Through bioinformatic analysis of whole-genome sequences of 10,634 international gonococcal clinical isolates, other fusA alleles were frequently detected, but genetic studies revealed that they could not decrease Gen susceptibility in a similar manner to fusA2 . In contrast to these diverse international fusA alleles, the fusA2- encoded A563V substitution was detected in only a single gonococcal clinical isolate. We hypothesize that the rare occurrence of fusA2 in N. gonorrhoeae clinical isolates is likely due to a fitness cost during infection, but compensatory mutations which alleviate this fitness cost could emerge and promote Gen R in global strains.

Background: Gentamicin has been used for the treatment of gonorrhea in Malawi since 1993. However, declining clinical cure rates have been suspected. We evaluated current Neisseria gonorrhoeae susceptibility to gentamicin in vitro and clinically., Methods: Men with acute urethritis were recruited at the Bwaila District Hospital STI Clinic in Lilongwe, Malawi, between January 2017 and August 2019. All men provided urethral swabs for etiological testing at enrollment and test of cure (TOC), 1 week later, using Gram-stained microscopy and culture. We used Etest to determine minimum inhibitory concentrations (MICs) of gentamicin, azithromycin, cefixime, ceftriaxone, ciprofloxacin, and spectinomycin; disc diffusion for tetracycline susceptibility; and whole-genome sequencing (WGS) to verify/refute treatment failure., Results: Among 183 N. gonorrhoeae culture-positive men enrolled, 151 (82.5%) had a swab taken for TOC. Of these 151 men, 16 (10.6%) had a positive culture at TOC. One hundred forty-one baseline isolates were tested for gentamicin susceptibility using Etest: 2 (1.4%), MIC = 2 μg/mL; 111 (78.7%), MIC = 4 μg/mL; and 28 (19.9%), MIC = 8 μg/mL. All isolates were susceptible to azithromycin, cefixime, ceftriaxone, and spectinomycin, whereas 63.1% had intermediate susceptibility or resistance to ciprofloxacin. Almost all (96.1%) isolates were resistant to tetracycline. All examined isolates cultured at TOC (n = 13) had gentamicin MICs ≤8 μg/mL. Ten men had pretreatment and posttreatment isolates examined by whole-genome sequencing; 2 (20%) were verified new infections (4119 and 1272 single-nucleotide polymorphisms), whereas 8 (80%) were confirmed treatment failures (0-1 single-nucleotide polymorphism)., Conclusions: Gentamicin MICs poorly predict gonorrhea treatment outcome with gentamicin, and treatment failures are verified with gonococcal strains with in vitro susceptibility to gentamicin. The first-line treatment of gonorrhea in Malawi should be reassessed., Competing Interests: Conflict of Interest and Sources of Funding: None declared., (Copyright © 2021 American Sexually Transmitted Diseases Association. All rights reserved.)

Introduction: Voluntary medical male circumcision (VMMC) is one of the key interventions for HIV prevention. However, its uptake among men in Malawi is low. Implementation science strategies for demand creation of VMMC increase uptake. We designed an implementation science demand-creation intervention to increase the uptake of VMMC among men with sexually transmitted infections (STIs)., Methods and Analysis: We designed a pragmatic pre-interventional and post-interventional quasi-experimental study combined with a prospective observational design to determine the uptake, acceptability, appropriateness and feasibility of a multifaceted intervention for scale up of uptake of VMMC among men with STIs at Bwaila STI clinic in Lilongwe, Malawi. The intervention includes transport reimbursement (R), intensified health education (I) and short messaging service (SMS)/telephonic tracing (Te) (RITe). The intervention will be implemented in phases: pre-implementation and implementation. Pre-implementation phase will be used for collecting baseline data, while the RITe intervention will be rolled-out in the implementation phase. The RITe intervention will be implemented in a sequential and incremental manner called implementation blocks: block 1: intensified health education; block 2: intensified health education and SMS/telephonic tracing; and block 3: intensified health education, SMS/telephonic tracing and transport reimbursement. The target sample size is 80 uncircumcised men for each intervention block, including the pre-implementation sample, making a total of 320 men (280 total, 70 per block will be surveyed). The primary outcome is uptake of VMMC during the implementation period. Mixed methods assessments will be conducted to evaluate the acceptability, appropriateness and feasibility of the RITe intervention., Ethics and Dissemination: The study protocol was approved by the Malawi's National Health Sciences Research Ethics Committee (approval number: 19/10/2412), University of North Carolina at Chapel Hill's Institutional Review Board (approval number: 19-2559) and University of the Witwatersrand's Health Research Ethics Committee (approval number: M200328). Results will be disseminated via publication in a peer-reviewed journal and presentations at relevant scientific conferences and meetings., Trial Registration Number: NCT04677374., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Prior to the widespread availability of antiretroviral therapy (ART), men living with human immunodeficiency virus (HIV) with urethritis had increased concentrations of HIV in semen. This study aims to better evaluate HIV shedding in men with urethritis receiving ART, and its implications for the cure of HIV., Methods: Men living with HIV with urethritis taking ART ≥12 weeks were enrolled at a sexually transmitted infections clinic in Lilongwe, Malawi. Study follow-up included visits at 1, 2, 4, 8, 12, 24, 36, and 48 weeks after urethritis diagnosis and treatment. Matched blood and semen samples were collected at all visits, and all additional episodes of urethritis were followed with extra visits 1, 2, and 4 weeks after treatment., Results: There were 111 men enrolled in the study between January 2017-March 2019, and 77 (69%) were suppressed in the blood (<400 copies/mL). Among the 77 men, 87 episodes of urethritis were evaluated during follow-up. Of the 87 episodes, 15 episodes (17%) had instances of seminal viral shedding ≥400 copies/mL despite viral suppression in the blood. During nonurethritis follow-up, ≤6% of men at each visit had a viral load ≥400 copies/mL in the semen while maintaining viral suppression in the blood., Conclusions: An HIV cure requires the elimination of HIV from every body compartment, but available ART does not currently accomplish this. Our study highlights the male genital tract as a local source of HIV that can be reversibly activated. A better understanding of this phenomenon is important to advance the HIV cure field., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The urine lipoarabinomannan (LAM) antigen test is a tuberculosis (TB) diagnostic test with highest sensitivity in individuals with advanced human immunodeficiency virus (HIV). Its role in TB diagnostic algorithms for HIV-positive outpatients remains unclear., Methods: The AIDS Clinical Trials Group (ACTG) A5274 trial demonstrated that empiric TB therapy did not improve 24-week survival compared to isoniazid preventive therapy (IPT) in TB screen-negative HIV-positive adults initiating antiretroviral therapy with CD4 counts <50 cells/µL. Retrospective LAM testing was performed on stored urine obtained at baseline. We determined the proportion of LAM-positive participants and conducted modified intent-to-treat analysis excluding LAM-positive participants to determine the effect on 24-week survival, TB incidence, and time to TB using Kaplan-Meier method., Results: A5274 enrolled 850 participants; 53% were male and the median CD4 count was 18 (interquartile range, 9-32) cells/µL. Of the 850, 566 (67%) had LAM testing (283 per arm); 28 (5%) were positive (21 [7%] and 7 [2%] in the empiric and IPT arms, respectively). Of those LAM-positive, 1 participant in each arm died and 5 of 21 and 0 of 7 in empiric and IPT arms, respectively, developed TB. After excluding these 28 cases, there were 19 and 21 deaths in the empiric and IPT arms, respectively (P = .88). TB incidence remained higher (4.6% vs 2%, P = .04) and time to TB remained faster in the empiric arm (P = .04)., Conclusions: Among outpatients with advanced HIV who screened negative for TB by clinical symptoms, microscopy, and Xpert testing, LAM testing identified an additional 5% of individuals with TB. Positive LAM results did not change mortality or TB incidence., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Abstract: Monitoring the burden of and trends in sexually transmitted infection syndromes is useful in informing syndromic management guidelines. Among sexually transmitted infection clinic patients in Lilongwe, Malawi, between 2006 and 2015, genital discharge, lower abdominal pain, and genital ulcer syndromes were common. Prevalence of most syndromes remained stable during the 10-year period., Competing Interests: Conflict of Interest and Sources of Funding: The authors do not have any conflicts of interest to declare. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under award numbers R01 AI083059, R01 AI114320, and 5R01 DK108424-03. M.M. was supported by NIH, The Fogarty Global Health Fellowship Program Grant No. D43 TW009340. J.S.C. was supported by NIH, National Institute of Allergy and Infectious Diseases (T32 AI070114). This work received support from Lilongwe DHO, Ministry of Health, Lilongwe, Malawi; UNC Project, Malawi, Lilongwe Malawi; and UNC Institute of Global Health and Infectious Diseases., (Copyright © 2020 American Sexually Transmitted Diseases Association. All rights reserved.)

Background: Cervical cancer is the leading cause of cancer incidence and mortality among Malawian women, despite being a largely preventable disease. Implementing a cervical cancer screening and preventive treatment (CCSPT) program that utilizes rapid human papillomavirus (HPV) testing on self-collected cervicovaginal samples for screening and thermal ablation for treatment may achieve greater coverage than current programs that use visual inspection with acetic acid (VIA) for screening and cryotherapy for treatment. Furthermore, self-sampling creates the opportunity for community-based screening to increase uptake in populations with low screening rates. Malawi's public health system utilizes regularly scheduled outreach and village-based clinics to provide routine health services like family planning. Cancer screening is not yet included in these community services. Incorporating self-sampled HPV testing into national policy could address cervical cancer screening barriers in Malawi, though at present the effectiveness, acceptability, appropriateness, feasibility, and cost-effectiveness still need to be demonstrated., Methods: We designed a cluster randomized feasibility trial to determine the effectiveness, acceptability, appropriateness, feasibility, and budget impact of two models for integrating a HPV-based CCSPT program into family planning (FP) services in Malawi: model 1 involves only clinic-based self-sampled HPV testing, whereas model 2 includes both clinic-based and community-based self-sampled HPV testing. Our algorithm involves self-collection of samples for HPV GeneXpert® testing, visual inspection with acetic acid for HPV-positive women to determine ablative treatment eligibility, and same-day thermal ablation for treatment-eligible women. Interventions will be implemented at 14 selected facilities. Our primary outcome will be the uptake of cervical cancer screening and family planning services during the 18 months of implementation, which will be measured through an Endline Household Survey. We will also conduct mixed methods assessments to understand the acceptability, appropriateness, and feasibility of the interventions, and a cost analysis to assess budget impact., Discussion: Our trial will provide in-depth information on the implementation of clinic-only and clinic-and-community models for integrating self-sampled HPV testing CCSPT with FP services in Malawi. Findings will provide valuable insight for policymakers and implementers in Malawi and other resource-limited settings with high cervical cancer burden., Trial Registration: ClinicalTrials.gov identifier: NCT04286243 . Registered on February 26, 2020.

Introduction: HIV diagnosis is the necessary first step towards HIV care initiation, yet many persons living with HIV (PLWH) remain undiagnosed. Employing multiple HIV testing strategies in tandem could increase HIV detection and promote linkage to care. We aimed to assess an intervention to improve HIV detection within socio-sexual networks of PLWH in two sexually transmitted infections (STI) clinics in Lilongwe, Malawi., Methods: We conducted a randomized controlled trial to evaluate an intervention combining acute HIV infection (AHI) screening, contract partner notification and social contact referral versus the Malawian standard of care: serial rapid serological HIV tests and passive partner referral. Enrolment occurred between 2015 and 2019. HIV-seropositive persons (two positive rapid tests) were randomized to the trial arms and HIV-seronegative (one negative rapid test) and -serodiscordant (one positive test followed by a negative confirmatory test) persons were screened for AHI with HIV RNA testing. Those found to have AHI were offered enrolment into the intervention arm. Our primary outcome of interest was the number of new HIV diagnoses made per index participant within participants' sexual and social networks. We also calculated total persons, sexual partners and PLWH (including those previously diagnosed) referred per index participant., Results: A total of 1230 HIV-seropositive persons were randomized to the control arm, and 561 to the intervention arm. Another 12,713 HIV-seronegative or -serodiscordant persons underwent AHI screening, resulting in 136 AHI cases, of whom 94 enrolled into the intervention arm. The intervention increased the number of new HIV diagnoses made per index participant versus the control (ratio: 1.9; 95% confidence interval (CI): 1.2 to 3.1). The intervention also increased the numbers of persons (ratio: 2.5; 95% CI: 2.0 to 3.2), sexual partners (ratio: 1.7; 95% CI: 1.4 to 2.0) and PLWH (ratio: 2.3; 95% CI: 1.7 to 3.2) referred per index participant., Conclusions: Combining three distinct HIV testing and referral strategies increased the detection of previously undiagnosed HIV infections within the socio-sexual networks of PLWH seeking STI care. Combination HIV detection strategies that leverage AHI screening and socio-sexual contact networks offer a novel and efficacious approach to increasing HIV status awareness., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Purpose of Review: Evidence of the protective effect of voluntary medical male circumcision (VMMC) against HIV is well established. However, evidence of the protective effect of VMMC against other sexually transmitted infections (STIs) has been inconsistent or scarce across different populations and settings. This review summarizes the current evidence on the effect of VMMC for HIV prevention on acquisition and transmission of other STIs in heterosexual men, women, and men who have sex with men (MSM)., Recent Findings: Recent findings continue to strongly support the protective effect of male medical circumcision against acquisition and transmission of herpes simplex virus type 2 (HSV-2), human papillomavirus (HPV) and syphilis infections in heterosexual men and women, and bacterial vaginosis and trichomoniasis in women. There is emerging evidence on the protective effect of VMMC against acquisition of hepatitis B and Mycoplasma genitalium infections in heterosexual men, and HSV-2, HPV, and syphilis in MSM., Summary: Evidence on the protective effect of VMMC against acquisition and transmission of common STIs is available for heterosexual men and women but more evidence is required for MSM. This review supports policy recommendations for the protective benefits of VMMC against STIs., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: People with advanced human immunodeficiency virus (HIV) (CD4 < 50) remain at high risk of tuberculosis (TB) or death despite the initiation of antiretroviral therapy (ART). We aimed to identify immunological profiles that were most predictive of incident TB disease and death., Methods: The REMEMBER randomized clinical trial enrolled 850 participants with HIV (CD4 < 50 cells/µL) at ART initiation to receive either empiric TB treatment or isoniazid preventive therapy (IPT). A case-cohort study (n = 257) stratified by country and treatment arm was performed. Cases were defined as incident TB or all-cause death within 48 weeks after ART initiation. Using multiplexed immunoassay panels and ELISA, 26 biomarkers were assessed in plasma., Results: In total, 52 (6.1%) of 850 participants developed TB; 47 (5.5%) died (13 of whom had antecedent TB). Biomarkers associated with incident TB overlapped with those associated with death (interleukin [IL]-1β, IL-6). Biomarker levels declined over time in individuals with incident TB while remaining persistently elevated in those who died. Dividing the cohort into development and validation sets, the final model of 6 biomarkers (CXCL10, IL-1β, IL-10, sCD14, tumor necrosis factor [TNF]-α, and TNF-β) achieved a sensitivity of 0.90 (95% confidence interval [CI]: .87-.94) and a specificity of 0.71(95% CI: .68-.75) with an area under the curve (AUC) of 0.81 (95% CI: .78-.83) for incident TB., Conclusion: Among people with advanced HIV, a parsimonious inflammatory biomarker signature predicted those at highest risk for developing TB despite initiation of ART and TB preventive therapies. The signature may be a promising stratification tool to select patients who may benefit from increased monitoring and novel interventions., Clinical Trials Registration: NCT01380080., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Concurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from antiretroviral therapy (ART)-naive men living in Malawi with ( n  = 19) and without ( n  = 5) STI-associated urethritis; for a subset of samples, full-length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of proinflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population, indicating a recent bottleneck followed by limited viral replication. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, and where specific genotypes can be amplified, perhaps initially by cellular proliferation but further by limited viral replication. IMPORTANCE HIV-1 infection is a sexually transmitted infection that coexists with other STI. Here, we examined the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI., (Copyright © 2020 American Society for Microbiology.)

Background: Sex differences in studies of antiretroviral (ART) drug exposure and treatment outcomes support the hypothesis that some ART combinations may not be well tolerated in women. We evaluated disparities in outcomes between men and women participating in ACTG A5288, an interventional strategy trial for individuals failing a protease inhibitor-based second-line ART regimen in low- and middle-income countries., Methods: Participants were assigned to one of 4 cohorts (A-D) based on resistance profiles and ART history. Cohort A had no lopinavir/ritonavir (LPV/r) resistance and stayed on their second-line regimen, and cohorts B, C, and D had increasing resistance and accessed novel ART regimens. In this secondary analysis, we evaluated sex differences in the primary endpoint, HIV-1 RNA ≤200 copies/mL at week 48; confirmed virologic failure ≥1000 copies/mL (VF); and clinical outcomes and adverse events (intent-to-treat)., Results: Women made up 258/545 (47%) of the study population. More women than men were assigned to cohort A. Median follow-up was 72 weeks. Fewer women than men had HIV-1 RNA ≤200 copies/mL at week 48: 39% vs. 49% in cohort A and 83% vs. 89% in cohorts B, C, and D combined. More women experienced VF, grade ≥3 signs and symptoms, but similar grade ≥3 diagnoses or laboratory abnormalities., Conclusions: More women than men entered the study with a resistance profile suggesting that their second-line regimen could have been effective in maintaining virologic suppression. The more frequent occurrence of grade ≥3 signs and symptoms in women suggests that tolerability issues were under recognized in women on protease inhibitor-based therapy.

The increasing use of cluster randomised trials in low-resource settings raises unique ethical issues. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomised Trials is the first international ethical guidance document specific to cluster trials, but it is unknown if it adequately addresses issues in low-resource settings. In this paper, we seek to identify any gaps in the Ottawa Statement relevant to cluster trials conducted in low-resource settings. Our method is (1) to analyse a prototypical cluster trial conducted in a low-resource setting ( PURE Malawi trial ) with the Ottawa Statement ; (2) to identify ethical issues in the design or conduct of the trial not captured adequately and (3) to make recommendations for issues needing attention in forthcoming revisions to the Ottawa Statement Our analysis identified six ethical aspects of cluster randomised trials in low-resource settings that require further guidance. The forthcoming revision of the Ottawa Statement should provide additional guidance on these issues: (1) streamlining research ethics committee review for collaborating investigators who are affiliated with other institutions; (2) the classification of lay health workers who deliver study interventions as health providers or research participants; (3) the dilemma experienced by investigators when national standards seem to prohibit waivers of consent; (4) the timing of gatekeeper engagement, particularly when researchers face funding constraints; (5) providing ancillary care in health services or implementation trials when a routine care control arm is known to fall below national standards and (6) defining vulnerable participants needing protection in low-resource settings., Competing Interests: Competing interests: CW receives consulting income from Eli Lilly and Company Canada., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We evaluated health-related quality of life (QoL) in HIV infection participants with virologic failure (VF) on first-line antiretroviral therapy (ART) in 9 resource-limited settings (RLS). ACTG SF-21 was completed by 512 participants at A5273 study entry; 8 domains assessed: general health perceptions (GHP), physical functioning (PF), role functioning (RF), social functioning (SF), cognitive functioning (CF), pain (P), mental health (MH), and energy/fatigue (E/F); each was scored between 0 (worst) to 100 (best). Mean QoL scores ranged from 67 (GHP) to 91 (PF, SF, CF). QoL varied by country; high VL and low CD4 were associated with worse QoL in most domains, except RF (VL only), SF (CD4 only) and CF (neither). Number of comorbidities, BMI and history of AIDS were associated with some domains. Relationships between QoL and VL varied among countries for all domains. The association of worse disease status with worse QoL may reflect low QoL when ART was initiated and/or deterioration associated with VF.

Background: Delivery of quality healthcare in resource-limited settings is an important, understudied public health priority. Thirty-day (early) hospital readmission is often avoidable and an important indicator of healthcare quality., Methods: We investigated the prevalence of all-cause early readmission and its associated factors using age and sex adjusted risk ratios (RR) and 95% confidence intervals (CI). A retrospective review of the medical ward database at Kamuzu Central Hospital in Lilongwe, Malawi was conducted between February and December 2013., Results: There were 3547 patients with an index admission of which 2776 (74.4%) survived and were eligible for readmission. Among these patients: 49.7% were male, mean age was 39.7 years, 36.1% were HIV-positive, 34.6% were HIV-negative, and 29.3% were HIV-unknown. The prevalence of early hospital readmission was 5.5%. Diagnoses associated with 30-day readmission were HIV-positive status (RR = 2.41; 95% CI: 1.64-3.53) and malaria (RR = 0.45; 95% CI: 0.22-0.91). Other factors associated with readmission were multiple diagnoses (excluding HIV) (RR = 1.52; 95% CI: 1.11-2.06), and prolonged length of stay (≥ 16 days) at the index hospitalization (RR = 3.63; 95% CI: 1.72-7.67)., Conclusion: Targeting HIV-infected inpatients with multiple diagnoses and longer index hospitalizations may prevent early readmission and improve quality of care.

Background: In the era of increased access to HIV testing and antiretroviral treatment (ART), the impact of HIV and ART status on inpatient mortality in Malawi is unknown., Methods: We prospectively followed adult inpatients at Kamuzu Central Hospital medical wards in Lilongwe, Malawi, between 2011 and 2012, to evaluate causes of mortality, and the impact of HIV and ART status on mortality. We divided the study population into five categories: HIV-negative, new HIV-positive, ART-naïve patients, new ART-initiators, and ART-experienced. We used multivariate binomial regression models to compare risk of death between categories., Results: Among 2911 admitted patients the mean age was 38.5 years, and 50% were women. Eighty-one percent (81%) of patients had a known HIV status at the time of discharge or death. Mortality was 19.4% and varied between 13.9% (HIV-negative patients) and 32.9% (HIV-positive patients on ART ≤1 year). In multivariable analyses adjusted for age, sex and leading causes of mortality, being new HIV-positive (RR = 1.64 95% CI: 1.16-2.32), ART-naive (RR = 2.28 95% CI: 1.66-2.32) or being a new ART-initiator (RR = 2.41 95% CI: 1.85-3.14) were associated with elevated risk of mortality compared to HIV-negative patients. ART-experienced patients had comparable mortality (RR = 1.33 95% CI: 0.94-1.88) to HIV-negative patients., Conclusion: HIV related mortality remains high among medical inpatients, especially among HIV-positive patients who recently initiated ART or have not started ART yet.

Introduction: Despite its wide use, passive partner notification (PN) has a low yield of sexual partners influenced by patient-related and health system (HS) factors., Methods: We conducted a qualitative study and clinic observations during a pre-intervention phase of a quality improvement (QI) project to identify HS factors that influenced passive PN at Bwaila STI unit (BSU) in Lilongwe Malawi from January to February 2016. We conducted 15 in-depth interviews with health workers and clinic observations for six clinic flow and PN processes at the clinic., Results: The majority of health workers felt that the lack of incentives for sexual partners or couples who presented to the clinic was the most important negative HS factor that influenced passive PN. We observed an average clinic start time of 09:02 hours. The average duration of the group health talk was 56 minutes and there was no difference in the time spent at the clinic between index cases and partners (1 hour 41 minutes versus 1 hour 36 minutes respectively)., Discussion: Lack of incentives for sexual partners or couples was the most important HS factors that impacted the yield of sexual partners. Interventions focusing on designing simple non-monetary incentives and QI of passive PN should be encouraged., Competing Interests: Conflict of Interest There are no conflicts of interests to declare.

Background: Many HIV-infected individuals present with advanced HIV disease. These patients are at high risk of death after antiretroviral therapy (ART) initiation, but risk factors for death in these patients are unclear., Methods: We used data from a multisite randomized trial comparing empiric vs. preventive tuberculosis therapy in HIV-infected adults initiating ART with CD4 T-cell counts less than 50 cells/μl to evaluate risk factors for death within 48 weeks after ART initiation. Cox proportional hazards models were fit to evaluate characteristics present at baseline and at 4 weeks after ART initiation, including the week 4 CD4 T-cell response and new opportunistic infections., Results: Of 850 enrolled, the median pre-ART CD4 T-cell count was 18 cells/μl and 67 (7.9%) died. Baseline risk factors for death included lymphadenopathy, lower CD4 T-cell count, lower serum albumin, high white blood cell count, elevated neutrophil percentage, and lower hemoglobin. Among 746 participants with data at week 4, the median changes in CD4 T-cell count and viral load for those who died (n = 43) vs. survived were 26 vs. 56 cells/μl and -2.7 vs. -2.7 log10 copies/ml, respectively. Each 20 cell/μl lower change in week 4 CD4 T-cell count was associated with a 20% increased risk of post week-4 mortality (adjusted hazard ratio 1.20, 1.01-1.42, P = .038)., Conclusion: Evidence of active infection and suboptimal immunologic response during the first month of ART are associated with death in the first year after ART initiation in those with advanced HIV disease taking tuberculosis preventive therapy. Strategies to reduce early mortality in this population warrant further investigation.

Background: Cardiovascular disease (CVD) is an emerging concern for HIV-infected patients. Hyperlipidaemia is a risk factor for CVD and a complication of protease-inhibitor-based antiretroviral therapy, but little is known about its incidence and risk factors in treated patients in resource-limited settings (RLS)., Methods: We conducted a secondary analysis of ACTG A5230 trial in which HIV-infected adults from India, Malawi, Tanzania, Thailand and South Africa, with virological relapse on first-line therapy were initiated on lopinavir/ritonavir (LPV/r) monotherapy. Hyperlipidaemia was a grade 2+ elevated fasting total cholesterol (FTC≥240 mg/dl) or fasting triglycerides (FTG≥500 mg/dl) or calculated low-density lipoprotein cholesterol (LDL≥160 mg/dl) based on measurements at weeks 12, 24, 48, 68 and 104. We evaluated factors potentially associated with quantitative lipid changes from baseline to week 12. These were age, sex, race, site and baseline body mass index, CD4 + T-cell count, HIV-1 RNA level and lipids., Results: 106 participants without hyperlipidaemia at baseline started LPV/r; median age 39 years, 68% Black African, 55% female. The cumulative incidence of hyperlipidaemia at week 104 was 48% (95% CI 36, 58%). At week 12, there were significant mean increases from baseline in FTC (17 mg/dl, P<0.001) and FTG (104 mg/dl, P<0.001). In multivariable analysis, higher baseline FTC (P=0.044), FTG (P=0.025), Thai (P<0.001) or Indian sites (P=0.020) versus African sites were associated with increased risk of hyperlipidaemia., Conclusions: In HIV-infected adults in RLS initiating LPV/r, hyperlipidaemia was common. Baseline lipid measurements and routine monitoring should be recommended in individuals starting LPV/r-based treatments with borderline high lipids.

Background: While previous research has provided evidence of the diagnostic accuracy of the GeneXpert MTB/RIF (GeneXpert), further information is needed about implementation in the real-world. This study evaluated the impact of the introduction of GeneXpert testing in a tertiary medical center according to the testing algorithm proposed by the National TB Control Program (NTP) guidelines., Methods: All adult medicine inpatient persons with presumptive TB admitted between November 2013 and March 2014 were eligible for GeneXpert sputum testing and followed to TB treatment initiation status., Results: We identified 932 persons with presumptive TB, of which 307 (32.9%) were GeneXpert tested. Those tested had an average age of 40 years, 49.2% (151) were male, 34.5% (106) were HIV positive, and 84.1% (249) presented with a cough. Of those GeneXpert tested, 28/307 (9.1%) tested positive, a 55.5% increase in detection compared to smear microscopy. However, the majority (44/72, 61%) of TB diagnoses were made by other modalities and not confirmed microbiologically. Of the 58 patients recommended to start treatment and discharged from the hospital, only 23 (40%) were documented to have started treatment at regional directly observed treatment short (DOTS) centers., Conclusions: GeneXpert contributed minimally to overall TB diagnosis and the cascade of care due to implementation challenges of sputum collection, empiric treatment, and weak linkage to care between inpatient and outpatient settings., (© The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The optimal approach of provider-initiated HIV testing and counseling (PITC) for inpatients in high-burden settings is unknown. We prospectively evaluated the implementation of task shifting from clinician-referral to counselor-initiated PITC on the medical wards of Kamuzu Central Hospital, Malawi. Most of patients (1905/3154, 60.4%) had an unknown admission HIV status. Counselors offered testing to 66.6% (1268/1905). HIV prevalence was 39.3%. Counselor-initiated PITC significantly increased HIV testing by 79% (643/2957 vs. 1228/3154), resulting in an almost 2-fold increase in patients with known HIV status (2447/3154 vs. 1249/3154) (both P < 0.0001), with 18.4% of those tested receiving a new diagnosis of HIV.

Introduction: The World Health Organization (WHO) recommends HIV Counseling and Testing (HCT) in a range of clinical settings. We describe the characteristics of patients diagnosed with HIV on the medical and surgical wards at a tertiary care hospital in Malawi., Methods: Under the universal opt-out HCT protocol we characterized the number of new HIV/AIDS infections and associated clinical features among hospitalized surgical and medical patients diagnosed during the course of admission., Results: All 2985 and 3959 medical and surgical patients, respectively, admitted between April 2012 and January 2013 were screened for HCT. 62% and 89% of medical and surgical patients, respectively, had an unknown status on admission and qualified for testing. Of the patients with an unknown status, a new HIV diagnosis was made in 20% and 7% of medical and surgical patients, respectively. Of the newly diagnosed patients with a CD4 count recorded, 91% and 67% of medical and surgical patients, respectively, had a count less than 350, qualifying for ART by Malawi ART guidelines. Newly HIV-diagnosed medical and surgical patients had an inpatient mortality of 20% and 2%, respectively., Discussion: While newly diagnosed HIV-positive medical patients had high inpatient mortality and higher rates of WHO stage 3 or 4 conditions, surgical patients presented with less advanced HIV, though still meeting ART initiation guidelines. The medical inpatient wards are an obvious choice for implementing voluntary counseling and testing (VCT), but surgical patients present with less advanced disease and starting treatment in this group could result in more years of life gained.

Background: Despite the high prevalence of HIV in adults (11 %) in Malawi, testing among surgical patients is not routine. We examined the feasibility of universal opt-out HIV testing and counseling (HTC) on the surgical wards of Kamuzu Central Hospital in Lilongwe, Malawi, and sought to further delineate the role of HIV in surgical presentation and outcome., Methods: We reviewed HTC and surgical admission records from May to October 2011 and compared these data to data collected prospectively on patients admitted from November 2011 through April 2012, after universal HTC implementation., Results: Prior to universal HTC, 270 of the 2,606 (10.4 %) surgical admissions were tested; 13 % were HIV-infected. After universal HTC implementation, HTC counselors reviewed 1,961 of the 2,488 admissions (79 %): 310 (16 %) had known status (157 seropositive, 153 seronegative) and 1,651 had unknown status (81 %). Among those with unknown status, 97 % (1,598, of 64 % of all admissions) accepted testing, of whom 9 % were found to be HIV-infected. Patients with longer lengths of stay (LOS) (mean = 11 vs. 5 days, p < 0.01) and those who underwent surgical intervention (odds ratio [OR] 2.5; confidence interval [CI] 2.0-3.1) were more likely to have a known status on discharge. HIV was more prevalence in patients with infection and genital/anal warts or ulcers and lower in trauma patients. HIV-positive patients received less surgical intervention (OR 0.69; CI 0.52-0.90), but there was no association between HIV status and length of stay or mortality., Conclusions: Universal opt-out HTC on the surgical wards was well accepted and increased the proportion of patients tested. High HIV prevalence in this setting merits implementation of universal HTC.