Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women.

BACKGROUND: There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women. METHODS: We conducted a phase 3, double-blind, randomized, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF. RESULTS: Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P = 0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions. CONCLUSIONS: No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 1 ClinicalTrials.gov number, NCT04994509.).

Comparison of 3 optimized delivery strategies for completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among people living with HIV in Uganda: A single-center randomized trial.

BACKGROUND: Expanding access to shorter regimens for tuberculosis (TB) prevention, such as once-weekly isoniazid and rifapentine taken for 3 months (3HP), is critical for reducing global TB burden among people living with HIV (PLHIV). Our coprimary hypotheses were that high levels of acceptance and completion of 3HP could be achieved with delivery strategies optimized to overcome well-contextualized barriers and that 3HP acceptance and completion would be highest when PLHIV were provided an informed choice between delivery strategies. METHODS AND FINDINGS: In a pragmatic, single-center, 3-arm, parallel-group randomized trial, PLHIV receiving care at a large urban HIV clinic in Kampala, Uganda, were randomly assigned (1:1:1) to receive 3HP by facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We assessed the primary outcome of acceptance and completion (≥11 of 12 doses of 3HP) within 16 weeks of treatment initiation using proportions with exact binomial confidence intervals (CIs). We compared proportions between arms using Fisher's exact test (two-sided α = 0.025). Trial investigators were blinded to primary and secondary outcomes by study arm. Between July 13, 2020, and July 8, 2022, 1,656 PLHIV underwent randomization, with equal numbers allocated to each study arm. One participant was erroneously enrolled a second time and was excluded in the primary intention-to-treat analysis. Among the remaining 1,655 participants, the proportion who accepted and completed 3HP exceeded the prespecified 80% target in the DOT (0.94; 97.5% CI [0.91, 0.96] p < 0.001), SAT (0.92; 97.5% CI [0.89, 0.94] p < 0.001), and Choice (0.93; 97.5% CI [0.91, 0.96] p < 0.001) arms. There was no difference in acceptance and completion between any 2 arms overall or in prespecified subgroup analyses based on sex, age, time on antiretroviral therapy, and history of prior treatment for TB or TB infection. Only 14 (0.8%) participants experienced an adverse event prompting discontinuation of 3HP. The main limitation of the study is that it was conducted in a single center. Multicenter studies are now needed to confirm the feasibility and generalizability of the facilitated 3HP delivery strategies in other settings. CONCLUSIONS: Short-course TB preventive treatment was widely accepted by PLHIV in Uganda, and very high levels of treatment completion were achieved in a programmatic setting with delivery strategies tailored to address known barriers. TRIAL REGISTRATION: ClinicalTrials.gov NCT03934931.

A randomized control trial to compare mortality in recipients of leucoreduced and non-leucoreduced whole blood transfusion in patients with cancer in Uganda.

BACKGROUND: Mortality benefit of transfusion with leucoreduced whole blood has not been demonstrated in the sub-Saharan Africa (SSA). We compared mortality in patients with cancer transfused with leucoreduced and non-leucoreduced whole blood in a SSA setting. METHODS: An open-label randomized controlled trial was conducted at the Uganda Cancer Institute where participants were randomized in a 1:1 ratio into the leucoreduced and non-leucoreduced whole blood transfusion arms. Leucocyte filtration of whole blood was performed within 72 h of blood collection. Patients aged ≥ 15 years who were prescribed blood transfusion by the primary physicians were eligible for study enrolment. Mortality difference was analyzed using intention-to-treat survival analysis and cox proportional hazard model was used to analyze factors associated with mortality. RESULTS: There were 137 participants randomized to the leucoreduced and 140 to the non-leucoreduced arms. Baseline characteristics were similar between the two arms. The median number of blood transfusions received was 1 (IQR, 1-3) unit and 2 (IQR, 1-3) units in the leucoreduced and non-leucoreduced arms respectively, p = 0.07. The 30-day mortality rate in the leucoreduced arm was 4.6% (95% CI, 2.1-10) and was 6.2% (95% CI, 3.2-12.1) in the non-leucoreduced arm (p = 0.57), representing an absolute effect size of only 1.6%. Increasing age (HR = 0.92, 95% CI, 0.86-0.98, p = 0.02) and Eastern Co-operative Oncology Group (ECOG) performance score of 1 (HR = 0.03, 95% CI, 0.00-0.31, p < 0.01) were associated with reduced 30-day mortality. CONCLUSIONS: The study failed to demonstrate mortality difference between cancer patients transfused with leucoreduced and non-leucoreduced whole blood. Although this study does not support nor refute universal leucoreduction to reduce mortality in patients with cancer in SSA, it demonstrates the feasibility of doing transfusion RCTs in Uganda, where a multi-center trial with an appropriate sample size is needed. TRIAL REGISTRATION: Pan African Clinical Trial Registry, https://pactr.samrc.ac.za/ (PACTR202302787440132). Registered on 06/02/2023.

M. tuberculosis Infection Attributable to Exposure in Social Networks of Tuberculosis Cases in an Urban African Community.

Background: The persistence of tuberculosis today and its global disparity send a powerful message that effective tuberculosis control must respond to its regional epidemiology. Active case finding through contact investigation is a standard protocol used for tuberculosis control, but its effectiveness has not been established, especially in endemic areas. Methods: To quantify the potential effectiveness of contact investigation in Kampala, Uganda, we used a cross-sectional design to evaluate the social networks of 123 tuberculosis index cases and 124 controls without tuberculosis. Results: Tuberculous infection was present in 515 of 989 tuberculosis case contacts (52.1%) and 396 of 1026 control contacts (38.6%; adjusted prevalence ratio, 1.4; 95% CI, 1.3-1.6). The proportion of infected participants with known exposure within the social network of the tuberculosis case was 35%. The population-attributable fraction was 11.1% for any known exposure, with 7.3% attributable to household exposure and 3.4% attributable to extrahousehold exposure. Conclusions: This low population-attributable fraction indicates that contact tracing in the social networks of index cases will have only a modest effect in reducing tuberculous infection in a community. New approaches to community-level active case finding are needed.

Evaluation of a national program to distribute free face masks in Uganda: Evidence from Mbale District.

BACKGROUND: COVID-19 posed a major threat to countries around the world, but many nations in sub-Saharan Africa avoided large-scale outbreaks. In Uganda, the government first enacted strict lockdowns but later focused on public health policies like masking and distancing. The government also embarked on an ambitious campaign to deliver a free face mask to all Ugandan citizens (approx. 30 million masks). We test whether mask distribution, and public education and encouragement of mask use by community health volunteers, affected mask behavior. METHODS: We collected data about mask behavior before and after masks were distributed in the Mbale district of Uganda. Trained enumerators directly observed mask wearing in public places and asked about mask use via phone surveys. We compared observed and self-reported mask behavior before and after masks were distributed. We also tested whether training volunteers from randomly selected villages to educate the public about COVID-19 and masks affected behavior, attitudes, and knowledge among mask recipients. RESULTS: We collected 6,381 direct observations of mask use at baseline (February 2021) and 19,855 observations at endline (April 2021). We conducted a listing of 9,410 households eligible for phone surveys and randomly selected 399 individuals (4.2%) at baseline and 640 (6.8%) at endline. Fewer than 1% of individuals were observed wearing masks at baseline: 0.9% were seen with a mask and 0.5% wore masks over mouth and nose. Mask wearing significantly increased at endline but remained low: 1.8% of people were observed with masks and 1.1% were seen wearing masks correctly after the distribution campaign. At the same time, a high proportion of people reported using masks: 63.0% of people reported using masks at baseline and 65.3% at endline when walking around their villages. When respondents were asked about mask use in public places, 94.7% reported using masks at baseline and 97.4% reported using masks at endline. We found no differences in knowledge, behavior, or attitudes among mask recipients in villages where volunteers were tasked with conveying information about COVID-19 and masks during distribution. CONCLUSION: Mask use remained low in Mbale district of Uganda during study observation period even after free masks were distributed. Encouraging new health behaviors may need to involve more intensive interventions that include reminders and address social norms.

Implementation challenges in preeclampsia care: perspectives from health care professionals in urban Uganda.

BACKGROUND: Sub-Saharan Africa bears the burden of 70% of maternal deaths worldwide, of which ∼10% are attributable to hypertensive disorders of pregnancy, primarily complications of preeclampsia. In other global settings, outcomes of pregnancies affected by preeclampsia are improved with timely and effective medical care. OBJECTIVE: This study aimed to explore the perspectives of local health care professionals on how preeclampsia care is currently delivered in the study setting and what challenges they experience in providing prompt and safe care. We identified specific objectives of exploring stakeholder perceptions of (1) recognizing preeclampsia and (2) timely intervention when preeclampsia is diagnosed. We also explored the wider system factors (eg, cultural, financial, and logistic challenges) that health care professionals perceived as affecting their ability to deliver optimal preeclampsia care. STUDY DESIGN: Individual semistructured interviews were conducted with health care professionals and stakeholders. The findings were analyzed using thematic analysis. RESULTS: Thirty-three participants contributed to the study, including doctors and midwives with varying degrees of clinical experience and external stakeholders. The following 5 key themes emerged: delayed patient presentation, recognizing the unwell patient with preeclampsia, the challenges of the existing triage system, stakeholder disconnect, and ways of learning from each other. Health care professionals referenced an important psychosocial perspective associated with preeclampsia in the study setting, which may influence the likelihood of seeking care through traditional healers rather than hospital-based routes. CONCLUSION: We identify the key barriers to improving maternal and neonatal outcomes of preeclampsia, described at both the institutional level and within the wider setting. The study provides invaluable contextual information that suggests that a systems-based approach to health care quality improvement may be effective in reducing rates of maternal and neonatal morbidity and mortality.

In Utero Mother-to-Child Transmission of HIV-1 and the Associated Factors in Rwanda, Africa.

Mother-to-child transmission (MTCT) of HIV-1 and associated mortality continue to occur at unacceptably high rates, despite the extensive rollout and implementation of Prevention of Mother-to-Child Transmission (PMTCT) Programs, including the modified versions of Option B and B+ in 2010 and 2012, respectively. Maternal HIV viral load (VL) and socio-behavioral factors sustaining MTCT in Rwanda remain largely unexplored. The study examined the effects of socio-behavioral factors on maternal VL and their contribution to in utero transmission of HIV-1 in the context of Rwanda's HIV epidemic. A prospective cohort study was conducted in 862 mother-baby pairs enrolled in 10 PMTCT clinics in Rwanda. VL was determined on plasma and Dried Blood Spots samples, whereas HIV DNA PCR was performed to determine in utero MTCT of HIV of the babies immediately at birth and then at 3 weeks, 4 weeks, 6 months, and 18 months, together with HIV antibody testing to determine other forms of MTCT of HIV. Quantitative data on socio-behavioral factors were collected through a structured questionnaire. Linear regression and univariate analysis of variances using SPSS 25.0 were used to test the hypotheses. We found 22/862 (2.55%) cases of in utero transmission and a total of 32/862 (3.7%) cases of MTCT of HIV-1 over 18 study months. Maternal VL at delivery was significantly associated with the risk of in utero transmission of HIV-1. Socio-behavioral factors associated with elevated maternal VL at delivery included alcohol, smoking, multiple sexual partners, mothers' income, being a casual laborer, and distance to health care services. We report an MTCT rate of 3.7% in our study population over the 18 months, higher than the national average of 1.5%, the majority of which occurred in utero. MTCT cases were attributable to failure to suppress maternal VL.

Prevalence of alcohol use by gender and HIV status in rural Uganda.

BACKGROUND: Alcohol use is a major contributor to mortality and morbidity worldwide. Uganda has a high level of alcohol use per capita. Compared to men, women are less likely to consume alcohol globally; however, women who drink have increased risks for co-occurring conditions, including depression, intimate partner violence, and HIV. This study assessed the prevalence of alcohol use and correlates of harmful alcohol use by gender and HIV status in rural Uganda. METHODS: We used cross-sectional data from a study among women and men aged 15-59 residing in rural, central Uganda and accepting home-based HIV testing (Nov 2017 to Dec 2020). We estimated the prevalence of levels of alcohol use (categorized as no alcohol use (score 0), low (score 1-3 for men; 1-2 for women), medium (score 4-5 for men; 3-5 for women), high (score 6-7), and very-high (score 8-12) use with the AUDIT-C), stratified by gender and HIV status. We assessed correlates of harmful alcohol use using multivariable logistic regression models for women and men. RESULTS: Among 18,460 participants, 67% (95% CI: 66-67%) reported no alcohol use, 16% (95% CI: 16-17%) reported low, 5% (95% CI: 4.8-5%) reported medium, 5% (95% CI: 4-5%) reported high, and 3% (95% CI: 2.8-3) reported very high alcohol use. Compared to women, men were more likely to report alcohol use (Chi-squared p-value<0.0001). People diagnosed with HIV (both newly diagnosed and previously aware of their status prior to home-based HIV testing) were more likely to report low, medium, high, and very high alcohol use compared to those who were HIV negative (Chi-squared p-value<0.0001). Among women, those who were newly diagnosed were more likely report alcohol use, compared to those who were HIV negative. In multivariable models, being newly diagnosed with HIV (compared to HIV negative) increased the odds of harmful alcohol use among women, but not men. CONCLUSION: While alcohol use was higher among men and people living with HIV, being newly diagnosed with HIV had a stronger relationship with harmful alcohol use among women than men. More research is needed to understand how alcohol use may increase the risks of HIV acquisition among women and to identify gender-responsive services to address harmful alcohol use and increase access to HIV testing and linkage to care for women who use harmful levels of alcohol.

Adverse events reported during weekly isoniazid-rifapentine (3HP) tuberculosis preventive treatment among people living with HIV in Uganda.

Background: Short-course tuberculosis (TB) prevention regimens, including 12 weeks of isoniazid and rifapentine (3HP), are increasingly used in high TB-burden countries. Despite established safety and tolerability in efficacy trials, 3HP-related adverse events (AE) could differ in routine settings. Real-world data on AE type, frequency, and timing is crucial for health systems considering 3HP programmatic scale-up. Methods: We reviewed AEs among people living with HIV (PLHIV) participating in a pragmatic implementation trial of facilitated 3HP taken by directly observed therapy (DOT) or self-administered therapy (SAT) in Kampala, Uganda, and classified them using the Common Terminology Criteria for Adverse Events. We assessed AE timing and summarized related clinical actions including lab tests, diagnoses made, medications prescribed, and treatment interruptions. Results: Among 1655 PLHIV treated between July 2020-September 2022, 270 (16.3%) reported 451 events; main issues included general (7%), nervous system (6%), musculoskeletal (5%), gastrointestinal (5%), and dermatologic (3%) disorders. Most (61%) occurred within 6 weeks of initiating 3HP. Among those with events, 211 (78%) required further clinician evaluation, 202 (75%) required laboratory testing, 102 (38%) had medications prescribed, 40 (15%) had treatment paused, and 14 (5%) discontinued 3HP. Women, those multidimensionally impoverished, and DOT recipients were more likely to report an AE. SAT users and later enrollees were more likely to have 3HP interrupted or stopped due to an AE. Conclusions: In a routine setting, 3HP was safe with 16% of PLHIV reporting AEs and only 3% requiring temporary or permanent treatment interruption. These findings support 3HP expansion in routine HIV/AIDS care settings for TB prevention.

COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase.

Little is known about the pathobiology of SARS-CoV-2 infection in sub-Saharan Africa, where severe COVID-19 fatality rates are among the highest in the world and the immunological landscape is unique. In a prospective cohort study of 306 adults encompassing the entire clinical spectrum of SARS-CoV-2 infection in Uganda, we profile the peripheral blood proteome and transcriptome to characterize the immunopathology of COVID-19 across multiple phases of the pandemic. Beyond the prognostic importance of myeloid cell-driven immune activation and lymphopenia, we show that multifaceted impairment of host protein synthesis and redox imbalance define core biological signatures of severe COVID-19, with central roles for IL-7, IL-15, and lymphotoxin-α in COVID-19 respiratory failure. While prognostic signatures are generally consistent in SARS-CoV-2/HIV-coinfection, type I interferon responses uniquely scale with COVID-19 severity in persons living with HIV. Throughout the pandemic, COVID-19 severity peaked during phases dominated by A.23/A.23.1 and Delta B.1.617.2/AY variants. Independent of clinical severity, Delta phase COVID-19 is distinguished by exaggerated pro-inflammatory myeloid cell and inflammasome activation, NK and CD8+ T cell depletion, and impaired host protein synthesis. Combining these analyses with a contemporary Ugandan cohort of adults hospitalized with influenza and other severe acute respiratory infections, we show that activation of epidermal and platelet-derived growth factor pathways are distinct features of COVID-19, deepening translational understanding of mechanisms potentially underlying SARS-CoV-2-associated pulmonary fibrosis. Collectively, our findings provide biological rationale for use of broad and targeted immunotherapies for severe COVID-19 in sub-Saharan Africa, illustrate the relevance of local viral and host factors to SARS-CoV-2 immunopathology, and highlight underemphasized yet therapeutically exploitable immune pathways driving COVID-19 severity.

Autologous adipose-derived stromal vascular fraction (SVF) in scar treatment among patients with keloids and hypertrophic scars: a systematic review and meta-analysis of current practices and outcomes.

BACKGROUND: Keloids and hypertrophic scars are some of the most common skin conditions globally, associated with poor treatment response and high recurrence rates. Autologous adipose-derived stromal vascular fraction (SVF) is increasingly recognized as an emerging therapy albeit limited literature on its outcome in scar treatment. This review aimed to describe the current practices and outcomes of adipose-derived stromal Vascular Fraction in scar treatment. METHODS: This systematic review assessed articles describing the use of SVF in scar treatment published between 2000 and 2023. Article searches of Medline/PubMed, Cochrane Library, and Embase databases using Mesh terms and the Boolean operators ("AND", "OR") by two independent researchers were done whilst following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Clinical studies assessing SVF in scar treatment with a primary outcome measure being an improvement in scar characteristics including the thickness, scar assessment scores were included. RESULTS: Among the 1425 studies identified in the search, 20 studies met the inclusion criteria with a total of 493 patients included. Eight of these were clinical trials with the rest being observational studies. Follow-up ranged from 3 months to 24 months. In all studies, there was an improvement in scar characteristics following single-dose treatment with SVF or its equivalent. All studies reported SVF to be safe. CONCLUSION: The review found that autologous adipose-derived SVF is a clinically effective therapy for keloids and scar treatment.

Frequency of red blood cell allo-immunization in patients undergoing blood transfusion at the Uganda Cancer Institute.

Background: There is limited data on red blood cell (RBC) alloimmunization in patients with cancer in sub-Saharan Africa (SSA). We examined the frequency of RBC alloimmunization in transfused patients with cancers in Uganda. Methods: A randomized control trial was conducted on participants at the Uganda Cancer Institute. Eligible participants were age ≥15 years and required blood transfusion. Participants were randomized to receive either leucoreduced or non-leucoreduced blood transfusion. Participants' plasma samples were screened for RBC alloantibodies at enrolment and 3-4 weeks after blood transfusion using a 2-cell panel of reagent group O RBCs using the tube method. Antibody identification was performed using a 10-cell panels of reagent RBCs. Participants were considered alloimmunized if antibodies to RBC antigens were identified. Results: A total of 277 participants were randomized (leucoreduced blood, n=137; non-leucoreduced blood, n=140). Overall, the most represented diagnoses were gynaecological cancers (n=88, 31.8%), acute leukaemia (n=35, 12.6%), and gastrointestinal cancers (n=25, 9.0%). Concomitant HIV infection was present in 26 (9.4%) participants. Most participants received <5 units of blood during the study. No study participant developed allo-antibodies. Conclusion: There was no RBC alloimmunization in participants with cancers. Routine RBC allo-antibody screening in all patients with cancer in SSA requires further research.

Prevalence and antimicrobial resistance profiles of Neisseria gonorrhea and Chlamydia trachomatis isolated from individuals attending STD clinics in Kampala, Uganda

Background: Sexually transmitted diseases (STDs) management in sub-Saharan Africa is syndromic but molecular diagnostics provide quicker, sensitive diagnosis and treatment. Effective STD control hinges on identification and treatment of infected persons and sexual partner contact tracing. Objectives: This study assessed feasibility of using the Xpert CT/NG test to identify prevalent Chlamydia trachomatis (CT) and Neisseria gonorrhea (NG) infections among STD clinic attendees and their sexual partners and tested for antimicrobial resistance for N. gonorrhea. Methods: A cross-sectional study was conducted at 4 outpatient STD clinics in Kampala, Uganda from February 2019 to October 2019. Participants received a syndromic diagnosis, were tested for NG and CT, as well as their sexual partners. Urine (men) and high vaginal swabs (women) were collected, examined using Xpert CT/NG assay. A total of 79 participants were enrolled at baseline of whom 25 had CT/NG. 21 partners of infected baseline participants and 7 partners of the 21 primary partners were enrolled. Results: The mean age of the reported sexual partners was 26 (18-43) years. The prevalence of NG was 25% at baseline and 18 % for CT. Nine (11.4%) people were dually infected. Men were more likely to have NG (p<0.001) at multivariable level. Two participants tested HIV-1 positive. On microbiological culture, 8 samples (2.5%) grew NG, and all were resistant to penicillin, ciprofloxacin. For CT, we found a preponderance of the F-serovar in this population. Conclusion: The most prevalent organism was Neisseria gonorrhea. Generally, the prevalence of CT and NG was high. Infection proportions increased among primary partners, particularly women. Etiologic testing without partner tracing and treatment may underestimate burden of CT/NG in this population and contribute to re-infection