Implementation of a safer conception programme for HIV-affected men and women in rural Uganda.

We integrated safer conception care into a Ugandan HIV clinic. People with HIV (PWH), or partnered with a PWH, and desiring children were eligible for the Healthy Families Clinic Program. Clients completed quarterly safer conception counselling visits and questionnaires to provide information around method preferences and outcomes (partner pregnancy, partner seroconversion). We used clinic level data to evaluate longitudinal viral suppression among PWH. Between November 2016 and January 2020, 361 clients (53% men) accessed services. 75% were PWH (51% women, 96% men): 99% were on antiretroviral therapy (ART) and most reported HIV-sero-different partnerships (97%). Frequently selected safer conception methods included ART (86%), timed condomless sex (74%), and PrEP (40%) with important differences by HIV-serostatus and gender. 22.5% reported pregnancy. Most (97%) PWH were virally suppressed at enrolment and 81% of non-virally suppressed PWH were virally suppressed at 15 months. Two HIV-negative clients (2%) had HIV seroconversion. There is demand for safer conception care in a public sector HIV-clinic in Uganda. Men and women have unique safer conception care preferences. The majority of clients engaged in safer conception care had viral suppression at follow up.

Sexually transmitted infection (STI) knowledge and perceptions among people in HIV-sero-different partnerships in rural southwestern Uganda.

Globally, over one million people acquire curable sexually transmitted infections (STI) each day. Understanding how people think about STIs is key to building culturally appropriate STI prevention and treatment programs. We explored STI knowledge and perceptions in rural, southwestern Uganda to inform future interventions. From August 2020 to December 2020, we conducted individual in-depth interviews among adult men and women (≥18 years) with recent or current personal or partner pregnancy, a history of an STI diagnosis and treatment, and membership in an HIV-sero-different relationship. Interviews explored STI knowledge, perceptions, and barriers and facilitators to engaging in STI care. We used inductive and deductive approaches to generate a codebook guided by the healthcare literacy skills framework in a thematic analysis. Ten men with STI, five of their female partners, eighteen women with STI, and four of their male partners participated in individual in-depth interviews. The median age was 41 (range 27-50) for men and 29 (range 22-40) for women. Sixteen (43%) participants were with HIV. Significant themes include: 1) Participants obtained STI knowledge and information from the community (friends, family members, acquaintances) and medical professionals; 2) While participants knew STIs were transmitted sexually, they also believed transmission occurred via non-sexual mechanisms. 3) Participants associated different connotations and amounts of stigma with each STI, for example, participants reported that syphilis was passed down "genetically" from parent to child. 4) Participants reported uncertainty about whether STIs affected pregnancy outcomes and whether antenatal STI treatment was safe. The complicated nature of STIs has led to understandable confusion in settings without formal sexual healthcare education. Robust counseling and education prior to sexual debut will help allow men and women to understand the signs, symptoms, and treatments necessary for STI cure and to navigate often complicated and overburdened healthcare systems.

Social networks and HIV treatment adherence among people with HIV initiating treatment in rural Uganda and peri-urban South Africa.

Timely initiation of and adherence to antiretroviral therapy (ART) is critical for improving HIV outcomes and reducing HIV transmissibility. Social networks, or the social relationships individuals have with each other, have been linked with positive health outcomes, but less is known about the extent to which social network composition and structure are associated with improved ART adherence among people living with HIV (PLWH). We conducted an ego-centric network study among 828 previously ART-naïve PLWH presenting for ART initiation at 11 clinics in Mbarara, Uganda (rural population) and Gugulethu, South Africa (peri-urban population). We collected social network data using name generator and name interpreter questions. ART adherence was monitored over 12 months using wireless monitors (Wisepill). Our primary outcome of interest was ART adherence during the 12-month follow-up period. We used generalized linear models to estimate the associations between network measures and ART adherence. PLWH at the Uganda site (compared with the South Africa site) were less isolated, had larger social networks, and had more social ties providing sufficient social support; they were also more likely to bridge different social groups whereby not all social ties were connected to each other. In Uganda, social isolation was associated with a 5.5 percentage point reduction in ART adherence (95% confidence interval [CI] -9.95 to -1.13; p = 0.014), while having more same gender social ties was associated with higher ART adherence (b = 0.13, 95% CI 0.02-0.25, p = 0.025). In South Africa, there was no association between social isolation and ART adherence, and having more friendship ties (vs. family ties) was associated with lower ART adherence (b = -2.20, 95% CI -3.56 to -0.84; p = 0.002). Identifying and supporting PLWH who are isolated may facilitate optimal adherence, but understanding how networks differentially affect ART adherence by country context is important.

Determinants of health-related quality of life in people with Human Immunodeficiency Virus, failing first-line treatment in Africa.

BACKGROUND: Antiretroviral treatment improves health related quality of life (HRQoL) of people with human immunodeficiency virus (PWH). However, one third initiating first-line treatment experience virological failure and the determinants of HRQoL in this key population are unknown. Our study aims to identify determinants of among PWH failing antiretroviral treatment in sub-Saharan Africa. METHODS: We analysed data from a cohort of PWH having virological failure (> 1,000 copies/mL) on first-line ART in South Africa and Uganda. We measured HRQoL using the EuroQOL EQ-5D-3L and used a two-part regression model to obtain by-country analyses for South Africa and Uganda. The first part identifies risk factors that were associated with the likelihood of participants reporting perfect health (utility = 1) versus non-perfect health (utility < 1). The second part identifies risk factors that were associated with the EQ-5 L-3L utility scores for participants reporting non-perfect health. We performed sensitivity analyses to compare the results between the two-part model using tobit models and ordinary least squares regression. RESULTS: In both countries, males were more likely to report perfect health and participants with at least one comorbidity were less likely to report perfect health. In South Africa, participants with side effects and in Uganda those with opportunistic infections were also less likely to report perfect health. In Uganda, participants with 100% ART adherence were more likely to report perfect health. In South Africa, high HIV viral load, experiencing ART side effects, and the presence of opportunistic infections were each associated with lower HRQoL, whereas participants with 100% ART adherence reported higher HRQoL. In Uganda participants with lower CD4 count had lower HRQoL. CONCLUSION: Markers of advanced disease (opportunistic infection, high viral load, low CD4), side effects, comorbidities and lack of ART adherence negatively impacted HRQoL for PWH experiencing virological failure. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02787499.

Seemingly Unrelated Regression Analysis of the Cost and Health-Related Quality of Life Outcomes of the REVAMP Randomized Clinical Trial.

OBJECTIVE: This study aimed to evaluate the 9-month cost and health-related quality of life (HRQOL) outcomes of resistance versus viral load testing strategies to manage virological failure in low-middle income countries. METHODS: We analyzed secondary outcomes from the REVAMP clinical trial: a pragmatic, open label, parallel-arm randomized trial investigating resistance versus viral load testing for individuals failing first-line treatment in South Africa and Uganda. We collected resource data, valued according to local cost data and used the 3-level version of EQ-5D to measure HRQOL at baseline and 9 months. We applied seemingly unrelated regression equations to account for the correlation between cost and HRQOL. We conducted intention-to-treat analyses with multiple imputation using chained equations for missing data and performed sensitivity analyses using complete cases. RESULTS: For South Africa, resistance testing and opportunistic infections were associated with statistically significantly higher total costs, and virological suppression was associated with lower total cost. Higher baseline utility, higher cluster of differentiation 4 (CD4) count, and virological suppression were associated with better HRQOL. For Uganda, resistance testing and switching to second-line treatment were associated with higher total cost, and higher CD4 was associated with lower total cost. Higher baseline utility, higher CD4 count, and virological suppression were associated with better HRQOL. Sensitivity analyses of the complete-case analysis confirmed the overall results. CONCLUSION: Resistance testing showed no cost or HRQOL advantage in South Africa or Uganda over the 9-month REVAMP clinical trial.

High PrEP uptake and objective longitudinal adherence among HIV-exposed women with personal or partner plans for pregnancy in rural Uganda: A cohort study.

BACKGROUND: In Uganda, fertility rates and adult HIV prevalence are high, and many women conceive with partners living with HIV. Pre-exposure prophylaxis (PrEP) reduces HIV acquisition for women and, therefore, infants. We developed the Healthy Families-PrEP intervention to support PrEP use as part of HIV prevention during periconception and pregnancy periods. We conducted a longitudinal cohort study to evaluate oral PrEP use among women participating in the intervention. METHODS AND FINDINGS: We enrolled HIV-negative women with plans for pregnancy with a partner living, or thought to be living, with HIV (2017 to 2020) to evaluate PrEP use among women participating in the Healthy Families-PrEP intervention. Quarterly study visits through 9 months included HIV and pregnancy testing and HIV prevention counseling. PrEP was provided in electronic pillboxes, providing the primary adherence measure ("high" adherence when pillbox was opened ≥80% of days). Enrollment questionnaires assessed factors associated with PrEP use. Plasma tenofovir (TFV) and intraerythrocytic TFV-diphosphate (TFV-DP) concentrations were determined quarterly for women who acquired HIV and a randomly selected subset of those who did not; concentrations TFV ≥40 ng/mL and TFV-DP ≥600 fmol/punch were categorized as "high." Women who became pregnant were initially exited from the cohort by design; from March 2019, women with incident pregnancy remained in the study with quarterly follow-up until pregnancy outcome. Primary outcomes included (1) PrEP uptake (proportion who initiated PrEP); and (2) PrEP adherence (proportion of days with pillbox openings during the first 3 months following PrEP initiation). We used univariable and multivariable-adjusted linear regression to evaluate baseline predictors selected based on our conceptual framework of mean adherence over 3 months. We also assessed mean monthly adherence over 9 months of follow-up and during pregnancy. We enrolled 131 women with mean age 28.7 years (95% CI: 27.8 to 29.5). Ninety-seven (74%) reported a partner with HIV and 79 (60%) reported condomless sex. Most women (N = 118; 90%) initiated PrEP. Mean electronic adherence during the 3 months following initiation was 87% (95% CI: 83%, 90%). No covariates were associated with 3-month pill-taking behavior. Concentrations of plasma TFV and TFV-DP were high among 66% and 47%, 56% and 41%, and 45% and 45% at months 3, 6, and 9, respectively. We observed 53 pregnancies among 131 women (1-year cumulative incidence 53% [95% CI: 43%, 62%]) and 1 HIV-seroconversion in a non-pregnant woman. Mean pillcap adherence for PrEP users with pregnancy follow-up (N = 17) was 98% (95% CI: 97%, 99%). Study design limitations include lack of a control group. CONCLUSIONS: Women in Uganda with PrEP indications and planning for pregnancy chose to use PrEP. By electronic pillcap, most were able to sustain high adherence to daily oral PrEP prior to and during pregnancy. Differences in adherence measures highlight challenges with adherence assessment; serial measures of TFV-DP in whole blood suggest 41% to 47% of women took sufficient periconception PrEP to prevent HIV. These data suggest that women planning for and with pregnancy should be prioritized for PrEP implementation, particularly in settings with high fertility rates and generalized HIV epidemics. Future iterations of this work should compare the outcomes to current standard of care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03832530 https://clinicaltrials.gov/ct2/show/NCT03832530?term=lynn+matthews&cond=hiv&cntry=UG&draw=2&rank=1.

'I still desire to have a child': a qualitative analysis of intersectional HIV- and childlessness-related stigma in rural southwestern Uganda.

This study explored the intersecting forms of stigma experienced by HIV-serodifferent couples with unmet reproductive goals in rural Uganda. The parent mixed-methods study, which included 131 HIV-exposed women with plans for pregnancy, offered comprehensive HIV prevention counselling and care over a nine-month period. In-depth interviews were conducted with 37 women and seven male partners to explore care experiences and the use of safer conception strategies. This secondary analysis explored how challenges conceiving informed pregnancy plans and HIV prevention behaviours. The following themes were developed (1) partnership conflicts arise from HIV- and infertility-related forms of stigma, contributing to gender-based violence, partnership dissolution and the pursuit of new partners; (2) cultural and gender norms pressure men and women to conceive and maintain partnerships, which is complicated by the stigma directed towards serodifferent couples; (3) frustration with low partner participation in safer conception strategies led to the decreased use of these methods of HIV prevention; (4) health care provider support promotes continued hope of conception and helps overcome stigma. In HIV-affected partnerships, these intersecting forms of stigma may impact HIV prevention. Seeking to fulfil their reproductive needs, partners may increase HIV transmission opportunities as they engage in condomless sex with additional partners and decrease adherence to prevention strategies. Future research programmes should consider the integration of fertility counselling with reproductive and sexual health care.

STI prevalence, incidence, and partner notification among women in a periconception HIV prevention program in Uganda.

BACKGROUND: We provided sexually transmitted infection (STI) screening and facilitated partner notification and treatment among women participating in a periconception HIV prevention program in southwestern Uganda to understand follow-up STI incidence. METHODS: Women at-risk for HIV exposure while planning for pregnancy completed laboratory screening for chlamydia, gonorrhea, trichomoniasis, and syphilis at enrollment and 6 months of follow-up and/or incident pregnancy; facilitated partner notification and treatment were offered for those with positive tests. We performed a logistic regression to determine correlates of follow-up STI. RESULTS: Ninety-four participants completed enrollment STI screening with a median age of 29 (IQR 26-34); 23 (24%) had ≥1 STI. Of the 23 participants with enrollment STI(s), all completed treatment and 19 (83%) returned for follow-up; 18 (78%) reported delivering partner notification cards and discussing STIs with partner(s), and 14 (61%) reported all partners received STI treatment. Of the 81 (86%) who successfully completed follow-up STI screening, 17 (21%) had ≥1 STI. The STI incidence rate was 29.0 per 100 person-years. In univariable regression analysis, enrollment STI, younger age, less education, and alcohol consumption were all significantly associated with follow-up STI. CONCLUSIONS: We demonstrated high enrollment and follow-up STI rates and moderate participant-reported partner treatment among women planning for pregnancy in Uganda despite partner notification and treatment. Novel STI partner notification and treatment interventions are needed to decrease the STI burden, especially among women planning for and with pregnancy.

A qualitative exploration to understand barriers and facilitators to daily oral PrEP uptake and sustained adherence among HIV-negative women planning for or with pregnancy in rural Southwestern Uganda.

INTRODUCTION: Antiretroviral pre-exposure prophylaxis (PrEP) may reduce periconception and pregnancy HIV incidence among women in settings, where gender power imbalances limit HIV testing, engagement in care and HIV viral suppression. We conducted qualitative interviews to understand factors influencing periconception and pregnancy PrEP uptake and use in a cohort of women (Trial registration: NCT03832530) offered safer conception counselling in rural Southwestern Uganda, where PrEP uptake was high. METHODS: Between March 2018 and January 2019, in-depth interviews informed by conceptual frameworks for periconception risk reduction and PrEP adherence were conducted with 37 women including those with ≥80% and <80% adherence to PrEP doses measured by electronic pill cap, those who never initiated PrEP, and seven of their male partners. Content and dyadic analyses were conducted to identify emergent challenges and facilitators of PrEP use within individual and couple narratives. RESULTS: The median age for women was 33 years (IQR 28, 35), 97% felt likely to acquire HIV and 89% initiated PrEP. Individual-level barriers included unwillingness to take daily pills while healthy, side effects and alcohol use. Women overcame these barriers through personal desires to have control over their HIV serostatus, produce HIV-negative children and prevent HIV transmission within partnerships. Couple-level barriers included nondisclosure, mistrust and gender-based violence; facilitators included shared goals and perceived HIV protection, which improved communication, sexual intimacy and emotional support within partnerships through a self-controlled method. Community-level barriers included multi-level stigma related to HIV, ARVs/PrEP and serodifference; facilitators included active peer, family or healthcare provider support as women aspired to safely meet socio-cultural expectations to conceive and preserve serodifferent relationships. Confidence in PrEP effectiveness was promoted by positive peer experiences with PrEP and ongoing HIV testing. CONCLUSIONS: Multi-level forms of HIV-, serodifference- and disclosure-related stigma, side effects, pill burden, alcohol use, relationship dynamics, social, professional and partnership support towards adaptation and HIV risk reduction influence PrEP uptake and adherence among HIV-negative women with plans for pregnancy in rural Southwestern Uganda. Confidence in PrEP, individually controlled HIV prevention and improved partnership communication and intimacy promoted PrEP adherence. Supporting individuals to overcome context-specific barriers to PrEP use may be an important approach to improving uptake and prolonged use.

Client and Provider Experiences in Uganda Suggest Demand for and Highlight the Importance of Addressing HIV Stigma and Gender Norms Within Safer Conception Care.

Safer conception counseling supports HIV-serodifferent couples to meet reproductive goals while minimizing HIV transmission risk, but has not been integrated into routine HIV care. We piloted a novel safer conception program in an established public-sector HIV clinic in Uganda to inform future implementation. In-depth interviews and counseling observations explored experiences of program clients and healthcare providers to assess program acceptability, appropriateness, and feasibility. Fifteen index clients (8 women, 7 men), 10 pregnancy partners, and 10 providers completed interviews; 15 participants were living with HIV. Ten observations were conducted. We identified four emergent themes: (1) High demand for safer conception services integrated within routine HIV care, (2) Evolving messages of antiretroviral treatment as prevention contribute to confusion about HIV prevention options, (3) Gender and sexual relationship power inequities shape safer conception care, and (4) HIV-related stigma impacts safer conception care uptake. These findings confirm the need for safer conception care and suggest important implementation considerations.

Sexual and Relationship Benefits of a Safer Conception Intervention Among Men with HIV Who Seek to Have Children with Serodifferent Partners in Uganda.

Many men with HIV (MWH) in Uganda desire children, yet seldom receive reproductive counseling related to HIV care. Because men are under engaged in safer conception programming, they miss opportunities to reap the benefits of these programs. The objective of this sub-analysis was to explore the relationship and intimacy benefits of integrating safer conception counseling and strategies into HIV care, an emergent theme from exit interviews with men who participated in a pilot safer conception program and their partners. Twenty interviews were conducted with MWH who desired a child in the next year with an HIV-uninfected/status unknown female partner, and separate interviews were conducted with female partners (n = 20); of the 40 interviews, 28 were completed by both members of a couple. Interviews explored experiences participating in The Healthy Families program, which offered MWH safer conception counseling and access to specific strategies. Data were analyzed using thematic analysis. Three major subthemes or "pathways" to the relationship and intimacy benefits associated with participation in the program emerged: (1) improved dyadic communication; (2) joint decision-making and power equity in the context of reproduction; and (3) increased sexual and relational intimacy, driven by reduced fear of HIV transmission and relationship dissolution. These data suggest that the intervention not only helped couples realize their reproductive goals; it also improved relationship dynamics and facilitated intimacy, strengthening partnerships and reducing fears of separation. Directly addressing these benefits with MWH and their partners may increase engagement with HIV prevention strategies for conception.

Who's slipping through the cracks? A comprehensive individual, clinical and health system characterization of people with virological failure on first-line HIV treatment in Uganda and South Africa.

OBJECTIVES: HIV virological failure remains a major threat to programme success in sub-Saharan Africa. While HIV drug resistance (HIVDR) and inadequate adherence are the main drivers of virological failure, the individual, clinical and health system characteristics that lead to poor outcomes are not well understood. The objective of this paper is to identify those characteristics among people failing first-line antiretroviral therapy (ART). METHODS: We enrolled a cohort of adults in HIV care experiencing virological failure on first-line ART at five sites and used standard statistical methods to characterize them with a focus on three domains: individual/demographic, clinical, and health system, and compared each by country of enrolment. RESULTS: Of 840 participants, 51% were women, the median duration on ART was 3.2 years [interquartile range (IQR) 1.1, 6.4 years] and the median CD4 cell count prior to failure was 281 cells/µL (IQR 121, 457 cells/µL). More than half of participants [53%; 95% confidence interval (CI) 49-56%] stated that they had > 90% adherence and 75% (95% CI 72-77%) took their ART on time all or most of the time. Conversely, the vast majority (90%; 95% CI 86-92%) with a completed genotypic drug resistance test had any HIV drug resistance. This population had high health system use, reporting a median of 3 (IQR 2.6) health care visits and a median of 1 (IQR 1.1) hospitalization in the preceding 6 months. CONCLUSIONS: Patients failing first-line ART in sub-Saharan Africa generally report high rates of adherence to ART, have extremely high rates of HIV drug resistance and utilize significant health care resources. Health systems interventions to promptly detect and manage treatment failure will be a prerequisite to establishing control of the HIV epidemic.

Resistance Testing for Management of HIV Virologic Failure in Sub-Saharan Africa : An Unblinded Randomized Controlled Trial.

BACKGROUND: Virologic failure in HIV predicts the development of drug resistance and mortality. Genotypic resistance testing (GRT), which is the standard of care after virologic failure in high-income settings, is rarely implemented in sub-Saharan Africa. OBJECTIVE: To estimate the effectiveness of GRT for improving virologic suppression rates among people with HIV in sub-Saharan Africa for whom first-line therapy fails. DESIGN: Pragmatic, unblinded, randomized controlled trial. (ClinicalTrials.gov: NCT02787499). SETTING: Ambulatory HIV clinics in the public sector in Uganda and South Africa. PATIENTS: Adults receiving first-line antiretroviral therapy with a recent HIV RNA viral load of 1000 copies/mL or higher. INTERVENTION: Participants were randomly assigned to receive standard of care (SOC), including adherence counseling sessions and repeated viral load testing, or immediate GRT. MEASUREMENTS: The primary outcome of interest was achievement of an HIV RNA viral load below 200 copies/mL 9 months after enrollment. RESULTS: The trial enrolled 840 persons, divided equally between countries. Approximately half (51%) were women. Most (72%) were receiving a regimen of tenofovir, emtricitabine, and efavirenz at enrollment. The rate of virologic suppression did not differ 9 months after enrollment between the GRT group (63% [263 of 417]) and SOC group (61% [256 of 423]; odds ratio [OR], 1.11 [95% CI, 0.83 to 1.49]; P = 0.46). Among participants with persistent failure (HIV RNA viral load ≥1000 copies/mL) at 9 months, the prevalence of drug resistance was higher in the SOC group (76% [78 of 103] vs. 59% [48 of 82]; OR, 2.30 [CI, 1.22 to 4.35]; P = 0.014). Other secondary outcomes, including 9-month survival and retention in care, were similar between groups. LIMITATION: Participants were receiving nonnucleoside reverse transcriptase inhibitor-based therapy at enrollment, limiting the generalizability of the findings. CONCLUSION: The addition of GRT to routine care after first-line virologic failure in Uganda and South Africa did not improve rates of resuppression. PRIMARY FUNDING SOURCE: The President's Emergency Plan for AIDS Relief and the National Institute of Allergy and Infectious Diseases.

Feasibility of Rapid Case Ascertainment for Cancer in East Africa: An Investigation of Community-Representative Kaposi Sarcoma in the Era of Antiretroviral Therapy.

BACKGROUND: Rapid case ascertainment (RCA) refers to the expeditious and detailed examination of patients with a potentially rapidly fatal disease shortly after diagnosis. RCA is frequently performed in resource-rich settings to facilitate cancer research. Despite its utility, RCA is rarely implemented in resource-limited settings and has not been performed for malignancies. One cancer and context that would benefit from RCA in a resource-limited setting is HIV-related Kaposi sarcoma (KS) in sub-Saharan Africa. METHODS: To determine the feasibility of RCA for KS, we searched for all potential newly diagnosed KS among HIV-infected adults attending three community-based facilities in Uganda and Kenya. Searching involved querying of electronic medical records, pathology record review, and notification by clinicians. Upon identification, a team verified eligibility and attempted to locate patients to perform RCA, which included epidemiologic, clinical and laboratory measurements. RESULTS: We identified 593 patients with suspected new KS. Of the 593, 171 were ineligible, mainly because biopsy failed to confirm KS (65%) or KS was not new (30%). Among the 422 remaining, RCA was performed within 1 month for 56% of patients and within 3 months for 65% (95% confidence interval: 59 to 70%). Reasons for not performing RCA included intervening death (47%), inability to contact (44%), refusal/unsuitable to consent (8.3%), and patient re-location (0.7%). CONCLUSIONS: We found that RCA - an important tool for cancer research in resource-rich settings - is feasible for the investigation of community-representative KS in East Africa. Feasibility of RCA for KS suggests feasibility for other cancers in Africa.

Beyond T Staging in the "Treat-All" Era: Severity and Heterogeneity of Kaposi Sarcoma in East Africa.

BACKGROUND: Although many patients with Kaposi sarcoma (KS) in sub-Saharan Africa are diagnosed with AIDS Clinical Trials Group (ACTG) T1 disease, T1 staging insufficiently captures clinical heterogeneity of advanced KS. Using a representative community-based sample, we detailed disease severity at diagnosis to inform KS staging and treatment in sub-Saharan Africa. METHODS: We performed rapid case ascertainment on people living with HIV, aged 18 years or older, newly diagnosed with KS from 2016 to 2019 at 3 clinic sites in Kenya and Uganda to ascertain disease stage as close as possible to diagnosis. We reported KS severity using ACTG and WHO staging criteria and detailed measurements that are not captured in the current staging systems. RESULTS: We performed rapid case ascertainment within 1 month for 241 adults newly diagnosed with KS out of 389 adult patients with suspected KS. The study was 68% men with median age 35 years and median CD4 count 239. Most of the patients had advanced disease, with 82% qualifying as ACTG T1 and 64% as WHO severe/symptomatic KS. The most common ACTG T1 qualifiers were edema (79%), tumor-associated ulceration (24%), extensive oral KS (9%), pulmonary KS (7%), and gastrointestinal KS (4%). There was marked heterogeneity within T1 KS, with 25% of patients having 2 T1 qualifying symptoms and 3% having 3 or more. CONCLUSION: Most of the patients newly diagnosed with KS had advanced stage disease, even in the current antiretroviral therapy "treat-all" era. We observed great clinical heterogeneity among advanced stage patients, leading to questions about whether all patients with advanced KS require the same treatment strategy.

STI prevalence among men living with HIV engaged in safer conception care in rural, southwestern Uganda.

HIV care provides an opportunity to integrate comprehensive sexual and reproductive healthcare, including sexually transmitted infection (STI) management. We describe STI prevalence and correlates among men living with HIV (MLWH) accessing safer conception care to conceive a child with an HIV-uninfected partner while minimizing HIV transmission risks. This study reflects an ongoing safer conception program embedded within a regional referral hospital HIV clinic in southwestern Uganda. We enrolled MLWH, planning for pregnancy with an HIV-uninfected partner and accessing safer conception care. Participants completed interviewer-administered questionnaires detailing socio-demographics, gender dynamics, and sexual history. Participants also completed STI laboratory screening for syphilis (immunochromatographic testing confirmed by rapid plasma reagin), and chlamydia, gonorrhea, trichomoniasis, and HIV-RNA via GeneXpert nucleic acid amplification testing. Bivariable associations of STI covariates were assessed using Fisher's exact test. Among the 50 men who completed STI screening, median age was 33 (IQR 31-37) years, 13/50 (26%) had ≥2 sexual partners in the prior three months, and 46/50 (92%) had HIV-RNA <400 copies/mL. Overall, 11/50 (22%) had STIs: 16% active syphilis, 6% chlamydia. All participants initiated STI treatment. STI prevalence was associated with the use of threats/intimidation to coerce partners into sex (27% vs 3%; p = 0.03), although absolute numbers were small. We describe a 22% curable STI prevalence among a priority population at higher risk for transmission to partners and neonates. STI screening and treatment as a part of comprehensive sexual and reproductive healthcare should be integrated into HIV care to maximize the health of men, women, and children.

Pre-treatment integrase inhibitor resistance is uncommon in antiretroviral therapy-naive individuals with HIV-1 subtype A1 and D infections in Uganda.

OBJECTIVE: Dolutegravir (DTG) is now a preferred component of first-line antiretroviral therapy (ART). However, prevalence data on natural resistance to integrase inhibitors [integrase strand transfer inhibitors (INSTIs)] in circulating non-subtype B HIV-1 in sub-Saharan Africa is scarce. Our objective is to report prevalence of pre-treatment integrase polymorphisms associated with resistance to INSTIs in an ART-naive cohort with diverse HIV-1 subtypes. DESIGN: We retrospectively examined HIV-1 integrase sequences from Uganda. METHODS: Plasma samples were derived from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort, reflecting enrollment from 2002 to 2010, prior to initiation of ART. HIV-1 integrase was amplified using nested-PCR and Sanger-sequenced (HXB2 4230-5093). Stanford HIVdb v8.8 was used to infer clinically significant INSTI-associated mutations. Human leukocyte antigen (HLA) typing was performed for all study participants. RESULTS: Plasma samples from 511 ART-naive individuals (subtype: 48% A1, 39% D) yielded HIV-1 integrase genotyping results. Six out of 511 participants (1.2%) had any major INSTI-associated mutations. Of these, two had E138T (subtype A1), three had E138E/K (subtype D), and one had T66T/I (subtype D). No participants had mutations traditionally associated with high levels of INSTI resistance. HLA genotypes A∗02:01/05/14, B∗44:15, and C∗04:07 predicted the presence of L74I, a mutation recently observed in association with long-acting INSTI cabotegravir virologic failure. CONCLUSION: We detected no HIV-1 polymorphisms associated with high levels of DTG resistance in Uganda in the pre-DTG era. Our results support widespread implementation of DTG but careful monitoring of patients on INSTI with virologic failure is warranted to determine if unique mutations predict failure for non-B subtypes of HIV-1.

Brief Report: The Impact of Disease Stage on Early Gaps in ART in the "Treatment for All" Era-A Multisite Cohort Study.

BACKGROUND: Adoption of "Treat All" policies has increased antiretroviral therapy (ART) initiation in sub-Saharan Africa; however, unexplained early losses continue to occur. More information is needed to understand why treatment discontinuation continues at this vulnerable stage in care. METHODS: The Monitoring Early Treatment Adherence Study involved a prospective observational cohort of individuals initiating ART at early-stage versus late-stage disease in South Africa and Uganda. Surveys and HIV-1 RNA levels were performed at baseline, 6, and 12 months, with adherence monitored electronically. This analysis included nonpregnant participants in the first 6 months of follow-up; demographic and clinical factors were compared across groups with χ2, univariable, and multivariable models. RESULTS: Of 669 eligible participants, 91 (14%) showed early gaps of ≥30 days in ART use (22% in South Africa and 6% in Uganda) with the median time to gap of 77 days (interquartile range: 43-101) and 87 days (74, 105), respectively. Although 71 (78%) ultimately resumed care, having an early gap was still significantly associated with detectable viremia at 6 months (P ≤ 0.01). Multivariable modeling, restricted to South Africa, found secondary education and higher physical health score protected against early gaps [adjusted odds ratio (aOR) 0.4, 95% confidence interval (CI): 0.2 to 0.8 and (aOR 0.93, 95% CI: 0.9 to 1.0), respectively]. Participants reporting clinics as "too far" had double the odds of early gaps (aOR 2.2: 95% CI: 1.2 to 4.1). DISCUSSION: Early gaps in ART persist, resulting in higher odds of detectable viremia, particularly in South Africa. Interventions targeting health management and access to care are critical to reducing early gaps.

Internalized stigma, depressive symptoms, and the modifying role of antiretroviral therapy: A cohort study in rural Uganda.

Depression affects over 40% of people with HIV (PHIV) in low- and middle-income countries, and over half of PHIV report HIV-related internalized stigma. However, few longitudinal studies of PHIV have examined the relationship between HIV-related stigma and depression. Data were analyzed from the 2007-15 Uganda AIDS Rural Treatment Outcomes (UARTO) Study, a cohort of 454 antiretroviral therapy (ART)-naïve PHIV (68% women) starting ART. Our primary outcome was depression symptom severity over the first two years of ART, measured using a locally adapted version of the Hopkins Symptom Checklist; our primary exposure was the 6-item Internalized AIDS-Related Stigma Scale. Both scores were measured at enrollment and at quarterly follow-up visits. We fit linear generalized estimating equations (GEE) regression models to estimate the association between stigma and depression symptom severity, adjusting for potential confounders. We included a stigma×time product term to assess the modifying effect of ART on the association between internalized stigma and depression symptom severity. UARTO participants had a median age of 32 years and median enrollment CD4 count of 217 cells/mm3. Both depression symptom severity and internalized stigma declined on ART, particularly during the first treatment year. In multivariable regression models, depression symptom severity was positively associated with internalized stigma (b=0.03; 95% confidence interval [CI], 0.02 to 0.04) and negatively associated with ART duration >6 months (b =- 0.16; 95% CI,- 0.19 to -0.13). The estimated product term coefficient was negative and statistically significant (P = 0.004), suggesting that the association between internalized stigma and depression symptom severity weakened over time on ART. Thus, in this large cohort of PHIV initiating ART in rural Uganda, depression symptom severity was associated with internalized stigma but the association declined with time on ART. These findings underscore the potential value of ART as a stigma reduction intervention for PHIV, particularly during early treatment.

Variation in HIV-1 Nef function within and among viral subtypes reveals genetically separable antagonism of SERINC3 and SERINC5.

HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis.