Brief Report: Low-Dose Methotrexate Does Not Affect Measures of HIV-1 Persistence in Individuals With Chronically Treated HIV-1 Infection.

BACKGROUND: People with HIV-1 often have chronic inflammation leading to severe non-AIDS morbidity and mortality. The AIDS Clinical Trials Group Study A5314 sought to lower inflammation with low-dose methotrexate (LDMTX). The primary study outcomes were reported previously but here we present the impact of LDMTX on multiple measures of HIV-1 persistence. METHODS: A5314 was a phase 2 randomized, double-blind, multicenter trial in 176 adult people with HIV-1 on virally suppressive antiretroviral therapy. LDMTX (5-15 mg/wk) was administered for 24 weeks with an additional 12 weeks of participant follow-up. The current analyses of HIV-1 persistence were restricted to 60 participants (30 LDMTX and 30 placebo) randomly selected from the total population. Plasma HIV-1 RNA, total HIV-1 DNA, and cell-associated HIV-1 RNA (CA HIV-1 RNA) were measured by sensitive quantitative PCR assays. RESULTS: LDMTX treatment had no significant effect on sensitive measures of plasma HIV-1 RNA, HIV-1 DNA, CA HIV-1 RNA, or CA HIV-1 RNA/DNA ratio at any time point or from baseline to week 24. As observed in the main study, absolute peripheral CD4+ and CD8+ T-cell numbers decreased from baseline to week 24 among the 30 participants receiving LDMTX compared with placebo (median decrease of -31.5 CD4+ T cells/µL, -83.5 CD8+ T cells/µL). CONCLUSIONS: LDMTX had no significant effect on any measure of HIV-1 persistence in plasma or peripheral blood mononuclear cells. Further studies are needed to determine whether other immunosuppressive and/or immunoreductive interventions are safe and capable of affecting HIV-1 persistence.

CROI 2024: Tuberculosis, Mpox, and Other Infectious Complications in People With HIV.

Several novel antituberculosis agents, including long-acting injectable agents in mouse models, have shown promise in preclinical and early clinical studies. This encouraging news is offset by the failures of a tuberculosis (TB) vaccine to prevent disease recurrence and a 3-month clofazimine-based treatment regimen for drug-susceptible TB. Clinically focused insights regarding TB, mpox, and other HIV-associated infectious complications that were presented at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) are summarized in this review.

Prevalence and Predictors of Tuberculosis Infection in Children and Adolescents in Rural Uganda: A Cross-sectional Study.

BACKGROUND: Much of the latent tuberculosis (TB) reservoir is established in childhood and adolescence. Yet, age-specific data on prevalence and predictors of infection in this population are sparse and needed to guide prevention and case finding. METHODS: From December 2021 to June 2023, we measured TB infection in children 1-17 years in 25 villages in rural Southwestern Uganda. We defined TB infection as a positive QuantiFERON Gold Plus Test (QFT). We estimated overall and age-stratified population-level prevalence and adjusted risk ratios (aRR) of TB infection for individual, household, and community-based predictors, accounting for age, TB contact, and clustering by household. RESULTS: Estimated TB infection prevalence was 9.6% [95% confidence interval (CI): 8.7-10.5%] among the 5789 participants, and prevalence varied slightly with age. Household-level risk factors included crowding (aRR: 1.25, 95% CI: 1.03-1.53), indoor cooking (aRR: 1.62, 95% CI: 1.14-2.30), living with ≥2 persons who drink alcohol (aRR: 1.47, 95% CI: 1.04-2.07). The predominant community-based risk factor was child mobility (aRR: 1.67, 95% CI: 1.24-2.26). In age-stratified analyses, household predictors were important in early childhood but not adolescence, where mobility was predominant (aRR: 1.66, 95% CI: 1.13-2.44). CONCLUSION: We detected a high prevalence of TB infection in children and adolescents in rural Uganda. On a population level, TB risk factors change throughout the early life course, with child mobility a key risk factor in adolescence. Age-specific TB case finding and prevention strategies that address both household and extra-household risk factors are needed to address TB transmission.

Client experiences with "Dynamic Choice Prevention," a model for flexible patient-centred HIV prevention delivery in rural Eastern Africa.

INTRODUCTION: Identifying the optimal approaches to offering HIV prevention to meet the needs of those at risk is a high priority, particularly given the expanding toolkit of biomedical HIV prevention options. An ongoing study in rural East African communities evaluated the uptake of choices in product, testing mode and location of care delivery through a structured patient-centred HIV prevention delivery model. In this qualitative study, we sought to understand clients' experiences of this "dynamic choice prevention model" (DCP) and highlight pathways of action to inform HIV prevention delivery models. METHODS: In-depth semi-structured interviews were conducted from November 2021 through March 2022 with a purposively selected sample of n = 56 participants in DCP trials (across outpatient departments, antenatal clinics and community settings), and n = 21 healthcare providers (total n = 77). A seven-person multi-regional team translated and inductively coded transcript data. We used a framework analysis approach to identify emergent themes. RESULTS: Individuals taking up HIV pre-exposure prophylaxis (PrEP) reported feelings of relief, liberation from fears of acquiring HIV and satisfaction with being able to take action despite partners' behaviours. Couples used a range of approaches afforded by the study to persuade partners to get tested and opt for PrEP. Post-exposure prophylaxis (PEP) use was less common, although women welcomed it in the event of sexual coercion or assault. Participants discussed switching from PEP to PrEP after familiarizing themselves with usage and ascertaining ongoing risk. Participants felt respected by providers, trusted them and appreciated being able to contact them directly for telephone support. Prevention uptake was hindered by stigma, limited experience with and knowledge of prevention methods, gendered and generational power dynamics within intimate partnerships and families, and negative perceptions of methods due to the products themselves. Participants anticipated long-acting injectable PrEP could solve their challenges regarding pill size, daily pill burden and the likelihood of unwanted disclosure. CONCLUSIONS: Diverse preferences and barriers to uptake of prevention require a choice of HIV prevention options, locations and delivery modalities-but in addition, flexible, competent and friendly care provision is crucial to promote uptake. Helping clients feel valued, and addressing their unique needs and challenges, enables their agency to prioritize their health.

Illness Narratives Without the Illness: Biomedical HIV Prevention Narratives from East Africa.

Illness narratives invite practitioners to understand how biomedical and traditional health information is incorporated, integrated, or otherwise internalized into a patient's own sense of self and social identity. Such narratives also reveal cultural values, underlying patterns in society, and the overall life context of the narrator. Most illness narratives have been examined from the perspective of European-derived genres and literary theory, even though theorists from other parts of the globe have developed locally relevant literary theories. Further, illness narratives typically examine only the experience of illness through acute or chronic suffering (and potential recovery). The advent of biomedical disease prevention methods like post- and pre-exposure prophylaxis (PEP and PrEP) for HIV, which require daily pill consumption or regular injections, complicates the notion of an illness narrative by including illness prevention in narrative accounts. This paper has two aims. First, we aim to rectify the Eurocentrism of existing illness narrative theory by incorporating insights from African literary theorists; second, we complicate the category by examining prevention narratives as a subset of illness narratives. We do this by investigating several narratives of HIV prevention from informants enrolled in an HIV prevention trial in Kenya and Uganda in 2022.

Incident Tuberculosis Infection is Associated with Alcohol use in Adults in Rural Uganda.

Data on alcohol use and incident Tuberculosis (TB) infection are needed. In adults aged 15+ in rural Uganda (N=49,585), estimated risk of incident TB infection was 29.2% with alcohol use vs. 19.2% without (RR: 1.49; 95%CI: 1.40-1.60). There is potential for interventions to interrupt transmission among people who drink alcohol.

Exploring HIV risk perception mechanisms among youth in a test-and-treat trial in Kenya and Uganda.

Understanding risk perception and risk-taking among youth can inform targeted prevention efforts. Using a health beliefs model-informed framework, we analysed 8 semi-structured, gender-specific focus group discussions with 93 youth 15-24 years old (48% male, 52% female), drawn from the SEARCH trial in rural Kenya and Uganda in 2017-2018, coinciding with the widespread introduction of PrEP. Highly connected social networks and widespread uptake of antiretrovirals shaped youth HIV risk perception. Amid conflicting information about HIV prevention methods, youth felt exposed to multiple HIV risk factors like the high prevalence of HIV, belief that people with HIV(PWH) purposefully infect others, dislike of condoms, and doubts about PrEP efficacy. Young women also reported minimal sexual autonomy in the context of economic disadvantages, the ubiquity of intergenerational and transactional sex, and peer pressure from other women to have many boyfriends. Young men likewise reported vulnerability to intergenerational sex, but also adopted a sexual conquest mentality. Comprehensive sexuality education and economic empowerment, through credible and trusted sources, may moderate risk-taking. Messaging should leverage youth's social networks to spread fact-based, gender- and age-appropriate information. PrEP should be offered alongside other reproductive health services to address both pregnancy concerns and reduce HIV risk.

Clinical Implications of HIV Treatment and Prevention for Polygamous Families in Kenya and Uganda: "My Co-Wife Is the One Who Used to Encourage Me".

Polygamy is the practice of marriage to multiple partners. Approximately 6-11% of households in Uganda and 4-11% of households in Kenya are polygamous. The complex families produced by polygamous marriage customs give rise to additional considerations for healthcare providers and public health messaging around HIV care. Using 27 in-depth, semi-structured qualitative interviews with participants in two studies in rural Kenya and Uganda, we analysed challenges and opportunities that polygamous families presented in the diagnosis, treatment and prevention of HIV, and provider roles in improving HIV outcomes in these families. Overall, prevention methods seemed more justifiable to families where co-wives live far apart than when all members live in the same household. In treatment, diagnosis of one member did not always lead to disclosure to other members, creating an adverse home environment; but sometimes diagnosis of one wife led not only to diagnosis of the other, but also to greater household support.

Clinical implications of HIV treatment and prevention for polygamous families in Kenya and UgandaPolygamy is the practice of marriage to multiple partners. Approximately 6-11% of households in Uganda and 4-11% of households in Kenya are polygamous. The complex families produced by polygamous marriage customs give rise to additional considerations for healthcare providers and public health messaging around HIV care.

Rapid Biphasic Decay of Intact and Defective HIV DNA Reservoir During Acute Treated HIV Disease.

Despite antiretroviral therapy (ART), HIV persists in latently-infected cells ("the reservoir") which decay slowly over time. Here, leveraging >500 longitudinal samples from 67 people with HIV (PWH) treated during acute infection, we developed a novel mathematical model to predict reservoir decay from peripheral CD4+ T cells. Nonlinear generalized additive models demonstrated rapid biphasic decay of intact DNA (week 0-5: t 1/2 ∼2.83 weeks; week 5-24: t 1/2 ∼15.4 weeks) that extended out to 1 year. These estimates were ∼5-fold faster than prior decay estimates among chronic treated PWH. Defective DNA had a similar biphasic pattern, but data were more variable. Predicted intact and defective decay rates were faster for PWH with earlier timing of ART initiation, higher initial CD4+ T cell count, and lower pre-ART viral load. These data add to our limited understanding of HIV reservoir decay at the time of ART initiation, informing future curative strategies targeting this critical time.

Lessons from Two Latino Communities Working with Academic Partners to Increase Access to COVID-19 Testing.

OBJECTIVE: We sought to examine the experiences of community partners in a community-academic partnership to promote COVID-19 testing in two majority Latino communities. METHODS: We conducted semistructured, in-depth interviews in English and Spanish with community-based organization leaders and community health workers/promotoras (n = 10) from June to July 2021. Interviews focused on identifying partner roles in planning and testing implementation and evaluating communication among partners. Interviews were transcribed and analyzed in ATLAS.ti version 8.4.5. Analyses involved deductive and inductive approaches to identify key themes. RESULTS: Participants described both strengths and challenges to the collaborative approach within each of three core themes: building relationships in the time of COVID-19; uplifting existing community leadership; and commitment of the academic partners and community-based organizations to conduct partnership activities in Spanish. CONCLUSION: Community-academic partnerships that invest in strong relationships, community leadership, and a commitment to the community's preferred language offer a promising approach to addressing COVID-19 testing barriers. Findings provide direction for future research on how community members and academic partners can come together to inform strategies to continue addressing the COVID-19 pandemic.

Randomized Trial of Dynamic Choice HIV Prevention at Antenatal and Postnatal Care Clinics in Rural Uganda and Kenya.

BACKGROUND: Pregnant and postpartum women in Sub-Saharan Africa are at high risk of HIV acquisition. We evaluated a person-centered dynamic choice intervention for HIV prevention (DCP) among women attending antenatal and postnatal care. SETTING: Rural Kenya and Uganda. METHODS: Women (aged 15 years or older) at risk of HIV acquisition seen at antenatal and postnatal care clinics were individually randomized to DCP vs. standard of care (SEARCH; NCT04810650). The DCP intervention included structured client choice of product (daily oral pre-exposure prophylaxis or postexposure prophylaxis), service location (clinic or out of facility), and HIV testing modality (self-test or provider-administered), with option to switch over time and person-centered care (phone access to clinician, structured barrier assessment and counseling, and provider training). The primary outcome was biomedical prevention coverage-proportion of 48-week follow-up with self-reported pre-exposure prophylaxis or postexposure prophylaxis use, compared between arms using targeted maximum likelihood estimation. RESULTS: Between April and July 2021, we enrolled 400 women (203 intervention and 197 control); 38% were pregnant, 52% were aged 15-24 years, and 94% reported no pre-exposure prophylaxis or postexposure prophylaxis use for ≥6 months before baseline. Among 384/400 participants (96%) with outcome ascertained, DCP increased biomedical prevention coverage 40% (95% CI: 34% to 47%; P < 0.001); the coverage was 70% in intervention vs. 29% in control. DCP also increased coverage during months at risk of HIV (81% in intervention, 43% in control; 38% absolute increase; 95% CI: 31% to 45%; P < 0.001). CONCLUSION: A person-centered dynamic choice intervention that provided flexibility in product, testing, and service location more than doubled biomedical HIV prevention coverage in a high-risk population already routinely offered access to biomedical prevention options.

Identifying Implementation Determinants and Strategies for Long-Acting Injectable Cabotegravir-Rilpivirine in People With HIV Who Are Virally Unsuppressed.

BACKGROUND: Early evidence suggests long-acting injectable cabotegravir and rilpivirine (LA-CAB/RPV) may be beneficial for people with HIV (PWH) who are unable to attain viral suppression (VS) on oral therapy. Limited guidance exists on implementation strategies for this population. SETTING: Ward 86, a clinic serving publicly insured PWH in San Francisco. METHODS: We describe multilevel determinants of and strategies for LA-CAB/RPV implementation for PWH without VS, using the Consolidated Framework for Implementation Research. To assess patient and provider-level determinants, we drew on pre-implementation qualitative data. To assess inner and outer context determinants, we undertook a structured mapping process. RESULTS: Key patient-level determinants included perceived ability to adhere to injections despite oral adherence difficulties and care engagement challenges posed by unmet subsistence needs; strategies to address these determinants included a direct-to-inject approach, small financial incentives, and designated drop-in days. Provider-level determinants included lack of time to obtain LA-CAB/RPV, assess injection response, and follow-up late injections; strategies included centralizing eligibility review with the clinic pharmacist, a pharmacy technician to handle procurement and monitoring, regular multidisciplinary review of patients, and development of a clinic protocol. Ward 86 did not experience many outer context barriers because of rapid and unconstrained inclusion of LA-CAB/RPV on local formularies and ability of its affiliated hospital pharmacy to stock the medication. CONCLUSIONS: Multilevel strategies to support LA-CAB/RPV implementation for PWH without VS are required, which may necessitate additional resources in some settings to implement safely and effectively. Advocacy to eliminate outer-context barriers, including prior authorizations and specialty pharmacy restrictions, is needed.

Mid-level managers' perspectives on implementing isoniazid preventive therapy for people living with HIV in Ugandan health districts: a qualitative study.

BACKGROUND: Isoniazid preventive therapy (IPT) works to prevent tuberculosis (TB) among people living with HIV (PLHIV), but uptake remains low in Sub-Saharan Africa. In this analysis, we sought to identify barriers mid-level managers face in scaling IPT in Uganda and the mechanisms by which the SEARCH-IPT trial intervention influenced their abilities to increase IPT uptake. METHODS: The SEARCH-IPT study was a cluster randomized trial conducted from 2017-2021. The SEARCH-IPT intervention created collaborative groups of district health managers, facilitated by local HIV and TB experts, and provided leadership and management training over 3-years to increase IPT uptake in Uganda. In this qualitative study we analyzed transcripts of annual Focus Group Discussions and Key Informant Interviews, from a subset of SEARCH-IPT participants from intervention and control groups, and participant observation field notes. We conducted the analysis using inductive and deductive coding (with a priori codes and those derived from analysis) and a framework approach for data synthesis. RESULTS: When discussing factors that enabled positive outcomes, intervention managers described feeling ownership over interventions, supported by the leadership and management training they received in the SEARCH-IPT study, and the importance of collaboration between districts facilitated by the intervention. In contrast, when discussing factors that impeded their ability to make changes, intervention and control managers described external funders setting agendas, lack of collaboration in meetings that operated with more of a 'top-down' approach, inadequate supplies and staffing, and lack of motivation among frontline providers. Intervention group managers mentioned redistribution of available stock within districts as well as between districts, reflecting efforts of the SEARCH-IPT intervention to promote between-district collaboration, whereas control group managers mentioned redistribution within their districts to maximize the use of available IPT stock. CONCLUSIONS: In Uganda, mid-level managers' perceptions of barriers to scaling IPT included limited power to set agendas and control over funding, inadequate resources, lack of motivation of frontline providers, and lack of political prioritization. We found that the SEARCH-IPT intervention supported managers to design and implement strategies to improve IPT uptake and collaborate between districts. This may have contributed to the overall intervention effect in increasing the uptake of IPT among PLHIV compared to standard practice. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03315962 , Registered 20 October 2017.

Community-Wide Universal HIV Test and Treat Intervention Reduces Tuberculosis Transmission in Rural Uganda: A Cluster-Randomized Trial.

BACKGROUND: Human immunodeficiency virus (HIV) treatment reduces tuberculosis (TB) disease and mortality; however, the population-level impact of universal HIV-test-and-treat interventions on TB infection and transmission remain unclear. METHODS: In a sub-study nested in the SEARCH trial, a community cluster-randomized trial (NCT01864603), we assessed whether a universal HIV-test-and-treat intervention reduced population-level incident TB infection in rural Uganda. Intervention communities received annual, population-level HIV testing and patient-centered linkage. Control communities received population-level HIV testing at baseline and endline. We compared estimated incident TB infection by arms, defined by tuberculin skin test conversion in a cohort of persons aged 5 and older, adjusting for participation and predictors of infection, and accounting for clustering. RESULTS: Of the 32 trial communities, 9 were included, comprising 90 801 participants (43 127 intervention and 47 674 control). One-year cumulative incidence of TB infection was 16% in the intervention and 22% in the control; SEARCH reduced the population-level risk of incident TB infection by 27% (adjusted risk ratio = 0.73; 95% confidence interval [CI]: .57-.92, P = .005). In pre-specified analyses, the effect was largest among children aged 5-11 years and males. CONCLUSIONS: A universal HIV-test-and-treat intervention reduced incident TB infection, a marker of population-level TB transmission. Investments in community-level HIV interventions have broader population-level benefits, including TB reductions.

Dynamic choice HIV prevention intervention at outpatient departments in rural Kenya and Uganda.

OBJECTIVE: HIV prevention service delivery models that offer product choices, and the option to change preferences over time, may increase prevention coverage. Outpatient departments in sub-Saharan Africa diagnose a high proportion of new HIV infections, but are an understudied entry point to biomedical prevention. DESIGN: Individually randomized trial of dynamic choice HIV prevention (DCP) intervention vs. standard-of-care (SOC) among individuals with current/anticipated HIV exposure risk at outpatient departments in rural Kenya and Uganda (SEARCH; NCT04810650). METHODS: Our DCP intervention included 1) product choice (oral preexposure prophylaxis [PrEP] or postexposure prophylaxis [PEP]) with an option to switch over time, 2) HIV provider- or self-testing, 3) service location choice (community vs. clinic-based), and 4) provider training on patient-centered care. Primary outcome was proportion of follow-up covered by PrEP/PEP over 48 weeks assessed via self-report. RESULTS: We enrolled 403 participants (61% women; median 27 years, IQR 22-37). In the DCP arm, 86% ever chose PrEP, 15% ever chose PEP over 48 weeks; selection of HIV self-testing increased from 26 to 51% and of out-of-facility visits from 8 to 52%. Among 376 of 403 (93%) with outcomes ascertained, time covered by PrEP/PEP was higher in DCP (47.5%) vs. SOC (18.3%); difference = 29.2% (95% confidence interval: 22.7-35.7; P  < 0.001). Effects were similar among women and men (28.2 and 31.0% higher coverage in DCP, respectively) and larger during periods of self-reported HIV risk (DCP 64.9% vs. SOC 26.3%; difference = 38.6%; 95% confidence interval: 31.0-46.2; P  < 0.001). CONCLUSION: A dynamic choice HIV prevention intervention resulted in two-fold greater time covered by biomedical prevention products compared to SOC in general outpatient departments in eastern Africa.

Randomized Trial of a "Dynamic Choice" Patient-Centered Care Intervention for Mobile Persons With HIV in East Africa.

BACKGROUND: Persons with HIV (PWH) with high mobility face obstacles to HIV care engagement and viral suppression. We sought to understand whether a patient-centered intervention for mobile PWH would improve viral suppression and retention in care, and if so, which subgroups would benefit most. METHODS: In a randomized trial, we evaluated the effect of an intervention designed to address barriers to care among mobile (≥2 weeks out of community in previous year) PWH with viral nonsuppression or recent missed visits in Kenya and Uganda (NCT04810650). The intervention included dynamic choice of a "travel pack" (emergency antiretroviral therapy [ART] supply, discrete ART packaging, and travel checklist), multimonth and offsite refills, facilitated transfer to out-of-community clinics, and hotline access to a mobility coordinator. The primary outcome was viral suppression (<400 copies/mL) at 48 weeks. Secondary outcomes included retention in care and ART possession. RESULTS: From April 2021 to July 2022, 201 participants were enrolled and randomized (102 intervention, 99 control): 109 (54%) were female participants and 101 (50%) from Kenya; median age was 37 years (interquartile range: 29-43). At 48 weeks, there was no significant difference in viral suppression in intervention (85%) vs. control (86%). The intervention improved retention in care (risk ratio: 1.06[1.02-1.1]; P < 0.001) and ART possession (risk ratio: 1.07[1.03-1.11]; P < 0.001), with larger effect sizes among persons with baseline nonsuppression and high mobility (≥2 weeks out of community in previous 3 months). CONCLUSIONS: Mobile PWH-centered care should be considered for high-risk mobile populations, including nonsuppressed and highly mobile PWH, to improve retention in care and sustain viral suppression over time. TRIAL REGISTRATION: NCT04810650.