Potent transmission-blocking monoclonal antibodies from naturally exposed individuals target a conserved epitope on Plasmodium falciparum Pfs230.

Pfs230 is essential for Plasmodium falciparum transmission to mosquitoes and is the protein targeted by the most advanced malaria-transmission-blocking vaccine candidate. Prior understanding of functional epitopes on Pfs230 is based on two monoclonal antibodies (mAbs) with moderate transmission-reducing activity (TRA), elicited from subunit immunization. Here, we screened the B cell repertoire of two naturally exposed individuals possessing serum TRA and identified five potent mAbs from sixteen Pfs230 domain-1-specific mAbs. Structures of three potent and three low-activity antibodies bound to Pfs230 domain 1 revealed four distinct epitopes. Highly potent mAbs from natural infection recognized a common conformational epitope that is highly conserved across P. falciparum field isolates, while antibodies with negligible TRA derived from natural infection or immunization recognized three distinct sites. Our study provides molecular blueprints describing P. falciparum TRA, informed by contrasting potent and non-functional epitopes elicited by natural exposure and vaccination.

Highly potent, naturally acquired human monoclonal antibodies against Pfs48/45 block Plasmodium falciparum transmission to mosquitoes.

Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that interrupt malaria parasite development in the mosquito, thereby blocking onward transmission, and provide a much-needed tool for malaria control and elimination. The parasite surface protein Pfs48/45 is a leading TBV candidate. Here, we isolated and characterized a panel of 81 human Pfs48/45-specific monoclonal antibodies (mAbs) from donors naturally exposed to Plasmodium parasites. Genetically diverse mAbs against each of the three domains (D1-D3) of Pfs48/45 were identified. The most potent mAbs targeted D1 and D3 and achieved >80% transmission-reducing activity in standard membrane-feeding assays, at 10 and 2 µg/mL, respectively. Co-crystal structures of D3 in complex with four different mAbs delineated two conserved protective epitopes. Altogether, these Pfs48/45-specific human mAbs provide important insight into protective and non-protective epitopes that can further our understanding of transmission and inform the design of refined malaria transmission-blocking vaccine candidates.

Evolution of Partial Resistance to Artemisinins in Malaria Parasites in Uganda.

BACKGROUND: Partial resistance of Plasmodium falciparum to the artemisinin component of artemisinin-based combination therapies, the most important malaria drugs, emerged in Southeast Asia and now threatens East Africa. Partial resistance, which manifests as delayed clearance after therapy, is mediated principally by mutations in the kelch protein K13 (PfK13). Limited longitudinal data are available on the emergence and spread of artemisinin resistance in Africa. METHODS: We performed annual surveillance among patients who presented with uncomplicated malaria at 10 to 16 sites across Uganda from 2016 through 2022. We sequenced the gene encoding kelch 13 (pfk13) and analyzed relatedness using molecular methods. We assessed malaria metrics longitudinally in eight Ugandan districts from 2014 through 2021. RESULTS: By 2021-2022, the prevalence of parasites with validated or candidate resistance markers reached more than 20% in 11 of the 16 districts where surveillance was conducted. The PfK13 469Y and 675V mutations were seen in far northern Uganda in 2016-2017 and increased and spread thereafter, reaching a combined prevalence of 10 to 54% across much of northern Uganda, with spread to other regions. The 469F mutation reached a prevalence of 38 to 40% in one district in southwestern Uganda in 2021-2022. The 561H mutation, previously described in Rwanda, was first seen in southwestern Uganda in 2021, reaching a prevalence of 23% by 2022. The 441L mutation reached a prevalence of 12 to 23% in three districts in western Uganda in 2022. Genetic analysis indicated local emergence of mutant parasites independent of those in Southeast Asia. The emergence of resistance was observed predominantly in areas where effective malaria control had been discontinued or transmission was unstable. CONCLUSIONS: Data from Uganda showed the emergence of partial resistance to artemisinins in multiple geographic locations, with increasing prevalence and regional spread over time. (Funded by the National Institutes of Health.).

Varied prevalence of antimalarial drug resistance markers in different populations of newly arrived refugees in Uganda.

Newly arrived refugees offer insights into malaria epidemiology in their countries of origin. We evaluated asymptomatic refugee children within 7 days of arrival in Uganda from South Sudan and the Democratic Republic of Congo (DRC) in 2022 for parasitemia, parasite species, and Plasmodium falciparum drug resistance markers. Asymptomatic P. falciparum infections were common in both populations. Co-infection with P. malariae was more common in DRC refugees. Prevalences of markers of aminoquinoline resistance (PfCRT K76T, PfMDR1 N86Y) were much higher in South Sudan refugees, of antifolate resistance (PfDHFR C59R and I164L, PfDHPS A437G and K540E) much higher in DRC refugees, and of artemisinin partial resistance (ART-R; PfK13 C469Y and A675V) moderate in both populations. Prevalences of most mutations differed from those seen in Ugandans attending health centers near the refugee centers. Refugee evaluations yielded insights into varied malaria epidemiology and identified markers of ART-R in two previously little-studied countries.

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.

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.

Limited threat of Plasmodium falciparum pfhrp2 and pfhrp3 gene deletion to the utility of HRP2-based malaria RDTs in Northern Uganda.

BACKGROUND: Rapid diagnostic tests (RDTs) that detect Plasmodium falciparum histidine-rich protein-2 (PfHRP2) are exclusively deployed in Uganda, but deletion of the pfhrp2/3 target gene threatens their usefulness as malaria diagnosis and surveillance tools. METHODS: A cross-sectional survey was conducted at 40 sites across four regions of Uganda in Acholi, Lango, W. Nile and Karamoja from March 2021 to June 2023. Symptomatic malaria suspected patients were recruited and screened with both HRP2 and pan lactate dehydrogenase (pLDH) detecting RDTs. Dried blood spots (DBS) were collected from all patients and a random subset were used for genomic analysis to confirm parasite species and pfhrp2 and pfhrp3 gene status. Plasmodium species was determined using a conventional multiplex PCR while pfhrp2 and pfhrp3 gene deletions were determined using a real-time multiplex qPCR. Expression of the HRP2 protein antigen in a subset of samples was further assessed using a ELISA. RESULTS: Out of 2435 symptomatic patients tested for malaria, 1504 (61.8%) were positive on pLDH RDT. Overall, qPCR confirmed single pfhrp2 gene deletion in 1 out of 416 (0.2%) randomly selected samples that were confirmed of P. falciparum mono-infections. CONCLUSION: These findings show limited threat of pfhrp2/3 gene deletions in the survey areas suggesting that HRP2 RDTs are still useful diagnostic tools for surveillance and diagnosis of P. falciparum malaria infections in symptomatic patients in this setting. Periodic genomic surveillance is warranted to monitor the frequency and trend of gene deletions and its effect on RDTs.

LLIN evaluation in Uganda project (LLINEUP2): association between housing construction and malaria burden in 32 districts.

BACKGROUND: Well-built housing limits mosquito entry and can reduce malaria transmission. The association between community-level housing and malaria burden in Uganda was assessed using data from randomly selected households near 64 health facilities in 32 districts. METHODS: Houses were classified as 'improved' (synthetic walls and roofs, eaves closed or absent) or 'less-improved' (all other construction). Associations between housing and parasitaemia were made using mixed effects logistic regression (individual-level) and multivariable fractional response logistic regression (community-level), and between housing and malaria incidence using multivariable Poisson regression. RESULTS: Between November 2021 and March 2022, 4.893 children aged 2-10 years were enrolled from 3.518 houses; of these, 1.389 (39.5%) were classified as improved. Children living in improved houses had 58% lower odds (adjusted odds ratio = 0.42, 95% CI 0.33-0.53, p < 0.0001) of parasitaemia than children living in less-improved houses. Communities with > 67% of houses improved had a 63% lower parasite prevalence (adjusted prevalence ratio 0.37, 95% CI 0.19-0.70, p < 0.0021) and 60% lower malaria incidence (adjusted incidence rate ratio 0.40, 95% CI 0.36-0.44, p < 0.0001) compared to communities with < 39% of houses improved. CONCLUSIONS: Improved housing was strongly associated with lower malaria burden across a range of settings in Uganda and should be utilized for malaria control.

LLIN Evaluation in Uganda Project (LLINEUP): modelling the impact of COVID-19-related disruptions on delivery of long-lasting insecticidal nets on malaria indicators in Uganda.

BACKGROUND: Disruptions in malaria control due to COVID-19 mitigation measures were predicted to increase malaria morbidity and mortality in Africa substantially. In Uganda, long-lasting insecticidal nets (LLINs) are distributed nationwide every 3-4 years, but the 2020-2021 campaign was altered because of COVID-19 restrictions so that the timing of delivery of new nets was different from the original plans made by the National Malaria Control Programme. METHODS: A transmission dynamics modelling exercise was conducted to explore how the altered delivery of LLINs in 2020-2021 impacted malaria burden in Uganda. Data were available on the planned LLIN distribution schedule for 2020-2021, and the actual delivery. The transmission model was used to simulate 100 health sub-districts, and parameterized to match understanding of local mosquito bionomics, net use estimates, and seasonal patterns based on data collected in 2017-2019 during a cluster-randomized trial (LLINEUP). Two scenarios were compared; simulated LLIN distributions matching the actual delivery schedule, and a comparable scenario simulating LLIN distributions as originally planned. Model parameters were otherwise matched between simulations. RESULTS: Approximately 70% of the study population received LLINs later than scheduled in 2020-2021, although some areas received LLINs earlier than planned. The model indicates that malaria incidence in 2020 was substantially higher in areas that received LLINs late. In some areas, early distribution of LLINs appeared less effective than the original distribution schedule, possibly due to attrition of LLINs prior to transmission peaks, and waning LLIN efficacy after distribution. On average, the model simulations predicted broadly similar overall mean malaria incidence in 2021 and 2022. After accounting for differences in cluster population size and LLIN distribution dates, no substantial increase in malaria burden was detected. CONCLUSIONS: The model results suggest that the disruptions in the 2020-2021 LLIN distribution campaign in Uganda did not substantially increase malaria burden in the study areas.

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.

Effect of Malaria and Malaria Chemoprevention Regimens in Pregnancy and Childhood on Neurodevelopmental and Behavioral Outcomes in Children at 12, 24, and 36 Months: A Randomized Clinical Trial.

BACKGROUND: Malaria in pregnancy has been associated with worse cognitive outcomes in children, but its association with behavioral outcomes and the effectiveness of malaria chemoprevention on child neurodevelopment are not well characterized. METHODS: To determine if more effective malaria chemoprevention in mothers and their children results in better neurodevelopment, 305 pregnant women were randomly assigned to 3 doses of sulfadoxine-pyrimethamine, 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP during pregnancy, and their 293 children were assigned to DP every 3 months or monthly DP from 2 to 24 months of age. Cognition, language, and motor function were assessed at 12, 24. and 36 months of age, and attention, memory, behavior, and executive function were assessed at 24 and 36 months of age. RESULTS: Children of mothers with versus without malaria in pregnancy had worse scores on cognitive, behavioral, and executive function outcomes at 24 months. Clinical malaria in children within the first 12 months was similarly associated with poorer scores in behavior and executive function at 24 months, language at 24 and 36 months, and motor function scores at 36 months. However, more effective malaria chemoprevention in the mothers and children was not associated with better outcomes. CONCLUSIONS: Malaria in pregnancy was associated with worse cognitive, behavioral, and executive function scores in affected children, but more effective malaria chemoprevention measures did not result in better outcomes. Malaria chemoprevention prior to and early in gestation and with even higher efficacy in mothers and children may be required to prevent neurodevelopmental impairment in children. Clinical Trials Registration. NCT02557425.

The Association Between Social Network Characteristics and Tuberculosis Infection Among Adults in 9 Rural Ugandan Communities.

BACKGROUND: Social network analysis can elucidate tuberculosis transmission dynamics outside the home and may inform novel network-based case-finding strategies. METHODS: We assessed the association between social network characteristics and prevalent tuberculosis infection among residents (aged ≥15 years) of 9 rural communities in Eastern Uganda. Social contacts named during a census were used to create community-specific nonhousehold social networks. We evaluated whether social network structure and characteristics of first-degree contacts (sex, human immunodeficiency virus [HIV] status, tuberculosis infection) were associated with revalent tuberculosis infection (positive tuberculin skin test [TST] result) after adjusting for individual-level risk factors (age, sex, HIV status, tuberculosis contact, wealth, occupation, and Bacillus Calmette-Guérin [BCG] vaccination) with targeted maximum likelihood estimation. RESULTS: Among 3 335 residents sampled for TST, 32% had a positive TST results and 4% reported a tuberculosis contact. The social network contained 15 328 first-degree contacts. Persons with the most network centrality (top 10%) (adjusted risk ratio, 1.3 [95% confidence interval, 1.1-1.1]) and the most (top 10%) male contacts (1.5 [1.3-1.9]) had a higher risk of prevalent tuberculosis, than those in the remaining 90%. People with ≥1 contact with HIV (adjusted risk ratio, 1.3 [95% confidence interval, 1.1-1.6]) and ≥2 contacts with tuberculosis infection were more likely to have tuberculosis themselves (2.6 [ 95% confidence interval: 2.2-2.9]). CONCLUSIONS: Social networks with higher centrality, more men, contacts with HIV, and tuberculosis infection were positively associated with tuberculosis infection. Tuberculosis transmission within measurable social networks may explain prevalent tuberculosis not associated with a household contact. Further study on network-informed tuberculosis case finding interventions is warranted.

Impact of high human genetic diversity in Africa on immunogenicity and efficacy of RTS,S/AS01 vaccine.

In modern medicine, vaccination is one of the most effective public health strategies to prevent infectious diseases. Indisputably, vaccines have saved millions of lives by reducing the burden of many serious infections such as polio, tuberculosis, measles, pneumonia, and tetanus. Despite the recent recommendation by the World Health Organization (WHO) to roll out RTS,S/AS01, this malaria vaccine still faces major challenges of variability in its efficacy partly due to high genetic variation in humans and malaria parasites. Immune responses to malaria vary between individuals and populations. Human genetic variation in immune system genes is the probable cause for this heterogeneity. In this review, we will focus on human genetic factors that determine variable responses to vaccination and how variation in immune system genes affect the immunogenicity and efficacy of the RTS,S/AS01 vaccine.

Integrated malaria prevention in low- and middle-income countries: a systematic review.

BACKGROUND: As many countries aim to eliminate malaria, use of comprehensive approaches targeting the mosquito vector and environment are needed. Integrated malaria prevention advocates the use of several malaria prevention measures holistically at households and in the community. The aim of this systematic review was to collate and summarize the impact of integrated malaria prevention in low- and middle-income countries on malaria burden. METHODS: Literature on integrated malaria prevention, defined as the use of two or more malaria prevention methods holistically, was searched from 1st January 2001 to 31st July 2021. The primary outcome variables were malaria incidence and prevalence, while the secondary outcome measures were human biting and entomological inoculation rates, and mosquito mortality. RESULTS: A total of 10,931 studies were identified by the search strategy. After screening, 57 articles were included in the review. Studies included cluster randomized controlled trials, longitudinal studies, programme evaluations, experimental hut/houses, and field trials. Various interventions were used, mainly combinations of two or three malaria prevention methods including insecticide-treated nets (ITNs), indoor residual spraying (IRS), topical repellents, insecticide sprays, microbial larvicides, and house improvements including screening, insecticide-treated wall hangings, and screening of eaves. The most common methods used in integrated malaria prevention were ITNs and IRS, followed by ITNs and topical repellents. There was reduced incidence and prevalence of malaria when multiple malaria prevention methods were used compared to single methods. Mosquito human biting and entomological inoculation rates were significantly reduced, and mosquito mortality increased in use of multiple methods compared to single interventions. However, a few studies showed mixed results or no benefits of using multiple methods to prevent malaria. CONCLUSION: Use of multiple malaria prevention methods was effective in reducing malaria infection and mosquito density in comparison with single methods. Results from this systematic review can be used to inform future research, practice, policy and programming for malaria control in endemic countries.

House modifications as a malaria control tool: how does local context shape participants' experience and interpretation in Uganda?

BACKGROUND: Evidence that house design can provide protection from malaria is growing. Housing modifications such as screening windows, doors, and ceilings, and attaching insecticide-impregnated materials to the eaves (the gap between the top of the wall and bottom of the roof), can protect against malaria. To be effective at scale, however, these modifications must be adopted by household residents. There is evidence that housing modifications can be acceptable, but in-depth knowledge on the experiences and interpretation of modifications is lacking. This qualitative study was carried out to provide a holistic account of the relationship between experiences and interpretations of four types of piloted housing modifications and the local context in Jinja, Uganda. METHODS: Qualitative research was conducted between January to June 2021, before and during the installation of four types of housing modifications. The methods included nine weeks of participant observations in two study villages, nine focus group discussions with primary caregivers and heads of households (11-12 participants each), and nine key informant interviews with stakeholders and study team members. RESULTS: Most residents supported the modifications. Experiences and interpretation of the housing modifications were shaped by the different types of housing in the area and the processes through which residents finished their houses, local forms of land and property ownership, and cultural and spiritual beliefs about houses. CONCLUSIONS: To maximize the uptake and benefit of housing modifications against malaria, programme development needs to take local context into account. Forms of local land and house ownership, preferences, the social significance of housing types, and religious and spiritual ideas shape the responses to housing modifications in Jinja. These factors may be important in other setting. Trial registration Trial registration number is NCT04622241. The first draft was posted on November 9th 2020.

Mobility is Associated with Higher-risk Sexual Partnerships Among Both Men and Women in Co-resident Couples in Rural Kenya and Uganda: A Longitudinal Cohort Study.

Population mobility is associated with higher-risk sexual behaviors in sub-Saharan Africa and is a key driver of the HIV epidemic. We conducted a longitudinal cohort study to estimate associations between recent mobility (overnight travel away from home in past six months) or migration (changes of residence over defined geopolitical boundaries) and higher-risk sexual behavior among co-resident couples (240 couples aged ≥ 16) from 12 rural communities in Kenya and Uganda. Data on concurrent mobility and sexual risk behaviors were collected every 6-months between 2015 and 2020. We used sex-pooled and sex-stratified multilevel models to estimate associations between couple mobility configurations (neither partner mobile, male mobile/female not mobile, female mobile/male not mobile, both mobile) and the odds of higher-risk (casual, commercial sex worker/client, one night stand, inherited partner, stranger) and concurrent sexual partnerships based on who was mobile. On average across all time points and subjects, mobile women were more likely than non-mobile women to have a higher-risk partner; similarly, mobile men were more likely than non-mobile men to report a higher-risk partnership. Men with work-related mobility versus not had higher odds of higher-risk partnerships. Women with work-related mobility versus not had higher odds of higher-risk partnerships. Couples where both members were mobile versus neither had greater odds of higher-risk partnerships. In analyses using 6-month lagged versions of key predictors, migration events of men, but not women, preceded higher-risk partnerships. Findings demonstrate HIV risks for men and women associated with mobility and the need for prevention approaches attentive to the risk-enhancing contexts of mobility.

Effects of a COVID-19 Public Health Lockdown on Drinking and Health Behavior Among Persons with HIV and with Unhealthy Alcohol use in Uganda.

To better understand the impact of Uganda's initial COVID-19 lockdown on alcohol use, we conducted a cross-sectional survey (August 2020-September 2021) among persons with HIV (PWH) with unhealthy alcohol use (but not receiving an alcohol intervention), enrolled in a trial of incentives to reduce alcohol use and improve isoniazid preventive therapy. We examined associations between bar-based drinking and decreased alcohol use, and decreased alcohol use and health outcomes (antiretroviral therapy [ART] access, ART adherence, missed clinic visits, psychological stress and intimate partner violence), during lockdown. Of 178 adults surveyed whose data was analyzed, (67% male, median age: 40), 82% reported bar-based drinking at trial enrollment; 76% reported decreased alcohol use during lockdown. In a multivariate analysis, bar-based drinking was not associated with greater decreases in alcohol use during lockdown compared to non-bar-based drinking (OR = 0.81, 95% CI: 0.31-2.11), adjusting for age and sex. There was a significant association between decreased alcohol use and increased stress during lockdown (adjusted ß = 2.09, 95% CI: 1.07-3.11, P < 0.010), but not other health outcomes.

Two or more significant life-events in 6-months are associated with lower rates of HIV treatment and virologic suppression among youth with HIV in Uganda and Kenya.

Youth living with HIV in sub-Saharan Africa have poor HIV care outcomes. We determined the association of recent significant life-events with HIV antiretroviral treatment (ART) initiation and HIV viral suppression in youth aged 15-24 years living with HIV in rural Kenya and Uganda. This was a cross-sectional analysis of 995 youth enrolled in the SEARCH Youth study. At baseline, providers assessed recent (within 6 months) life-events, defined as changes in schooling/employment, residence, partnerships, sickness, incarceration status, family strife or death, and birth/pregnancy, self-reported alcohol use, being a parent, and HIV-status disclosure. We examined the frequencies of events and their association with ART status and HIV viral suppression (<400 copies/ul). Recent significant life-events were prevalent (57.7%). Having >2 significant life-events (aOR = 0.61, 95% CI:0.45-0.85) and consuming alcohol (aOR = 0.61, 95% CI:0.43-0.87) were associated with a lower odds of HIV viral suppression, while disclosure of HIV-status to partner (aOR = 2.39, 95% CI:1.6-3.5) or to family (aOR = 1.86, 95% CI:1.3-2.7), being a parent (aOR = 1.8, 95% CI:1.2-2.5), and being single (aOR = 1.6, 95% CI:1.3-2.1) had a higher odds. This suggest that two or more recent life-events and alcohol use are key barriers to ART initiation and achievement of viral suppression among youth living with HIV in rural East Africa.Trial registration: ClinicalTrials.gov identifier: NCT03848728..

Feasibility and preliminary effectiveness of integrating HIV prevention into an adolescent empowerment and livelihood intervention at youth clubs in rural Uganda.

The uptake of HIV prevention services is lower among youth than adults in sub-Saharan Africa. Existing youth livelihood trainings offer a potential entry point to HIV prevention services. We determined feasibility and preliminary effectiveness of integrating HIV prevention into youth clubs implementing an empowerment and livelihood for adolescents (ELA) intervention in rural Uganda. Staff conducted community mobilization for youth (15-24 years) over one month. Clubs met (3×/week) over six months, with local peer mentors trained to teach life-skills and sexual/reproductive health education. We integrated mentor-led education on HIV prevention, including pre- and post-exposure prophylaxis (PrEP/PEP). Clubs offered on-site HIV testing, a field trip to a local clinic and PrEP referrals after one month and six months. Surveys were conducted at baseline and six months. Forty-two participants (24 adolescent girls/young women (AGYW) and 18 adolescent boys/young men (ABYM)) joined the clubs. At baseline, no participants accepted referral for PrEP, whereas 5/18 (28%) sexually active, HIV-negative AGYW requested PrEP referral at follow-up. One ABYM requested PEP referral. Integration of HIV prevention services into an established ELA curriculum at mentor-led youth clubs in rural Uganda was feasible. PrEP uptake increased among sexually active AGYW. Evaluation of this approach for HIV prevention among youth merits further study.

In Utero Activation of Natural Killer Cells in Congenital Cytomegalovirus Infection.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is the most common infectious cause of birth defects and neurological damage in newborns. Despite a well-established role for natural killer (NK) cells in control of CMV infection in older children and adults, it remains unknown whether fetal NK cells can sense and respond to CMV infection acquired in utero. METHODS: Here, we investigate the impact of congenital CMV infection on the neonatal NK-cell repertoire by assessing the frequency, phenotype, and functional profile of NK cells in cord blood samples from newborns with congenital CMV and from uninfected controls enrolled in a birth cohort of Ugandan mothers and infants. RESULTS: We find that neonatal NK cells from congenitally CMV infected newborns show increased expression of cytotoxic mediators, signs of maturation and activation, and an expansion of mature CD56- NK cells, an NK-cell subset associated with chronic viral infections in adults. Activation was particularly prominent in NK cell subsets expressing the Fcγ receptor CD16, indicating a role for antibody-mediated immunity against CMV in utero. CONCLUSIONS: These findings demonstrate that NK cells can be activated in utero and suggest that NK cells may be an important component of the fetal and infant immune response against CMV. CLINICAL TRIALS REGISTRATION: NCT02793622.