RESUMEN
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.
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Vacunas contra la Malaria , Malaria Falciparum , Humanos , Animales , Plasmodium falciparum , Epítopos , Proteínas Protozoarias , Antígenos de Protozoos , Anticuerpos Monoclonales , Anticuerpos Antiprotozoarios , Malaria Falciparum/prevención & controlRESUMEN
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.
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Culicidae , Vacunas contra la Malaria , Malaria Falciparum , Malaria , Animales , Humanos , Plasmodium falciparum , Culicidae/metabolismo , Proteínas Protozoarias , Anticuerpos Monoclonales , Malaria Falciparum/prevención & control , Anticuerpos AntiprotozoariosRESUMEN
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.).
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Artemisininas , Resistencia a Medicamentos , Malaria , Parásitos , Proteínas Protozoarias , Animales , Humanos , Artemisininas/farmacología , Artemisininas/uso terapéutico , Benchmarking , Parásitos/efectos de los fármacos , Parásitos/genética , Uganda/epidemiología , Resistencia a Medicamentos/genética , Malaria/tratamiento farmacológico , Malaria/genética , Malaria/parasitología , Proteínas Protozoarias/genéticaRESUMEN
HLA class I (HLA-I) allotypes vary widely in their dependence on tapasin (TAPBP), an integral component of the peptide-loading complex, to present peptides on the cell surface. We identified two single-nucleotide polymorphisms that regulate TAPBP messenger RNA (mRNA) expression in Africans, rs111686073 (G/C) and rs59097151 (A/G), located in an AP-2α transcription factor binding site and a microRNA (miR)-4486 binding site, respectively. rs111686073G and rs59097151A induced significantly higher TAPBP mRNA expression relative to the alternative alleles due to higher affinity for AP-2α and abrogation of miR-4486 binding, respectively. These variants associated with lower Plasmodium falciparum parasite prevalence and lower incidence of clinical malaria specifically among individuals carrying tapasin-dependent HLA-I allotypes, presumably by augmenting peptide loading, whereas tapasin-independent allotypes associated with relative protection, regardless of imputed TAPBP mRNA expression levels. Thus, an attenuated course of malaria may occur through enhanced breadth and/or magnitude of antigen presentation, an important consideration when evaluating vaccine efficacy.
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Antígenos de Histocompatibilidad Clase I , Malaria Falciparum , Proteínas de Transporte de Membrana , Plasmodium falciparum , Sitios de Unión , Variación Genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Malaria Falciparum/genética , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , MicroARNs/metabolismo , Péptidos/inmunología , Plasmodium falciparum/inmunología , ARN Mensajero/genética , Factor de Transcripción AP-2/metabolismoRESUMEN
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.
RESUMEN
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.
RESUMEN
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.
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Infecciones por VIH , Población Rural , Tuberculosis , Humanos , Uganda/epidemiología , Masculino , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/transmisión , Infecciones por VIH/prevención & control , Tuberculosis/epidemiología , Tuberculosis/prevención & control , Tuberculosis/transmisión , Tuberculosis/diagnóstico , Adulto , Preescolar , Niño , Adulto Joven , Adolescente , Incidencia , Persona de Mediana Edad , Prueba de VIH , Análisis por Conglomerados , Tamizaje Masivo/métodosRESUMEN
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.
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Infecciones por VIH , Tuberculosis Latente , Rifampin/análogos & derivados , Tuberculosis , Humanos , Isoniazida/efectos adversos , Tuberculosis/tratamiento farmacológico , Tuberculosis/prevención & control , Antituberculosos/efectos adversos , Uganda , Tuberculosis Latente/tratamiento farmacológico , Quimioterapia Combinada , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológicoRESUMEN
Cluster randomized trials (CRTs) randomly assign an intervention to groups of individuals (e.g., clinics or communities) and measure outcomes on individuals in those groups. While offering many advantages, this experimental design introduces challenges that are only partially addressed by existing analytic approaches. First, outcomes are often missing for some individuals within clusters. Failing to appropriately adjust for differential outcome measurement can result in biased estimates and inference. Second, CRTs often randomize limited numbers of clusters, resulting in chance imbalances on baseline outcome predictors between arms. Failing to adaptively adjust for these imbalances and other predictive covariates can result in efficiency losses. To address these methodological gaps, we propose and evaluate a novel two-stage targeted minimum loss-based estimator to adjust for baseline covariates in a manner that optimizes precision, after controlling for baseline and postbaseline causes of missing outcomes. Finite sample simulations illustrate that our approach can nearly eliminate bias due to differential outcome measurement, while existing CRT estimators yield misleading results and inferences. Application to real data from the SEARCH community randomized trial demonstrates the gains in efficiency afforded through adaptive adjustment for baseline covariates, after controlling for missingness on individual-level outcomes.
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Evaluación de Resultado en la Atención de Salud , Proyectos de Investigación , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Probabilidad , Sesgo , Análisis por Conglomerados , Simulación por ComputadorRESUMEN
BACKGROUND: Scale up of proven malaria control interventions has not been sufficient to control malaria in Uganda, emphasizing the need to explore innovative new approaches. Improved housing is one such promising strategy. This paper describes housing characteristics and their association with malaria burden in a moderate to high transmission setting in Uganda. METHODS: Between October and November 2021, a household survey was conducted in 1500 randomly selected households in Jinja and Luuka districts. Information on demographics, housing characteristics, use of malaria prevention measures, and proxy indicators of wealth were collected for each household. A finger-prick blood sample was obtained for thick blood smears for malaria from all children aged 6 months to 14 years in the surveyed households. Febrile children had a malaria rapid diagnostics test (RDT) done; positive cases were managed according to national treatment guidelines. Haemoglobin was assessed in children aged < 5 years. Households were stratified as having modern houses (defined as having finished materials for roofs, walls, and floors and closed eaves) or traditional houses (those not meeting the definition of modern house). Associations between malaria burden and house type were estimated using mixed effects models and adjusted for age, wealth, and bed net use. RESULTS: Most (65.5%) of the households surveyed lived in traditional houses. Most of the houses had closed eaves (85.5%), however, the use of other protective features like window/vent screens and installed ceilings was limited (0.4% had screened windows, 2.8% had screened air vents, and 5.2% had ceiling). Overall, 3,443 children were included in the clinical survey, of which 31.4% had a positive smear. RDT test positivity rate was 56.6% among children with fever. Participants living in modern houses had a significantly lower parasite prevalence by microscopy (adjusted prevalence ratio [aPR = 0.80]; 95% confidence interval [CI] 0.71 - 0.90), RDT test positivity rate (aPR = 0.90, 95%CI 0.81 - 0.99), and anaemia (aPR = 0.80, 95%CI 0.65 - 0.97) compared to those in traditional houses. CONCLUSION: The study found that even after adjusting for wealth, higher quality housing had a moderate protective effect against malaria, on top of the protection already afforded by recently distributed nets.
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Vivienda , Malaria , Uganda/epidemiología , Vivienda/estadística & datos numéricos , Preescolar , Lactante , Humanos , Niño , Adolescente , Malaria/epidemiología , Malaria/prevención & control , Femenino , Masculino , Prevalencia , Composición FamiliarRESUMEN
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.
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Malaria Falciparum , Malaria , Humanos , Antígenos de Protozoos/genética , Estudios Transversales , Pruebas Diagnósticas de Rutina , Eliminación de Gen , L-Lactato Deshidrogenasa/genética , Malaria/diagnóstico , Malaria/genética , Malaria Falciparum/diagnóstico , Malaria Falciparum/genética , Plasmodium falciparum/genética , Proteínas Protozoarias/genética , Prueba de Diagnóstico Rápido , UgandaRESUMEN
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.
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Vivienda , Mosquiteros Tratados con Insecticida , Malaria , Control de Mosquitos , Uganda/epidemiología , Preescolar , Vivienda/estadística & datos numéricos , Niño , Humanos , Malaria/epidemiología , Malaria/prevención & control , Mosquiteros Tratados con Insecticida/estadística & datos numéricos , Femenino , Control de Mosquitos/estadística & datos numéricos , Masculino , Incidencia , Prevalencia , Parasitemia/epidemiología , Parasitemia/parasitologíaRESUMEN
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.
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COVID-19 , Mosquiteros Tratados con Insecticida , Malaria , Control de Mosquitos , Uganda/epidemiología , Malaria/prevención & control , Malaria/epidemiología , Mosquiteros Tratados con Insecticida/estadística & datos numéricos , Humanos , Control de Mosquitos/estadística & datos numéricos , Control de Mosquitos/métodos , COVID-19/prevención & control , COVID-19/epidemiologíaRESUMEN
Alcohol use is an important factor in achieving and maintaining viral suppression and optimal mental health among persons with HIV (PWH), however, the effect of age at first regular drinking on viral suppression and depression remains poorly understood. Here, using secondary data from the Alcohol Drinkers' Exposure to Preventive Therapy for Tuberculosis (ADEPT-T) study, we used logistic regression analyses to explore whether there is an association between age at first regular drinking and viral suppression (< 40 copies/ml), or presence of depressive symptoms (Center for Epidemiologic Studies Depression, CES-D ≥ 16) among 262 PWH. The median age at first regular drinking was 20.5 years (IQR: 10), with high proportions starting under age 12 (12.2%) and as teens (13.4%). The majority had an undetectable viral load (91.7%) and 11% had symptoms of probable depression. We found no significant association between age at first regular drinking and viral suppression (i.e., child (aOR = 0.76 95%CI: 0.18, 3.26), adolescent (aOR = 0.74 95%CI: 0.18, 2.97) and young adult (aOR = 1.27 95%CI: 0.40, 3.97)) nor with depressive symptoms (i.e., child (aOR = 0.72 95%CI: 0.19, 2.83), adolescent (aOR = 0.59 95%CI: 0.14, 2.50) and young adult (aOR = 0.57 95%CI: 0.22, 1.53)). Age at first regular drinking among PWH did not appear to be associated with either viral suppression or the presence of depressive symptoms, suggesting interventions may best be focused on the harmful effects of current alcohol use.
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Infecciones por VIH , Niño , Adulto Joven , Adolescente , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Infecciones por VIH/psicología , Uganda/epidemiología , Depresión/epidemiología , Depresión/psicología , Carga Viral , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/psicologíaRESUMEN
Targeted strategies are central to increasing HIV-status awareness and progress on the care cascade among men. We implemented Village-Health-Team (VHT)-delivered HIV self-testing (HIVST) among men in a peri-urban Ugandan district and assessed linkage to confirmatory-testing, antiretroviral-therapy (ART) initiation and HIV-status disclosure following HIVST. We conducted a prospective cohort study from November 2018 to June 2019 and enrolled 1628 men from 30-villages of Mpigi district. VHTs offered each participant one HIVST-kit and a linkage-to-care information leaflet. At baseline, we collected data on demographics, testing history and risk behavior. At one-month, we measured linkage to confirmatory-testing and HIV-status disclosure, and at three months ART-initiation if tested HIV-positive. We used Poisson regression generalized estimating equations to evaluate predictors of confirmatory-testing. We found that 19.8% had never tested for HIV and 43% had not tested in the last 12-months. After receiving HIVST-kits, 98.5% self-reported HIVST-uptake in 10-days, 78.8% obtained facility-based confirmation in 30-days of HIVST with 3.9% tested HIV-positive. Of the positives, 78.8% were newly diagnosed, 88% initiated ART and 57% disclosed their HIV-status to significant others. Confirmatory testing was associated with having a higher level of education and knowing a partner's HIV-status. VHT-delivered HIVST may be effective for boosting testing, ART-initiation and HIV-status disclosure among men.
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Infecciones por VIH , Masculino , Humanos , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , VIH , Autoevaluación , Uganda , Estudios Prospectivos , Autocuidado , Tamizaje MasivoRESUMEN
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.
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Infecciones por VIH , Tuberculosis , Humanos , Antituberculosos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Isoniazida/uso terapéutico , Investigación Cualitativa , Ensayos Clínicos Controlados Aleatorios como Asunto , Tuberculosis/prevención & control , Tuberculosis/tratamiento farmacológico , UgandaRESUMEN
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.
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Antimaláricos , Artemisininas , Malaria , Quinolinas , Niño , Femenino , Embarazo , Humanos , Antimaláricos/uso terapéutico , Malaria/tratamiento farmacológico , Pirimetamina/uso terapéutico , Sulfadoxina/uso terapéutico , Artemisininas/uso terapéutico , Combinación de Medicamentos , Quinolinas/uso terapéutico , Quimioprevención/métodosRESUMEN
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.
Asunto(s)
Infecciones por VIH , Tuberculosis Latente , Mycobacterium tuberculosis , Tuberculosis , Adulto , Masculino , Humanos , Femenino , Uganda/epidemiología , Población Rural , Prueba de Tuberculina , Tuberculosis/epidemiología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiologíaRESUMEN
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.
Asunto(s)
Vacunas contra la Malaria , Malaria Falciparum , Malaria , Humanos , Lactante , África , Variación GenéticaRESUMEN
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.