Showing papers by "Moses R. Kamya published in 2015"

Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities.

Abstract: Tools to reliably measure Plasmodium falciparum (Pf) exposure in individuals and communities are needed to guide and evaluate malaria control interventions. Serologic assays can potentially produce precise exposure estimates at low cost; however, current approaches based on responses to a few characterized antigens are not designed to estimate exposure in individuals. Pf-specific antibody responses differ by antigen, suggesting that selection of antigens with defined kinetic profiles will improve estimates of Pf exposure. To identify novel serologic biomarkers of malaria exposure, we evaluated responses to 856 Pf antigens by protein microarray in 186 Ugandan children, for whom detailed Pf exposure data were available. Using data-adaptive statistical methods, we identified combinations of antibody responses that maximized information on an individual's recent exposure. Responses to three novel Pf antigens accurately classified whether an individual had been infected within the last 30, 90, or 365 d (cross-validated area under the curve = 0.86-0.93), whereas responses to six antigens accurately estimated an individual's malaria incidence in the prior year. Cross-validated incidence predictions for individuals in different communities provided accurate stratification of exposure between populations and suggest that precise estimates of community exposure can be obtained from sampling a small subset of that community. In addition, serologic incidence predictions from cross-sectional samples characterized heterogeneity within a community similarly to 1 y of continuous passive surveillance. Development of simple ELISA-based assays derived from the successful selection strategy outlined here offers the potential to generate rich epidemiologic surveillance data that will be widely accessible to malaria control programs.

Mind the gap: house structure and the risk of malaria in Uganda.

Abstract: Background: Good house construction may reduce the risk of malaria by limiting the entry of mosquito vectors. We assessed how house design may affect mosquito house entry and malaria risk in Uganda. Methods: 100 households were enrolled in each of three sub-counties: Walukuba, Jinja district; Kihihi, Kanungu district; and Nagongera, Tororo district. CDC light trap collections of mosquitoes were done monthly in all homes. All children aged six months to ten years (n = 878) were followed prospectively for a total of 24 months to measure parasite prevalence every three months and malaria incidence. Homes were classified as modern (cement, wood or metal walls; and tiled or metal roof; and closed eaves) or traditional (all other homes). Results: A total of 113,618 female Anopheles were collected over 6,765 nights. 6,816 routine blood smears were taken of which 1,061 (15.6%) were malaria parasite positive. 2,582 episodes of uncomplicated malaria were diagnosed after 1,569 person years of follow-up, giving an overall incidence of 1.6 episodes per person year at risk. The human biting rate was lower in modern homes than in traditional homes (adjusted incidence rate ratio (IRR) 0.48, 95% confidence interval (CI) 0.37–0.64, p<0.001). The odds of malaria infection were lower in modern homes across all the sub-counties (adjusted odds ratio 0.44, 95%CI 0.30–0.65, p<0.001), while malaria incidence was lower in modern homes in Kihihi (adjusted IRR 0.61, 95%CI 0.40–0.91, p = 0.02) but not in Walukuba or Nagongera. Conclusions: House design is likely to explain some of the heterogeneity of malaria transmission in Uganda and represents a promising target for future interventions, even in highly endemic areas.

Estimating malaria parasite prevalence from community surveys in Uganda: a comparison of microscopy, rapid diagnostic tests and polymerase chain reaction.

Abstract: Household surveys are important tools for monitoring the malaria disease burden and measuring impact of malaria control interventions with parasite prevalence as the primary metric. However, estimates of parasite prevalence are dependent on a number of factors including the method used to detect parasites, age of the population sampled, and level of immunity. To better understand the influence of diagnostics, age, and endemicity on estimates of parasite prevalence and how these change over time, community-based surveys were performed for two consecutive years in three settings and the sensitivities of microscopy and immunochromatographic rapid diagnostic tests (RDTs) were assessed, considering polymerase chain reaction (PCR) as the gold standard. Surveys were conducted over the same two-month period in 2012 and 2013 in each of three sub-counties in Uganda: Nagongera in Tororo District (January–February), Walukuba in Jinja District (March–April), and Kihihi in Kanungu District (May–June). In each sub-county, 200 households were randomly enrolled and a household questionnaire capturing information on demographics, use of malaria prevention methods, and proxy indicators of wealth was administered to the head of the household. Finger-prick blood samples were obtained for RDTs, measurement of hemoglobin, thick and thin blood smears, and to store samples on filter paper. A total of 1200 households were surveyed and 4433 participants were included in the analysis. Compared to PCR, the sensitivity of microscopy was low (65.3 % in Nagongera, 49.6 % in Walukuba and 40.9 % in Kihihi) and decreased with increasing age. The specificity of microscopy was over 98 % at all sites and did not vary with age or year. Relative differences in parasite prevalence across different age groups, study sites, and years were similar for microscopy and PCR. The sensitivity of RDTs was similar across the three sites (range 77.2–82.8 %), was consistently higher than microscopy (p < 0.001 for all pairwise comparisons), and decreased with increasing age. The specificity of RDTs was lower than microscopy (76.3 % in Nagongera, 86.3 % in Walukuba, and 83.5 % in Kihihi) and varied significantly by year and age. Relative differences in parasite prevalence across age groups and study years differed for RDTs compared to microscopy and PCR. Malaria prevalence estimates varied with diagnostic test, age, and transmission intensity. It is important to consider the effects of these parameters when designing and interpreting community-based surveys.

Hair concentrations of antiretrovirals predict viral suppression in HIV-infected pregnant and breastfeeding Ugandan women.

Abstract: Objective Hair concentrations are a non-invasive measure of cumulative antiretroviral (ARV) exposure and the strongest predictor of viral suppression in large cohorts of non-pregnant patients. We examined hair concentrations of ARVs in relation to virologic outcomes in pregnant and breastfeeding women for the first time.

Atorvastatin reduces T-cell activation and exhaustion among HIV-infected cART-treated suboptimal immune responders in Uganda: a randomised crossover placebo-controlled trial

Abstract: Objective T-cell activation independently predicts mortality, poor immune recovery and non-AIDS illnesses during combination antiretroviral therapy (cART). Atorvastatin showed anti-immune activation effects among HIV-infected cART-naive individuals. We investigated whether adjunct atorvastatin therapy reduces T-cell activation among cART-treated adults with suboptimal immune recovery. Methods A randomised double-blind placebo-controlled crossover trial, of atorvastatin 80 mg daily vs. placebo for 12 weeks, was conducted among individuals with CD4 increase <295 cells/μl after seven years of suppressive cART. Change in T-cell activation (CD3 + CD4 + /CD8 + CD38 + HLADR+) and in T-cell exhaustion (CD3 + CD4 + /CD8 + PD1 + ) was measured using flow cytometry. Results Thirty patients were randomised, 15 to each arm. Atorvastatin resulted in a 28% greater reduction in CD4 T-cell activation (60% reduction) than placebo (32% reduction); P = 0.001. Atorvastatin also resulted in a 35% greater reduction in CD8-T-cell activation than placebo (49% vs. 14%, P = 0.0009), CD4 T-cell exhaustion (27% vs. 17% in placebo), P = 0.001 and CD8 T-cell exhaustion (27% vs. 16%), P = 0.004. There was no carry-over/period effect. Expected adverse events were comparable in both groups, and no serious adverse events were reported. Conclusion Atorvastatin reduced T-cell immune activation and exhaustion among cART-treated adults in a Ugandan cohort. Atorvastatin adjunct therapy should be explored as a strategy to improve HIV treatment outcomes among people living with HIV in sub-Saharan Africa. Objectif L'activation des cellules T predit independamment la mortalite, la faible reconstitution immunitaire et les maladies non-SIDA au cours du traitement de combinaison antiretroviral (cART). L'atorvastatine a montre des effets d'activation anti-immunitaire chez les personnes infectes par le VIH et naives pour le cART. Nous avons investigue si la therapie d'appoint avec l'atorvastatine reduisait l'activation des cellules T chez les adultes traites au cART ayant une reconstitution immunitaire sous-optimale. Methodes Un essai randomise, placebo controle, en cross-over et en double aveugle avec de l'atorvastatine a 80 mg par jour versus placebo pendant 12 semaines, chez les individus avec une augmentation des CD4 <295cells/μl apres sept ans sous cART suppressif. Les variations dans l'activation des cellules T (CD3+ CD4+/CD8+ CD38+ HLADR+) et dans l’epuisement des cellules T (CD3+ CD4+/CD8+ PD1+) ont ete mesurees par cytometrie de flux. Resultats Trente patients ont ete randomises, 15 dans chaque bras. L'atorvastatine a entraine une reduction plus importante de l'activation des cellules T CD4 (reduction de 60%) que le placebo (reduction de 32%); p = 0,001 chez 28% des patients. L'atorvastatine a egalement entraine une plus grande reduction de l'activation des cellules T CD8 que le placebo (49% contre 14%, p = 0,0009), de l’epuisement des cellules T CD4 (27% contre 17% dans le groupe placebo), p = 0,001 et de l’epuisement des cellules T CD8 (27% contre 16%), p = 0,004, chez 35% des patients. Il n'y a pas eu d'effet residuel du traitement/periode precedent. Les evenements indesirables attendus etaient comparables dans les deux groupes et aucun effet indesirable severe n'a ete signale. Conclusion L'atorvastatine reduit l'activation immunitaire et l’epuisement des cellules T chez les adultes traites au cART dans une cohorte ougandaise. Le traitement d'appoint a l'atorvastatine devrait etre explore comme une strategie visant a ameliorer les resultats du traitement du VIH chez les personnes vivant avec le VIH en Afrique subsaharienne. Objetivo La activacion de celulas T predice la mortalidad de forma independiente, una mala recuperacion inmunologica y enfermedades no relacionadas con el SIDA durante la terapia antirretroviral combinada (TARc) La Atorvastatina mostraba efectos de activacion anti-inmune en individuos infectados con VIH y que no habian recibido TARc. Hemos investigado si la terapia adjunta con atorvastatina reduce la activacion de celulas T en adultos tratados con TARc y con una recuperacion inmune suboptima. Metodos Ensayo aleatorizado, doble ciego, cruzado y controlado con placebo, de 80 mg diarios de atorvastatina versus placebo durante 12 semanas, entre individuos con un aumento de CD4 <295cells/μl despues de siete anos de TARc supresivo. El cambio en la activacion de las celulas T (CD3+CD4+/CD8+ CD38+HLADR+) y el agotamiento de celulas T (CD3+CD4+/ CD8+PD1+) se midieron mediante citometria de flujo. Resultados Se aleatorizaron 30 pacientes, 15 en cada brazo. La Atorvastatina resulto en un 28% mas de reduccion de la activacion de celulas T (reduccion del 60%) que el placebo (reduccion del 32%); p=0.001. La Atorvastatina tambien resulto en una reduccion de la activacion de celulas T - CD8 un 35% mayor que el placebo (49% versus 14%, p=0.0009), un agotamiento de celulas T - CD4 T (27% versus 17% en placebo), p=0.001, y agotamiento de CD8 T (27% versus 16%), p=0.004. No habia efecto de arrastre. Los eventos adversos esperados eran comparables en ambos grupos y no se reporto ningun evento adverso serio. Conclusion La atorvastatina reduce la activacion inmune de celulas T y su agotamiento entre adultos tratados con TARc en una cohorte de Uganda. La terapia adjunta con atorvastatina deberia explorarse como estrategia para mejorar los resultados del tratamiento del VIH entre personas viviendo con VIH en Africa subsahariana.

Determinants of hypertension in a young adult Ugandan population in epidemiological transition - The MEPI-CVD survey

Abstract: High blood pressure is the principal risk factor for stroke, heart failure and kidney failure in the young population in Africa. Control of hypertension is associated with a larger reduction in morbidity and mortality in younger populations compared with the elderly; however, blood pressure control efforts in the young are hampered by scarcity of data on prevalence and factors influencing awareness, treatment and control of hypertension. We aimed to describe the prevalence of prehypertension and hypertension among young adults in a peri-urban district of Uganda and the factors associated with occurrence of hypertension in this population. This cross-sectional study was conducted between August, 2012 and May 2013 in Wakiso district, a suburban district that that encircles Kampala, Uganda’s capital city. We collected data on socio-demographic characteristics and hypertension status using a modified STEPs questionnaire from 3685 subjects aged 18–40 years selected by multistage cluster sampling. Blood pressure and anthropometric measurements were performed using standardized protocols. Fasting blood sugar and HIV status were determined using a venous blood sample. Association between hypertension status and various biosocial factors was assessed using logistic regression. The overall prevalence of hypertension was 15 % (95 % CI 14.2 – 19.6) and 40 % were pre-hypertensive. Among the 553 hypertensive participants, 76 (13.7 %) were aware of their diagnosis and all these participants had initiated therapy with target blood pressure control attained in 20 % of treated subjects. Hypertension was significantly associated with the older age-group, male sex and obesity. There was a significantly lower prevalence of hypertension among participants with HIV OR 0.6 (95 % CI 0.4–0.8, P = 0.007). There is a high prevalence of high blood pressure in this young periurban population of Uganda with sub-optimal diagnosis and control. There is previously undocumented high rate of treatment, a unique finding that may be exploited to drive efforts to control hypertension. Specific programs for early diagnosis and treatment of hypertension among the young should be developed to improve control of hypertension. The relationship between HIV infection and blood pressure requires further clarification by longitudinal studies.

Factors Associated with Malaria Parasitemia, Anemia and Serological Responses in a Spectrum of Epidemiological Settings in Uganda

Abstract: Background Understanding the current epidemiology of malaria and the relationship between intervention coverage, transmission intensity, and burden of disease is important to guide control activities. We aimed to determine the prevalence of anemia, parasitemia, and serological responses to P. falciparum antigens, and factors associated with these indicators, in three different epidemiological settings in Uganda. Methods and Findings In 2012, cross-sectional surveys were conducted in 200 randomly selected households from each of three sites: Walukuba, Jinja district (peri-urban); Kihihi, Kanungu district (rural); and Nagongera, Tororo district (rural) with corresponding estimates of annual entomologic inoculation rates (aEIR) of 3.8, 26.6, and 125.0, respectively. Of 2737 participants, laboratory testing was done in 2227 (81.4%), including measurement of hemoglobin, parasitemia using microscopy, and serological responses to P. falciparum apical membrane antigen 1 (AMA-1) and merozoite surface protein 1, 19 kilodalton fragment (MSP-119). Analysis of laboratory results was restricted to 1949 (87.5%) participants aged ≤ 40 years. Prevalence of anemia (hemoglobin < 11.0 g/dL) was significantly higher in Walukuba (18.9%) and Nagongera (17.4%) than in Kihihi (13.1%), and was strongly associated with decreasing age for those ≤ 5 years at all sites. Parasite prevalence was significantly higher in Nagongera (48.3%) than in Walukuba (12.2%) and Kihihi (12.8%), and significantly increased with age to 11 years, and then significantly decreased at all sites. Seropositivity to AMA-1 was 53.3% in Walukuba, 63.0% in Kihihi, and 83.7% in Nagongera and was associated with increasing age at all sites. AMA-1 seroconversion rates strongly correlated with transmission intensity, while serological responses to MSP-119 did not. Conclusion Anemia was predominant in young children and parasitemia peaked by 11 years across 3 sites with varied transmission intensity. Serological responses to AMA-1 appeared to best reflect transmission intensity, and may be a more accurate indicator for malaria surveillance than anemia or parasitemia.

Fertility desires and unmet need for family planning among HIV infected individuals in two HIV clinics with differing models of family planning service delivery

Abstract: Background Eliminating family planning (FP) unmet need among HIV-infected individuals (PLHIV) is critical to elimination of mother-to-child HIV transmission. We assessed FP unmet need among PLHIV attending two clinics with differing models of FP services. Nsambya Home Care provided only FP information while Mulago HIV clinic provided information and contraceptives onsite.

The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

Abstract: Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

Accuracy of Two Malaria Rapid Diagnostic Tests (RDTS) for Initial Diagnosis and Treatment Monitoring in a High Transmission Setting in Uganda

Abstract: Malaria rapid diagnostic tests (RDTs) may improve fever management in areas without microscopy. We compared the accuracy of histidine-rich protein 2 (HRP2) and Plasmodium lactate dehydrogenase (pLDH)-based RDTs, using expert microscopy as a gold standard, for initial diagnosis, treatment monitoring, and diagnosis of recurrent malaria in a cohort of children followed longitudinally in a high-transmission area in Uganda. For 305 initial fever episodes, sensitivity was 98% for HRP2 and 87% for pLDH, whereas specificity was 55% and 96%, respectively. The HRP2 gave 51% false-positive results on Day 28, whereas pLDH gave no false positives after Day 7. For 59 recurrent fever episodes during follow-up, sensitivity was 100% for HRP2 and 91% for pLDH, whereas specificity was 33% and 100%, respectively. The HRP2-based RDTs are useful for initial diagnosis of malaria caused by superior sensitivity; however, as a result of superior specificity, pLDH-based RDTs are more appropriate to monitor treatment and diagnose recurrent malaria.

Outcomes in a Cohort of Patients Started on Antiretroviral Treatment and Followed up for a Decade in an Urban Clinic in Uganda.

Abstract: BACKGROUND: Short-medium term studies from sub-Saharan Africa show that despite high early mortality substantial loss to program and high rates toxicity patients on antiretroviral treatment have achieved outcomes comparable to those in developed settings. However these studies were unable to account for long term outcomes of patients as they stayed longer on treatment. OBJECTIVES: We aim to describe ten years outcomes of one of the first cohort of HIV positive patients started on antiretroviral treatment (ART) in Sub-Saharan Africa. METHODS: We report 10-years outcomes including mortality retention CD4-count response virological outcomes ART regimens change from a prospective cohort of 559 patients initiating ART and followed up for 10 years Uganda. RESULTS: Of 559 patients 69.1% were female median age (IQR) was 38 (33-44) years median CD4-count (IQR) 98 (21-163) cell/muL; 74% were started on stavudine lamivudine and nevirapine 26% on zidovudine lamivudine and efavirenz. After 10 years 361 (65%) patients were still in the study; 127 (22.7%) had died; 30 (5%) were lost to follow-up; 27 (5%) transferred; 18 (3%) withdrew consent. The probability of death was high in the first year (0.15 95% CI 0.12-0.18). The median CD4 count increased from 98 to 589 cell/muL (IQR: 450-739 cell/muL) with a median increase of 357 cells/muL (IQR: 128-600 cells/muL); 7.4% never attained initial viral suppression and of those who did 31.7% experienced viral failure. Three hundred and two patients had at least one drug substitution while on first line after a median of 40 months; 66 (11.9%) of the patients were switched to a second line PI-based regimen due to confirmed treatment failure. CONCLUSIONS: Despite the high rate of early mortality due to advanced disease at presentation the outcomes from this cohort are encouraging particularly the remarkable and incremental immune-recovery and a satisfactory rate of virologic suppression.

Bacteremia Among Febrile Ugandan Children Treated with Antimalarials Despite a Negative Malaria Test

Abstract: Bacteremia may be inappropriately treated as malaria in children admitted with a febrile illness in Africa. We determined the prevalence, clinical features, and spectrum of bacteremia among febrile children younger than 5 years of age admitted with a negative malaria test, but prescribed antimalarials at a referral hospital in Jinja, Uganda. After initial evaluation, a blood sample was drawn from 250 children for a complete blood count and bacterial culture. Of 250 samples cultured, 15 grew organisms presumed to be skin contaminants, and of the remaining 235 samples, 45 (19.1%) had bacteremia. Staphylococcus aureus (42%), non-typhoidal Salmonella (24%), Pseudomonas aeruginosa (11%), and Streptococcus pneumoniae (9%) were the most common bacterial isolates. On multivariate analysis, history of weight loss (odds ratio [OR] = 2.75; 95% confidence interval [CI] = 1.27-5.95), presence of pulmonary crackles (OR = 3.63; 95% CI = 1.40-9.45), and leukocytosis (OR = 2.21; 95% CI = 1.09-4.47) were independent predictors of bacteremia. At a referral hospital in Uganda, bacteremia was a remarkably common finding in children with febrile illness who were treated for malaria despite negative malaria test results.

Benchmarking health system performance across regions in Uganda: a systematic analysis of levels and trends in key maternal and child health interventions, 1990–2011

Abstract: Globally, countries are increasingly prioritizing the reduction of health inequalities and provision of universal health coverage. While national benchmarking has become more common, such work at subnational levels is rare. The timely and rigorous measurement of local levels and trends in key health interventions and outcomes is vital to identifying areas of progress and detecting early signs of stalled or declining health system performance. Previous studies have yet to provide a comprehensive assessment of Uganda’s maternal and child health (MCH) landscape at the subnational level. By triangulating a number of different data sources – population censuses, household surveys, and administrative data – we generated regional estimates of 27 key MCH outcomes, interventions, and socioeconomic indicators from 1990 to 2011. After calculating source-specific estimates of intervention coverage, we used a two-step statistical model involving a mixed-effects linear model as an input to Gaussian process regression to produce regional-level trends. We also generated national-level estimates and constructed an indicator of overall intervention coverage based on the average of 11 high-priority interventions. National estimates often veiled large differences in coverage levels and trends across Uganda’s regions. Under-5 mortality declined dramatically, from 163 deaths per 1,000 live births in 1990 to 85 deaths per 1,000 live births in 2011, but a large gap between Kampala and the rest of the country persisted. Uganda rapidly scaled up a subset of interventions across regions, including household ownership of insecticide-treated nets, receipt of artemisinin-based combination therapies among children under 5, and pentavalent immunization. Conversely, most regions saw minimal increases, if not actual declines, in the coverage of indicators that required multiple contacts with the health system, such as four or more antenatal care visits, three doses of oral polio vaccine, and two doses of intermittent preventive therapy during pregnancy. Some of the regions with the lowest levels of overall intervention coverage in 1990, such as North and West Nile, saw marked progress by 2011; nonetheless, sizeable disparities remained between Kampala and the rest of the country. Countrywide, overall coverage increased from 40 % in 1990 to 64 % in 2011, but coverage in 2011 ranged from 57 % to 70 % across regions. The MCH landscape in Uganda has, for the most part, improved between 1990 and 2011. Subnational benchmarking quantified the persistence of geographic health inequalities and identified regions in need of additional health systems strengthening. The tracking and analysis of subnational health trends should be conducted regularly to better guide policy decisions and strengthen responsiveness to local health needs.

Associations between urbanicity and malaria at local scales in Uganda

Abstract: Sub-Saharan Africa is expected to show the greatest rates of urbanization over the next 50 years. Urbanization has shown a substantial impact in reducing malaria transmission due to multiple factors, including unfavourable habitats for Anopheles mosquitoes, generally healthier human populations, better access to healthcare, and higher housing standards. Statistical relationships have been explored at global and local scales, but generally only examining the effects of urbanization on single malaria metrics. In this study, associations between multiple measures of urbanization and a variety of malaria metrics were estimated at local scales. Cohorts of children and adults from 100 households across each of three contrasting sub-counties of Uganda (Walukuba, Nagongera and Kihihi) were followed for 24 months. Measures of urbanicity included density of surrounding households, vegetation index, satellite-derived night-time lights, land cover, and a composite urbanicity score. Malaria metrics included the household density of mosquitoes (number of female Anopheles mosquitoes captured), parasite prevalence and malaria incidence. Associations between measures of urbanicity and malaria metrics were made using negative binomial and logistic regression models. One site (Walukuba) had significantly higher urbanicity measures compared to the two rural sites. In Walukuba, all individual measures of higher urbanicity were significantly associated with a lower household density of mosquitoes. The higher composite urbanicity score in Walukuba was also associated with a lower household density of mosquitoes (incidence rate ratio = 0.28, 95 % CI 0.17–0.48, p < 0.001) and a lower parasite prevalence (odds ratio, OR = 0.44, CI 0.20–0.97, p = 0.04). In one rural site (Kihihi), only a higher density of surrounding households was associated with a lower parasite prevalence (OR = 0.15, CI 0.07–0.34, p < 0.001). And, in only one rural site (Nagongera) was living where NDVI ≤0.45 associated with higher incidence of malaria (IRR = 1.35, CI 1.35–1.70, p = 0.01). Urbanicity has been shown previously to lead to a reduction in malaria transmission at large spatial scales. At finer scales, individual household measures of higher urbanicity were associated with lower mosquito densities and parasite prevalence only in the site that was generally characterized as being urban. The approaches outlined here can help better characterize urbanicity at the household level and improve targeting of control interventions.

Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children

Abstract: Anti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure. Children were enrolled in a non directly-observed trial of DHA/PQ chemoprevention in a high transmission setting in Uganda. Children were randomized at 6 months of age to no chemoprevention (n = 89) or monthly DHA/PQ (n = 87) and followed through 24 months of age, with pharmacokinetic sampling performed at variable times following monthly dosing of DHA/PQ. A previously published pharmacokinetic model was used to estimate piperaquine (PQ) exposure in each child, and associations between PQ exposure and the protective efficacy (PE) of DHA/PQ were explored. The incidence of malaria was 6.83 and 3.09 episodes per person year at risk in the no chemoprevention and DHA/PQ arms, respectively (PE 54 %, 95 % CI 39–66 %, P < 0.001). Among children randomized to DHA/PQ, 493 pharmacokinetic samples were collected. Despite nearly 100 % reported adherence to study drug administration at home, there was wide variability in PQ exposure, and children were stratified into three groups based on average PQ exposure during the intervention that was determined by model generated percentiles (low, n = 40; medium, n = 37, and high, n = 10). Gender and socioeconomic factors were not significantly associated with PQ exposure. In multivariate models, the PE of DHA/PQ was 31 % in the low PQ exposure group (95 % CI 6–49 %, P = 0.02), 67 % in the medium PQ exposure group (95 % CI 54–76 %, P < 0.001), and 97 % in the high PQ exposure group (95 % CI 89–99 %, P < 0.001). The protective efficacy of DHA/PQ chemoprevention in young children was strongly associated with higher drug exposure; in children with the highest PQ exposure, monthly DHA/PQ chemoprevention was nearly 100 % protective against malaria. Strategies to ensure good adherence to monthly dosing and optimize drug exposure are critical to maximize the efficacy of this promising malaria control strategy. Trial Registration: Current Controlled Trials Identifier NCT00948896

Estimated Costs for Delivery of HIV Antiretroviral Therapy to Individuals with CD4+ T-Cell Counts >350 cells/uL in Rural Uganda.

Abstract: Author(s): Jain, Vivek; Chang, Wei; Byonanebye, Dathan M; Owaraganise, Asiphas; Twinomuhwezi, Ellon; Amanyire, Gideon; Black, Douglas; Marseille, Elliot; Kamya, Moses R; Havlir, Diane V; Kahn, James G | Abstract: BackgroundEvidence favoring earlier HIV ART initiation at high CD4+ T-cell counts (CD4g350/uL) has grown, and guidelines now recommend earlier HIV treatment. However, the cost of providing ART to individuals with CD4g350 in Sub-Saharan Africa has not been well estimated. This remains a major barrier to optimal global cost projections for accelerating the scale-up of ART. Our objective was to compute costs of ART delivery to high CD4+count individuals in a typical rural Ugandan health center-based HIV clinic, and use these data to construct scenarios of efficient ART scale-up.MethodsWithin a clinical study evaluating streamlined ART delivery to 197 individuals with CD4+ cell counts g350 cells/uL (EARLI Study: NCT01479634) in Mbarara, Uganda, we performed a micro-costing analysis of administrative records, ART prices, and time-and-motion analysis of staff work patterns. We computed observed per-person-per-year (ppy) costs, and constructed models estimating costs under several increasingly efficient ART scale-up scenarios using local salaries, lowest drug prices, optimized patient loads, and inclusion of viral load (VL) testing.FindingsAmong 197 individuals enrolled in the EARLI Study, median pre-ART CD4+ cell count was 569/uL (IQR 451-716). Observed ART delivery cost was $628 ppy at steady state. Models using local salaries and only core laboratory tests estimated costs of $529/$445 ppy (+/-VL testing, respectively). Models with lower salaries, lowest ART prices, and optimized healthcare worker schedules reduced costs by $100-200 ppy. Costs in a maximally efficient scale-up model were $320/$236 ppy (+/- VL testing). This included $39 for personnel, $106 for ART, $130/$46 for laboratory tests, and $46 for administrative/other costs. A key limitation of this study is its derivation and extrapolation of costs from one large rural treatment program of high CD4+ count individuals.ConclusionsIn a Ugandan HIV clinic, ART delivery costs--including VL testing--for individuals with CD4g350 were similar to estimates from high-efficiency programs. In higher efficiency scale-up models, costs were substantially lower. These favorable costs may be achieved because high CD4+ count patients are often asymptomatic, facilitating more efficient streamlined ART delivery. Our work provides a framework for calculating costs of efficient ART scale-up models using accessible data from specific programs and regions.

Anti-malarial prescription practices among children admitted to six public hospitals in Uganda from 2011 to 2013

Abstract: In 2011, Uganda’s Ministry of Health switched policy from presumptive treatment of malaria to recommending parasitological diagnosis prior to treatment, resulting in an expansion of diagnostic services at all levels of public health facilities including hospitals. Despite this change, anti-malarial drugs are often prescribed even when test results are negative. Presented is data on anti-malarial prescription practices among hospitalized children who underwent diagnostic testing after adoption of new treatment guidelines. Anti-malarial prescription practices were collected as part of an inpatient malaria surveillance program generating high quality data among children admitted for any reason at government hospitals in six districts. A standardized medical record form was used to collect detailed patient information including presenting symptoms and signs, laboratory test results, admission and final diagnoses, treatments administered, and final outcome upon discharge. Between July 2011 and December 2013, 58,095 children were admitted to the six hospitals (hospital range 3294–20,426).A total of 56,282 (96.9 %) patients were tested for malaria, of which 26,072 (46.3 %) tested positive (hospital range 5.9–57.3 %). Among those testing positive, only 84 (0.3 %) were first tested after admission and 295 of 30,389 (1.0 %) patients who tested negative at admission later tested positive. Of 30,210 children with only negative test results, 11,977 (39.6 %) were prescribed an anti-malarial (hospital range 14.5–53.6 %). The proportion of children with a negative test result who were prescribed an anti-malarial fluctuated over time and did not show a significant trend at any site with the exception of one hospital where a steady decline was observed. Among those with only negative test results, children 6–12 months of age (aOR 3.78; p < 0.001) and those greater than 12 months of age (aOR 4.89; p < 0.001) were more likely to be prescribed an anti-malarial compared to children less than 6 months of age. Children with findings suggestive of severe malaria were also more likely to be prescribed an anti-malarial after a negative test result (aOR 1.98; p < 0.001). Despite high testing rates for malaria at all sites, prescription of anti-malarials to patients with negative test results remained high, with the exception of one site where a steady decline occurred.

8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015).

Abstract: Sensitive assays are needed for detection of residual HIV in patients with undetectable plasma viral loads to determine if eradication strategies are effective. The gold standard quantitative viral outgrowth assay (QVOA) underestimates the magnitude of the viral reservoir, while sensitive PCR‐based assays lack the ability to distinguish replication competent from defective virus. We sought to determine whether xenograft of leukocytes from HIV‐1 infected patients with undetectable plasma viral loads into severely immunocompromised mice would result in viral amplification and measurable viral loads within the aberrant murine host.

Quality of Inpatient Pediatric Case Management for Four Leading Causes of Child Mortality at Six Government-Run Ugandan Hospitals

Abstract: Background A better understanding of case management practices is required to improve inpatient pediatric care in resource-limited settings. Here we utilize data from a unique health facility-based surveillance system at six Ugandan hospitals to evaluate the quality of pediatric case management and the factors associated with appropriate care. Methods All children up to the age of 14 years admitted to six district or regional hospitals over 15 months were included in the study. Four case management categories were defined for analysis: suspected malaria, selected illnesses requiring antibiotics, suspected anemia, and diarrhea. The quality of case management for each category was determined by comparing recorded treatments with evidence-based best practices as defined in national guidelines. Associations between variables of interest and the receipt of appropriate case management were estimated using multivariable logistic regression. Results A total of 30,351 admissions were screened for inclusion in the analysis. Ninety-two percent of children met criteria for suspected malaria and 81% received appropriate case management. Thirty-two percent of children had selected illnesses requiring antibiotics and 89% received appropriate antibiotics. Thirty percent of children met criteria for suspected anemia and 38% received appropriate case management. Twelve percent of children had diarrhea and 18% received appropriate case management. Multivariable logistic regression revealed large differences in the quality of care between health facilities. There was also a strong association between a positive malaria diagnostic test result and the odds of receiving appropriate case management for comorbid non-malarial illnesses - children with a positive malaria test were more likely to receive appropriate care for anemia and less likely for illnesses requiring antibiotics and diarrhea. Conclusions Appropriate management of suspected anemia and diarrhea occurred infrequently. Pediatric quality improvement initiatives should target deficiencies in care unique to each health facility, and interventions should focus on the simultaneous management of multiple diagnoses.

Impact of Patient-Selected Care Buddies on Adherence to HIV Care, Disease Progression, and Conduct of Daily Life Among Pre-antiretroviral HIV-Infected Patients in Rakai, Uganda: A Randomized Controlled Trial.

Abstract: BACKGROUND: Data are limited on effects of household or community support persons ("care buddies") on enrollment into and adherence to pre-antiretroviral HIV care. We assessed the impact of care buddies on adherence to HIV clinic appointments HIV progression and conduct of daily life among pre-antiretroviral therapy (pre-ART) HIV-infected individuals in Rakai Uganda. METHODS: A total of 1209 HIV-infected pre-ART patients aged >/=15 years were randomized to standard of care (SOC) (n = 604) or patient-selected care buddy (PSCB) (n = 605) and followed at 6 and 12 months. Outcomes were adherence to clinic visits HIV disease progression and self-reported conduct of daily life. Incidence and prevalence rate ratios and 95% confidence intervals (CIs) were used to assess outcomes in the intent-to-treat and as-treated analyses. RESULTS: Baseline characteristics were comparable. In the intent to treat analysis both arms were comparable with respect to adherence to CD4 monitoring visits [adjusted prevalence risk ratio (adjPRR) 0.98; 95% CI: 0.93 to 1.04; P = 0.529] and ART eligibility (adjPRR 1.00; 95% CI: 0.77 to 1.31; P = 0.946). Good conduct of daily life was significantly higher in the PSCB than the SOC arm (adjPRR 1.08; 95% CI: 1.03 to 1.13; P = 0.001). More men (61%) compared with women (30%) selected spouses/partners as buddies (P < 0.0001). Twenty-two percent of PSCB arm participants discontinued use of buddies. CONCLUSIONS: In pre-ART persons having care buddies improved the conduct of daily life of the HIV-infected patients but had no effect on HIV disease progression and only limited effect on clinic appointment adherence.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria in the setting of three different chemopreventive regimens

Abstract: Background The burden of malaria remains high for children in parts of Africa despite the use of insecticide-treated bed nets (ITNs). Chemoprevention has the potential of reducing the malaria burden; however, limited data exist on the efficacy and safety of anti-malarial therapy in the setting of chemoprevention.

Impact of mycobacterial culture among HIV-infected adults with presumed TB in Uganda: a prospective cohort study.

Abstract: Implementation of new tuberculosis (TB) diagnostic strategies in resource-constrained settings is challenging. We measured the impact of solid and liquid mycobacterial cultures on treatment practices for patients undergoing TB evaluation in Kampala, Uganda.We enrolled consecutive smear-negative, human immunodeficiency virus positive adults with cough of ⩾2 weeks from September 2009 to April 2010. Laboratory technicians performed mycobacterial cultures on solid and liquid media. We compared empiric treatment decisions with solid and liquid culture in terms of diagnostic yield and time to results, and assessed impact on patient management.Of 200 patients enrolled, 26 (13%) had culture-confirmed TB: 22 (85%) on solid culture alone, 2 (8%) on liquid culture alone, and 2 (8%) on both solid and liquid culture. Thirty-four patients received empiric anti-tuberculosis treatment, but only 10 (29%) were culture-positive. Median time to a positive result on solid culture was 92 days (interquartile range [IQR] 69-148) compared to 106 days (IQR 66-157) for liquid culture. No patients initiated treatment following a positive result on liquid culture.The introduction of mycobacterial culture did not influence care for patients undergoing evaluation for TB in Kampala, Uganda. Attention to contextual factors surrounding implementation is needed to ensure the effective introduction of new testing strategies in low-income countries.

Structured career development for global health research in resource-limited settings: A pilot of career development series for faculty at Makerere university college of health sciences

Abstract: Program/Project Purpose: Effective mentoring is critical to sustainability of global health research leadership in low and middle income countries (LMICs). Experiences of clinicians, academicians, educators and researchers in LMICs should be utilized to design locally appropriate case studies to mentor the next generation of scientists that will understand and take up critical gaps in global health research leadership. A structured staff career development (SCaD) program at Makerere University College of Health Sciences (MakCHS), was established to develop evidence-based culturally-appropriate training modules to build global health research mentors among junior and midcareer scientists. Structure/Method/Design: Under SCaD, skills’ building workshops for junior and mid-level faculty (including doctoral and postdoctoral fellows) were facilitated by senior faculty, two-hour bi-monthly meetings were held for discussion of case studies based on local experiences in academic career development, and expert-speaker talks were organized to tackle listed priority areas such as practical steps in personal development planning. Targeted participants were all academic faculty, clinicians and researchers; invited through the staff mailing lists and notice board announcements. Lessons learnt and frequently asked questions were documented to contribute the institutional staff career development plan. An institutional-led career development working group is established, with departmental representation. Departmental-specific faculty career development needs were addressed to enhance faculty productivity and sustainable research engagement/funding. Outcomes & Evaluation: Between February and October 2014, six career development series were held, including one five-day scientific writing workshop and 5 two-hour meetings on authorship, grantsmanship, balancing career development and family, and the role of research interest groups with a good mix of junior, mid-career and senior researchers to enhance mentoring in academic research. A highlighted major challenge was limited protected time for faculty to engage in academic research, due to overwhelming clinical and administrative responsibilities. Real-life culturally-appropriate case studies of common challenges to faculty career development were developed and discussed to generate evidence-based strategies to strengthen sustainable career development for global health research. To enhance leadership, ten (2 senior, 3 mid-career and 5 junior) faculty attended an international John-Maxwell leadership workshop in Uganda. Going Forward: We recommended structured implementation of personal development plans by faculty at MakCHS, and strengthening institutional research interest groups to increase opportunities for senior faculty tomentor junior faculty to engage in academic and researchFunding: Research Education Project, Department of Health and Human Services, National Institute of Health, Fogarty International Center, Grant# R25TW009343, sub-award# 7186SC and Malaria Capacity Development Consortium, London School of Hygiene and Tropical Medicine. Abstract #: 02ETC060