Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 44 Records) |
Query Trace: Kamya M[original query] |
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House modifications as a malaria control tool: how does local context shape participants' experience and interpretation in Uganda
Kayendeke M , Nabirye C , Nayiga S , Westercamp N , Gonahasa S , Katureebe A , Kamya MR , Staedke SG , Hutchinson E . Malar J 2023 22 (1) 244 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. |
Population-level viremia predicts HIV incidence at the community level across the Universal Testing and Treatment Trials in eastern and southern Africa
Larmarange J , Bachanas P , Skalland T , Balzer LB , Iwuji C , Floyd S , Mills LA , Pillay D , Havlir D , Kamya MR , Ayles H , Wirth K , Dabis F , Hayes R , Petersen M . PLOS Glob Public Health 2023 3 (7) e0002157 Universal HIV testing and treatment (UTT) strategies aim to optimize population-level benefits of antiretroviral treatment. Between 2012 and 2018, four large community randomized trials were conducted in eastern and southern Africa. While their results were broadly consistent showing decreased population-level viremia reduces HIV incidence, it remains unclear how much HIV incidence can be reduced by increasing suppression among people living with HIV (PLHIV). We conducted a pooled analysis across the four UTT trials. Leveraging data from 105 communities in five countries, we evaluated the linear relationship between i) population-level viremia (prevalence of non-suppression-defined as plasma HIV RNA >500 or >400 copies/mL-among all adults, irrespective of HIV status) and HIV incidence; and ii) prevalence of non-suppression among PLHIV and HIV incidence, using parametric g-computation. HIV prevalence, measured in 257 929 persons, varied from 2 to 41% across the communities; prevalence of non-suppression among PLHIV, measured in 31 377 persons, from 3 to 70%; population-level viremia, derived from HIV prevalence and non-suppression, from < 1% to 25%; and HIV incidence, measured over 345 844 person-years (PY), from 0.03/100PY to 3.46/100PY. Decreases in population-level viremia were strongly associated with decreased HIV incidence in all trials (between 0.45/100PY and 1.88/100PY decline in HIV incidence per 10 percentage points decline in viremia). Decreases in non-suppression among PLHIV were also associated with decreased HIV incidence in all trials (between 0.06/100PY and 0.17/100PY decline in HIV incidence per 10 percentage points decline in non-suppression). Our results support both the utility of population-level viremia as a predictor of incidence, and thus a tool for targeting prevention interventions, and the ability of UTT approaches to reduce HIV incidence by increasing viral suppression. Implementation of universal HIV testing approaches, coupled with interventions to leverage linkage to treatment, adapted to local contexts, can reduce HIV acquisition at population level. |
Achieving the UNAIDS 90-90-90 targets: a comparative analysis of four large community randomised trials delivering universal testing and treatment to reduce HIV transmission in sub-Saharan Africa
Sabapathy K , Balzer L , Larmarange J , Block L , Floyd S , Iwuji C , Wirth K , Ayles H , Fidler S , Kamya M , Petersen M , Havlir D , Dabis F , Moore J , Hayes R . BMC Public Health 2022 22 (1) 2333 BACKGROUND: Four large community-randomized trials examining universal testing and treatment (UTT) to reduce HIV transmission were conducted between 2012-2018 in Botswana, Kenya, Uganda, Zambia and South Africa. In 2014, the UNAIDS 90-90-90 targets were adopted as a useful metric to monitor coverage. We systematically review the approaches used by the trials to measure intervention delivery, and estimate coverage against the 90-90-90 targets. We aim to provide in-depth understanding of the background contexts and complexities that affect estimation of population-level coverage related to the 90-90-90 targets. METHODS: Estimates were based predominantly on "process" data obtained during delivery of the interventions which included a combination of home-based and community-based services. Cascade coverage data included routine electronic health records, self-reported data, survey data, and active ascertainment of HIV viral load measurements in the field. RESULTS: The estimated total adult populations of trial intervention communities included in this study ranged from 4,290 (TasP) to 142,250 (Zambian PopART Arm-B). The estimated total numbers of PLHIV ranged from 1,283 (TasP) to 20,541 (Zambian PopART Arm-B). By the end of intervention delivery, the first-90 target (knowledge of HIV status among all PLHIV) was met by all the trials (89.2%-94.0%). Three of the four trials also achieved the second- and third-90 targets, and viral suppression in BCPP and SEARCH exceeded the UNAIDS target of 73%, while viral suppression in the Zambian PopART Arm-A and B communities was within a small margin (~3%) of the target. CONCLUSIONS: All four UTT trials aimed to implement wide-scale testing and treatment for HIV prevention at population level and showed substantial increases in testing and treatment for HIV in the intervention communities. This study has not uncovered any one estimation approach which is superior, rather that several approaches are available and researchers or policy makers seeking to measure coverage should reflect on background contexts and complexities that affect estimation of population-level coverage in their specific settings. All four trials surpassed UNAIDS targets for universal testing in their intervention communities ahead of the 2020 milestone. All but one of the trials also achieved the 90-90 targets for treatment and viral suppression. UTT is a realistic option to achieve 95-95-95 by 2030 and fast-track the end of the HIV epidemic. |
Efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria and prevalence of molecular markers associated with artemisinin and partner drug resistance in Uganda.
Ebong C , Sserwanga A , Namuganga JF , Kapisi J , Mpimbaza A , Gonahasa S , Asua V , Gudoi S , Kigozi R , Tibenderana J , Bwanika JB , Bosco A , Rubahika D , Kyabayinze D , Opigo J , Rutazana D , Sebikaari G , Belay K , Niang M , Halsey ES , Moriarty LF , Lucchi NW , Souza SSS , Nsobya SL , Kamya MR , Yeka A . Malar J 2021 20 (1) 484 BACKGROUND: In Uganda, artemether-lumefantrine (AL) is first-line therapy and dihydroartemisinin-piperaquine (DP) second-line therapy for the treatment of uncomplicated malaria. This study evaluated the efficacy and safety of AL and DP in the management of uncomplicated falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites in Uganda from 2018 to 2019. METHODS: This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR. RESULTS: There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2 to 71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2 to 94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8 to 97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9 to 100%. The uncorrected 42-day efficacy of DP ranged from 73.5 to 87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1 to 97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene. CONCLUSIONS: DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. Trial registration The trail was also registered with the ISRCTN registry with study Trial No. PACTR201811640750761. |
Cost-effectiveness of intermittent preventive treatment with dihydroartemisinin-piperaquine for malaria during pregnancy: an analysis using efficacy results from Uganda and Kenya, and pooled data
Fernandes S , Were V , Gutman J , Dorsey G , Kakuru A , Desai M , Kariuki S , Kamya MR , Ter Kuile FO , Hanson K . Lancet Glob Health 2020 8 (12) e1512-e1523 BACKGROUND: Prevention of malaria infection during pregnancy in HIV-negative women currently relies on the use of long-lasting insecticidal nets together with intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). Increasing sulfadoxine-pyrimethamine resistance in Africa threatens current prevention of malaria during pregnancy. Thus, a replacement for IPTp-SP is urgently needed, especially for locations with high sulfadoxine-pyrimethamine resistance. Dihydroartemisinin-piperaquine is a promising candidate. We aimed to estimate the cost-effectiveness of intermittent preventive treatment in pregnancy with dihydroartemisinin-piperaquine (IPTp-DP) versus IPTp-SP to prevent clinical malaria infection (and its sequelae) during pregnancy. METHODS: We did a cost-effectiveness analysis using meta-analysis and individual trial results from three clinical trials done in Kenya and Uganda. We calculated disability-adjusted life-years (DALYs) arising from stillbirths, neonatal death, low birthweight, mild and moderate maternal anaemia, and clinical malaria infection, associated with malaria during pregnancy. Cost estimates were obtained from data collected in observational studies, health-facility costings, and from international drug procurement databases. The cost-effectiveness analyses were done from a health-care provider perspective using a decision tree model with a lifetime horizon. Deterministic and probabilistic sensitivity analyses using appropriate parameter ranges and distributions were also done. Results are presented as the incremental cost per DALY averted and the likelihood that an intervention is cost-effective for different cost-effectiveness thresholds. FINDINGS: Compared with three doses of sulfadoxine-pyrimethamine, three doses of dihydroartemisinin-piperaquine, delivered to a hypothetical cohort of 1000 pregnant women, averted 892 DALYs (95% credibility interval 274 to 1517) at an incremental cost of US$7051 (2653 to 13 038) generating an incremental cost-effectiveness ratio (ICER) of $8 (2 to 29) per DALY averted. Compared with monthly doses of sulfadoxine-pyrimethamine, monthly doses of dihydroartemisinin-piperaquine averted 534 DALYS (-141 to 1233) at a cost of $13 427 (4994 to 22 895), resulting in an ICER of $25 (-151 to 224) per DALY averted. Both results were highly robust to most or all variations in the deterministic sensitivity analysis. INTERPRETATION: Our findings suggest that among HIV-negative pregnant women with high uptake of long-lasting insecticidal nets, IPTp-DP is cost-effective in areas with high malaria transmission and high sulfadoxine-pyrimethamine resistance. These data provide a comprehensive overview of the current evidence on the cost-effectiveness of IPTp-DP. Nevertheless, before a policy change is advocated, we recommend further research into the effectiveness and costs of different regimens of IPTp-DP in settings with different underlying sulfadoxine-pyrimethamine resistance. FUNDING: Malaria in Pregnancy Consortium, which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Hygiene and Tropical Medicine. |
Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis
Roh ME , Kuile FOT , Rerolle F , Glymour MM , Shiboski S , Gosling R , Gutman J , Kakuru A , Desai M , Kajubi R , L'Ianziva A , Kamya MR , Dorsey G , Chico RM . Lancet Glob Health 2020 8 (7) e942-e953 BACKGROUND: Trials of intermittent preventive treatment (IPTp) of malaria in pregnant women that compared dihydroartemisinin-piperaquine with the standard of care, sulfadoxine-pyrimethamine, showed dihydroartemisinin-piperaquine was superior at preventing malaria infection, but not at improving birthweight. We aimed to assess whether sulfadoxine-pyrimethamine shows greater non-malarial benefits for birth outcomes than does dihydroartemisinin-piperaquine, and whether dihydroartemisinin-piperaquine shows greater antimalarial benefits for birth outcomes than does sulfadoxine-pyrimethamine. METHODS: We defined treatment as random assignment to sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine before pooling individual participant-level data from 1617 HIV-uninfected pregnant women in Kenya (one trial; n=806) and Uganda (two trials; n=811). We quantified the relative effect of treatment on birthweight (primary outcome) attributed to preventing placental malaria infection (mediator). We estimated antimalarial (indirect) and non-malarial (direct) effects of IPTp on birth outcomes using causal mediation analyses, accounting for confounders. We used two-stage individual participant data meta-analyses to calculate pooled-effect sizes. FINDINGS: Overall, birthweight was higher among neonates of women randomly assigned to sulfadoxine-pyrimethamine compared with women assigned to dihydroartemisinin-piperaquine (mean difference 69 g, 95% CI 26 to 112), despite placental malaria infection being lower in the dihydroartemisinin-piperaquine group (relative risk [RR] 0.64, 95% CI 0.39 to 1.04). Mediation analyses showed sulfadoxine-pyrimethamine conferred a greater non-malarial effect than did dihydroartemisinin-piperaquine (mean difference 87 g, 95% CI 43 to 131), whereas dihydroartemisinin-piperaquine conferred a slightly larger antimalarial effect than did sulfadoxine-pyrimethamine (8 g, -9 to 26), although more frequent dosing increased the antimalarial effect (31 g, 3 to 60). INTERPRETATION: IPTp with sulfadoxine-pyrimethamine appears to have potent non-malarial effects on birthweight. Further research is needed to evaluate monthly dihydroartemisinin-piperaquine with sulfadoxine-pyrimethamine (or another compound with non-malarial effects) to achieve greater protection against malarial and non-malarial causes of low birthweight. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation, and Worldwide Antimalarial Resistance Network. |
What do the Universal Test and Treat trials tell us about the path to HIV epidemic control
Havlir D , Lockman S , Ayles H , Larmarange J , Chamie G , Gaolathe T , Iwuji C , Fidler S , Kamya M , Floyd S , Moore J , Hayes R , Petersen M , Dabis F . J Int AIDS Soc 2020 23 (2) e25455 INTRODUCTION: Achieving HIV epidemic control globally will require new strategies to accelerate reductions in HIV incidence and mortality. Universal test and treat (UTT) was evaluated in four randomized population-based trials (BCPP/Ya Tsie, HPTN 071/PopART, SEARCH, ANRS 12249/TasP) conducted in sub-Saharan Africa (SSA) during expanded antiretroviral treatment (ART) eligibility by World Health Organization guidelines and the UNAIDS 90-90-90 campaign. DISCUSSION: These three-year studies were conducted in Botswana, Zambia, Uganda, Kenya and South Africa in settings with baseline HIV prevalence from 4% to 30%. Key observations across studies were: (1) Universal testing (implemented via a variety of home and community-based testing approaches) achieved >90% coverage in all studies. (2) When coupled with robust linkage to HIV care, rapid ART start and patient-centred care, UTT achieved among the highest reported population levels of viral suppression in SSA. Significant gains in population-level viral suppression were made in regions with both low and high baseline population viral load; however, viral suppression gains were not uniform across all sub-populations and were lower among youth. (3) UTT resulted in marked reductions in community HIV incidence when universal testing and robust linkage were present. However, HIV elimination targets were not reached. In BCPP and HPTN 071, annualized HIV incidence was approximately 20% to 30% lower in the intervention (which included universal testing) compared to control arms (no universal testing). In SEARCH (where both arms had universal testing), incidence declined 32% over three years. (4) UTT reduced HIV associated mortality by 23% in the intervention versus control communities in SEARCH, a study in which mortality was comprehensively measured. CONCLUSIONS: These trials provide strong evidence that UTT inclusive of universal testing increases population-level viral suppression and decreases HIV incidence and mortality faster than the status quo in SSA and should be adapted at a sub-country level as a public health strategy. However, more is needed, including integration of new prevention interventions into UTT, in order to reach UNAIDS HIV elimination targets. |
The prevalence of histologic acute chorioamnionitis among HIV infected pregnant women in Uganda and its association with adverse birth outcomes
Ategeka J , Wasswa R , Olwoch P , Kakuru A , Natureeba P , Muehlenbachs A , Kamya MR , Dorsey G , Rizzuto G . PLoS One 2019 14 (4) e0215058 BACKGROUND: Preterm birth (PTB) is a leading cause of neonatal mortality and longer-term morbidity. Acute chorioamnionitis (ACA) is a common cause of PTB, however, there are limited data on the prevalence of ACA and its association with PTB in resource limited settings. METHODS: Data and samples came from a clinical trial evaluating novel strategies for the prevention of malaria in HIV infected pregnant women in Uganda. Women were enrolled between 12-28 weeks of gestation and followed through delivery. For each placenta delivered, three placental tissue types (membrane roll, umbilical cord and chorionic plate/villous parenchyma) were collected. Slides were assessed for diagnosis of maternal and fetal ACA by microscopic evaluation of neutrophilic infiltration using a standardized grading scale. The primary outcomes were PTB (<37 weeks), low birth weight (LBW, <2500 grams), and small-for-gestational age (SGA, birth weight <10th percentile for age). Univariate and multivariate logistic regression were used to estimate associations between 1) maternal characteristics (age, education, wealth, gravidity, gestational age at enrollment, placental malaria, anti-malarial prophylaxis treatment regimen, HIV disease parameters) and ACA, and 2) associations between ACA and adverse birth outcomes. FINDINGS: A total of 193 placentas were included in the analysis. The prevalence of maternal and fetal ACA was 44.5% and 28.0%, respectively. HIV infected women between 28-43 years of age had a higher risk of maternal ACA compared to those between 17-21 years of age (50.9% vs. 19.1%; aOR = 4.00 (1.10-14.5), p = 0.04) and the diagnosis of severe maternal ACA was associated with a significantly higher risk of PTB (28.6% vs. 6.0%; aOR = 6.04 (1.87-19.5), p = 0.003), LBW (33.3% vs. 9.4%; aOR = 4.86 (1.65-14.3); p = 0.004), and SGA (28.6% vs. 10.1%; aOR = 3.70 (1.20-11.4), p = 0.02). No maternal characteristics were significantly associated with fetal ACA and the diagnosis of fetal ACA was not associated with adverse birth outcomes. CONCLUSIONS: Histological evidence of severe maternal ACA was associated with an increased risk of PTB, LBW, and SGA in HIV infected, pregnant Ugandan women. |
A cross-cutting approach to surveillance and laboratory capacity as a platform to improve health security in Uganda
Lamorde M , Mpimbaza A , Walwema R , Kamya M , Kapisi J , Kajumbula H , Sserwanga A , Namuganga JF , Kusemererwa A , Tasimwa H , Makumbi I , Kayiwa J , Lutwama J , Behumbiize P , Tagoola A , Nanteza JF , Aniku G , Workneh M , Manabe Y , Borchert JN , Brown V , Appiah GD , Mintz ED , Homsy J , Odongo GS , Ransom RL , Freeman MM , Stoddard RA , Galloway R , Mikoleit M , Kato C , Rosenberg R , Mossel EC , Mead PS , Kugeler KJ . Health Secur 2018 16 S76-s86 Global health security depends on effective surveillance for infectious diseases. In Uganda, resources are inadequate to support collection and reporting of data necessary for an effective and responsive surveillance system. We used a cross-cutting approach to improve surveillance and laboratory capacity in Uganda by leveraging an existing pediatric inpatient malaria sentinel surveillance system to collect data on expanded causes of illness, facilitate development of real-time surveillance, and provide data on antimicrobial resistance. Capacity for blood culture collection was established, along with options for serologic testing for select zoonotic conditions, including arboviral infection, brucellosis, and leptospirosis. Detailed demographic, clinical, and laboratory data for all admissions were captured through a web-based system accessible at participating hospitals, laboratories, and the Uganda Public Health Emergency Operations Center. Between July 2016 and December 2017, the expanded system was activated in pediatric wards of 6 regional government hospitals. During that time, patient data were collected from 30,500 pediatric admissions, half of whom were febrile but lacked evidence of malaria. More than 5,000 blood cultures were performed; 4% yielded bacterial pathogens, and another 4% yielded likely contaminants. Several WHO antimicrobial resistance priority pathogens were identified, some with multidrug-resistant phenotypes, including Acinetobacter spp., Citrobacter spp., Escherichia coli, Staphylococcus aureus, and typhoidal and nontyphoidal Salmonella spp. Leptospirosis and arboviral infections (alphaviruses and flaviviruses) were documented. The lessons learned and early results from the development of this multisectoral surveillance system provide the knowledge, infrastructure, and workforce capacity to serve as a foundation to enhance the capacity to detect, report, and rapidly respond to wide-ranging public health concerns in Uganda. |
Comparative assessment of five trials of universal HIV testing and treatment in sub-Saharan Africa
Perriat D , Balzer L , Hayes R , Lockman S , Walsh F , Ayles H , Floyd S , Havlir D , Kamya M , Lebelonyane R , Mills LA , Okello V , Petersen M , Pillay D , Sabapathy K , Wirth K , Orne-Gliemann J , Dabis F . J Int AIDS Soc 2018 21 (1) DESIGN: Universal voluntary HIV counselling and testing followed by prompt initiation of antiretroviral therapy (ART) for all those diagnosed HIV-infected (universal test and treat, UTT) is now a global health standard. However, its population-level impact, feasibility and cost remain unknown. Five community-based trials have been implemented in sub-Saharan Africa to measure the effects of various UTT strategies at population level: BCPP/YaTsie in Botswana, MaxART in Swaziland, HPTN 071 (PopART) in South Africa and Zambia, SEARCH in Uganda and Kenya and ANRS 12249 TasP in South Africa. This report describes and contrasts the contexts, research methodologies, intervention packages, themes explored, evolution of study designs and interventions related to each of these five UTT trials. METHODS: We conducted a comparative assessment of the five trials using data extracted from study protocols and collected during baseline studies, with additional input from study investigators. We organized differences and commonalities across the trials in five categories: trial contexts, research designs, intervention packages, trial themes and adaptations. RESULTS: All performed in the context of generalized HIV epidemics, the trials highly differ in their social, demographic, economic, political and health systems settings. They share the common aim of assessing the impact of UTT on the HIV epidemic but differ in methodological aspects such as study design and eligibility criteria for trial populations. In addition to universal ART initiation, the trials deliver a wide range of biomedical, behavioural and structural interventions as part of their UTT strategies. The five studies explore common issues, including the uptake rates of the trial services and individual health outcomes. All trials have adapted since their initiation to the evolving political, economic and public health contexts, including adopting the successive national recommendations for ART initiation. CONCLUSIONS: We found substantial commonalities but also differences between the five UTT trials in their design, conduct and multidisciplinary outputs. As empirical literature on how UTT may improve efficiency and quality of HIV care at population level is still scarce, this article provides a foundation for more collaborative research on UTT and supports evidence-based decision making for HIV care in country and internationally. |
Relationships between infection with Plasmodium falciparum during pregnancy, measures of placental malaria, and adverse birth outcomes
Kapisi J , Kakuru A , Jagannathan P , Muhindo MK , Natureeba P , Awori P , Nakalembe M , Ssekitoleko R , Olwoch P , Ategeka J , Nayebare P , Clark TD , Rizzuto G , Muehlenbachs A , Havlir DV , Kamya MR , Dorsey G , Gaw SL . Malar J 2017 16 (1) 400 BACKGROUND: Malaria in pregnancy has been associated with maternal morbidity, placental malaria, and adverse birth outcomes. However, data are limited on the relationships between longitudinal measures of malaria during pregnancy, measures of placental malaria, and birth outcomes. METHODS: This is a nested observational study of data from a randomized controlled trial of intermittent preventive therapy during pregnancy among 282 participants with assessment of placental malaria and delivery outcomes. HIV-uninfected pregnant women were enrolled at 12-20 weeks of gestation. Symptomatic malaria during pregnancy was measured using passive surveillance and monthly detection of asymptomatic parasitaemia using loop-mediated isothermal amplification (LAMP). Placental malaria was defined as either the presence of parasites in placental blood by microscopy, detection of parasites in placental blood by LAMP, or histopathologic evidence of parasites or pigment. Adverse birth outcomes assessed included low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) infants. RESULTS: The 282 women were divided into three groups representing increasing malaria burden during pregnancy. Fifty-two (18.4%) had no episodes of symptomatic malaria or asymptomatic parasitaemia during the pregnancy, 157 (55.7%) had low malaria burden (0-1 episodes of symptomatic malaria and < 50% of samples LAMP+), and 73 (25.9%) had high malaria burden during pregnancy (≥ 2 episodes of symptomatic malaria or ≥ 50% of samples LAMP+). Women with high malaria burden had increased risks of placental malaria by blood microscopy and LAMP [aRR 14.2 (1.80-111.6) and 4.06 (1.73-9.51), respectively], compared to the other two groups combined. Compared with women with no malaria exposure during pregnancy, the risk of placental malaria by histopathology was higher among low and high burden groups [aRR = 3.27 (1.32-8.12) and aRR = 7.07 (2.84-17.6), respectively]. Detection of placental parasites by any method was significantly associated with PTB [aRR 5.64 (1.46-21.8)], and with a trend towards increased risk for LBW and SGA irrespective of the level of malaria burden during pregnancy. CONCLUSION: Higher malaria burden during pregnancy was associated with placental malaria and together with the detection of parasites in the placenta were associated with increased risk for adverse birth outcomes. Trial Registration Current Controlled Trials Identifier NCT02163447. |
Resurgence of malaria following discontinuation of indoor residual spraying of insecticide in a previously high transmission intensity area of Uganda
Raouf S , Mpimbaza A , Kigozi R , Sserwanga A , Rubahika D , Katamba H , Lindsay SW , Kapella BK , Belay KA , Kamya MR , Staedke SG , Dorsey G . Clin Infect Dis 2017 65 (3) 453-460 Background: Indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) are the primary tools for malaria prevention in Africa. It is not known whether reductions in malaria can be sustained after IRS is discontinued. The aim of this study was to assess changes in malaria morbidity in a historically high transmission area of Uganda where IRS was discontinued after a four-year period of effective control followed by a universal LLIN distribution campaign. Methods: Individual-level malaria surveillance data were collected from one outpatient department and one inpatient setting in Apac District, Uganda from July 2009 through November 2015. Rounds of IRS were delivered approximately every six months from February 2010 through May 2014 followed by universal LLIN distribution in June 2014. Temporal changes in the malaria test positivity rate (TPR) were estimated during and after IRS using interrupted time series analyses, controlling for age, rainfall, and autocorrelation. Results: Data include 65,421 outpatient visits and 13,955 pediatric inpatient admissions for which a diagnostic test for malaria was performed. In outpatients under five years, baseline TPR was 60-80% followed by a rapid and then sustained decrease to 15-30%. Over 4-18 months following discontinuation of IRS, absolute TPR values increased by an average of 3.29% per month (95% CI 2.01-4.57%), returning to baseline levels. Similar trends were seen in outpatients over five years of age and pediatric admissions. Conclusions: Discontinuation of IRS in a historically high transmission intensity area was associated with a rapid increase in malaria morbidity to pre-IRS levels. |
Intermittent preventive treatment with dihydroartemisinin-piperaquine for the prevention of malaria among HIV-infected pregnant women
Natureeba P , Kakuru A , Muhindo M , Littmann E , Ochieng T , Ategeka J , Koss CA , Plenty A , Charlebois ED , Clark TD , Nzarubara B , Nakalembe M , Cohan D , Rizzuto G , Muehlenbachs A , Ruel T , Jagannathan P , Havlir DV , Kamya MR , Dorsey G . J Infect Dis 2017 216 (1) 29-35 Background.: Daily trimethoprim-sulfamethoxazole (TMP-SMX) and insecticide treated nets (ITNs) remain the main interventions for prevention of malaria in HIV-infected pregnant women in Africa. However, antifolate and pyrethroid resistance threaten the effectiveness of these intervention and new ones are needed. Methods.: We conducted a double-blind randomized placebo-controlled trial comparing daily TMP-SMX plus monthly dihydroartemisinin-piperaquine (DP) to daily TMP-SMX alone in HIV-infected pregnant women in an area of Uganda where indoor residual spraying of insecticide (IRS) had recently been implemented. Participants were enrolled between 12-28 weeks gestation and provided an ITN. The primary outcome was placental malaria by histopathology (active or past infection). Secondary outcomes included incidence of malaria; parasite prevalence; and adverse birth outcomes. Results.: All 200 women enrolled were followed through delivery and the primary outcome was assessed in 194. There was no statistically significant difference in the risk of placental malaria by histopathology between the daily TMP-SMX plus DP and daily TMP-SMX alone arms (6.1 vs. 3.1%, RR=1.96, 95%CI 0.50-7.61, P=0.50). Similarly, there were no differences in secondary outcomes. Conclusions.: Among HIV-infected pregnant women in the setting of IRS, adding monthly DP to daily TMP-SMX did not reduce the risk of placental or maternal malaria or improve birth outcomes. |
Reductions in malaria in pregnancy and adverse birth outcomes following indoor residual spraying of insecticide in Uganda
Muhindo MK , Kakuru A , Natureeba P , Awori P , Olwoch P , Ategeka J , Nayebare P , Clark TD , Muehlenbachs A , Roh M , Mpeka B , Greenhouse B , Havlir DV , Kamya MR , Dorsey G , Jagannathan P . Malar J 2016 15 (1) 437 BACKGROUND: Indoor residual spraying of insecticide (IRS) is a key intervention for reducing the burden of malaria in Africa. However, data on the impact of IRS on malaria in pregnancy and birth outcomes is limited. METHODS: An observational study was conducted within a trial of intermittent preventive therapy during pregnancy in Tororo, Uganda. Women were enrolled at 12-20 weeks of gestation between June and October 2014, provided with insecticide-treated bed nets, and followed through delivery. From December 2014 to February 2015, carbamate-containing IRS was implemented in Tororo district for the first time. Exact spray dates were collected for each household. The exposure of interest was the proportion of time during a woman's pregnancy under protection of IRS, with three categories of protection defined: no IRS protection, >0-20 % IRS protection, and 20-43 % IRS protection. Outcomes assessed included malaria incidence and parasite prevalence during pregnancy, placental malaria, low birth weight (LBW), pre-term delivery, and fetal/neonatal deaths. RESULTS: Of 289 women followed, 134 had no IRS protection during pregnancy, 90 had >0-20 % IRS protection, and 65 had >20-43 % protection. During pregnancy, malaria incidence (0.49 vs 0.10 episodes ppy, P = 0.02) and parasite prevalence (20.0 vs 8.9 %, P < 0.001) were both significantly lower after IRS. At the time of delivery, the prevalence of placental parasitaemia was significantly higher in women with no IRS protection (16.8 %) compared to women with 0-20 % (1.1 %, P = 0.001) or >20-43 % IRS protection (1.6 %, P = 0.006). Compared to women with no IRS protection, those with >20-43 % IRS protection had a lower risk of LBW (20.9 vs 3.1 %, P = 0.002), pre-term birth (17.2 vs 1.5 %, P = 0.006), and fetal/neonatal deaths (7.5 vs 0 %, P = 0.03). CONCLUSION: In this setting, IRS was temporally associated with lower malaria parasite prevalence during pregnancy and at delivery, and improved birth outcomes. IRS may represent an important tool for combating malaria in pregnancy and for improving birth outcomes in malaria-endemic settings. Trial Registration Current Controlled Trials Identifier NCT02163447. |
Quantifying heterogeneous malaria exposure and clinical protection in a cohort of Ugandan children
Rodriguez-Barraquer I , Arinaitwe E , Jagannathan P , Boyle MJ , Tappero J , Muhindo M , Kamya MR , Dorsey G , Drakeley C , Ssewanyana I , Smith DL , Greenhouse B . J Infect Dis 2016 214 (7) 1072-80 BACKGROUND: Plasmodium falciparum malaria remains a leading cause of childhood morbidity and mortality. There are important gaps in our understanding of the factors driving the development of anti-malaria immunity as a function of age and exposure. METHODS: We use data from a cohort of 93 children participating in a clinical trial in an area of very high exposure to P. falciparum in Tororo, Uganda. We jointly quantify individual heterogeneity in risk of infection, and development of immunity against infection and clinical disease. RESULTS: Results show significant heterogeneity in the hazard of infection, and independent effects of age and cumulative number of infections on the risk of infection and disease. The risk of developing clinical malaria upon infection decreased on average by 6% (95%CI 0 - 12%) for each additional year of age and by 2% (95%CI 1%-3%) for each additional prior infection. Children randomized to dihydroartemisinin-piperaquine (DP) for treatment appeared to develop immunity more slowly than those receiving artemether-lumefrantine (AL). CONCLUSION: Heterogeneity in P. falciparum exposure and immunity can be independently evaluated using detailed longitudinal studies. Improved understanding of the factors driving immunity will provide key information to anticipate the impact of malaria-control interventions and to understand the mechanisms of clinical immunity. |
B cell sub-types following acute malaria and associations with clinical immunity
Sullivan RT , Ssewanyana I , Wamala S , Nankya F , Jagannathan P , Tappero JW , Mayanja-Kizza H , Muhindo MK , Arinaitwe E , Kamya M , Dorsey G , Feeney ME , Riley EM , Drakeley CJ , Greenhouse B , Sullivan R . Malar J 2016 15 (1) 139 BACKGROUND: Repeated exposure to Plasmodium falciparum is associated with perturbations in B cell sub-set homeostasis, including expansion atypical memory B cells. However, B cell perturbations immediately following acute malaria infection have been poorly characterized, especially with regard to their relationship with immunity to malaria. METHODS: To better understand the kinetics of B cell sub-sets following malaria, the proportions of six B cell sub-sets were assessed at five time points following acute malaria in four to 5 years old children living in a high transmission region of Uganda. B cell sub-set kinetics were compared with measures of clinical immunity to malaria-lower parasite density at the time of malaria diagnosis and recent asymptomatic parasitaemia. RESULTS: Atypical memory B cell and transitional B cell proportions increased following malaria. In contrast, plasmablast proportions were highest at the time of malaria diagnosis and rapidly declined following treatment. Increased proportions of atypical memory B cells were associated with greater immunity to malaria, whereas increased proportions of transitional B cells were associated with evidence of less immunity to malaria. CONCLUSIONS: These findings highlight the dynamic changes in multiple B cell sub-sets following acute, uncomplicated malaria, and how these sub-sets are associated with developing immunity to malaria. |
Dihydroartemisinin-piperaquine for the prevention of malaria in pregnancy
Kakuru A , Jagannathan P , Muhindo MK , Natureeba P , Awori P , Nakalembe M , Opira B , Olwoch P , Ategeka J , Nayebare P , Clark TD , Feeney ME , Charlebois ED , Rizzuto G , Muehlenbachs A , Havlir DV , Kamya MR , Dorsey G . N Engl J Med 2016 374 (10) 928-939 BACKGROUND: Intermittent treatment with sulfadoxine-pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine-pyrimethamine, new interventions are needed. METHODS: We conducted a double-blind, randomized, controlled trial involving 300 human immunodeficiency virus (HIV)-uninfected pregnant adolescents or women in Uganda, where sulfadoxine-pyrimethamine resistance is widespread. We randomly assigned participants to a sulfadoxine-pyrimethamine regimen (106 participants), a three-dose dihydroartemisinin-piperaquine regimen (94 participants), or a monthly dihydroartemisinin-piperaquine regimen (100 participants). The primary outcome was the prevalence of histopathologically confirmed placental malaria. RESULTS: The prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine-pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin-piperaquine group (34.1%, P=0.03) or the monthly dihydroartemisinin-piperaquine group (27.1%, P=0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin-piperaquine group (9.2%) than in the sulfadoxine-pyrimethamine group (18.6%, P=0.05) or the three-dose dihydroartemisinin-piperaquine group (21.3%, P=0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine-pyrimethamine group (41 episodes over 43.0 person-years at risk) than in the three-dose dihydroartemisinin-piperaquine group (12 episodes over 38.2 person-years at risk, P=0.001) or the monthly dihydroartemisinin-piperaquine group (0 episodes over 42.3 person-years at risk, P<0.001), as was the prevalence of parasitemia (40.5% in the sulfadoxine-pyrimethamine group vs. 16.6% in the three-dose dihydroartemisinin-piperaquine group [P<0.001] and 5.2% in the monthly dihydroartemisinin-piperaquine group [P<0.001]). In each treatment group, the risk of vomiting after administration of any dose of the study agents was less than 0.4%, and there were no significant differences among the groups in the risk of adverse events. CONCLUSIONS: The burden of malaria in pregnancy was significantly lower among adolescent girls or women who received intermittent preventive treatment with dihydroartemisinin-piperaquine than among those who received sulfadoxine-pyrimethamine, and monthly treatment with dihydroartemisinin-piperaquine was superior to three-dose dihydroartemisinin-piperaquine with regard to several outcomes. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT02163447 .). |
Artesunate/amodiaquine versus artemether/lumefantrine for the treatment of uncomplicated malaria in Uganda: a randomized trial
Yeka A , Kigozi R , Conrad MD , Lugemwa M , Okui P , Katureebe C , Belay K , Kapella BK , Chang MA , Kamya MR , Staedke SG , Dorsey G , Rosenthal PJ . J Infect Dis 2015 213 (7) 1134-42 BACKGROUND: In treating malaria in Uganda, artemether-lumefantrine (AL) has been associated with a lower risk of recurrent parasitemia compared to artesunate-amodiaquine (AS/AQ), but changing treatment practices may have altered parasite sensitivities. METHODS: We enrolled 602 children aged 6-59 months with uncomplicated falciparum malaria from 3 health centers in 2013-14 and randomly assigned treatment with AS/AQ or AL. Primary outcomes were risks of recurrent parasitemia within 28 days, unadjusted or adjusted to distinguish recrudescence from new infection. Drug safety and tolerability and Plasmodium falciparum resistance-mediating polymorphisms were assessed. RESULTS: Of enrolled patients, 594 (98.7%) completed the 28-day study. Risks of recurrent parasitemia were lower with AS/AQ at all three sites (overall 28.6% vs. 44.6%; p<0.001). Recrudescences were uncommon and all after AL (0% vs. 2.5%; p=0.006). Hemoglobin recovery was greater with AS/AQ (1.73 vs. 1.39 g/dl, p=0.04). Both regimens were well tolerated; serious adverse events were uncommon (1.7% AS/AQ; 1.0% AL). AS/AQ selected for mutant and AL for wild type pfcrt/pfmdr1 polymorphisms associated with altered drug sensitivity. CONCLUSIONS: AS/AQ was followed by fewer recurrences than AL, contrasting with older data. Each regimen selected for polymorphisms associated with decreased response. Research should consider multiple or rotating regimens to maintain treatment efficacies. |
Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data
Abdulla S , Adam I , Adjei GO , Adjuik MA , Alemayehu B , Allan R , Arinaitwe E , Ashley EA , Ba MS , Barennes H , Barnes KI , Bassat Q , Baudin E , Berens-Riha N , Bjorkman A , Bompart F , Bonnet M , Borrmann S , Bousema T , Brasseur P , Bukirwa H , Checchi F , Dahal P , D'Alessandro U , Desai M , Dicko A , Djimde AA , Dorsey G , Doumbo OK , Drakeley CJ , Duparc S , Eshetu T , Espie E , Etard JF , Faiz AM , Falade CO , Fanello CI , Faucher JF , Faye B , Faye O , Filler S , Flegg JA , Fofana B , Fogg C , Gadalla NB , Gaye O , Genton B , Gething PW , Gil JP , Gonzalez R , Grandesso F , Greenhouse B , Greenwood B , Grivoyannis A , Guerin PJ , Guthmann JP , Hamed K , Hamour S , Hay SI , Hode EM , Humphreys GS , Hwang J , Ibrahim ML , Jima D , Jones JJ , Jullien V , Juma E , Kachur PS , Kager PA , Kamugisha E , Kamya MR , Karema C , Kayentao K , Kieche JR , Kironde F , Kofoed PE , Kremsner PG , Krishna S , Lameyre V , Lell B , Lima A , Makanga M , Malik EM , Marsh K , Martensson A , Massougbodji A , Menan H , Menard D , Menendez C , Mens PF , Meremikwu M , Moreira C , Nabasumba C , Nambozi M , Ndiaye JL , Ngasala BE , Nikiema F , Nsanzabana C , Ntoumi F , Oguike M , Ogutu BR , Olliaro P , Omar SA , Ouedraogo JB , Owusu-Agyei S , Penali LK , Pene M , Peshu J , Piola P , Plowe CV , Premji Z , Price RN , Randrianarivelojosia M , Rombo L , Roper C , Rosenthal PJ , Sagara I , Same-Ekobo A , Sawa P , Schallig HDFH , Schramm B , Seck A , Shekalaghe SA , Sibley CH , Sinou V , Sirima SB , Some FA , Sow D , Staedke SG , Stepniewska K , Sutherland CJ , Swarthout TD , Sylla K , Talisuna AO , Taylor WRJ , Temu EA , Thwing JI , Tine RCK , Tinto H , Tommasini S , Toure OA , Ursing J , Vaillant MT , Valentini G , Van den Broek I , Vugt MV , Ward SA , Winstanley PA , Yavo W , Yeka A , Zolia YM , Zongo I , WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group . BMC Med 2015 13 212 BACKGROUND: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). METHODS: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. RESULTS: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 degreeC) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). CONCLUSIONS: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility. |
Anti-malarial prescription practices among children admitted to six public hospitals in Uganda from 2011 to 2013
Sserwanga A , Sears D , Kapella BK , Kigozi R , Rubahika D , Staedke SG , Kamya M , Yoon SS , Chang MA , Dorsey G , Mpimbaza A . Malar J 2015 14 (1) 331 BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. |
Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities
Helb DA , Tetteh KK , Felgner PL , Skinner J , Hubbard A , Arinaitwe E , Mayanja-Kizza H , Ssewanyana I , Kamya MR , Beeson JG , Tappero J , Smith DL , Crompton PD , Rosenthal PJ , Dorsey G , Drakeley CJ , Greenhouse B . Proc Natl Acad Sci U S A 2015 112 (32) E4438-47 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. |
Decline of FoxP3+ regulatory CD4 T cells in peripheral blood of children heavily exposed to malaria
Boyle MJ , Jagannathan P , Farrington LA , Eccles-James I , Wamala S , McIntyre TI , Vance HM , Bowen K , Nankya F , Auma A , Nalubega M , Sikyomu E , Naluwu K , Rek J , Katureebe A , Bigira V , Kapisi J , Tappero J , Muhindo MK , Greenhouse B , Arinaitwe E , Dorsey G , Kamya MR , Feeney ME . PLoS Pathog 2015 11 (7) e1005041 FoxP3+ regulatory CD4 T cells (Tregs) help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that Tregs are induced by P. falciparum both in vivo and in vitro; however, the factors influencing Treg homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of Tregs in well-characterized cohorts of children residing in a region of high malaria endemicity in Uganda. We found that both the frequency and absolute numbers of FoxP3+ Tregs in peripheral blood declined markedly with increasing prior malaria incidence. Longitudinal measurements confirmed that this decline occurred only among highly malaria-exposed children. The decline of Tregs from peripheral blood was accompanied by reduced in vitro induction of Tregs by parasite antigen and decreased expression of TNFR2 on Tregs among children who had intense prior exposure to malaria. While Treg frequencies were not associated with protection from malaria, there was a trend toward reduced risk of symptomatic malaria once infected with P. falciparum among children with lower Treg frequencies. These data demonstrate that chronic malaria exposure results in altered Treg homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations. |
Quality of inpatient pediatric case management for four leading causes of child mortality at six government-run Ugandan hospitals
Sears D , Mpimbaza A , Kigozi R , Sserwanga A , Chang MA , Kapella BK , Yoon S , Kamya MR , Dorsey G , Ruel T . PLoS One 2015 10 (5) e0127192 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. |
Protective efficacy of prolonged co-trimoxazole prophylaxis in HIV-exposed children up to age 4 years for the prevention of malaria in Uganda: a randomised controlled open-label trial
Homsy J , Dorsey G , Arinaitwe E , Wanzira H , Kakuru A , Bigira V , Muhindo M , Kamya MR , Sandison TG , Tappero JW . Lancet Glob Health 2014 2 (12) e727-36 BACKGROUND: WHO recommends daily co-trimoxazole for children born to HIV-infected mothers from 6 weeks of age until breastfeeding cessation and exclusion of HIV infection. We have previously reported on the effectiveness of continuation of co-trimoxazole prophylaxis up to age 2 years in these children. We assessed the protective efficacy and safety of prolonging co-trimoxazole prophylaxis until age 4 years in HIV-exposed children. METHODS: We undertook an open-label randomised controlled trial alongside two observational cohorts in eastern Uganda, an area with high HIV prevalence, malaria transmission intensity, and antifolate resistance. We enrolled HIV-exposed infants between 6 weeks and 9 months of age and prescribed them daily co-trimoxazole until breastfeeding cessation and HIV-status confirmation. At the end of breastfeeding, children who remained HIV-uninfected were randomly assigned (1:1) to discontinue co-trimoxazole or to continue taking it up to age 2 years. At age 2 years, children who continued co-trimoxazole prophylaxis were randomly assigned (1:1) to discontinue or continue prophylaxis from age 2 years to age 4 years. The primary outcome was incidence of malaria (defined as the number of treatments for new episodes of malaria diagnosed with positive thick smear) at age 4 years. For additional comparisons, we observed 48 HIV-infected children who took continuous co-trimoxazole prophylaxis and 100 HIV-unexposed uninfected children who never received prophylaxis. We measured grade 3 and 4 serious adverse events and hospital admissions. All children were followed up to age 5 years and all analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00527800. FINDINGS: 203 HIV-exposed infants were enrolled between Aug 10, 2007, and March 28, 2008. After breastfeeding ended, 185 children were not infected with HIV and were randomly assigned to stop (n=87) or continue (n=98) co-trimoxazole up to age 2 years. At age 2 years, 91 HIV-exposed children who had remained on co-trimoxazole prophylaxis were randomly assigned to discontinue (n=46) or continue (n=45) co-trimoxazole from age 2 years to age 4 years. We recorded 243 malaria episodes (2.91 per person-years) in the 45 HIV-exposed children assigned to continue co-trimoxazole until age 4 years compared with 503 episodes (5.60 per person-years) in the 46 children assigned to stop co-trimoxazole at age 2 years (incidence rate ratio 0.53, 95% CI 0.39-0.71; p<0.0001). There was no evidence of malaria incidence rebound in the year after discontinuation of co-trimoxazole in the HIV-exposed children who stopped co-trimoxazole at age 2 years, but incidence increased significantly in HIV-exposed children who stopped co-trimoxazole at age 4 years (odds ratio 1.78, 95% CI 1.19-2.66; p=0.005). Incidence of grade 3 or 4 serious adverse events, hospital admissions, or deaths did not significantly differ between HIV-exposed, HIV-unexposed, and HIV-infected children. INTERPRETATION: Continuation of co-trimoxazole prophylaxis up to 4 years of age seems safe and efficacious to protect HIV-exposed children living in malaria-endemic areas. FUNDING: Centers for Disease Control and Prevention Global AIDS Program, Doris Duke Charitable Foundation. |
Comparison of routine health management information system versus enhanced inpatient malaria surveillance for estimating the burden of malaria among children admitted to four hospitals in Uganda
Mpimbaza A , Miles M , Sserwanga A , Kigozi R , Wanzira H , Rubahika D , Nasr S , Kapella BK , Yoon SS , Chang M , Yeka A , Staedke SG , Kamya MR , Dorsey G . Am J Trop Med Hyg 2014 92 (1) 18-21 The primary source of malaria surveillance data in Uganda is the Health Management Information System (HMIS), which does not require laboratory confirmation of reported malaria cases. To improve data quality, an enhanced inpatient malaria surveillance system (EIMSS) was implemented with emphasis on malaria testing of all children admitted in select hospitals. Data were compared between the HMIS and the EIMSS at four hospitals over a period of 12 months. After the implementation of the EIMSS, over 96% of admitted children under 5 years of age underwent laboratory testing for malaria. The HMIS significantly overreported the proportion of children under 5 years of age admitted with malaria (average absolute difference = 19%, range = 8-27% across the four hospitals) compared with the EIMSS. To improve the quality of the HMIS data for malaria surveillance, the National Malaria Control Program should, in addition to increasing malaria testing rates, focus on linking laboratory test results to reported malaria cases. |
Loss and dysfunction of Vdelta2+ gammadelta T cells are associated with clinical tolerance to malaria
Jagannathan P , Kim CC , Greenhouse B , Nankya F , Bowen K , Eccles-James I , Muhindo MK , Arinaitwe E , Tappero JW , Kamya MR , Dorsey G , Feeney ME . Sci Transl Med 2014 6 (251) 251ra117 Although clinical immunity to malaria eventually develops among children living in endemic settings, the underlying immunologic mechanisms are not known. The Vdelta2(+) subset of gammadelta T cells have intrinsic reactivity to malaria antigens, can mediate killing of Plasmodium falciparum merozoites, and expand markedly in vivo after malaria infection in previously naive hosts, but their role in mediating immunity in children repeatedly exposed to malaria is unclear. We evaluated gammadelta T cell responses to malaria among 4-year-old children enrolled in a longitudinal study in Uganda. We found that repeated malaria was associated with reduced percentages of Vdelta2(+) gammadelta T cells in peripheral blood, decreased proliferation and cytokine production in response to malaria antigens, and increased expression of immunoregulatory genes. Further, loss and dysfunction of proinflammatory Vdelta2(+) gammadelta T cells were associated with a reduced likelihood of symptoms upon subsequent P. falciparum infection. Together, these results suggest that repeated malaria infection during childhood results in progressive loss and dysfunction of Vdelta2(+) gammadelta T cells that may facilitate immunological tolerance of the parasite. |
Artemisinin-based combination therapies are efficacious and safe for treatment of uncomplicated malaria in HIV-infected Ugandan children
Kakuru A , Achan J , Muhindo MK , Ikilezi G , Arinaitwe E , Mwangwa F , Ruel T , Clark TD , Charlebois E , Rosenthal PJ , Havlir D , Kamya MR , Tappero JW , Dorsey G . Clin Infect Dis 2014 59 (3) 446-53 BACKGROUND: Artemisinin-based combination therapies (ACTs) are highly efficacious and safe, but data from human immunodeficiency virus (HIV)-infected children concurrently receiving antiretroviral therapy (ART) and ACTs are limited. METHODS: We evaluated 28-day outcomes following malaria treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in 2 cohorts of HIV-infected Ugandan children taking various ART regimens. In one cohort, children <6 years of age were randomized to lopinavir/ritonavir (LPV/r) or nonnucleoside reverse transcriptase inhibitor-based ART and treated with AL for uncomplicated malaria. In another cohort, children <12 months of age were started on nevirapine-based ART if they were eligible, and randomized to AL or DP for the treatment of their first and all subsequent uncomplicated malaria episodes. RESULTS: There were 773 and 165 treatments for malaria with AL and DP, respectively. Initial response to therapy was excellent, with 99% clearance of parasites and <1% risk of repeat therapy within 3 days. Recurrent parasitemia within 28 days was common following AL treatment. The risk of recurrent parasitemia was significantly lower among children taking LPV/r-based ART compared with children taking nevirapine-based ART following AL treatment (15.3% vs 35.5%, P = .009), and those treated with DP compared with AL (8.6% vs 36.2%, P < .001). Both ACT regimens were safe and well tolerated. CONCLUSIONS: Treatment of uncomplicated malaria with AL or DP was efficacious and safe in HIV-infected children taking ART. However, there was a high risk of recurrent parasitemia following AL treatment, which was significantly lower in children taking LPV/r-based ART compared with nevirapine-based ART. |
Longitudinal outcomes in a cohort of Ugandan children randomized to artemether-lumefantrine versus dihydroartemisinin-piperaquine for the treatment of malaria
Wanzira H , Kakuru A , Arinaitwe E , Bigira V , Muhindo MK , Conrad M , Rosenthal PJ , Kamya MR , Tappero JW , Dorsey G . Clin Infect Dis 2014 59 (4) 509-16 BACKGROUND: Artemisinin-based combination therapy (ACT) has become the standard of care for the treatment of uncomplicated Plasmodium falciparum malaria. Although several ACT regimens are approved, data guiding optimal choices of ACTs are limited. We compared short- and long-term outcomes in a cohort of young Ugandan children randomized to 2 leading ACTs. METHODS: Overall, 312 children were randomized to artemether-lumefantrine or dihydroartemisinin-piperaquine (DP) at the time of the first episode of uncomplicated malaria (median age, 10.5 months). The same treatment was given for all subsequent episodes of uncomplicated malaria and children were followed until they reached 5 years of age. The cohort included a subgroup that was human immunodeficiency virus (HIV) infected (n = 44) or HIV exposed (n = 175) and prescribed trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. Outcomes included time to recurrent malaria following individual treatments and the overall incidences of treatments for malaria, complicated malaria, and hospitalizations. RESULTS: Among children not prescribed TMP-SMX prophylaxis, 4443 treatments for malaria were given over 790 person-years following randomization. Treatment with DP was associated with a lower hazard of recurrent malaria over the 84 days after treatment (hazard ratio, 0.66; 95% confidence interval [CI], .61-.70; P < .001). Children randomized to DP had a lower incidence of all treatments for malaria (incidence rate ratio [IRR], 0.85; 95% CI, .75-.96; P = .01), complicated malaria (IRR, 0.12; 95% CI, .04-.39; P < .001), and hospitalizations (IRR, 0.31; 95% CI, .13-.77; P = .01). Among children prescribed TMP-SMX prophylaxis, there were no significant differences in longitudinal outcomes. CONCLUSIONS: Compared to artemether-lumefantrine, the use of DP to treat uncomplicated malaria delayed the time to recurrent malaria and reduced the incidences of treatments for malaria, complicated malaria, and hospitalizations. Clinical Trials Registration. NCT00527800. |
Comparative impacts over 5 years of artemisinin-based combination therapies on Plasmodium falciparum polymorphisms that modulate drug sensitivity in Ugandan children.
Conrad MD , LeClair N , Arinaitwe E , Wanzira H , Kakuru A , Bigira V , Muhindo M , Kamya MR , Tappero JW , Greenhouse B , Dorsey G , Rosenthal PJ . J Infect Dis 2014 210 (3) 344-53 BACKGROUND: Artemisinin-based combination therapies, including artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), are recommended to treat uncomplicated falciparum malaria. Sensitivities to components of AL and DP are impacted by polymorphisms in pfmdr1 and pfcrt. We monitored changes in prevalences of polymorphisms in Tororo, Uganda, from 2008 to 2012. METHODS: Polymorphic loci in pfmdr1 and pfcrt were characterized in samples from 312 children randomized to AL or DP for each episode of uncomplicated malaria (50 samples per arm for each 3-month interval) utilizing a fluorescent microsphere assay. Treatment outcomes and impacts of prior therapies were also characterized. RESULTS: Prevalence increased significantly over time for pfmdr1 N86 (AL: odds ratio [OR], 2.08 [95% confidence interval {CI}, 1.83-2.38]; DP: 1.41 [95% CI, 1.25-1.57]), pfmdr1 D1246 (AL: 1.46 [95% CI, 1.29-1.64]; DP: 1.36 [95% CI, 1.23-1.50]), and pfcrt K76 (AL: 3.37 [95% CI, 1.85-6.16]; DP: 5.84 [95% CI, 1.94-17.53], and decreased for pfmdr1 Y184 (AL: 0.78 [95% CI, .70-.86]; DP: 0.84 [95% CI, .76-1.50]); changes were consistently greater in the AL arm. Recent AL treatment selected for pfmdr1 N86, D1246, and 184F in subsequent episodes; DP selected for the opposite alleles. CONCLUSIONS: Genotypes with decreased sensitivity to AL components increased over time. This increase was greater in children receiving AL, suggesting that the choice of treatment regimen can profoundly influence parasite genetics and drug sensitivity. CLINICAL TRIALS REGISTRATION: NCT00527800. |
Long-lasting insecticide-treated bed net ownership and use among children under five years of age following a targeted distribution in central Uganda
Wanzira H , Yeka A , Kigozi R , Rubahika D , Nasr S , Sserwanga A , Kamya M , Filler S , Dorsey G , Steinhardt L . Malar J 2014 13 (1) 185 BACKGROUND: Universal coverage of long-lasting insecticide-treated bed nets (LLINs) for prevention of malaria was adopted by the Uganda National Malaria Control Programme in 2007. The first mass distribution of LLINs was implemented in 2010. Initially, a campaign targeted to households with pregnant women and children aged <five years was carried out, prior to a planned fill-in campaign to achieve universal LLIN coverage. This survey was conducted after the targeted distribution in central Uganda to assess progress in LLIN ownership and usage among children <five years. METHODS: A two-stage, cluster-sample, cross-sectional household survey was carried out in early 2011 in Central region districts surveyed during the 2009 Malaria Indicator Survey (MIS). In the first sampling stage, 30 enumeration areas (EAs) were selected and all households were enumerated. Within each sampled EA, 20 households were randomly selected for interview using two questionnaires: a household questionnaire and a woman's questionnaire for all women aged 15-49 years, both modified from the MIS. RESULTS: When compared to 2009 MIS results, household ownership of at least one LLIN increased by 47%, from 22 to 69% after the targeted campaign. LLIN use among children <five years increased by 40%, from 11 to 51%. Households with a child <six years old at the time of the survey, a proxy for those targeted, were significantly more likely to have received a campaign bed net (80.7 vs 35.2%, p < 0.001). LLIN ownership and use was equitable after the targeted campaign, with no significant differences by household wealth status. However, the proportion of households with at least one LLIN per two people was still low after the first campaign phase, increasing from 8.5 to 25.9%. CONCLUSIONS: The first phase of the campaign led to substantial increases in both LLIN ownership and equitable use among children <five years in the Central region. However, access to an LLIN within the household was still low after the first phase of the campaign, indicating the need for the universal fill-in campaign. |
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