Showing papers by "Moses R. Kamya published in 2014"

Estimating the annual entomological inoculation rate for Plasmodium falciparum transmitted by Anopheles gambiae s.l. using three sampling methods in three sites in Uganda

Abstract: The Plasmodium falciparum entomological inoculation rate (Pf EIR) is a measure of exposure to infectious mosquitoes. It is usually interpreted as the number of P. falciparum infective bites received by an individual during a season or annually (aPf EIR). In an area of perennial transmission, the accuracy, precision and seasonal distribution (i.e., month by month) of aPf EIR were investigated. Data were drawn from three sites in Uganda with differing levels of transmission where falciparum malaria is transmitted mainly by Anopheles gambiae s.l. Estimates of aPf EIR derived from human-landing catches – the classic method for estimating biting rates – were compared with data from CDC light traps, and with catches of knock down and exit traps separately and combined. Entomological surveillance was carried out over one year in 2011/12 in three settings: Jinja, a peri-urban area with low transmission; Kanungu, a rural area with moderate transmission; and Nagongera, Tororo District, a rural area with exceptionally high malaria transmission. Three sampling approaches were used from randomly selected houses with collections occurring once a month: human-landing collections (eight houses), CDC light traps (100 houses) and paired knock-down and exit traps each month (ten houses) for each setting. Up to 50 mosquitoes per month from each household were tested for sporozoites with P. falciparum by ELISA. Human biting rate (HBR) data were estimated month by month. P. falciparum Sporozoite rate (Pf SR) for yearly and monthly data and confidence intervals were estimated using the binomial exact test. Monthly and yearly estimates of the HBR, the Pf SR, and the Pf EIR were estimated and compared. The estimated aPf EIR values using human-landing catch data were 3.8 (95% Confidence Intervals, CI 0-11.4) for Jinja, 26.6 (95% CI 7.6-49.4) for Kanungu, and 125 (95% CI 72.2-183.0) for Tororo. In general, the monthly Pf EIR values showed strong seasonal signals with two peaks from May-June and October-December, although the precise timing of the peaks differed between sites. Estimated HBRs using human-landing catches were strongly correlated with those made using CDC light traps (r2 = 0.67, p < 0.001), and with either knock-down catches (r2 = 0.56, p < 0.001) and exit traps (r2 = 0.82, p < 0.001) or the combined catches (r2 = 0.73, p < 0.001). Using CDC light trap catch data, the Pf SR in Tororo was strongly negatively correlated with monthly HBR (r2 = 0.44, p = 0.01). In other sites, no patterns in the Pf SR were discernible because either the number P. falciparum of sporozoite positive mosquitoes or the total number of mosquitoes caught was too low. In these settings, light traps provide an alternative method for sampling indoor-resting mosquitoes to human-landing catches and have the advantage that they protect individuals from being bitten during collection, are easy to use and are not subject to collector bias. Knock-down catches and exit traps could also be used to replace human-landing catches. Although these are cheaper, they are subject to collector bias.

Polymorphisms in K13 and Falcipain-2 Associated with Artemisinin Resistance Are Not Prevalent in Plasmodium falciparum Isolated from Ugandan Children

Abstract: The emergence of resistance to artemisinin derivatives in Southeast Asia, manifested as delayed clearance of Plasmodium falciparum following treatment with artemisinins, is a major concern. Recently, the artemisinin resistance phenotype was attributed to mutations in portions of a P. falciparum gene (PF3D7_1343700) encoding kelch (K13) propeller domains, providing a molecular marker to monitor the spread of resistance. The P. falciparum cysteine protease falcipain-2 (FP2; PF3D7_1115700) has been shown to contribute to artemisinin action, as hemoglobin degradation is required for potent drug activity, and a stop mutation in the FP2 gene was identified in parasites selected for artemisinin resistance. Although delayed parasite clearance after artemisinin-based combination therapy (ACT) has not yet been noted in Uganda and ACTs remain highly efficacious, characterizing the diversity of these genes is important to assess the potential for resistance selection and to provide a baseline for future surveillance. We therefore sequenced the K13-propeller domain and FP2 gene in P. falciparum isolates from children previously treated with ACT in Uganda, including samples from 2006–7 (n = 49) and from 2010–12 (n = 175). Using 3D7 as the reference genome, we identified 5 non-synonymous polymorphisms in the K13-propeller domain (133 isolates) and 35 in FP2 (160 isolates); these did not include the polymorphisms recently associated with resistance after in vitro selection or identified in isolates from Asia. The prevalence of K13-propeller and FP2 polymorphisms did not increase over time, and was not associated with either time since prior receipt of an ACT or the persistence of parasites ≥2 days following treatment with an ACT. Thus, the K13-propeller and FP2 polymorphisms associated with artemisinin resistance are not prevalent in Uganda, and we did not see evidence for selection of polymorphisms in these genes.

Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, dose-ranging trial

Abstract: Methods We undertook this randomised, double-blind, placebo-controlled trial with four parallel groups in Jinja district, eastern Uganda. We randomly allocated Ugandan children aged 1–10 years with uncomplicated falciparum malaria and normal G6PD enzyme function to receive artemether–lumefantrine, combined with either placebo or with 0∙1 mg/kg, 0∙4 mg/kg, or 0∙75 mg/kg (WHO reference dose) primaquine base. Randomisation was done with computer -generated four-digit treatment assignment codes allocated to random dose groups in block sizes of 16. Study staff who provided care or assessed outcomes and the participants remained masked to the intervention group after assignment. The primary effi cacy endpoint was the non-inferiority of the mean duration of gametocyte carriage in the test doses compared with the reference group of 0∙75 mg primaquine per kg, with a non-inferiority margin of 2·5 days. The primary safety endpoint was the superiority of the arithmetic mean maximum decrease in haemoglobin concentration from enrolment to day 28 of follow-up in the primaquine treatment groups compared with placebo, with use of signifi cance testing of pairwise comparisons with a cutoff of p=0·05. The trial is registered with ClinicalTrials.gov, number NCT01365598. Findings We randomly allocated 468 participants to receive artemether–lumefantrine combined with placebo (119 children) or with 0∙1 mg/kg (116), 0∙4 mg/kg (116), or 0∙75 mg/kg (117) primaquine base. The mean duration of gametocyte carriage was 6∙6 days (95% CI 5∙3–7∙8) in the 0∙75 mg/kg reference group, 6·3 days (5·1–7·5) in the 0∙4 mg/kg primaquine group (p=0∙74), 8·0 days (6∙6–9∙4) in the 0∙1 mg/kg primaquine group (p=0∙14), and 12∙4 days (9∙9–15∙0) in the placebo group (p<0∙0001). No children showed evidence of treatment-related haemolysis, and the mean maximum decrease in haemoglobin concentration was not associated with the dose of primaquine received—it did not diff er signifi cantly compared with placebo (10·7 g/L, SD 11·1) in the 0∙1 mg/kg (11·4 g/L, 9·4; p=0∙61), 0∙4 mg/kg (11·3 g/L, 10·0; p=0∙67), or 0∙75 mg/kg (12·7 g/L, 8·2; p=0∙11) primaquine groups.

Comparative Impacts Over 5 Years of Artemisinin-Based Combination Therapies on Plasmodium falciparum Polymorphisms That Modulate Drug Sensitivity in Ugandan Children

Abstract: (See the editorial commentary by Taylor and Juliano on pages 335–7.) Artemisinin-based combination therapies (ACTs) have shown excellent efficacy and are now recommended to treat falciparum malaria in nearly all countries [1]. ACTs include potent, short-acting artemisinins that rapidly reduce parasite biomass and alleviate malaria symptoms and longer-acting partner drugs that improve antimalarial efficacy and reduce the risk of selection for artemisinin resistance [2]. However, as partner drugs circulate well after artemisinins have been cleared, there is concern that subsequent infections will be exposed to subtherapeutic concentrations, facilitating the selection of parasites with reduced sensitivity to the partner drugs. Artemether-lumefantrine (AL) is the most widely recommended ACT in Africa and the national malaria treatment regimen in Uganda [1, 3]. It has shown outstanding efficacy [4, 5], but treatment selects in recurrent Plasmodium falciparum infections for polymorphisms in pfcrt and pfmdr1 [6–11]—genes encoding 2 putative drug transporters—that reduce sensitivity to artemether, lumefantrine, and other antimalarial drugs [12–15]. AL exerts an opposite selective pressure compared to that of the aminoquinolines chloroquine and amodiaquine. Specifically, the aminoquinolines select for the mutant pfcrt 76T, pfmdr1 86Y, and pfmdr1 1246Y alleles, which decrease sensitivity to these drugs, whereas AL selects for the wild-type alleles [6–11, 16]. AL also selected for the I876 polymorphism in pfmrp1, which encodes another putative drug transporter, in Tanzania [17]. Three additional pfmdr1 polymorphisms (S1034C, N1042D, and increased gene copy number) are associated with altered sensitivity to some drugs, but are primarily seen outside of Africa [12, 15, 18–20]. Ex vivo sensitivities of field isolates to lumefantrine have varied widely, but clinically relevant resistance does not appear to be a problem [14, 21, 22]. Analysis of parasites selected in vitro for high-level lumefantrine resistance demonstrated multiple differentially expressed genes, including pfmdr1, but the phenotype was unstable [23]. Dihydroartemisinin-piperaquine (DP) has shown excellent efficacy in clinical trials in Africa [16, 24–27], but has only been adopted as a first-line therapy in Southeast Asia [1]. Particularly in areas with high malaria transmission intensity, DP benefits from the pharmacokinetics of piperaquine, which has a much longer half-life (3–4 weeks) than that of lumefantrine (3–5 days) and other ACT partner drugs [28], yielding a long posttreatment prophylactic effect [5, 24, 27]. Piperaquine was used extensively to prevent and treat malaria decades ago in China [29, 30], but reported resistance led to reduced use by the 1980s. More recently, with implementation of DP as a standard therapy, piperaquine resistance does not appear to be a major problem, although ex vivo sensitivities of field isolates to piperaquine have varied [14, 22, 31, 32]. Mechanisms of resistance to piperaquine are poorly understood. Parasites selected in vitro for resistance acquired a number of genetic changes, including a novel mutation in pfcrt and deamplification of pfmdr1, but the phenotype was unstable [33]. AL replaced chloroquine plus sulfadoxine-pyrimethamine as the first-line regimen for uncomplicated malaria in Uganda in 2004, although implementation did not begin until 2006 and was initially slow [34, 35]. With improved utilization of AL in recent years, it was of interest to determine the prevalence over time of parasite polymorphisms that alter sensitivity to ACT components and to determine how use of AL impacts upon these polymorphisms. Therefore, we analyzed the prevalence of polymorphisms of interest in samples from a 5-year longitudinal trial comparing the antimalarial efficacies of AL and DP in Ugandan children. Polymorphisms associated with reduced sensitivity to AL increased markedly in prevalence over the course of the study, and this increase was greater in children treated with AL compared to those treated with DP, consistent with our demonstration of opposite selective pressures of the 2 regimens.

Impact of Intermittent Preventive Treatment With Dihydroartemisinin-Piperaquine on Malaria in Ugandan Schoolchildren: A Randomized, Placebo-Controlled Trial

Abstract: fidence interval [CI], 88%–99%, P< .0001), the prevalence of asymptomatic parasitemia by 94% (95% CI, 92%–96%, P< .0001), and the prevalence of anemia by 40% (95% CI, 19%–56%, P< .0001). IPTst had no significant effect on the incidence of symptomatic malaria or the prevalence of anemia, but reduced the prevalence of asymptomatic parasitemia by 54% (95% CI, 47%–60%, P< .0001). Conclusions. Monthly IPT with DPoffered remarkable protection against clinical malaria, parasitemia, and anemia in schoolchildren living in a high-malaria-transmission setting. Clinical Trials Registration. NCT01231880.

Uptake of community-based HIV testing during a multi-disease health campaign in rural Uganda.

Abstract: BACKGROUND: The high burden of undiagnosed HIV in sub-Saharan Africa is a major obstacle for HIV prevention and treatment. Multi-disease community health campaigns (CHCs) offering HIV testing are a successful approach to rapidly increase HIV testing rates and identify undiagnosed HIV. However a greater understanding of population-level uptake is needed to maximize effectiveness of this approach. METHODS: After community sensitization and a census a five-day campaign was performed in May 2012 in a rural Ugandan community. The census enumerated all residents capturing demographics household location and fingerprint biometrics. The CHC included point-of-care screening for HIV malaria TB hypertension and diabetes. Residents who attended vs. did not attend the CHC were compared to determine predictors of participation. RESULTS: Over 12 days 18 census workers enumerated 6343 residents. 501 additional residents were identified at the campaign for a total community population of 6844. 4323 (63%) residents and 556 non-residents attended the campaign. HIV tests were performed in 4795/4879 (98.3%) participants; 1836 (38%) reported no prior HIV testing. Of 2674 adults tested 257 (10%) were HIV-infected; 125/257 (49%) reported newly diagnosed HIV. In unadjusted analyses adult resident campaign non-participation was associated with male sex (62% male vs. 67% female participation p = 0.003) younger median age (27 years in non-participants vs. 32 in participants; p<0.001) and marital status (48% single vs. 71% married/widowed/divorced participation; p<0.001). In multivariate analysis single adults were significantly less likely to attend the campaign than non-single adults (relative risk [RR]: 0.63 [95% CI: 0.53-0.74]; p<0.001) and adults at home vs. not home during census activities were significantly more likely to attend the campaign (RR: 1.20 [95% CI: 1.13-1.28]; p<0.001). CONCLUSIONS: CHCs provide a rapid approach to testing a majority of residents for HIV in rural African settings. However complementary strategies are still needed to engage young single adults and achieve universal testing.

Protective Efficacy and Safety of Three Antimalarial Regimens for the Prevention of Malaria in Young Ugandan Children: A Randomized Controlled Trial

Abstract: © 2014 Bigira et al.Chemoprevention offers a promising strategy for prevention of malaria in African children. However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial

Pharmacokinetics of lopinavir/ritonavir and efavirenz in food insecure HIV-infected pregnant and breastfeeding women in Tororo, Uganda.

Abstract: Pregnancy and food insecurity may impact antiretroviral (ART) pharmacokinetics (PK) adherence and response. We sought to quantify and characterize the PK of lopinavir/ritonavir (LPV/r) and efavirenz (EFV) by pregnancy and nutritional status among HIV-infected women in Tororo Uganda. In 2011 62/225 ante-partum/post-partum single dried blood spot samples DBS and 43 post-partum hair samples for LPV/r were derived from 116 women 51/194 ante-/post-partum DBS and 53 post-partum hair samples for EFV from 105 women. Eighty percent of Ugandan participants were severely food insecure 26% lost weight ante-partum and median BMI post-partum was only 20.2 kg/m(2) . Rich PK-data of normally nourished (pregnant) women and healthy Ugandans established prior information. Overall drug exposure was reduced (LPV -33% EFV -15% ritonavir -17%) compared to well-nourished controls (P < 0.001) attributable to decreased bioavailability. Pregnancy increased LPV/r clearance 68% (P < 0.001) whereas EFV clearance remained unchanged. Hair concentrations correlated with plasma-exposure (P < 0.001) explaining 29% PK-variability. In conclusion pregnancy and food insecurity were associated with lower ART exposures in this cohort of predominantly underweight women compared to well-nourished women. Much variability in plasma-exposure was quantified using hair concentrations. Addressing malnutrition as well as ART-PK in this setting should be a priority. (c) 2013 The American College of Clinical Pharmacology.

Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir- or efavirenz-based antiretroviral therapy.

Abstract: BACKGROUND Protease inhibitor-based antiretroviral therapy (ART) has been associated with preterm birth in some studies. We examined risk factors for preterm birth among women randomized to lopinavir/ritonavir (LPV/r)- or efavirenz (EFV)-based ART. METHODS This was a planned secondary analysis of the PROMOTE-Pregnant Women and Infants Study, an open-label, randomized controlled trial comparing the risk of placental malaria among HIV-infected, ART-naive pregnant Ugandan women assigned to initiate LPV/r- or EFV-based ART at 12-28 weeks gestation. Gestational age was determined based on last menstrual period and ultrasound biometry. All women received bednets and trimethoprim-sulfamethoxazole. Stillbirths, spontaneous abortions, and multiple gestations were excluded from the primary analysis. Potential risk factors for preterm birth (<37 weeks gestation) were evaluated by univariate and multivariate logistic regression. RESULTS Three hundred fifty-six women were included in this analysis. At enrollment, median gestational age was 21 weeks and median CD4 cell count was 368 cells per cubic millimeter. 14.7% of deliveries in the EFV arm and 16.2% in the LPV/r arm were preterm. Preterm birth was associated with gestational weight gain below 0.1 kg/week versus 0.1 kg/week or more [odds ratio (OR) = 2.49; 95% confidence interval (CI): 1.38 to 4.47; P = 0.003]. Neither ART regimen of LPV/r versus EFV (OR = 1.12; 95% CI: 0.63 to 2.00; P = 0.69) nor placental malaria (OR = 0.74; 95% CI: 0.38 to 1.44; P = 0.37) was associated with preterm birth. CONCLUSIONS LPV/r was not associated with an increased risk of preterm birth compared with EFV. However, interventions are needed to address modifiable risk factors for preterm birth, such as nutritional status (ClinicalTrials.gov, NCT00993031).

Lopinavir/Ritonavir-Based Antiretroviral Treatment (ART) Versus Efavirenz-Based ART for the Prevention of Malaria Among HIV-Infected Pregnant Women

Abstract: Malaria in pregnancy is associated with adverse maternal and neonatal outcomes, such as spontaneous abortions, stillbirth, intrauterine growth restriction, preterm delivery, low birth weight (LBW), maternal anemia, and neonatal death [1]. Human immunodeficiency virus (HIV)–infected pregnant women have an increased risk of parasitemia, clinical malaria, and placental malaria, compared with HIV-uninfected pregnant women [2]. In addition, coinfection with HIV and placental malaria parasites is associated with an increased risk of low birth weight and preterm delivery, compared with either infection alone [2]. The attributable risk for placental malaria due to HIV infection is more pronounced with higher parity, a phenomenon supported by laboratory studies indicating that HIV impairs parity-specific immunity [3, 4]. Current strategies for the prevention of malaria during pregnancy include the use of insecticide-treated bed nets (ITNs) and intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP). For HIV-infected pregnant women receiving daily trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, the World Health Organization (WHO) recommends avoiding the use of IPTp with SP because of the risk of adverse drug reactions [5]. However, the spread of resistance to the pyrethroid class of insecticides used in ITNs and to the antifolate class of drugs used for ITPp and prophylaxis suggest the need for novel strategies for the prevention of malaria among HIV-infected and uninfected pregnant women [6, 7]. Combination antiretroviral therapy (ART) is now recommended for all HIV-infected pregnant and breast-feeding women per 2013 WHO consolidated guidelines [8]. In addition to benefits in improving women's health and reducing the risk of HIV transmission, the protease inhibitor class of antiretroviral agents may also provide protection against malaria. HIV protease inhibitors demonstrate in vitro activity against Plasmodium falciparum [9–11], and it is thought that this occurs through inhibition of plasmepsins, although the exact mechanism remains unclear [12]. Lopinavir is the most potent of these inhibitors and is active in vitro at levels commonly achieved with ritonavir boosting [10, 11]. In a recent randomized controlled trial of HIV-infected Ugandan children, coformulated lopinavir/ritonavir (LPV/r)–based ART was associated with a 41% reduction in the incidence of malaria, compared with nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based ART, with the lower incidence attributable largely to a significant reduction in the recurrence of malaria after treatment with artemether-lumefantrine (AL) [13]. The efficacy of HIV protease inhibitors for the prevention of malaria and its complications among pregnant women has not been previously evaluated in clinical trials. To test the hypothesis that HIV protease inhibitors are protective against malaria, HIV-infected, ART-naive pregnant women living in an area of Uganda where malaria is highly endemic were randomly assigned to receive LPV/r-based or efavirenz (EFV)–based ART and followed up to 1 year after delivery. Outcomes of interest included measures of placental malaria, adverse birth outcomes, incidence of malaria, and prevalence of asymptomatic parasitemia.

Increased morbidity in early childhood among HIV-exposed uninfected children in Uganda is associated with breastfeeding duration.

Abstract: Human immunodeficiency virus (HIV)-exposed uninfected children (HEU) have an increased risk of morbidity and mortality compared with HIV-unexposed uninfected children (HUU); however, prior studies have not fully accounted for the role of both breastfeeding and age on this association. In this cohort of HEU and HUU in Uganda, non-breastfeeding HEU, from 6–11 months compared with non-breastfeeding HUU had a higher risk of hospitalizations [relative risk (RR): 10.1, 95% confidence interval (CI): 3.70–27.6], severe febrile illness (RR: 3.84, 95% CI: 2.06–7.17), severe diarrhea (RR: 6.37, 95% CI: 2.32–17.4) and severe malnutrition (RR: 18.4, 95% CI: 4.68–72.0). There were no differences between morbidity outcomes between breastfeeding HEU and HUU children, aged 6–11 months. In the 12–24 month age group, the only difference in morbidity outcomes among non-breast feeding children was an increased risk of severe malnutrition for HEU. These data suggest that the increased risk of morbidity among HEU aged 6–11 years is partially explained by early cessation of breastfeeding.

Longitudinal Outcomes in a Cohort of Ugandan Children Randomized to Artemether-Lumefantrine Versus Dihydroartemisinin-Piperaquine for the Treatment of Malaria

Abstract: 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.

Long-lasting insecticide-treated bed net ownership and use among children under five years of age following a targeted distribution in central Uganda

Abstract: 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

Efficacy and safety of fixed-dose artesunate-amodiaquine vs. artemether-lumefantrine for repeated treatment of uncomplicated malaria in Ugandan children.

Abstract: The safety and efficacy of the two most widely used fixed-dose artemisinin-based combination therapies (ACT), artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are well established for single episodes of uncomplicated Plasmodium falciparum malaria, but the effects of repeated, long-term use are not well documented. We conducted a 2-year randomized, open-label, longitudinal, phase IV clinical trial comparing the efficacy and safety of fixed-dose ASAQ and AL for repeated treatment of uncomplicated malaria in children under 5 years at Nagongera Health Centre, Uganda. Participants were randomized to ASAQ or AL and all subsequent malaria episodes were treated with the same regimen. 413 children were enrolled and experienced a total of 6027 malaria episodes (mean 15; range, 1–26). For the first malaria episode, the PCR-corrected-cure rate for ASAQ (97.5%) was non-inferior to that for AL (97.0%; 95% CI [−0.028; 0.037]). PCR-corrected cure rates for subsequent malaria episodes that had over 100 cases (episodes 2–18), ranged from 88.1% to 98.9% per episode, with no clear difference between the treatment arms. Parasites were completely cleared by day 3 for all malaria episodes and gametocyte carriage was less than 1% by day 21. Fever clearance was faster in the ASAQ group for the first episode. Treatment compliance for subsequent episodes (only first dose administration observed) was close to 100%. Adverse events though common were similar between treatment arms and mostly related to the disease. Serious adverse events were uncommon, comparable between treatment arms and resolved spontaneously. Anemia and neutropenia occurred in <0.5% of cases per episode, abnormal liver function tests occurred in 0.3% to 1.4% of cases. Both regimens were safe and effective for repeated treatment of malaria.

Decreases in self-reported alcohol consumption following HIV counseling and testing at Mulago Hospital, Kampala, Uganda

Abstract: Alcohol use has a detrimental impact on the HIV epidemic, especially in sub-Saharan Africa. HIV counseling and testing (HCT) may provide a contact opportunity to intervene with hazardous alcohol use; however, little is known about how alcohol consumption changes following HCT. We utilized data from 2056 participants of a randomized controlled trial comparing two methods of HCT and subsequent linkage to HIV care conducted at Mulago Hospital in Kampala, Uganda. Those who had not previously tested positive for HIV and whose last HIV test was at least one year in the past were eligible. Participants were asked at baseline when they last consumed alcohol, and prior three month alcohol consumption was measured using the Alcohol Use Disorders Identification Test – Consumption (AUDIT-C) at baseline and quarterly for one year. Hazardous alcohol consumption was defined as scoring ≥3 or ≥4 for women and men, respectively. We examined correlates of alcohol use at baseline, and of hazardous and non-hazardous drinking during the year of follow-up using multinomial logistic regression, clustered at the participant level to account for repeated measurements. Prior to HCT, 30% were current drinkers (prior three months), 27% were past drinkers (>3 months ago), and 44% were lifetime abstainers. One-third (35%) of the current drinkers met criteria for hazardous drinking. Hazardous and non-hazardous self-reported alcohol consumption declined after HCT, with 16% of baseline current drinkers reporting hazardous alcohol use 3 months after HCT. Independent predictors (p < 0.05) of continuing non-hazardous and hazardous alcohol consumption after HCT were sex (male), alcohol consumption prior to HCT (hazardous), and HIV status (negative). Among those with HIV, non-hazardous drinking was less likely among those taking antiretroviral therapy (ART). HCT may be an opportune time to intervene with alcohol consumption. Those with HIV experienced greater declines in alcohol consumption after HCT, and non-hazardous drinking decreased for those with HIV initiating ART. HCT and ART initiation may be ideal times to intervene with alcohol consumption. Screening and brief intervention (SBI) to reduce alcohol consumption should be considered for HCT and HIV treatment venues.

Determining health-care facility catchment areas in Uganda using data on malaria-related visits

Abstract: Objective To illustrate the use of a new method for defining the catchment areas of health-care facilities based on their utilization. Methods The catchment areas of six health-care facilities in Uganda were determined using the cumulative case ratio: the ratio of the observed to expected utilization of a facility for a particular condition by patients from small administrative areas. The cumulative case ratio for malaria-related visits to these facilities was determined using data from the Uganda Malaria Surveillance Project. Catchment areas were also derived using various straight line and road network distances from the facility. Subsequently, the 1-year cumulative malaria case rate was calculated for each catchment area, as determined using the three methods. Findings The 1-year cumulative malaria case rate varied considerably with the method used to define the catchment areas. With the cumulative case ratio approach, the catchment area could include noncontiguous areas. With the distance approaches, the denominator increased substantially with distance, whereas the numerator increased only slightly. The largest cumulative case rate per 1000 population was for the Kamwezi facility: 234.9 (95% confidence interval, CI: 226.2–243.8) for a straight-line distance of 5 km, 193.1 (95% CI: 186.8–199.6) for the cumulative case ratio approach and 156.1 (95% CI: 150.9–161.4) for a road network distance of 5 km. Conclusion Use of the cumulative case ratio for malaria-related visits to determine health-care facility catchment areas was feasible. Moreover, this approach took into account patients' actual addresses, whereas using distance from the facility did not.

Doctoral training in Uganda: evaluation of mentoring best practices at Makerere university college of health sciences

Abstract: Background Good mentoring is a key variable for determining success in completing a doctoral program. We identified prevailing mentoring practices among doctoral students and their mentors, identified common challenges facing doctoral training, and proposed some solutions to enhance the quality of the doctoral training experience for both candidates and mentors at Makerere University College of Health Sciences (MakCHS).

Successful antiretroviral therapy delivery and retention in care among asymptomatic individuals with high CD4+ T-cell counts above 350 cells/μl in rural Uganda.

Abstract: BACKGROUND HIV antiretroviral therapy (ART) is being rapidly scaled up in sub-Saharan Africa, including recently patients with CD4 T-cell counts above 350 cells/μl. However, concerns persist about adherence and virologic suppression among these asymptomatic, high CD4 cell count individuals. OBJECTIVE To determine the virologic efficacy and safety of ART among asymptomatic HIV-positive Ugandan adults with high CD4 cell counts above 350 cells/μl via a streamlined model of care. DESIGN Prospective nonrandomized clinical study (EARLI Study: clinicaltrials.gov NCT#01479634). SETTING Prototypic rural Ugandan HIV clinic. PATIENTS/PARTICIPANTS Asymptomatic, ART-naive adults (aged >18 years, N = 197) with CD4 at least 350 cells/μl, without pregnancy or WHO stage 3/4 illness. INTERVENTIONS ART included tenofovir/emtricitabine/efavirenz, with ritonavir/lopinavir substitution for efavirenz available. Streamlined ART model included nurse-driven visits with physician back-up, basic safety laboratory monitoring with HIV viral load, clinician telephone contact, and defaulter tracking. No incentives were provided. OUTCOMES Undetectable viral load (≤400 copies/ml) at 24 and 48 weeks [intention to treat (ITT); missing = detectable), self-reported ART adherence, retention in care, and laboratory/clinical ART toxicities. RESULTS Of the 197 patients with CD4 above 350 cells/μl, median CD4 cell count was 569 cells/μl (interquartile range 451-716). Undetectable viral load was achieved in 189 of 197 (95.9%, ITT) and 189 of 195 (96.9%, ITT) of participants at weeks 24 and 48, respectively. Self-reported adherence was 98% and 192 of 197 (97%) of the patients were retained at week 48. Laboratory adverse events and hospitalizations were rare. CONCLUSIONS We demonstrate high virologic suppression, retention, and safety among asymptomatic individuals with CD4 above 350 cells/μl in a prototypic Ugandan clinic. Our results challenge current concerns that individuals with high CD4 cell count lack motivation for ART, and may not achieve sustained virologic suppression.

Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or nonnucleoside reverse transcriptase inhibitor therapy.

Abstract: BACKGROUND In the Prevention of Malaria and HIV disease in Tororo pediatrics trial, HIV-infected Ugandan children randomized to receive lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) experienced a lower incidence of malaria compared with children receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Here we present the results of the noninferiority analysis of virologic efficacy and comparison of immunologic outcomes. METHODS ART-naive or -experienced (HIV RNA <400 copies/mL) children aged 2 months to 6 years received either LPV/r or NNRTI-based ART. The proportion of children with virologic suppression (HIV RNA <400 copies/mL) at 48 weeks was compared using a prespecified noninferiority margin of -11% in per-protocol analysis. Time to virologic failure by 96 weeks, change in CD4 counts and percentages, and incidence of adverse event rates were also compared. RESULTS Of 185 children enrolled, 91 initiated LPV/r and 92 initiated NNRTI-based ART. At baseline, the median age was 3.1 years (range, 0.4-5.9), and 131 (71%) children were ART-naive. The proportion of children with virologic suppression at 48 weeks was 80% (67/84) in the LPV/r arm vs. 76% (59/78) in the NNRTI arm, a difference of 4% (95% confidence interval: -9% to +17%). Time to virologic failure, CD4 changes, and the incidence of Division of AIDS grade III/IV adverse events were similar between arms. CONCLUSIONS LPV/r-based ART was not associated with worse virologic efficacy, immunologic efficacy, or adverse event rates compared with NNRTI-based ART. Considering these results and the reduction in malaria incidence associated with LPV/r previously reported for this trial, wider use of LPV/r to treat HIV-infected African children in similar malaria-endemic settings could be considered.

Glucose-6-Phosphate Dehydrogenase Status and Risk of Hemolysis in Plasmodium falciparum-Infected African Children Receiving Single-Dose Primaquine

Abstract: Glucose-6-phosphate dehydrogenase (G6PD) enzyme function and genotype were determined in Ugandan children with uncomplicated falciparum malaria enrolled in a primaquine trial after exclusion of severe G6PD deficiency by fluorescent spot test. G6PD A- heterozygotes and hemizygotes/homozygotes experienced dose-dependent lower hemoglobin concentrations after treatment. No severe anemia was observed.

Household food insecurity, maternal nutritional status, and infant feeding practices among HIV-infected Ugandan women receiving combination antiretroviral therapy

Abstract: Household food insecurity (HHFI) may be a barrier to both optimal maternal nutritional status and infant feeding practices, but few studies have tested this relationship quantitatively, and never among HIV-infected individuals. We therefore described the prevalence of HHFI and explored if it was associated with poorer maternal nutritional status, shorter duration of exclusive breastfeeding (EBF) and fewer animal-source complementary foods. We assessed these outcomes using bivariate and multivariate analyses among 178 HIV-infected pregnant and breastfeeding (BF) women receiving combination antiretroviral therapy in the PROMOTE trial (NCT00993031), a prospective, longitudinal cohort study in Tororo, Uganda. HHFI was common; the prevalence of severe, moderate, and little to no household hunger was 7.3, 39.9, and 52.8 %, respectively. Poor maternal nutritional status was common and women in households experiencing moderate to severe household hunger (MSHH) had statistically significantly lower body mass index (BMIs) at enrollment (21.3 vs. 22.5, p < 0.01) and prior to delivery (22.6 vs. 23.8, p < 0.01). BMI across time during pregnancy, but not gestational weight gain, was significantly lower for MSHH [adjusted beta (95 % CI) -0.79 (-1.56, -0.02), p = 0.04; -2.06 (-4.31, 0.19), p = 0.07], respectively. The prevalence (95 % CI) of EBF at 6 months was 67.2 % (59.7-73.5 %), and the proportion of women BF at 12 months was 80.4 % (73.3-85.7 %). MSHH was not associated with prevalence of EBF at 6 months or BF at 12 months. However, among those women still EBF at 4 months (81.4 % of population), those experiencing MSHH were significantly more likely to cease EBF between 4 and 6 months (aHR 2.38, 95 % CI 1.02-5.58). The prevalence of HHFI, maternal malnutrition, and suboptimal infant feeding practices are high and the causal relationships among these phenomena must be further explored.

Validation of the ligase detection reaction fluorescent microsphere assay for the detection of Plasmodium falciparum resistance mediating polymorphisms in Uganda

Abstract: Malaria remains a major public health problem, and its control has been hampered by drug resistance. For a number of drugs, Plasmodium falciparum single nucleotide polymorphisms (SNPs) are associated with altered drug sensitivity and can be used as markers of drug resistance. Several techniques have been studied to assess resistance markers. The most widely used methodology is restriction fragment length polymorphism (RFLP) analysis. The ligase detection reaction fluorescent microsphere (LDR-FM) assay was recently shown to provide high throughput assessment of P. falciparum SNPs associated with drug resistance. The aim of this study was to validate the reliability and accuracy of the LDR-FM assay in a field setting. For 223 samples from a clinical trial in Tororo, Uganda in which P. falciparum was identified by blood smear, DNA was extracted from dried blood spots, genes of interest were amplified by PCR, amplicons were analysed by both RFLP and LDR-FM assays, and results were compared. SNP prevalence (wild type/mixed/mutant) with RFLP analysis was 8/5/87% for pfcrt K76T, 34/37/29% for pfmdr1 N86Y, 64/17/19% for pfmdr1 Y184F, and 42/21/37% for pfmdr1 D1246Y. These prevalences with the LDR-FM assay were 7/5/88%, 31/24/45%, 62/20/18%, and 48/19/33% for the four SNPs, respectively. Combining mixed and mutant outcomes for analysis, agreement between the assays was 97% (K = 0.77) for pfcrt K76T, 79% (K = 0.55) for pfmdr1 N86Y, 83% (K = 0.65) for pfmdr1 Y184F, and 91% (K = 0.82) for pfmdr1 D1246Y, with most disagreements due to discrepant readings of mixed genotypes. The LDR-FM assay provides a high throughput, relatively inexpensive and accurate assay for the surveillance of P. falciparum SNPs associated with drug resistance in resource-limited countries.

Estimation of malaria haplotype and genotype frequencies: a statistical approach to overcome the challenge associated with multiclonal infections

Abstract: Reliable measures of anti-malarial resistance are crucial for malaria control. Resistance is typically a complex trait: multiple mutations in a single parasite (a haplotype or genotype) are necessary for elaboration of the resistant phenotype. The frequency of a genetic motif (proportion of parasite clones in the parasite population that carry a given allele, haplotype or genotype) is a useful measure of resistance. In areas of high endemicity, malaria patients generally harbour multiple parasite clones; they have multiplicities of infection (MOIs) greater than one. However, most standard experimental procedures only allow measurement of marker prevalence (proportion of patient blood samples that test positive for a given mutation or combination of mutations), not frequency. It is misleading to compare marker prevalence between sites that have different mean MOIs; frequencies are required instead. A Bayesian statistical model was developed to estimate Plasmodium falciparum genetic motif frequencies from prevalence data collected in the field. To assess model performance and computational speed, a detailed simulation study was implemented. Application of the model was tested using datasets from five sites in Uganda. The datasets included prevalence data on markers of resistance to sulphadoxine-pyrimethamine and an average MOI estimate for each study site. The simulation study revealed that the genetic motif frequencies that were estimated using the model were more accurate and precise than conventional estimates based on direct counting. Importantly, the model did not require measurements of the MOI in each patient; it used the average MOI in the patient population. Furthermore, if a dataset included partially genotyped patient blood samples, the model imputed the data that were missing. Using the model and the Ugandan data, genotype frequencies were estimated and four biologically relevant genotypes were identified. The model allows fast, accurate, reliable estimation of the frequency of genetic motifs associated with resistance to anti-malarials using prevalence data collected from malaria patients. The model does not require per-patient MOI measurements and can easily analyse data from five markers. The model will be a valuable tool for monitoring markers of anti-malarial drug resistance, including markers of resistance to artemisinin derivatives and partner drugs.

Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial.

Abstract: OBJECTIVE Trimethoprim-sulfamethoxazole prophylaxis is recommended for HIV-exposed infants until breastfeeding ends and HIV infection has been excluded. Extending prophylaxis with a focus on preventing malaria may be beneficial in high transmission areas. We investigated three regimens for the prevention of malaria in young HIV-exposed children. DESIGN An open-label, randomized controlled trial. SETTING Tororo, Uganda, a rural area with intense, year-round, malaria transmission. PARTICIPANTS Two hundred infants aged 4-5 months enrolled and 186 randomized after cessation of breastfeeding and confirmed to be HIV uninfected (median 10 months of age). INTERVENTION No chemoprevention, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole or monthly dihydroartemisinin-piperaquine given from randomization to 24 months of age. MAIN OUTCOME MEASURES The primary outcome was the incidence of malaria during the intervention period. Secondary outcomes included the incidence of hospitalization, diarrhoeal illness, or respiratory tract infection; prevalence of anaemia and asymptomatic parasitemia; measures of safety; and incidence of malaria over 1 year after the intervention was stopped. RESULTS During the intervention, the incidence of malaria in the no chemoprevention group was 6.28 episodes per person-year at risk. Protective efficacy was 69% [95% confidence interval (95% CI) 53-80, P < 0.001] for dihydroartemisinin-piperaquine, 49% (95% CI 23-66, P = 0.001) for trimethoprim-sulfamethoxazole and 9% for sulfadoxine-pyrimethamine (95% CI -35 to 38, P = 0.65). There were no significant differences in any secondary outcomes, with the exception of a lower prevalence of asymptomatic parasitemia in the dihydroartemisinin-piperaquine arm. CONCLUSION Monthly chemoprevention with dihydroartemisinin-piperaquine was well tolerated and associated with a significant reduction in malaria in young HIV-exposed children.

High CD56 ++ CD16 - natural killer (NK) cells among suboptimal immune responders after four years of suppressive antiretroviral therapy in an African adult HIV treatment cohort

Abstract: Up to 40% of HIV-infected individuals receiving Highly Active Antiretroviral Therapy (HAART) have poor CD4+ T-cell recovery. The role of natural killer (NK) cells in immune recovery during HAART is not well understood. We described the profiles of NK cell subsets and their expression of activating receptor, NKG2D and cytotoxicity receptor NKp46 among suboptimal immune responders to despite four years of suppressive HAART. A case control study utilized frozen peripheral blood mononuclear cells (PBMC) from a cohort of HIV-infected adults that initiated HAART in 2004/5, at CD4 < 200 cells/μl. Cases were ‘suboptimal’ responders; patients within the lowest quartile of CD4+ T-cell reconstitution, with a median CD4 count increase of 129 (-43-199) cells/μl (difference between CD4 count at baseline and after 4 years of HAART) and controls were ‘super-optimal’ responders; patients within the highest quartile of CD4 T-cell reconstitution with a median CD4 count increase of 528 (416-878) cells/μl). Expression of NK cell lineage markers (CD56+/-CD16+/-) and receptors NKG2D and NKp46, was measured among PBMC from 29 cases of ‘suboptimal’ responders’ and 23 controls of ‘super-optimal responders’, and compared among ‘suboptimal’ and ‘super-optimal’ responders. NK cell populations were compared using the Holm Sidak multiple comparison test and p values < 0.05 were considered statistically significant. Data was analyzed using FLOWJO and GraphPad Prism 6. ‘Suboptimal responders’ had a higher proportion of cytokine producing CD56++CD16+/- (CD56bri) NK cells than the ‘super-optimal responders’ p = 0.017, and CD56neg NK cells were lower among suboptimal than super-optimal responders (p = 0.007). The largest NK cell subset, CD56dim, was comparable among suboptimal responders and ‘super-optimal immune responders’. Expression of NKG2D and NKp46 receptors on NK cell subsets (CD56bri, CD56neg and CD56dim), was comparable among ‘suboptimal’ and ‘super-optimal’ immune responders. The pro-inflammatory CD56++CD16-- NK cells were higher among ‘suboptimal’ responders relative to ‘super-optimal’ responders, despite four years of suppressive HAART. Alteration of NK cell populations could inhibit host immune responses to infections among suboptimal responders. We recommend further analysis of NK cell function among suboptimal immune responders in order to inform targeted interventions to optimize immune recovery among HAART-treated adults.

Causes and outcome of hospitalization among HIV-infected adults receiving antiretroviral therapy in Mulago hospital Uganda.

Abstract: Background: Cohorts describing cause specific mortality in HIV-infected patients initiating antiretroviral therapy (ART) operate on an outpatient basis. Hospitalized patients represent the spectrum and burden of severe morbidity and mortality in patients on ART. Objective: To determine the causes and outcomes of hospitalization among adults receiving ART. Methods: A prospective cohort study. We enrolled 201 participants (50% female) with median (IQR) age and CD4 count of 34 (28-40) years and 91(29-211) cells/uL respectively. Results: The most frequent causes of hospitalization were tuberculosis (TB) (37, 18%), cryptococcal meningitis (22, 11%), zidovudine (AZT) - associated anemia (19, 10%), sepsis (10, 5%) and Kaposi’s sarcoma (10, 5%). Forty two patients (21%) died: 10 (24%) had TB, 8 (19%) had cryptococcal meningitis and 5 (12%) had sepsis, 9 (21%) had undiagnosed neurological syndromes while 10 (24%) had other illnesses. Predictors of death included low Karnofsky performance score of 34 years (OR, 7.65; CI 1.09- 53.8). Conclusions: Opportunistic infections, malignancy and AZT-associated anemia contributed to most hospitalizations and mortality. It is important to intensify prevention, screening, and treatment for these opportunistic diseases and early ART initiation in HIV-infected patients. Tenofovir-based regimens, unless contraindicated should be scaled up to replace AZTbased regimens as first line ART drugs. Africa Health Sciences 2013; 13(4): 977 - 985 http://dx.doi.org/10.4314/ahs.v13i4.17

Changes in population HIV RNA levels in Mbarara, Uganda, during scale-up of HIV antiretroviral therapy access.

Abstract: OBJECTIVE In a rural Ugandan community scaling up antiretroviral therapy (ART), we sought to determine if population-based HIV RNA levels [population viral load (VL)] decreased from 2011 to 2012. DESIGN Serial cross-sectional analyses (May 2011 and May 2012) of a defined study community of 6300 persons in a district with HIV prevalence of 8%. METHODS We measured HIV-1 RNA (VL) levels on all individuals testing positive for HIV during a 5-day high-throughput multidisease community health campaign in May 2012 that recruited two-thirds of the population. We aggregated individual-level VL results into population VL metrics including the proportion of individuals with an undetectable VL and compared these VL metrics to those we previously reported for this geographic region in 2011. RESULTS In 2012, 223 of 2179 adults were HIV-seropositive adults (10%). Overall, among 208 of 223 HIV-seropositive adults in whom VL was tested, 53% had an undetectable VL [95% confidence interval (CI): 46 to 60], up from 37% (95% CI: 30 to 45; P = 0.02) in 2011. Seven (3%) individuals had a VL of >100,000 copies/mL in 2012, down from 21 (13%) in 2011 (P = 0.0007). Mean log (VL) (geometric mean) was 3.18 log (95% CI: 3.06 to 3.29 log) in 2012, down from 3.62 log (95% CI: 3.46 to 3.78 log) in 2011 (P < 0.0001). Similar reductions in population VL were seen among men and women. CONCLUSIONS Reductions in population VL metrics and a substantial increase in the proportion of persons with an undetectable VL were observed in a rural Ugandan community from 2011 to 2012. These findings from a resource-limited setting experiencing rapid ART scale-up may reflect a population-level effectiveness of expanding ART access.

Artemisinin-Based Combination Therapies Are Efficacious and Safe for Treatment of Uncomplicated Malaria in HIV-Infected Ugandan Children

Abstract: The majority of malaria-endemic countries now recommend artemisinin-based combination therapies (ACTs) for the treatment for uncomplicated falciparum malaria [1]. In sub-Saharan Africa, ACTs selected as first-line regimens include artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ). Dihydroartemisinin-piperaquine (DP), another ACT, was recently added to the World Health Organization (WHO) list of recommended drugs for the treatment of uncomplicated falciparum malaria and has been adopted as a second-line regimen in some African countries [2]. Numerous studies continue to demonstrate excellent efficacy and safety of AL, AS-AQ, and DP in Africa [3–11]. Although there is compelling evidence to support the use of ACTs for malaria treatment in the general population, data evaluating their efficacy and safety in human immunodeficiency virus (HIV)–infected populations are limited. Some studies have shown equivalent antimalarial efficacy in HIV-infected and -uninfected persons [12–14], but others have reported lower efficacy in HIV-infected populations [15–17]. These studies were generally limited to adult populations that received non-ACT antimalarial treatment regimens that are no longer recommended, and did not account for the increasing use of daily trimethoprim-sulfamethoxazole prophylaxis or antiretroviral therapy (ART) among HIV-infected persons in Africa. Moreover, data evaluating the relative safety of ACTs in HIV-infected individuals are even more limited. There is emerging evidence of potential adverse and beneficial pharmacokinetic interactions between various ART regimens and ACTs [18–21]. Currently, WHO guidelines state that there is insufficient information to modify the general malaria treatment recommendations for HIV-infected patients, with the exception that those on zidovudine or efavirenz (EFV) should avoid AQ-containing regimens if possible [22]. The new WHO consolidated HIV treatment guidelines now recommend ART for all children <5 years of age [23]. Thus, it is critical to understand efficacy and safety of ACTs among HIV-infected children. We evaluated efficacy and safety data of ACTs from 2 longitudinal clinic trials in cohorts of children living in a highly malaria-endemic area of eastern Uganda. In one trial (PROMOTE), HIV-infected children were randomized to either nonnucleoside reverse transcriptase inhibitor (NNRTI)–based or protease inhibitor–based ART, and all episodes of uncomplicated malaria were treated with AL. In the other trial (Tororo Child Cohort [TCC]), HIV-infected children were started on nevirapine (NVP)–based ART if they were eligible and randomized to either AL or DP for the treatment of their first and all subsequent episodes of uncomplicated malaria.

Global medical education partnerships to expand specialty expertise: a case report on building neurology clinical and research capacity

Abstract: Neurological disorders are a common cause of morbidity and mortality in sub-Saharan African, but resources for their management are scarce. Collaborations between training institutions in developed and resource-limited countries can be a successful model for supporting specialty medical education and increasing clinical and research capacity. This report describes a US National Institutes of Health (NIH) funded Medical Education Partnership Initiative (MEPI) to enhance expertise in neurology, developed between Makerere University College of Health Sciences in Kampala, Uganda, and Case Western Reserve University School of Medicine in Cleveland, OH, USA. This collaborative model is based on a successful medical education and research model that has been developed over the past two decades. The Ugandan and US teams have accumulated knowledge and 'lessons learned' that facilitate specialty expertise in neurological conditions, which are widespread and associated with substantial disability in resource-limited countries. Strengths of the model include a focus on community health care settings and a strong research component. Key elements include strong local leadership; use of remote technology, templates to standardize performance; shared exchanges; mechanisms to optimize sustainability and of dissemination activities that expand impact of the original initiative. Efficient collaborations are further enhanced by external and institutional support, and can be sequentially refined. Models such as the Makerere University College of Health Sciences - Case Western Reserve University partnership may help other groups initiate collaborative education programmes and establish successful partnerships that may provide the opportunity to expand to other chronic diseases. A benefit of collaboration is that learning is two-directional, and interaction with other international medical education collaborators is likely to be of benefit to the larger global health community.