Showing papers by "Moses R. Kamya published in 2013"

The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data

Abstract: Background:Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy.Methods and Findings:A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan-Meier survival estimates were 97.7% (95% CI 97.3%-98.1%) at day 42 and 97.2% (95% CI 96.7%-97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3-2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%-96.2%], p<0.001). After adjusting for confounding factors, the mg/kg dose of piperaquine was found to be a significant predictor for recrudescence, the risk increasing by 13% (95% CI 5.0%-21%) for every 5 mg/kg decrease in dose; p = 0.002. In a multivariable model increasing the target minimum total dose of piperaquine in children aged 1 to 5 years old from 48 mg/kg to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of patients; such an increment was not associated with gastrointestinal toxicity in the ten studies in which this could be assessed.Conclusions:DP demonstrates excellent efficacy in a wide range of transmission settings; however, treatment failure is associated with a lower dose of piperaquine, particularly in young children, suggesting potential for further dose optimisation.Please see later in the article for the Editors' Summary.

Asymptomatic Plasmodium Infection and Cognition among Primary Schoolchildren in a High Malaria Transmission Setting in Uganda

Abstract: Asymptomatic parasitemia is common among schoolchildren living in areas of high malaria transmission, yet little is known about its effect on cognitive function in these settings. To investigate associations between asymptomatic parasitemia, anemia, and cognition among primary schoolchildren living in a high malaria transmission setting, we studied 740 children enrolled in a clinical trial in Tororo, Uganda. Parasitemia, measured by thick blood smears, was present in 30% of the children. Infected children had lower test scores for abstract reasoning (adjusted mean difference [AMD] -0.6, 95% confidence interval [CI] -1.01 to -0.21) and sustained attention (AMD -1.6 95% CI -2.40 to -0.81) compared with uninfected children. There was also evidence for a dose-response relationship between parasite density and scores for sustained attention. No associations were observed between anemia and either test of cognition. Schoolchildren in high transmission settings may experience cognitive benefits, from interventions aimed at reducing the prevalence of asymptomatic parasitemia.

A Qualitative Study of Barriers to Enrollment into Free HIV Care:Perspectives of Never-in-Care HIV-Positive Patients and Providers in Rakai, Uganda

Abstract: Background. Early entry into HIV care is low in Sub-Saharan Africa. In Rakai, about a third (31.5%) of HIV-positive clients who knew their serostatus did not enroll into free care services. This qualitative study explored barriers to entry into care from HIV-positive clients who had never enrolled in care and HIV care providers. Methods. We conducted 48 in-depth interviews among HIV-infected individuals aged 15–49 years, who had not entered care within six months of result receipt and referral for free care. Key-informant interviews were conducted with 12 providers. Interviews were audio-recorded and transcripts subjected to thematic content analysis based on the health belief model. Results. Barriers to using HIV care included fear of stigma and HIV disclosure, women's lack of support from male partners, demanding work schedules, and high transport costs. Programmatic barriers included fear of antiretroviral drug side effects, long waiting and travel times, and inadequate staff respect for patients. Denial of HIV status, belief in spiritual healing, and absence of AIDS symptoms were also barriers. Conclusion. Targeted interventions to combat stigma, strengthen couple counseling and health education programs, address gender inequalities, and implement patient-friendly and flexible clinic service hours are needed to address barriers to HIV care.

Fertility and contraceptive decision-making and support for HIV infected individuals: client and provider experiences and perceptions at two HIV clinics in Uganda

Abstract: Background Some people living with HIV/AIDS (PLHIV) want to have children while others want to prevent pregnancies; this calls for comprehensive services to address both needs. This study explored decisions to have or not to have children and contraceptive preferences among PLHIV at two clinics in Uganda.

The Effect of Indoor Residual Spraying on Malaria and Anemia in a High-Transmission Area of Northern Uganda

Abstract: Indoor residual spraying (IRS) with insecticide is now recommended for malaria control in high-transmission settings. However, concerns about insecticide resistance have increased. We conducted a cross-sectional household survey in high-transmission northern Uganda in two districts previously sprayed with pyrethroids before documentation of pyrethroid resistance and at least one round of carbamates and in one contiguous district that was not sprayed. Parasitemia prevalence among children < 5 years of age was lower in the two IRS districts compared with the non-sprayed district: 37.0% and 16.7% versus 49.8%, P < 0.001. Anemia prevalence was also significantly lower in the two IRS districts: 38.8% and 36.8% versus 53.0%, P < 0.001. Multivariable Poisson regression models indicated that a child living in a sprayed district had a 46% and 32% lower risk of parasitemia and anemia, respectively, than a child in a non-sprayed district (P < 0.001). Carefully managed IRS can significantly reduce malaria burden in high-transmission settings.

Hair and plasma data show that lopinavir, ritonavir, and efavirenz all transfer from mother to infant in utero, but only efavirenz transfers via breastfeeding.

Abstract: BACKGROUND: As efforts intensify to eliminate perinatal HIV transmission understanding kinetics of maternal-to-child transfer of antiretrovirals during pregnancy and breastfeeding is critical. Antiretroviral levels in plasma cord blood and breastmilk reflect exposure over short intervals. Hair concentrations reflect cumulative exposure and can uniquely quantify in utero transfer of maternal medications to infants. We measured plasma and hair antiretroviral levels in HIV-infected Ugandan mothers and their infants at delivery and during breastfeeding to assess transfer. METHODS: HIV-infected pregnant women were randomized to lopinavir/ritonavir- or efavirenz-based therapy in a larger trial (the Prevention of Malaria and HIV disease in Tororo PROMOTE). At 0 8 and 12 weeks postpartum plasma antiretroviral levels were measured in 117 mother-infant pairs; hair levels were assayed at 12 weeks. Ratios and correlations of infant:maternal concentrations were calculated. RESULTS: By 12 weeks 90.4% of mothers reported exclusive breastfeeding. Hair and plasma levels over time suggest moderate (47%) to extensive (87%) in utero transfer of lopinavir and ritonavir respectively but negligible transfer of either via breastfeeding. Moderate transfer of efavirenz occurs during pregnancy and breastfeeding (40% cumulative; 15% during breastfeeding). Despite differences in exposure no infant seroconversions or correlations between infant hair/plasma antiretroviral levels and adverse effects were observed. CONCLUSIONS: Using a unique approach combining hair and plasma data we found that different antiretrovirals have distinct kinetics of mother-to-infant transfer. Efavirenz transfers during both pregnancy and breastfeeding whereas lopinavir and ritonavir transfer only in utero. Further study of the degree and timing of maternal-to-child transfer by antiretroviral will help optimize strategies that protect infants and minimize toxicities during periods of risk.

Improved employment and education outcomes in households of HIV-infected adults with high CD4 cell counts: evidence from a community health campaign in Uganda.

Abstract: BACKGROUND: There is limited evidence on the association between socioeconomic outcomes and CD4 counts in populations that include HIV-infected adults who have high CD4 counts or have not been diagnosed. We examined this association among adults in a rural Ugandan parish. METHODS: A community health campaign offering diagnostic and treatment services for HIV and other diseases was conducted with Ministry of Health support. Data on campaign participants education and employment were collected and a detailed household socioeconomic survey was conducted among a subset of participants. Regression analyses were used to assess relationships between CD4 count and employment and education outcomes. RESULTS: A total of 2323 adults (74% of the community) participated in the campaign; 179 of 2282 (7.8%) tested HIV-positive and 46% were newly diagnosed. Among HIV-infected adults not on antiretroviral therapy (ART) those with CD4 at least 500 worked 6.9 more days/month (P < 0.01; 39% more) and 2.5 more h per day (P < 0.05 44% more) than those with CD4 less than 200. These effects were not significantly different from the effects for those with CD4 350-499. Children aged 6-11 years in households of adults with CD4 at least 350 did not have significantly different school enrollment rates than children in households of adults with CD4 less than 350 but differences were larger among children aged 12-18 years. CONCLUSION: Outcomes of HIV-infected adults with CD4 at least 350 were better than those of adults with CD4 less than 200 and resembled those of HIV-uninfected adults. The results suggest that early ART initiation may generate economic benefits by preventing a decline in socioeconomic status but further research is needed to determine the CD4 threshold at which these benefits would be largest.

Assessment of Population-Based HIV RNA Levels in a Rural East African Setting Using a Fingerprick-Based Blood Collection Method

Abstract: Efforts to stem the tide of the human immunodeficiency virus (HIV) epidemic are increasing, with acceleration of antiretroviral therapy (ART) scale-up [1] and implementation of combination prevention strategies [2, 3]. Epidemiologic measurements at a population or community level—both of the burden of HIV and of the effectiveness of HIV treatment strategies—are critical to guiding and monitoring national and local treatment and prevention strategies. Population-level HIV type 1 (HIV-1) RNA levels (viral load [VL]) have been described among individuals in a geographic area or within specific demographic groups [4–7]. Population HIV RNA measurements have the potential to provide insight into the effectiveness of ART programs because increased ART penetration and treatment success are associated with lower average VLs and with a higher proportion of patients with an undetectable VL [4–6]. Because higher VL is correlated with greater infectivity [8, 9], and since ART-mediated virologic suppression has been shown to reduce the spread of HIV [10], population RNA levels may also provide insight into the risk of forward transmission of HIV, acknowledging its known limitations. To date, reports assessing population HIV RNA levels have been conducted only in urban settings in the developed world such as Vancouver, San Francisco, and Washington, D.C. [4–6]. Population-level VLs have not yet been measured in sub-Saharan Africa, where >23 million persons live with HIV [1]. Several key barriers have precluded population HIV RNA estimation in resource-limited settings. The high cost of measuring HIV RNA levels is a major impediment to availability. Apart from South Africa and Botswana [11, 12], VL testing is thus not used in routine clinical care. Therefore, centralized data collection systems (eg, clinic databases) that could be used to estimate population RNA levels lack necessary data on VLs. Compounding the problem are estimates that up to one-half of HIV-infected individuals are unaware of their serostatus [1], and many diagnosed individuals have not successfully linked to HIV care and ART. Additionally, in rural settings, laboratory facilities are often far from clinics, making blood collection and cold-chain specimen transport highly challenging. We sought to address the above challenges and estimate population-level HIV RNA levels in a rural community in southwestern Uganda by measuring VL using a fingerprick blood collection method during a 5-day community-wide health campaign offering diagnostic, prevention, and treatment services for communicable and noncommunicable diseases [13]. This approach may hold potential for assessing the rapid ongoing ART scale-up in resource-limited settings that do not offer VL testing during HIV care.

High Retention in Care Among HIV-Infected Patients Entering Care With CD4 Levels >350 Cells/μL Under Routine Program Conditions in Uganda

Abstract: Although the public health response to the human immunodeficiency virus (HIV) epidemic in Africa initially focused on starting emergency antiretroviral therapy (ART) for patients with overt immunosuppression, attention is now turning toward sustaining treatment benefits over time and preventing new infections. Retaining patients who enter care with CD4 levels above the treatment threshold of 350 cells/µL—many of whom are without overt symptoms—is critical to achieving these long-term goals. Care continuity in this population allows prompt ART initiation when the CD4 levels do reach 350 cells/µL, thus applying ART services to maintain rather than restore health—a less costly and less complex task [1]. Furthermore, ART initiation at CD4 thresholds >350 cells/µL—recently recommended for resource-limited settings by the World Health Organization—can mitigate long-term renal, liver, and cardiovascular disease and therefore long-term benefits of therapy [2–4]. In addition, recent trials show that treatment for persons with CD4 levels up to 550 cells/µL can dramatically reduce HIV transmission to stable seronegative partners [5]. Expanding treatment will only yield improved public health outcomes if patients who are healthy will remain in care. Using ART as prevention also depends on retaining persons with high CD4 levels in care. At present, retention in care among patients who enroll with CD4 counts above the 350 cells/µL treatment threshold in Africa is thought to be poor. In Malawi, a report found that >90% of patients with World Health Organization stage I or II disease were not in care 1 year later [6]. In an Ethiopian hospital-based care center, the rate of loss to follow-up was 1.9-fold higher among patients with stage I or II disease compared to those with a stage III or IV condition [7]. In KwaZulu Natal, a study using a repeat CD4 test as a sign of retention found that only 45% of patients without indications for ART returned for a 1-year monitoring CD4 count [8], and a study in Cape Town found the same figure to be 46% [9]. A systematic review summarizing these findings suggested that overall, 55% of patients who enroll with CD4 levels above treatment thresholds remain in care until ART eligibility and initiation [10]. These figures, at first glance, suggest that practices such as timely ART initiation following eligibility, reducing long-term morbidity and mortality with treatment at higher CD4 treatment thresholds, and “treatment as prevention” are unlikely to yield population-level health benefits in the real world. To further characterize retention and outcomes in patient populations who enter care with CD4 levels above the treatment threshold at the time of the study (ie, 350 cells/µL), we studied 2 prototypical scale-up HIV/AIDS care clinics, 1 rural and 1 urban, in Uganda. Whereas existing studies considered all patients who were lost to follow-up (LTFU) as no longer retained in care, we hypothesized that many of these patients would be healthy and working, and therefore may have relocated for work, marriage, or other reasons and continued to access care at other sites (ie, as “silent transfers”). At the same time, mortality among those lost is also likely to be hidden by losses to follow-up. To assess retention in care and mortality, we used a sampling-based approach to reassign outcomes among those LTFU through seeking updated vital status and healthcare utilization information in a numerically small but random sample of lost patients [11–13]. By using the outcomes in the sample to reclassify outcomes in all patients LTFU and therefore “fill in the blanks,” we sought to obtain a more complete understanding of retention in care for HIV-infected patients who enter care with CD4 levels above treatment thresholds in Africa.

The PROCESS study: a protocol to evaluate the implementation, mechanisms of effect and context of an intervention to enhance public health centres in Tororo, Uganda

Abstract: Background: Despite significant investments into health improvement programmes in Uganda, health indicators and access to healthcare remain poor across the country. The PRIME trial aims to evaluate the impact of a complex intervention delivered in public health centres on health outcomes of children and management of malaria in rural Uganda. The intervention consists of four components: Health Centre Management; Fever Case Management; Patient- Centered Services; and support for supplies of malaria diagnostics and antimalarial drugs. Methods: The PROCESS study will use mixed methods to evaluate the processes, mechanisms of change, and context of the PRIME intervention by addressing five objectives. First, to develop a comprehensive logic model of the intervention, articulating the project’s hypothesised pathways to trial outcomes. Second, to evaluate the implementation of the intervention, including health worker training, health centre management tools, and the supply of artemether-lumefantrine (AL) and rapid diagnostic tests (RDTs) for malaria. Third, to understand mechanisms of change of the intervention components, including testing hypotheses and interpreting realities of the intervention, including resistance, in context. Fourth, to develop a contextual record over time of factors that may have affected implementation of the intervention, mechanisms of change, and trial outcomes, including factors at population, health centre and district levels. Fifth, to capture broader expected and unexpected impacts of the intervention and trial activities among community members, health centre workers, and private providers. Methods will include intervention logic mapping, questionnaires, recorded consultations, in-depth interviews, focus group discussions, and contextual data documentation. Discussion: The findings of this PROCESS study will be interpreted alongside the PRIME trial results. This will enable a greater ability to generalise the findings of the main trial. The investigators will attempt to assess which methods are most informative in such evaluations of complex interventions in low-resource settings. Trial registration: Clinicaltrials.gov, NCT01024426

Anti-malarial prescription practices among outpatients with laboratory-confirmed malaria in the setting of a health facility-based sentinel site surveillance system in Uganda.

Abstract: Background: Most African countries have adopted artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. The World Health Organization now recommends limiting anti-malarial treatment to those with a positive malaria test result. Limited data exist on how these policies have affected ACT prescription practices. Methods: Data were collected from all outpatients presenting to six public health facilities in Uganda as part of a sentinel site malaria surveillance programme. Training in case management, encouragement of laboratory-based diagnosis of malaria, and regular feedback were provided. Data for this report include patients with laboratory confirmed malaria who were prescribed anti-malarial therapy over a two-year period. Patient visits were analysed in two groups: those considered ACT candidates (defined as uncomplicated malaria with no referral for admission in patients ≥4 months of age and ≥5 kg in weight) and those who may not have been ACT candidates. Associations between variables of interest and failure to prescribe ACT to patients who were ACT candidates were estimated using multivariable logistic regression. Results: A total of 51,355 patient visits were included in the analysis and 46,265 (90.1%) were classified as ACT candidates. In the ACT candidate group, 94.5% were correctly prescribed ACT. Artemether-lumefantrine made up 97.3% of ACT prescribed. There were significant differences across the sites in the proportion of patients for whom there was a failure to prescribe ACT, ranging from 3.0-9.3%. Young children and woman of childbearing age had higher odds of failure to receive an ACT prescription. Among patients who may not have been ACT candidates, the proportion prescribed quinine versus ACT differed based on if the patient had severe malaria or was referred for admission (93.4% vs 6.5%) or was below age or weight cutoffs for ACT (41.4% vs 57.2%).

Impaired T-cell proliferation among HAART-treated adults with suboptimal CD4 recovery in an African cohort

Abstract: Background: Most HIV-infected subjects exhibit a progressive rise in CD4 T-cell counts after initiation of highly active antiretroviral therapy (HAART). However, a subset of individuals exhibit very poor CD4 T-cell recovery despite effective control of HIV-RNA viraemia. We evaluated CD4 T-cell proliferation among suboptimal responders and its correlation with CD4 T-cell activation. Methods: The magnitude of CD4 increase (difference between absolute CD4 counts at baseline and absolute CD4 counts at 4 years of ART) was grouped into 4 quartiles for the 211 patients with sustained HIV-RNA viral suppression. Cases of ‘Suboptimal immune responders’ included patients within the lowest quartile [Median CD4 increase 165 (Range −43-298) cells/μl; n=52] and a comparison group of ‘Optimal immune responders’ was defined as patients within the highest quartile of CD4 increase [Median CD4 increase 528 (Range 417–878) cells/μl; n=52]. Frozen PBMC were thawed and analysed from a convenient sample of 39 suboptimal responders and 48 optimal responders after 4 years of suppressive antiretroviral therapy. T-cell activation was measured by proportions of T-cells expressing surface marker CD38 and HLADR (CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ cells). T-cell proliferation was determined by the extent of carboxyfluorescein diacetate succinimidyl ester (CFSE) dye dilution on culture day 5 of PBMCs in the presence of antigen (SEB, PPD, CMVpp65, GagA and GagD). Samples were analyzed on a FACS Calibur flow cytometer and flow data was analyzed using FlowJo and GraphPad. Results: Overall, CD4 T-cell proliferation on stimulation with SEB, PPD, CMVpp65, Gag A and Gag D.antigens, was lower among suboptimal than optimal responders; this was significant for SEB (CD4+ p=0.003; CD8+ p=0.048) and PPD antigens (CD8+ p=0.038). Among suboptimal responders, T-cell proliferation decreased with increasing immune activation (Negative correlation; slope = −0.13±−0.11) but not among optimal responders. Conclusion: T-cell immune activation and exhaustion were associated with poor proliferation among suboptimal responders to HAART despite sustained viral suppression. We recommend studies to further understand the mechanisms leading to impaired T-cell function among suboptimal responders as well as the potential role of immune modulation in optimizing CD4 count and functional recovery after HAART.

The PRIME trial protocol: Evaluating the impact of an intervention implemented in public health centres on management of malaria and health outcomes of children using a cluster-randomised design in Tororo Uganda.

Abstract: Background: In Africa, inadequate health services contribute to the lack of progress on malaria control. Evidence of the impact of interventions to improve health services on population-level malaria indicators is needed. We are conducting a cluster-randomised trial to assess whether a complex intervention delivered at public health centres in Uganda improves health outcomes of children and treatment of malaria, as compared to the current standard of care. Methods/Design: Twenty public health centres (level II and III) in Tororo district will be included; 10 will be randomly assigned to the intervention and 10 to control. Clusters will include households located within 2 km of health centres. The trial statistician will generate the random allocation sequence and assign clusters. Health centres will be stratified by level, and restricted randomisation will be employed to ensure balance on cluster location and size. Allocation will not be blinded. The intervention includes training in health centre management, fever case management with use of rapid diagnostic tests (RDTs) for malaria, and patient-centered services, and provision of artemether-lumefantrine (AL) and RDTs when stocks run low. The impact of the intervention on population-level health indicators will be assessed through community surveys conducted at baseline in randomly selected children from each cluster, and repeated annually for two years. The impact on individuals over time will be assessed in a cohort study of children recruited from households randomly selected per cluster. The impact on health centres will be assessed using patient exit interviews, monthly surveillance, and assessment of health worker knowledge and skills. The primary outcome is the prevalence of anaemia (haemoglobin <11.0 g/dL) in individual children under five measured in the annual community surveys. The primary analysis will be based on the cluster-level results. Discussion: The PRIME trial findings will be supplemented by the PROCESS study, an evaluation of the process, context, and wider impact of the PRIME intervention which will be conducted alongside the main trial, together providing evidence of the health impact of a public sector intervention in Uganda. Trial registration and funding: This trial is registered at Clinicaltrials.gov (NCT01024426) and is supported by the ACT Consortium.

The effects of ACT treatment and TS prophylaxis on Plasmodium falciparum gametocytemia in a cohort of young Ugandan children.

Abstract: Artemisinin-based combination therapies (ACTs) and trimethoprim-sulfamethoxazole (TS) prophylaxis are important tools for malaria control, but there are concerns about their effect on gametocytes, the stage of the parasite responsible for transmission. We conducted a longitudinal clinical trial in a cohort of HIV-infected and uninfected children living in an area of high malaria transmission intensity in Uganda. Study participants were randomized to artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) for all treatments of uncomplicated malaria (N = 4,380) as well as TS prophylaxis for different durations. The risks of gametocytemia detected by microscopy in the 28 days after antimalarial therapy were compared using multivariate analyses. The risk of gametocyte detection was significantly higher in patients treated with DP compared with AL (adjusted relative risk = 1.85, P < 0.001) and among children prescribed TS prophylaxis (adjusted relative risk = 1.76, P < 0.001). The risk of gametocytemia and its potential for increasing transmission should be considered when evaluating different ACTs and TS prophylaxis for malaria control.

Primary prophylaxis for cryptococcal meningitis and impact on mortality in HIV: a systematic review and meta-analysis.

Abstract: Aim: To determine the role of primary antifungal prophylaxis in the prevention of cryptococcal meningitis and all-cause mortality in advanced HIV infection. Materials & methods: This was a systematic review and meta-analysis of randomized trials and observational studies. Google Scholar™, PubMed and Embase databases were searched for relevant studies. Quality was assessed using different criteria, depending on study type. Publication bias was assessed and subgroup and sensitivity analyses were performed. When the results of the meta-analysis were homogeneous, the fixed-effects model was used; when the results of the meta-analysis were heterogenous, the random effects model was used. Results: Primary prophylaxis prevented cryptococcal meningitis but did not confer protection against overall mortality, although there was evidence of a reduction in cryptococcal-specific mortality in resource-limited settings. Conclusion: Primary antifungal prophylaxis should be recommended in patients with advanced HIV infec...

Among patients with sustained viral suppression in a resource-limited setting, CD4 gains are continuous although gender-based differences occur.

Abstract: INTRODUCTION There is conflicting data on long-term CD4 immune recovery after combination antiretroviral therapy (ART) in resource-limited settings. Virologic suppression is rarely documented in cohorts from sub-Saharan Africa so objective evidence of adherence is biologically unsubstantiated. We sought to investigate long-term patterns of immune recovery in Ugandan patients on ART with sustained viral suppression. METHODS A prospective cohort of patients starting ART between April, 2004 and April, 2005 at the Infectious Diseases Institute with sustained viral suppression (viral load ≤ 400 copies/ml at month 6 and 12) while on first-line ART. Propensity scores were used to adjust for treatment allocation (nevirapine or efavirenz) at ART initiation. Data were analyzed using Kaplan Meier methods and cross-sectional time series regression. RESULTS Three hundred and fifty-six patients were included in the analysis.71.6% were female, 87% in WHO stage 3 or 4, median age was 37 years, (IQR:32-43), and median CD4 count was 108 cells/µL, (IQR:35-174) at ART start. At multivariable analysis, lower immune recovery (measured by change in CD4 from ART start at each time interval) was associated with male-gender (-59, 95% CI: 90, -28, P 200 (-64, 95% CI: 101, -26, P=0.001), and use of AZT at baseline (-47, 95% CI: -74, -20, P=0.001). Median time to reach >400 cells/µL was longer in males (197.4 weeks, IQR:119.9-312.0), compared to females (144.7 weeks, IQR:96.6-219.7, P 400 cells/µL over 7 years was higher in females compared to males (P 400 cells/µL. The biologic mechanisms of these gender differences need further exploration.

Prevalence of asymptomatic parasitemia and gametocytemia among HIV-infected Ugandan children randomized to receive different antiretroviral therapies.

Abstract: In a recent randomized controlled trial, the use of protease inhibitor (PI)-based antiretroviral therapy (ART) was associated with a significantly lower incidence of malaria compared with non-nucleoside reverse transcriptase inhibitor-based ART in a cohort of human immunodeficiency virus-infected Ugandan children living in an area of high malaria transmission intensity. In this report, we compared the prevalence of asymptomatic parasitemia and gametocytemia using data from the same cohort. The prevalence of asymptomatic parasitemia did not differ between the two ART treatment arms. The PI-based arm was associated with a lower risk of gametocytemia at the time of diagnosis of malaria (6.6% versus 14.5%, P = 0.03) and during the 28 days after malaria diagnosis (3.4% versus 6.5%, P = 0.04). Thus, in addition to decreasing the incidence of malaria, the use of PI-based ART may lower transmission, as a result of a decrease in gametocytemia, in areas of high malaria transmission intensity.

Study protocol for a randomised controlled double-blinded trial of the dose-dependent efficacy and safety of primaquine for clearance of gametocytes in children with uncomplicated falciparum malaria in Uganda

Abstract: Objectives For the purpose of blocking transmission of Plasmodium falciparum malaria from humans to mosquitoes, a single dose of primaquine is recommended by the WHO as an addition to artemisinin combination therapy. Primaquine clears gametocytes but causes dose-dependent haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Evidence is needed to inform the optimal dosing of primaquine for malaria elimination programmes and for the purpose of interrupting the spread of artemisinin-resistant malaria. This study investigates the efficacy and safety of reducing doses of primaquine for clearance of gametocytes in participants with normal G6PD status. Methods and analysis In this prospective, four-armed randomised placebo-controlled double-blinded trial, children aged 1–10 years, weighing over 10 kg, with haemoglobin ≥8 g/dl and uncomplicated P falciparum malaria are treated with artemether lumefantrine and randomised to receive a dose of primaquine (0.1, 0.4 or 0.75 mg base/kg) or placebo on the third day of treatment. Participants are followed up for 28 days. Gametocytaemia is measured by quantitative nucleic acid sequence-based analysis on days 0, 2, 3, 7, 10 and 14 with a primary endpoint of the number of days to gametocyte clearance in each treatment arm and secondarily the area under the curve of gametocyte density over time. Analysis is for non-inferiority of efficacy compared to the reference dose, 0.75 mg base/kg. Safety is assessed by pair-wise comparisons of the arithmetic mean (±SD) change in haemoglobin concentration per treatment arm and analysed for superiority to placebo and incidence of adverse events. Ethics and dissemination Approval was obtained from the ethical committees of Makerere University School of Medicine, the Ugandan National Council of Science and Technology and the London School of Hygiene and Tropical Medicine. Results These will be disseminated to inform malaria elimination policy, through peer-reviewed publication and academic presentations.

Neonatal Mortality in HIV-Exposed Infants Born to Women Receiving Combination Antiretroviral Therapy in Rural Uganda

Abstract: As human immunodeficiency virus (HIV)-infected women gain access to combination antiretroviral therapy throughout sub-Saharan Africa, a growing number of infants are being born HIV-exposed but uninfected. Data about neonatal mortality and the impact of premature delivery, in this population are limited. We describe the 28-day mortality outcomes in a cohort of HIV-exposed infants who had ultrasound-confirmed gestational age in rural Uganda. There were 13 deaths among 351 infants, including 9 deaths in the perinatal period. Premature delivery was a strong predictor of mortality. The prevention of HIV transmission to infants is now possible in rural low-resource settings but the frequency of neonatal death among HIV-exposed infants remains extremely high, calling for new comprehensive interventions to reduce mortality in this growing population.

The effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin piperaquine: a pooled analysis of individual patient data - Supplementary Information 5

Abstract: Ric Price and colleagues pool individual patient data from efficacy trials of dihydroartemisinin-piperaquine shared with WWARN (Worldwide Antimalarial Resistance Network) to examine the potential for underdosing in young children. Please see later in the article for the Editors' Summary

Changes in the Timing of Antiretroviral Therapy Initiation in HIV-Infected Patients With Tuberculosis in Uganda: A Study of the Diffusion of Evidence Into Practice in the Global Response to HIV/AIDS

Abstract: Background We aimed to determine the extent to which emerging evidence and changing guidelines regarding timing of antiretroviral therapy (ART) among human immunodeficiency virus (HIV)–infected patients with tuberculosis influenced “real-world” clinical practice in Uganda Methods We evaluated ART-naive, HIV-infected adults starting tuberculosis therapy at 2 HIV clinics in Uganda between 26 August 2006 and 29 September 2012 We used multivariate regression to calculate associations between 4 calendar periods reflecting publication of seminal clinical studies or changes in guidelines and timing of ART after tuberculosis therapy initiation Results For patients with CD4 counts 50 cells/µL starting ART within 60 days increased from 16% to 28% After adjustment for sociodemographic factors, when comparing the most recent with the earliest calendar period, the rate of ART initiation increased by 457-fold (95% confidence interval [CI], 176-fold to 1186-fold) among patients with baseline CD4 counts ≤50 cells/µL and by 543-fold (95% CI, 316- fold to 931-fold) among those with baseline CD4 counts >50 cells/µL Conclusions We observed large changes in clinical practice during a period of emerging data and changing guidelines among HIV-infected patients with tuberculosis Nonetheless, a significant proportion of individuals with higher CD4 cell counts do not start ART within recommended time frames Targeted dissemination and implementation efforts are still needed to achieve target levels in practice

WHO Option B+: Early Experience of Antiretroviral Therapy Sequencing after Cessation of Breastfeeding and Risk of Dermatologic Toxicity

Abstract: To the Editors: The WHO recently updated guidelines for the use of antiretroviral therapy among pregnant women, including “Option B+” – the initiation of combination antiretroviral therapy (cART) during pregnancy and continued for life 1 regardless of CD4+ cell count Numerous countries have begun implementing Option B+ and scaling-up lifelong cART initiated during pregnancy Option B+ includes either lopinavir/ritonavir (LPV/r), abacavir, or efavirenz (EFV)-based cART initiated after the first trimester of pregnancy for women with CD4+ cell counts above 350 cells/mm3 versus nevirapine (NVP) or EFV-based cART for women with CD4+ cell counts 350 cells/mm3 or lower Option B+ is cost-effective for Uganda 2 and benefits include near elimination of perinatal and breastfeeding HIV transmission, promotion of women’s health, and markedly diminished risk of sexual HIV transmission As Option B+ is implemented, clinicians will face challenging management issues, particularly in resource constrained settings when women starting Option B+ regimens have indications for a change in antiretroviral therapy due to reasons such as desire for additional pregnancies, contraceptive choice, in-country availability or cost Moreover, women will be starting, and potentially changing, combination antiretroviral therapy at higher CD4+ cell counts raising questions regarding the safety of switching to NVP-based regimens We provide early data on HIV-infected pregnant women treated with combination antiretroviral therapy at all CD4+ cell counts who were switched to a NVP-based regimen at the cessation of breastfeeding We performed a secondary analysis of PROMOTE-Pregnant Women and Infant Study ({"type":"clinical-trial","attrs":{"text":"NCT00993031","term_id":"NCT00993031"}}NCT00993031), an open-label randomized controlled trial of HIV-infected pregnant women comparing efficacy of LPV/r versus EFV in preventing placental malaria in Tororo, Uganda Women at all CD4+ cell counts are enrolled at 12-28 weeks gestation and receive LPV/r or EFV-based cART from enrollment until 1 year postpartum At 1 year postpartum, women are given the opportunity to continue non-study cART, and care is transitioned to a community-based HIV clinic Women’s non-study regimens are chosen based on their reproductive intentions, contraceptive choice and available in-country regimens Between March 7, 2011 and April 3, 2012, women receiving LPV/r were switched to NVP at the end of trial participation if they were transitioning to a local clinic without LPV availability Women on EFV who desired future childbearing or were not using long-acting or permanent contraception were switched to NVP The day after study medication discontinuation, women on LPV/r received 2 weeks of once-daily NVP followed by twice daily NVP, while women on EFV switched to twice daily NVP 3-5 All women on NVP returned to the study clinic for a 2 week follow-up visit Community-based clinics in close proximity to the study provided follow-up for women after trial participation Adverse events were assessed at all unscheduled and scheduled visits and graded using Division of AIDS standardized Toxicity Table for Grading Severity of Adult and Pediatric Adverse Events, Version 10 We calculated the incidence of dermatologic adverse events among women transitioned to NVP Between March 7, 2011 and April 3, 2012, when the NVP transition plan was in place, 121 participants reached 1 year postpartum Of these 121 women, 79 were switched to a NVP-based regimen, including 42 women on LPV/r and 37 women on EFV Forty-two women remained on the same regimen, including 20 women on LPV and 22 women on EFV Among the 79 women in the NVP switch cohort, the median nadir CD4 + cell count was 272 cells/mm3 (interquartile range [IQR] 195-362) and nadir CD4 + cell count was > 250 cells/mm3 and > 350 cells/mm3 among 595% and 279%, respectively The median pre-treatment CD4 cell count was 318 cells/mm3 (IQR 246-441, range 55-1342) There were 5 cases (63%, 95% confidence interval [CI] 27-140) of dermatologic toxicity, all attributed to NVP (Table 1) Among women with a CD4+ nadir of >250 cells/mm3, the incidence of any dermatologic toxicity was 106% (95% CI 16-196) and incidence of grade 3 dermatologic toxicity was 21% (95% CI 0-63) Three cases occurred in women switched from EFV and two cases occurred among women switched from LPV/r The nadir CD4 + cell count was >250 cells/mm3 in all five cases and >350 cells/mm3 in three cases All reactions were noted within 8 weeks of switching to NVP, and 3 women (38%; 95% CI 13-106) required discontinuation of NVP There was 1 case (13%; 95% CI 02-68) of a grade 3 rash requiring hospitalization at day 48 following switching from LPV/r All women experienced resolution of their rash All women had normal alanine aminotransferase values prior to NVP switch, but follow-up studies at the time of the rash were not obtained Table 1 Dermatologic toxicity attributed to nevirapine Among women in our cohort switched to NVP with a CD4+ cell count nadir >250 cells/mm3, the incidence of any rash (106%) and grade 3 rash (21%) is similar to what has been described in NVP trials among ART-naive and NVP switch trials among ART-experienced adults Aaron et al reported a 93% risk of grade 2 or worse rash associated with initiation of NVP among 54 non-pregnant women in the US 6 There was 1 case (19%) of Stevens-Johnson Syndrome The nevirapine package insert reports a 2% incidence of grade 3 or 4 rash within the first 6 weeks of therapy 7 The manufacturer also reports a 5-7% incidence of moderate or severe rash associated with NVP in controlled trials Among 6 randomized controlled trials evaluating switching from suppressive PI to NVP-based cART, the cumulative incidence of rash requiring NVP discontinuation was 42% 8-14 The mean CD4+ cell count at time of switch to NVP was 501-650 cells/mm3 for these 6 studies, but there is no information on baseline CD4+ cell count prior to cART initiation Data suggest that while initiating NVP among ART-naive individuals at high CD4 + cell counts is associated with increased risk of dermatologic and hepatic toxicity, switching to NVP at high CD4+ cell counts is not associated with an increased risk of such adverse events 15,16 Our report extends the understanding of NVP rash by including women with a full range of pretreatment CD4 + cell counts In conclusion, women who transition from LPV/r or EFV during pregnancy to NVP after cessation of breastfeeding may experience serious dermatologic toxicity The severity and frequency of rashes attributed to NVP in this setting are in the range of what has been reported previously This remains the case when only evaluating women in our cohort with CD4+ cell count nadir > 250 Nonetheless, given the potential serious nature of dermatologic toxicity, particularly in resource-limited settings, the risks of switching to nevirapine purely for cost or to reduce the theoretical risks of teratogenicity from EFV need to be carefully weighed against the risk of toxicity requiring diligent monitoring Settings that choose to switch women to NVP following cessation of breastfeeding should establish systems to closely monitor these women for adverse events

Malaria Trends in Six Outpatient Sites in Uganda, 2008 - 2011

Abstract: With the intensification of malaria efforts in Uganda, accurate and timely data are needed to monitor impact and guide control program planning. We present trends in malaria burden from six health facilities; Aduku (community received IRS), Nagongera and Kamwezi (ITNs distributed), Walukuba, Kasambya and Kihihi (no major intervention). Between 2008 and 2011, the proportion of the <5 testing positive for malaria significantly decreased in Aduku (66% to 34%), Nagongera (61% to 41%), and Kamwezi (54% to 24%). Significant increases were seen in Kasambya (41% to 51%) and Kihihi (28% to 44%), while TPR remained stable at Walukuba (41% to 45%).