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Background: Understanding COVID-19's impact on children is vital for public health policy, yet age-specific data is scarce, especially in Uganda. This study examines SARS-CoV-2 seroprevalence and risk factors among Ugandan children at two timepoints, along with COVID-19-related knowledge and practices in households, including adult vaccination status., Methods: Baseline surveys were conducted in 12 communities from April to May 2021 (post-Alpha wave) and follow-up surveys in 32 communities from November 2021 to March 2022 (Omicron wave). Household questionnaires and blood samples were collected to test for malaria by microscopy and for SARS-CoV-2 using a Luminex assay. Seroprevalence was estimated at both the survey and community level. Mixed-effects logistic regression models assessed the association between individual and household factors and SARS-CoV-2 seropositivity in children, adjusting for household clustering., Results: More households reported disruptions in daily life at baseline compared to follow-up, though economic impacts lingered. By the follow-up survey, 52.7% of adults had received at least one COVID-19 vaccine dose. Overall seroprevalence in children was higher at follow-up compared to baseline (71.6% versus 19.2%, p < 0.001). Seroprevalence in children ranged across communities from 6-37% at baseline and 50-90% at follow-up. At baseline, children from the poorest households were more likely to be infected. Increasing age remained the only consistent risk factor for SARS-CoV-2 seroconversion at both timepoints., Conclusions: Results indicate that a larger number of children were infected during the Delta and Omicron waves of COVID-19 compared to the Alpha wave. This study is the largest seroprevalence survey in children in Uganda, providing evidence that most children were infected with SARS-CoV-2 before the vaccine was widely available to pediatric populations. Pediatric infections were vastly underreported by case counts, highlighting the importance of seroprevalence surveys in assessing disease burden when testing and reporting rates are limited and many cases are mild or asymptomatic., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bagala et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Adolescents with HIV (AWH) face the double burden of dealing with challenges presented by their developmental phase while coping with stigma related to HIV, affecting their mental health. Poor mental health complicates adherence to daily treatment regimens, requiring innovative psychosocial support strategies for use with adolescents. We assessed the effectiveness of a mindfulness and acceptance-based intervention on the mental health of AWH in Uganda. One hundred and twenty-two AWH, mean age 17 ±1.59 (range 15 to 19 years), 57% female, receiving care at a public health facility in Kampala were enrolled in an open-label randomized trial (ClinicalTrials.gov: NCT05010317) with assessments at pre-and post-intervention. The mindfulness and acceptance-based intervention involved weekly 90-minute group sessions for four consecutive weeks facilitated by two experienced trainers. Sessions involved clarifying values, skillfully relating to thoughts, allowing and becoming aware of experiences non-judgmentally, and exploring life through trial and error. The control group received the current standard of care. Three mental health domains (depression, anxiety, and internalized stigma) were compared between the intervention and control groups. A linear mixed effects regression was used to analyze the effect of the intervention across the two time points. Results showed that the intervention was associated with a statistically significant reduction in symptoms of depression (β = -10.72, 95%CI: 6.25, -15.20; p < .0001), anxiety (β = -7.55, 95%CI: 2.66, -12.43; p = .0003) and stigma (β = -1.40, 95%CI: 0.66 to -2.15; p = .0004) over time. Results suggest that mindfulness and acceptance-based interventions have the potential to improve the mental health of AWH., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Antiretroviral therapy (ART) assures major gains in health outcomes among people living with HIV, however, this benefit may not be realized by all due to care interruptions. Mobile populations comprise a subgroup that is likely to have sub-optimal care engagement, resulting in discontinuation of ART. We sought to evaluate the barriers to care engagement among highly mobile individuals living with HIV and explore options aimed at improving engagement in care for this group., Methods: Qualitative in-depth interviews were conducted in 2020 among a purposive sample of twelve persons living with HIV and eight health care providers in western Kenya, within a mixed methods study of mobility in communities participating in the SEARCH trial (NCT01864603). We explored the barriers to care engagement among mobile individuals living with HIV and explored different options aimed at enhancing care engagement. These included options such as a coded card containing treatment details, alternative drug packaging to conceal drug identity, longer refills to cover travel period, wrist bands with data storage capability to enable data transfer and "warm handoff" by providers to new clinics upon transfer. Data were inductively analyzed to understand the barriers and acceptability of potential interventions to address them., Results: Stigma and lack of disclosure, rigid work schedules, and unpredictability of travel were major barriers to care engagement for highly mobile individuals living with HIV. Additionally, lack of flexibility in clinic schedules and poor provider attitude were identified as health-system-associated barriers to care engagement. Options that enhance flexibility, convenience and access to care were viewed as the most effective means of addressing the barriers to care by both patients and providers. The most preferred option was a coded card with treatment details followed by alternative drug packaging to conceal drug identity due to stigma and longer refills to cover travel periods., Conclusion: Highly mobile individuals living with HIV desire responsive, flexible, convenient and patient-centered care delivery models to enhance care engagement. They embraced simple health delivery improvements such as coded cards, alternative drug packaging and longer refills to address challenges of mobility., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ayieko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: In Uganda, COVID-19 lockdown policies curbed the spread of SARS-CoV-2, but their effect on HIV care is poorly understood., Objectives: We examined the effects of COVID-19 lockdown policies on ART initiation, missed visits, and viral suppression in Uganda., Methods: We conducted a time series analysis using data from a dynamic cohort of persons with HIV enrolled between March 2017 and September 2021 at HIV clinics in Masaka and Mbarara Regional Referral Hospitals in Southwestern Uganda. Poisson and fractional probit regression were used to predict expected monthly antiretroviral therapy initiations, missed visits, and viral suppression based on pre-lockdown trends. Observed and expected trends were compared across three policy periods: April 2020-September 2021 (overall), April-May 2020 (1st lockdown), and June-August 2021 (2nd lockdown)., Results: We enrolled 7071 Persons living with HIV (PWH) (nMasaka = 4150; nMbarara = 2921). Average ART duration was 34 and 30 months in Masaka and Mbarara, respectively. During the 18-month post-lockdown period, monthly ART initiations were lower than expected in both Masaka (51 versus 63 visits; a decrease of 12 [95% CI: -2, 31] visits) and Mbarara (42 versus 55 visits; a decrase of 13 [95% CI: 0, 27] visits). Proportion of missed visits was moderately higher than expected post-lockdown in Masaka (10% versus 7%; 4% [95% CI: 1%, 7%] absolute increase), but not in Mbarara (13% versus 13%; 0% [95% CI: -4%, 6%] absolute decrease). Viral suppression rates were moderate-to-high in Masaka (64.7%) and Mbarara (92.5%) pre-lockdown and remained steady throughout the post-lockdown period., Conclusion: The COVID-19 lockdown in Uganda was associated with reductions in ART initiation, with minimal effects on retention and viral suppression, indicating a resilient HIV care system., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: The in-utero transfer of malaria specific IgG to the fetus in Plasmodium falciparum infected pregnant women potentially plays a role in provision of immune protection against malaria in the first birth year. However, the effect of Intermittent Prophylactic Treatment in Pregnancy (IPTp) and placental malaria on the extent of in-utero antibody transfer in malaria endemic regions like Uganda remain unknown. The aim of this study was thus to establish the effect of IPTp on in-utero transfer of malaria specific IgG to the fetus and the associated immune protection against malaria in the first birth year of children born to mothers who had P. falciparum infection during pregnancy in Uganda., Methods: We screened a total of 637 cord blood samples from a double blinded randomized clinical trial on Sulfadoxine-Pyrimethamine (SP) and Dihydroartemisinin-Piperaquine (DP) IPTp in a Ugandan birth cohort; study conducted from Busia, Eastern Uganda. Luminex assay was used to measure the cord levels of IgG sub-types (IgG1, IgG2, IgG3 and IgG4) against 15 different P. falciparum specific antigens, with tetanus toxoid (t.t) as a control antigen. Man-Whitney U test (non-parametric) in STATA (ver15) was used in statistical analysis of the samples. In addition, Multivariate cox regression analysis was used to determine the effect of maternal transfer of IgG on the incidence of malaria in the first birth year of children under study., Results: Mothers on SP expressed higher levels of cord IgG4 against erythrocyte binding antigens (EBA140, EBA175 and EBA181) (p<0.05). Placental malaria did not affect cord levels of IgG sub-types against selected P. falciparum specific antigens (p>0.05). Children who expressed higher levels (75th percentile) of total IgG against the six key P. falciparum antigens (Pf SEA, Rh4.2, AMA1, GLURP, Etramp5Ag1 and EBA 175) had higher risk of malaria in the first birth year; AHRs: 1.092, 95% CI: 1.02-1.17 (Rh4.2); 1.32, 95% CI: 1.00-1.74 (PfSEA); 1.21, 95%CI: 0.97-1.52 (Etramp5Ag1); 1.25, 95%CI: 0.98-1.60 (AMA1); 1.83, 95%CI: 1.15-2.93 (GLURP) (GLURP), and 1.35,; 95%CI: 1.03-1.78 (EBA175). Children born to mothers categorized as poorest had the highest risk of malaria infections in the first birth year (AHR: 1.79, 95% CI: 1.31-2.4). Children born to mothers who had malaria infections during gestation had higher risk of getting malaria in the first birth year (AHR 1.30; 95%CI: 0.97-1.7)., Conclusion: Malaria prophylaxis in pregnant mothers using either DP or SP does not affect expression of antibodies against P. falciparum specific antigens in the cord blood. Poverty and malaria infections during pregnancy are key risk factors of malaria infections in the first birth year of growth of children. Antibodies against P. falciparum specific antigens does not protect against parasitemia and malaria infections in the first birth year of children born in malaria endemic areas., Competing Interests: All Authors have declared that no competing interests exists., (Copyright: © 2023 Okek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Tororo District, in Eastern Uganda, experienced a dramatic decline in malaria burden starting in 2014 following the implementation of indoor residual spraying of insecticide (IRS) in the setting of repeated long-lasting insecticide treated nets (LLINs) distribution campaigns. However, in 2020 malaria began to resurge in Tororo following a change in the active ingredient used for IRS. In this study, epidemiological measures of malaria were compared shortly after the resurgence between two parishes in Tororo District (Kayoro and Osukuru) and one contiguous parish in Busia District (Buteba), where IRS has never been implemented. A cohort of 483 residents from 80 randomly selected households were followed from August 2020 to January 2021. Mosquitoes were collected every 2 weeks using CDC light traps in rooms where participants slept; parasitemia and gametoctyemia measured every 4 weeks by microscopy and PCR; and symptomatic malaria measured by passive surveillance. The annual entomological inoculation rate was significantly higher in Buteba (108.2 infective bites/person/year), compared to Osukuru (59.0, p = 0.001) and Kayoro (27.4, p<0.001). Overall, parasite prevalence was 19.5% by microscopy and 50.7% by PCR, with no significant differences between the three parishes. Among infected individuals, gametocyte prevalence by PCR was 45.5% and similar between sites. The incidence of malaria was significantly higher in Osukuru (2.46 episodes PPY) compared to Buteba (1.47, p = 0.005) and Kayoro (1.09, p<0.001). For participants over 15 years of age, the risk of symptomatic malaria if microscopic parasitemia was present was higher in Osukuru (relative risk [RR] = 2.99, p = 0.03) compared to Buteba. These findings highlight the complex relationships between measures of malaria transmission, infection, and disease, and the potential for excess disease burden, possibly due to waning immunity, in areas where vector control interventions begin to fail after a sustained period of highly effective control., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Nankabirwa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Fewer than 10% of people with hypertension in sub-Saharan Africa are diagnosed, linked to care, and achieve hypertension control. We hypothesized that a one-time financial incentive and phone call reminder for missed appointments would increase linkage to hypertension care following community-based screening in rural Uganda and Kenya., Methods: In a randomized controlled trial, we conducted community-based hypertension screening and enrolled adults ≥25 years with blood pressure ≥140/90 mmHg on three measures; we excluded participants with known hypertension or hypertensive emergency. The intervention was transportation reimbursement upon linkage (~$5 USD) and up to three reminder phone calls for those not linking within seven days. Control participants received a clinic referral only. Outcomes were linkage to hypertension care within 30 days (primary) and hypertension control &lt;140/90 mmHg measured in all participants at 90 days (secondary). We used targeted minimum loss-based estimation to compute adjusted risk ratios (aRR)., Results: We screened 1,998 participants, identifying 370 (18.5%) with uncontrolled hypertension and enrolling 199 (100 control, 99 intervention). Reasons for non-enrollment included prior hypertension diagnosis (n = 108) and hypertensive emergency (n = 32). Participants were 60% female, median age 56 (range 27-99); 10% were HIV-positive and 42% had baseline blood pressure ≥160/100 mmHg. Linkage to care within 30 days was 96% in intervention and 66% in control (aRR 1.45, 95%CI 1.25-1.68). Hypertension control at 90 days was 51% intervention and 41% control (aRR 1.22, 95%CI 0.92-1.66)., Conclusion: A one-time financial incentive and reminder call for missed visits resulted in a 30% absolute increase in linkage to hypertension care following community-based screening. Financial incentives can improve the critical step of linkage to care for people newly diagnosed with hypertension in the community., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Hickey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In Uganda, Artemether-Lumefantrine and Artesunate are recommended for uncomplicated and severe malaria respectively, but are currently threatened by parasite resistance. Genetic and epigenetic factors play a role in predisposing Plasmodium falciparum parasites to acquiring Pfkelch13 (K13) mutations associated with delayed artemisinin parasite clearance as reported in Southeast Asia. In this study, we report on the prevalence of mutations in the K13, pfmdr-2 (P. falciparum multidrug resistance protein 2), fd (ferredoxin), pfcrt (P. falciparum chloroquine resistance transporter), and arps10 (apicoplast ribosomal protein S10) genes in Plasmodium falciparum parasites prior to (2005) and after (2013) introduction of artemisinin combination therapies for malaria treatment in Uganda. A total of 200 P. falciparum parasite DNA samples were screened. Parasite DNA was extracted using QIAamp DNA mini kit (Qiagen, GmbH, Germany) procedure. The PCR products were sequenced using Sanger dideoxy sequencing method. Of the 200 P. falciparum DNA samples screened, sequencing for mutations in K13, pfmdr-2, fd, pfcrt, arps10 genes was successful in 142, 186, 141, 128 and 74 samples respectively. Overall, we detected six (4.2%, 6/142; 95%CI: 1.4-7.0) K13 single nucleotide polymorphisms (SNPs), of which 3.9% (2/51), 4.4% (4/91) occurred in 2005 and 2013 samples respectively. All four K13 SNPs in 2013 samples were non-synonymous (A578S, E596V, S600C and E643K) while of the two SNPs in 2005 samples, one (Y588N) is non-synonymous and the other (I587I) is synonymous. There was no statistically significant difference in the prevalence of K13 (p = 0.112) SNPs in the samples collected in 2005 and 2013. The overall prevalence of SNPs in pfmdr-2 gene was 39.8% (74/186, 95%CI: 25.1-50.4). Of this, 4.2% (4/95), 76.9% (70/91) occurred in 2005 and 2013 samples respectively. In 2005 samples only one SNP, Y423F (4.2%, 4/95) was found while in 2013, Y423F (38.5%, 35/91) and I492V (38.5%, 35/91) SNPs in the pfmdr-2 gene were found. There was a statistically significant difference in the prevalence of pfmdr-2 SNPs in the samples collected in 2005 and 2013 (p<0.001). The overall prevalence of arps10 mutations was 2.7% (2/72, 95%CI: 0.3-4.2). Two mutations, V127M (4.5%: 1/22) and D128H (4.5%: 1/22) in the arps10 gene were each found in P. falciparum parasite samples collected in 2013. There was no statistically significant difference in the prevalence of arps10 SNPs in the samples collected in 2005 and 2013 (p = 0.238). There were more pfmdr-2 SNPs in P. falciparum parasites collected after introduction of Artemisinin combination therapies in malaria treatment. This is an indicator of the need for continuous surveillance to monitor emergence of molecular markers of artemisinin resistance and its potential drivers in malaria affected regions globally., Competing Interests: The authors have declared that no competing interests exist.

HIV-related stigma is a frequently cited barrier to HIV testing and care engagement. A nuanced understanding of HIV-related stigma is critical for developing stigma-reduction interventions to optimize HIV-related outcomes. This qualitative study documented HIV-related stigma across eight communities in east Africa during the baseline year of a large HIV test-and-treat trial (SEARCH, NCT: 01864603), prior to implementation of widespread community HIV testing campaigns and efforts to link individuals with HIV to care and treatment. Findings revealed experiences of enacted, internalized and anticipated stigma that were highly gendered, and more pronounced in communities with lower HIV prevalence; women, overwhelmingly, both held and were targets of stigmatizing attitudes about HIV. Past experiences with enacted stigma included acts of segregation, verbal discrimination, physical violence, humiliation and rejection. Narratives among women, in particular, revealed acute internalized stigma including feelings of worthlessness, shame, embarrassment, and these resulted in anxiety and depression, including suicidality among a small number of women. Anticipated stigma included fears of marital dissolution, verbal and physical abuse, gossip and public ridicule. Anticipated stigma was especially salient for women who held internalized stigma and who had experienced enacted stigma from their partners. Anticipated stigma led to care avoidance, care-seeking at remote facilities, and hiding of HIV medications. Interventions aimed at reducing individual and community-level forms of stigma may be needed to improve the lives of PLHIV and fully realize the promise of test-and-treat strategies., Competing Interests: Gilead Sciences provided tenofovir-emtricitabine (Truvada) in kind. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors do not have any other competing interest to declare.

Background: Additional progress towards HIV epidemic control requires understanding who remains at risk of HIV infection in the context of high uptake of universal testing and treatment (UTT). We sought to characterize seroconverters and risk factors in the SEARCH UTT trial (NCT01864603), which achieved high uptake of universal HIV testing and ART coverage in 32 communities of adults (≥15 years) in rural Uganda and Kenya., Methods: In a pooled cohort of 117,114 individuals with baseline HIV negative test results, we described those who seroconverted within 3 years, calculated gender-specific HIV incidence rates, evaluated adjusted risk ratios (aRR) for seroconversion using multivariable targeted maximum likelihood estimation, and assessed potential infection sources based on self-report., Results: Of 704 seroconverters, 63% were women. Young (15-24 years) men comprised a larger proportion of seroconverters in Western Uganda (18%) than Eastern Uganda (6%) or Kenya (10%). After adjustment for other risk factors, men who were mobile [≥1 month of prior year living outside community] (aRR:1.68; 95%CI:1.09,2.60) or who HIV tested at home vs. health fair (aRR:2.44; 95%CI:1.89,3.23) were more likely to seroconvert. Women who were aged ≤24 years (aRR:1.91; 95%CI:1.27,2.90), mobile (aRR:1.49; 95%CI:1.04,2.11), or reported a prior HIV test (aRR:1.34; 95%CI:1.06,1.70), or alcohol use (aRR:2.07; 95%CI:1.34,3.22) were more likely to seroconvert. Among survey responders (N = 607, 86%), suspected infection source was more likely for women than men to be ≥10 years older (28% versus 8%) or a spouse (51% vs. 31%) and less likely to be transactional sex (10% versus 16%)., Conclusion: In the context of universal testing and treatment, additional strategies tailored to regional variability are needed to address HIV infection risks of young women, alcohol users, mobile populations, and those engaged in transactional sex to further reduce HIV incidence rates., Competing Interests: The authors have declared that no competing interests exist.

A 12-dose weekly regimen of rifapentine plus isoniazid (3HP) is recommended for the prevention of active tuberculosis (TB); however, it is unclear whether 3HP should be provided by directly observed therapy (DOT) or self-administered therapy (SAT). In addition, the introduction of patient informed choice between delivery modalities may have a positive impact on factors leading to treatment completion. The authors randomized 252 participants with HIV to a hypothetical scenario of providing preventive therapy by either DOT or an informed choice between DOT and SAT. Out of 104 participants who were randomized to a choice between DOT and SAT, 103 chose therapy by SAT. Participants rated their level of confidence and intention to complete therapy. Compared to those assigned to the DOT scenario, patients assigned to the choice scenario expressed greater confidence and intention to complete preventive therapy. Convenience and travel required to complete 3HP therapy were important factors in deciding between delivery modalities. Those assigned to DOT identified more barriers to completing therapy than those given a choice. Empowering patients to make informed decisions about how they receive TB preventive therapy may improve completion rates., Competing Interests: The authors have declared that no competing interests exist.

Background: Plasmodium falciparum histidine-rich protein 2 (HRP2)-based rapid diagnostic tests (RDTs) are exclusively recommended for malaria diagnosis in Uganda; however, their functionality can be affected by parasite-related factors that have not been investigated in field settings., Methods: Using a cross-sectional design, we analysed 219 RDT-/microscopy+ and 140 RDT+/microscopy+ dried blood spots obtained from symptomatic children aged 2-10 years from 48 districts in Uganda between 2017 and 2019. We aimed to investigate parasite-related factors contributing to false RDT results by molecular characterization of parasite isolates. ArcGIS software was used to map the geographical distribution of parasites. Statistical analysis was performed using chi-square or Fisher's exact tests, with P ≤ 0.05 indicating significance. Odds ratios (ORs) were used to assess associations, while logistic regression was performed to explore possible factors associated with false RDT results., Results: The presence of parasite DNA was confirmed in 92.5% (332/359) of the blood samples. The levels of agreement between the HRP2 RDT and PCR assay results in the (RDT+/microscopy+) and (RDT-/microscopy+) sample subsets were 97.8% (137/140) and 10.9% (24/219), respectively. Factors associated with false-negative RDT results in the (RDT-/microscopy+) samples were parasite density (<1,000/μl), pfhrp2/3 gene deletion and non-P. falciparum species (aOR 2.65, 95% CI: 1.62-4.38, P = 0.001; aOR 4.4, 95% CI 1.72-13.66, P = 0.004; and aOR 18.65, 95% CI: 5.3-38.7, P = 0.001, respectively). Overall, gene deletion and non-P. falciparum species contributed to 12.3% (24/195) and 19.0% (37/195) of false-negative RDT results, respectively. Of the false-negative RDTs results, 80.0% (156/195) were from subjects with low-density infections (< 25 parasites per 200 WBCs or <1,000/μl)., Conclusion: This is the first evaluation and report of the contributions of pfhrp2/3 gene deletion, non-P. falciparum species, and low-density infections to false-negative RDT results under field conditions in Uganda. In view of these findings, the use of HRP2 RDTs should be reconsidered; possibly, switching to combination RDTs that target alternative antigens, particularly in affected areas, may be beneficial. Future evaluations should consider larger and more representative surveys covering other regions of Uganda., Competing Interests: No authors have no competing interests.

Background: Although WHO recommends cotrimoxazole (CTX) discontinuation among HIV patients who have undergone immune recovery and are living in areas of low prevalence of malaria, some countries including Uganda recommend CTX discontinuation despite having a high malaria burden. We estimated the prevalence and factors associated with malaria parasitaemia among adults living with HIV attending hospital outpatient clinic before and after discontinuation of CTX prophylaxis., Methods: Between March and April 2019, 599 participants aged 18 years and above, and attending Kitgum hospital HIV clinic in Uganda were enrolled in a cross study. A standardized questionnaire was administered and physical examination conducted. A finger-prick blood sample was collected for identification of malaria parasites by microscopy. The prevalence of parasitaemia was estimated and compared among participants on and those who had discontinued CTX prophylaxis, and factors associated with malaria parasitaemia assessed., Results: Of the enrolled participants, 27 (4.5%) had malaria parasites and 452 (75.5%) had stopped CTX prophylaxis. Prevalence of malaria parasitaemia was significantly higher in participants who had stopped CTX prophylaxis (5.5% versus 1.4% p = 0.03) and increased with increasing duration since the discontinuation of prophylaxis. Compared to participants taking CTX, those who discontinued prophylaxis for 3-5 months and >5 months were more likely to have malaria parasites (adjusted prevalence ratio (aPR) = 1.64, 95% CI 0.37-7.29, p = 0.51, and aPR = 6.06, 95% CI 1.34-27.3, P = 0.02). Low CD4 count (< 250cells/mm3) was also associated with increased risk of having parasites (aPR = 4.31, 95% CI 2.13-8.73, p <0.001)., Conclusion: People from malaria endemic settings living with HIV have a higher prevalence of malaria parasitaemia following discontinuation of CTX compared to those still on prophylaxis. The risk increased with increasing duration since discontinuation of the prophylaxis. HIV patients should not discontinue CTX prophylaxis in areas of Uganda where the burden of malaria remains high. Other proven malaria control interventions may also be encouraged in HIV patients following discontinuation of CTX prophylaxis., Competing Interests: The authors have declared that no competing interests exist.

Background: Despite overall increase in HIV testing, more men than women remain untested. In 2018, 92% of Ugandan women but only 67% of men had tested for HIV. Understanding men's needs and concerns for testing could guide delivery of HIV testing services (HTS) to them. We assessed the prevalence of testing, associated factors and men's perspectives on HIV testing in urban and peri-urban communities in Central Uganda., Methods and Findings: We conducted a parallel-convergent mixed-methods study among men in Kampala and Mpigi districts from August to September 2018. Using two-stage sampling, we selected 1340 men from Mpigi. We administered a structured questionnaire to collect data on HIV testing history, socio-demographics, self-reported HIV risk-related behaviors, barriers and facilitators to HIV testing. We also conducted 10 focus-groups with men from both districts to learn their perspectives on HIV testing. We used modified Poisson regression to assess factors associated with HIV testing and inductive thematic analysis to identify barriers and facilitators. Though 84.0% of men reported having tested for HIV, only 65.7% had tested in the past 12-months despite nearly all (96.7%) engaging in at least one HIV risk-related behavior. Men were more likely to have tested if aged 25-49 years, Catholic, with secondary or higher education and circumcised. Being married was associated with ever-testing while being widowed or divorced was associated with testing in past 12-months. Men who engaged in HIV risk-related behavior were less likely to have tested in the past 12-months. Qualitative findings showed that men varied in their perspectives about the need for testing, access to HTS and were uncertain of HIV testing and its outcomes., Conclusions: Recent HIV testing among men remains low. Modifying testing strategies to attract men in all age groups could improve testing uptake, reduce gender disparity and initiate risk reduction interventions., Competing Interests: The authors have declared that no competing interests exist.

Background: Retesting for HIV is critical to identifying newly-infected persons and reinforcing prevention efforts among at-risk adults. Incentives can increase one-time HIV testing, but their role in promoting retesting is unknown. We sought to test feasibility and acceptability of incentive strategies, including commitment contracts, to promote HIV retesting among at-risk adults in rural Uganda., Methods: At-risk HIV-negative adults were enrolled in a pilot trial assessing feasibility and acceptability of incentive strategies to promote HIV retesting three months after enrollment. Participants were randomized (1:1:3) to: 1) no incentive; 2) standard cash incentive (~US$4); and 3) commitment contract: participants could voluntarily make a low- or high-value deposit that would be returned with added interest (totaling ~US$4 including the deposit) upon retesting or lost if participants failed to retest. Contracts sought to promote retesting by leveraging loss aversion and addressing present bias via pre-commitment. Outcomes included acceptability of trial enrollment, contract feasibility (proportion of participants making deposits), and HIV retesting uptake., Results: Of 130 HIV-negative eligible adults, 123 (95%) enrolled and were randomized: 74 (60%) to commitment contracts, 25 (20%) to standard incentives, and 24 (20%) to no incentive. Of contract participants, 69 (93%) made deposits. Overall, 93 (76%) participants retested for HIV: uptake was highest in the standard incentive group (22/25 [88%]) and lowest in high-value contract (26/36 [72%]) and no incentive (17/24 [71%]) groups., Conclusion: In a randomized trial of strategies to promote HIV retesting among at-risk adults in Uganda, incentive strategies, including commitment contracts, were feasible and had high acceptability. Our findings suggest use of incentives for HIV retesting merits further comparison in a larger trial., Trial Registration: ClinicalTrials.gov identifier: NCT:02890459., Competing Interests: The authors have declared that no competing interests exist.

Background: The age-specific epidemiology of child and adolescent tuberculosis (TB) is poorly understood, especially in rural areas of East Africa. We sought to characterize the age-specific prevalence and predictors of TB infection among children and adolescents living in rural Uganda, and to explore the contribution of household TB exposure on TB infection., Methods: From 2015-2016 we placed and read 3,121 tuberculin skin tests (TST) in children (5-11 years old) and adolescents (12-19 years old) participating in a nested household survey in 9 rural Eastern Ugandan communities. TB infection was defined as a positive TST (induration ≥10mm or ≥5mm if living with HIV). Age-specific prevalence was estimated using inverse probability weighting to adjust for incomplete measurement. Generalized estimating equations were used to assess the association between TB infection and multi-level predictors., Results: The adjusted prevalence of TB infection was 8.5% (95%CI: 6.9-10.4) in children and 16.7% (95% CI:14.0-19.7) in adolescents. Nine percent of children and adolescents with a prevalent TB infection had a household TB contact. Among children, having a household TB contact was strongly associated with TB infection (aOR 5.5, 95% CI: 1.7-16.9), but the strength of this association declined among adolescents and did not meet significance (aOR 2.3, 95% CI: 0.8-7.0). The population attributable faction of TB infection due to a household TB contact was 8% for children and 4% among adolescents. Mobile children and adolescents who travel outside of their community for school had a 1.7 (95% CI 1.0-2.9) fold higher odds of TB infection than those who attended school in the community., Conclusion: Children and adolescents in this area of rural eastern Uganda suffer a significant burden of TB. The majority of TB infections are not explained by a known household TB contact. Our findings underscore the need for community-based TB prevention interventions, especially among mobile youth., Competing Interests: The authors have declared that no competing interests exist.

Background: Hypertension (HTN) is the single leading risk factor for human mortality worldwide, and more prevalent in sub-Saharan Africa than any other region [1]-although resources for HTN screening, treatment, and control are few. Most regional pilot studies to leverage HIV programs for HTN control have achieved blood pressure control in half of participants or fewer [2,3,4]. But this control gap may be due to inconsistent delivery of services, rather than ineffective underlying interventions., Methods: We sought to evaluate the consistency of HTN program delivery within the SEARCH study (NCT01864603) among 95,000 adults in 32 rural communities in Uganda and Kenya from 2013-2016. To achieve this objective, we designed and performed a fidelity evaluation of the step-by-step process (cascade) of HTN care within SEARCH, calculating rates of HTN screening, linkage to care, and follow-up care. We evaluated SEARCH's assessment of each participant's HTN status against measured blood pressure and HTN history., Findings: SEARCH completed blood pressure screens on 91% of participants. SEARCH HTN screening was 91% sensitive and over 99% specific for HTN relative to measured blood pressure and patient history. 92% of participants screened HTN+ received clinic appointments, and 42% of persons with HTN linked to subsequent care. At follow-up, 82% of SEARCH clinic participants received blood pressure checks; 75% received medication appropriate for their blood pressure; 66% remained in care; and 46% had normal blood pressure at their most recent visit., Conclusion: The SEARCH study's consistency in delivering screening and treatment services for HTN was generally high, but SEARCH could improve effectiveness in linking patients to care and achieving HTN control. Its model for implementing population-scale HTN testing and care through an existing HIV test-and-treat program-and protocol for evaluating the intervention's stepwise fidelity and care outcomes-may be adapted, strengthened, and scaled up for use across multiple resource-limited settings., Competing Interests: DJH declares recent support from Teva Pharmaceuticals (https://www.tevapharm.com) for research unrelated to this manuscript; as noted above, DH and MRK report non-financial support from this research from Gilead Pharmaceuticals (https://www.gilead.com).

Background: Sub-Saharan Africa suffers from a dual burden of infectious and non-communicable diseases. There is limited data on causes and trends of admission and death among patients on the medical wards. Understanding the major drivers of morbidity and mortality would help inform health systems improvements. We determined the causes and trends of admission and mortality among patients admitted to Mulago Hospital, Kampala, Uganda., Methods and Results: The medical record data base of patients admitted to Mulago Hospital adult medical wards from January 2011 to December 2014 were queried. A detailed history, physical examination and investigations were completed to confirm the diagnosis and identify comorbidities. Any histopathologic diagnoses were made by hematoxylin and eosin tissue staining. We identified the 10 commonest causes of hospitalization, and used Poisson regression to generate annual percentage change to describe the trends in causes of hospitalization. Survival was calculated from the date of admission to the date of death or date of discharge. Cox survival analysis was used to identify factors associate with in-hospital mortality. We used a statistical significance level of p<0.05. A total of 50,624 patients were hospitalized with a median age of 38 (range 13-122) years and 51.7% females. Majority of patients (72%) had an NCD condition as the primary reason for admission. Specific leading causes of morbidity were HIV/AIDS in 30% patients, hypertension in 14%, tuberculosis (TB) in 12%), non-TB pneumonia in11%) and heart failure in 9.3%. There was decline in the proportion of hospitalization due to malaria, TB and pneumonia with an annual percentage change (apc) of -20% to -6% (all p<0.03) with an increase in proportions of admissions due to chronic kidney disease, hypertension, stroke and cancer, with apc 13.4% to 24%(p<0.001). Overall, 8,637(17.1%) died during hospitalization with the highest case fatality rates from non-TB pneumonia (28.8%), TB (27.1%), stroke (26.8%), cancer (26.1%) and HIV/AIDS (25%). HIV-status, age above 50yrs and being male were associated with increased risk of death among patients with infections., Conclusion: Admissions and case fatality rates for both infectious and non-infectious diseases were high, with declining trends in infectious diseases and a rising trend in NCDs. Health care systems in sub-Saharan region need to prepare to deal with dual burden of disease., Competing Interests: The authors have declared that no competing interests exist.

Background: Preterm birth (PTB) is a leading cause of neonatal mortality and longer-term morbidity. Acute chorioamnionitis (ACA) is a common cause of PTB, however, there are limited data on the prevalence of ACA and its association with PTB in resource limited settings., Methods: Data and samples came from a clinical trial evaluating novel strategies for the prevention of malaria in HIV infected pregnant women in Uganda. Women were enrolled between 12-28 weeks of gestation and followed through delivery. For each placenta delivered, three placental tissue types (membrane roll, umbilical cord and chorionic plate/villous parenchyma) were collected. Slides were assessed for diagnosis of maternal and fetal ACA by microscopic evaluation of neutrophilic infiltration using a standardized grading scale. The primary outcomes were PTB (<37 weeks), low birth weight (LBW, <2500 grams), and small-for-gestational age (SGA, birth weight <10th percentile for age). Univariate and multivariate logistic regression were used to estimate associations between 1) maternal characteristics (age, education, wealth, gravidity, gestational age at enrollment, placental malaria, anti-malarial prophylaxis treatment regimen, HIV disease parameters) and ACA, and 2) associations between ACA and adverse birth outcomes., Findings: A total of 193 placentas were included in the analysis. The prevalence of maternal and fetal ACA was 44.5% and 28.0%, respectively. HIV infected women between 28-43 years of age had a higher risk of maternal ACA compared to those between 17-21 years of age (50.9% vs. 19.1%; aOR = 4.00 (1.10-14.5), p = 0.04) and the diagnosis of severe maternal ACA was associated with a significantly higher risk of PTB (28.6% vs. 6.0%; aOR = 6.04 (1.87-19.5), p = 0.003), LBW (33.3% vs. 9.4%; aOR = 4.86 (1.65-14.3); p = 0.004), and SGA (28.6% vs. 10.1%; aOR = 3.70 (1.20-11.4), p = 0.02). No maternal characteristics were significantly associated with fetal ACA and the diagnosis of fetal ACA was not associated with adverse birth outcomes., Conclusions: Histological evidence of severe maternal ACA was associated with an increased risk of PTB, LBW, and SGA in HIV infected, pregnant Ugandan women., Competing Interests: The authors have declared that no competing interests exist.

Background: Previous research indicates clinical outcomes among HIV-infected men in sub-Saharan Africa are sub-optimal. The SEARCH test and treat trial (NCT01864603) intervention included antiretroviral care delivery designed to address known barriers to HIV-care among men by decreasing clinic visit frequency and providing flexible, patient-centered care with retention support. We sought to understand facilitators and barriers to retention in care in this universal treatment setting through quantitative and qualitative data analysis., Methods: We used a convergent mixed methods study design to evaluate retention in HIV care among adults (age > = 15) during the first year of the SEARCH (NCT01864603) test and treat trial. Cox proportional hazards regression was used to evaluate predictors of retention in care. Longitudinal qualitative data from n = 190 in-depth interviews with HIV-positive individuals and health care providers were analyzed to identify facilitators and barriers to HIV care engagement., Results: There were 1,863 men and 3,820 women who linked to care following baseline testing. Retention in care was 89.7% (95% CI 87.0-91.8%) among men and 89.0% (86.8-90.9%) among women at one year. In both men and women older age was associated with higher rates of retention in care at one year. Additionally, among men higher CD4+ at ART initiation and decreased time between testing and ART initiation was associated with higher rates of retention. Maintaining physical health, a patient-centered treatment environment, supportive partnerships, few negative consequences to disclosure, and the ability to seek care in facilities outside of their community of residence were found to promote retention in care., Conclusions: Features of the ART delivery system in the SEARCH intervention and social and structural advantages emerged as facilitators to retention in HIV care among men. Messaging around the health benefits of early ART start, decreasing logistical barriers to HIV care, support of flexible treatment environments, and accelerated linkage to care, are important to men's success in ART treatment programs. Men already benefit from increased social support following disclosure of their HIV-status. Future efforts to shift gender norms towards greater equity are a potential strategy to support high levels of engagement in care for both men and women., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LBB, CRC, EDC, MLP, MRK, DVH, and CSC have received grants from the National Institutes of Health. DVH has received non-financial support (donation of study drug Truvada) from Gilead Sciences. All other authors declare that no competing interests exist.

Background: Despite substantial progress, gaps in the HIV care cascade remain large: globally, while about 36.7 million people were living with HIV in 2015, 11.9 million of these individuals did not know their HIV status, 12.7 million were in need of antiretroviral therapy (ART) and 13.0 million were not virally suppressed. We sought to deepen understanding of the barriers to care engagement at three critical steps of the care cascade proposed to make greatest impact for attaining the UNAIDS 90-90-90 targets aimed at shutting down the HIV epidemic., Methods: Analyses were conducted among HIV-infected adults in rural East Africa. Qualitative data were collected using in-depth interviews among 63 individuals participating in an ongoing test-and treat trial (NCT01864683) in its baseline year (July 2013-June 2014). Audio recordings were transcribed, translated into English, and coded using Atlas.ti software. Data were analyzed using a thematic framework for explaining barriers to care engagement that drew upon both theory and prior empirical research in similar settings., Results: Multiple barriers to engagement in care were observed. HIV-related stigma across dimensions of anticipated, internalized and enacted stigma manifested in denial and fears of disclosure, and influenced lapses in care engagement across multiple steps in the cascade. Poverty (lack of food and transport), lack of social support, work interference, prior negative experiences with health services, drug side effects, and treatment fatigue also negatively affected ART adherence and viral suppression. Gender differences were observed, with work interference and denial disproportionately affecting men compared to women., Conclusion: Multiple barriers to HIV care engagement still pervade rural sub-Saharan settings threatening the realization of the UNAIDS 90-90-90 targets. To control the epidemic, efforts need to be accelerated to combat stigma. Patient economic empowerment, innovative drug formulations, as well as more patient-responsive health systems, may help overcome barriers to engagement in care., Competing Interests: DVH reports grants from National Institutes of Health, non-financial support from Gilead Sciences, during the conduct of the study; grants from National Institutes of Health, grants from Gates Foundation, outside the submitted work. EDC reports grants from National Institutes of Health, during the conduct of the study. We would like to confirm that this does not alter our adherence to PLOS ONE’s policies on sharing data and materials.

Background: Hypertension accounts for more than 212 million global disability-adjusted life-years, and more than 15 million in sub-Saharan Africa. Identifying factors underlying the escalating burden of hypertension in sub-Saharan Africa may inform delivery of targeted public health interventions., Methods: As part of the cross-sectional nationally representative Uganda National Asthma Survey conducted in 2016, we measured blood pressure (BP) in the general population across five regions of Uganda. We defined hypertension as systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg, or on-going use of medications for the purpose of lowering BP among adults (≥18 years of age); pre-hypertension as systolic BP between 120 and 140 mmHg and/or diastolic BP bteween 80 and 90 mmHg among adolescents and adults (≥12 years of age)., Findings: Of 3416 participants who met inclusion criteria, 38.9% were male, and mean age ± SD was 33.8 ± 16.9 years. The age- and sex-adjusted prevalence of hypertension was 31.5% (95% confidence interval [CI] 30.2 to 32.8). The adjusted prevalence of hypertension was highest in the Central Region (34.3%; 95% CI 32.6 to 36.0), and it was comparable to that in the West and East Regions. However, compared with the Central Region, hypertension was significantly less prevalent in the North (22.0%; 95 CI 19.4 to 24.6) and West Nile Regions (24.1%; 95% CI 22.0 to 26.3). Adjustment for demographic characteristics (occupation, monthly income, and educational attainment) of participants did not account for the significantly lower prevalence of hypertension in the North and West Nile Regions. The prevalence of pre-hypertension was 38.8% (95% CI 37.7 to 39.8), and it was highly prevalent among young adults (21-40 years of age: 42.8%; 95% CI 41.2-44.5%) in all regions., Conclusions: Hypertension is starkly prevalent in Uganda, and numerous more people, including young adults are at increased risk. The burden of hypertension is highest in the Central, Western, and Eastern regions of the country; demographic characteristics did not fully account for the disparate regional burden of hypertension. Future studies should explore the potential additional impact of epidemiological shifts, including diet and lifestyle changes, on the development of hypertension., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Incomplete understanding of TB transmission dynamics in high HIV prevalence settings remains an obstacle for prevention. Understanding where transmission occurs could provide a platform for case finding and interrupting transmission., Methods: From 2012-2015, we sought to recruit all adults starting TB treatment in a Ugandan community. Participants underwent household (HH) contact investigation, and provided names of social contacts, sites of work, healthcare and socializing, and two sputum samples. Mycobacterium tuberculosis culture-positive specimens underwent 24-loci MIRU-VNTR and spoligotyping. We sought to identify epidemiologic links between genotype-matched cases by analyzing social networks and mapping locations where cases reported spending ≥12 hours over the one-month pre-treatment. Sites of spatial overlap (≤100m) between genotype-matched cases were considered potential transmission sites. We analyzed social networks stratified by genotype clustering status, with cases linked by shared locations, and compared network density by location type between clustered vs. non-clustered cases., Results: Of 173 adults with TB, 131 (76%) were enrolled, 108 provided sputum, and 84/131 (78%) were MTB culture-positive: 52% (66/131) tested HIV-positive. Of 118 adult HH contacts, 105 (89%) were screened and 3 (2.5%) diagnosed with active TB. Overall, 33 TB cases (39%) belonged to 15 distinct MTB genotype-matched clusters. Within each cluster, no cases shared a HH or reported shared non-HH contacts. In 6/15 (40%) clusters, potential epidemiologic links were identified by spatial overlap at specific locations: 5/6 involved health care settings. Genotype-clustered TB social networks had significantly greater network density based on shared clinics (p<0.001) and decreased density based on shared marketplaces (p<0.001), compared to non-clustered networks., Conclusions: In this molecular epidemiologic study, links between MTB genotype-matched cases were only identifiable via shared locations, healthcare locations in particular, rather than named contacts. This suggests most transmission is occurring between casual contacts, and emphasizes the need for improved infection control in healthcare settings in rural Africa.

Background: Rapid diagnostic tests for malaria (mRDTs) have been scaled-up widely across Africa. The PRIME study evaluated an intervention aiming to improve fever case management using mRDTs at public health centers in Uganda., Methods: A cluster-randomized trial was conducted from 2010-13 in Tororo, a high malaria transmission setting. Twenty public health centers were randomized in a 1:1 ratio to intervention or control. The intervention included training in health center management, fever case management with mRDTs, and patient-centered services; plus provision of mRDTs and artemether-lumefantrine (AL) when stocks ran low. Three rounds of Interviews were conducted with caregivers of children under five years of age as they exited health centers (N = 1400); reference mRDTs were done in children with fever (N = 1336). Health worker perspectives on mRDTs were elicited through semi-structured questionnaires (N = 49) and in-depth interviews (N = 10). The primary outcome was inappropriate treatment of malaria, defined as the proportion of febrile children who were not treated according to guidelines based on the reference mRDT., Findings: There was no difference in inappropriate treatment of malaria between the intervention and control arms (24.0% versus 29.7%, adjusted risk ratio 0.81 [95% CI: 0.56, 1.17] p = 0.24). Most children (76.0%) tested positive by reference mRDT, but many were not prescribed AL (22.5% intervention versus 25.9% control, p = 0.53). Inappropriate treatment of children testing negative by reference mRDT with AL was also common (31.3% invention vs 42.4% control, p = 0.29). Health workers appreciated mRDTs but felt that integrating testing into practice was challenging given constraints on time and infrastructure., Conclusions: The PRIME intervention did not have the desired impact on inappropriate treatment of malaria for children under five. In this high transmission setting, use of mRDTs did not lead to the reductions in antimalarial prescribing seen elsewhere. Broader investment in health systems, including infrastructure and staffing, will be required to improve fever case management.

In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity'). In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity. Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months. Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype. Additionally, persistently infected mice displayed a dramatic increase in circulating nonclassical monocytes, a phenomenon that we also observed in humans with both chronic Plasmodium exposure and asymptomatic infection. Following pharmacological clearance of infection, previously persistently infected mice could not control a secondary challenge, indicating that persistent infection disrupts the sterilizing immunity that typically develops in mouse models of acute infection. This study establishes an animal model of asymptomatic, persistent Plasmodium infection that recapitulates several central aspects of the immune response in chronically exposed humans. As such, it provides a novel tool for dissection of immune responses that may prevent development of sterilizing immunity and limit pathology during infection., Competing Interests: LB is an employee of EPIRUS Biopharmaceuticals. This commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Antiretroviral therapy scale-up in Sub-Saharan Africa has created a growing, aging HIV-positive population at risk for non-communicable diseases such as hypertension. However, the prevalence and risk factors for hypertension in this population remain incompletely understood., Methods: We measured blood pressure and collected demographic data on over 65,000 adults attending multi-disease community health campaigns in 20 rural Ugandan communities (SEARCH Study: NCT01864603). Our objectives were to determine (i) whether HIV is an independent risk factor for hypertension, and (ii) awareness and control of hypertension in HIV-positive adults and the overall population., Results: Hypertension prevalence was 14% overall, and 11% among HIV-positive individuals. 79% of patients were previously undiagnosed, 85% were not taking medication, and 50% of patients on medication had uncontrolled blood pressure. Multivariate predictors of hypertension included older age, male gender, higher BMI, lack of education, alcohol use, and residence in Eastern Uganda. HIV-negative status was independently associated with higher odds of hypertension (OR 1.2, 95% CI: 1.1-1.4). Viral suppression of HIV did not significantly predict hypertension among HIV-positives., Significance: The burden of hypertension is substantial and inadequately controlled, both in HIV-positive persons and overall. Universal HIV screening programs could provide counseling, testing, and treatment for hypertension in Sub-Saharan Africa.

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

Background: Evidence favoring earlier HIV ART initiation at high CD4+ T-cell counts (CD4>350/uL) has grown, and guidelines now recommend earlier HIV treatment. However, the cost of providing ART to individuals with CD4>350 in Sub-Saharan Africa has not been well estimated. This remains a major barrier to optimal global cost projections for accelerating the scale-up of ART. Our objective was to compute costs of ART delivery to high CD4+count individuals in a typical rural Ugandan health center-based HIV clinic, and use these data to construct scenarios of efficient ART scale-up., Methods: Within a clinical study evaluating streamlined ART delivery to 197 individuals with CD4+ cell counts >350 cells/uL (EARLI Study: NCT01479634) in Mbarara, Uganda, we performed a micro-costing analysis of administrative records, ART prices, and time-and-motion analysis of staff work patterns. We computed observed per-person-per-year (ppy) costs, and constructed models estimating costs under several increasingly efficient ART scale-up scenarios using local salaries, lowest drug prices, optimized patient loads, and inclusion of viral load (VL) testing., Findings: Among 197 individuals enrolled in the EARLI Study, median pre-ART CD4+ cell count was 569/uL (IQR 451-716). Observed ART delivery cost was $628 ppy at steady state. Models using local salaries and only core laboratory tests estimated costs of $529/$445 ppy (+/-VL testing, respectively). Models with lower salaries, lowest ART prices, and optimized healthcare worker schedules reduced costs by $100-200 ppy. Costs in a maximally efficient scale-up model were $320/$236 ppy (+/- VL testing). This included $39 for personnel, $106 for ART, $130/$46 for laboratory tests, and $46 for administrative/other costs. A key limitation of this study is its derivation and extrapolation of costs from one large rural treatment program of high CD4+ count individuals., Conclusions: In a Ugandan HIV clinic, ART delivery costs--including VL testing--for individuals with CD4>350 were similar to estimates from high-efficiency programs. In higher efficiency scale-up models, costs were substantially lower. These favorable costs may be achieved because high CD4+ count patients are often asymptomatic, facilitating more efficient streamlined ART delivery. Our work provides a framework for calculating costs of efficient ART scale-up models using accessible data from specific programs and regions.

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

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

Unlabelled: 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., Trial Registration: Current Controlled Trials NCT00699920.

Background: Improving childhood tuberculosis (TB) evaluation and care is a global priority, but data on performance at community health centers in TB endemic regions are sparse., Objective: To describe the current practices and quality of TB evaluation for children with cough ≥2 weeks' duration presenting to community health centers in Uganda., Methods: Cross-sectional analysis of children (<15 years) receiving care at five Level IV community health centers in rural Uganda for any reason between 2009-2012. Quality of TB care was assessed using indicators derived from the International Standards of Tuberculosis Care (ISTC)., Results: From 2009-2012, 1713 of 187,601 (0.9%, 95% CI: 0.4-1.4%) children presenting to community health centers had cough ≥ 2 weeks' duration. Of those children, only 299 (17.5%, 95% CI: 15.7-19.3%) were referred for sputum microscopy, but 251 (84%, 95% CI: 79.8-88.1%) completed sputum examination if referred. The yield of sputum microscopy was only 3.6% (95% CI: 1.3-5.9%), and only 55.6% (95% CI: 21.2-86.3%) of children with acid-fast bacilli positive sputum were started on treatment. Children under age 5 were less likely to be referred for sputum examination and to receive care in accordance with ISTC. The proportion of children evaluated in accordance with ISTC increased over time (4.6% in 2009 to 27.9% in 2012, p = 0.03), though this did not result in increased case-detection., Conclusion: The quality of TB evaluation was poor for children with cough ≥2 weeks' duration presenting for health care. Referrals for sputum smear microscopy and linkage to TB treatment were key gaps in the TB evaluation process, especially for children under the age of five.

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&#95;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&#95;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.

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 6,343 residents. 501 additional residents were identified at the campaign, for a total community population of 6,844. 4,323 (63%) residents and 556 non-residents attended the campaign. HIV tests were performed in 4,795/4,879 (98.3%) participants; 1,836 (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.

Background: Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is widely recommended in sub-Saharan Africa to reduce the risk of malaria and improve birth outcomes. However, there are reports that the efficacy of IPTp with SP is waning, especially in parts of Africa where antimalarial resistance to this drug has become widespread., Methodology/principal Findings: We conducted a cross-sectional study of 565 HIV-uninfected women giving birth at Tororo District Hospital in southeastern Uganda. The primary objective of the study was to measure associations between use of SP during pregnancy from antenatal records and the risk of adverse outcomes including placental malaria, low birth weight, maternal parasitemia and maternal anemia. The proportion of women who reported taking 0, 1, 2, and 3 doses of SP during pregnancy was 5.7%, 35.8%, 56.6% and 2.0% respectively. Overall, the prevalence of placental malaria was 17.5%, 28.1%, and 66.2% by placental smear, PCR, and histopathology, respectively. In multivariate analyses controlling for potential confounders, ≥ 2 doses of SP was associated with non-significant trends towards lower odds of placental malaria by placental smear (OR = 0.75, p = 0.25), placental malaria by PCR (OR = 0.93, p = 0.71), placental malaria by histopathology (OR = 0.75, p = 0.16), low birth weight (OR = 0.63, p = 0.11), maternal parasitemia (OR = 0.88, p = 0.60) and maternal anemia (OR = 0.88, p = 0.48). Using a composite outcome, ≥ 2 doses of SP was associated with a significantly lower odds of placental malaria, low birth weight, maternal parasitemia, or maternal anemia (OR = 0.52, p = 0.01)., Conclusions/significance: In this area of Uganda with intense malaria transmission, the prevalence of placental malaria by histopathology was high even among women who reported taking at least 2 doses of SP during pregnancy. The reported use of ≥ 2 doses of SP was not associated with protection against individual birth and maternal outcome measures but did protect against a composite measure of any adverse outcome.

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<0.001), baseline CD4 count of 101-200 cells/µL (-35, 95% CI: 62, -9, P=0.009) and >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<0.001). The cumulative probability of attaining CD4 >400 cells/µL over 7 years was higher in females compared to males (P<0.001)., Conclusions: There was long-term, continuous, immunologic recovery up to 7 years after ART initiation in an urban Ugandan cohort. Virologically suppressed women had better sustained immune recovery than men. Men take longer to immune reconstitute and have a lower probability of reaching a CD4 cell count >400 cells/µL. The biologic mechanisms of these gender differences need further exploration.

Background: The high burden of undiagnosed HIV in sub-Saharan Africa limits treatment and prevention efforts. Community-based HIV testing campaigns can address this challenge and provide an untapped opportunity to identify non-communicable diseases (NCDs). We tested the feasibility and diagnostic yield of integrating NCD and communicable diseases into a rapid HIV testing and referral campaign for all residents of a rural Ugandan parish., Methods: A five-day, multi-disease campaign, offering diagnostic, preventive, treatment and referral services, was performed in May 2011. Services included point-of-care screening for HIV, malaria, TB, hypertension and diabetes. Finger-prick diagnostics eliminated the need for phlebotomy. HIV-infected adults met clinic staff and peer counselors on-site; those with CD4 ≤ 100/µL underwent intensive counseling and rapid referral for antiretroviral therapy (ART). Community participation, case-finding yield, and linkage to care three months post-campaign were analyzed., Results: Of 6,300 residents, 2,323/3,150 (74%) adults and 2,020/3,150 (69%) children participated. An estimated 95% and 52% of adult female and male residents participated respectively. Adult HIV prevalence was 7.8%, with 46% of HIV-infected adults newly diagnosed. Thirty-nine percent of new HIV diagnoses linked to care. In a pilot subgroup with CD4 ≤ 100, 83% linked and started ART within 10 days. Malaria was identified in 10% of children, and hypertension and diabetes in 28% and 3.5% of adults screened, respectively. Sixty-five percent of hypertensives and 23% of diabetics were new diagnoses, of which 43% and 61% linked to care, respectively. Screening identified suspected TB in 87% of HIV-infected and 19% of HIV-uninfected adults; 52% percent of HIV-uninfected TB suspects linked to care., Conclusions: In an integrated campaign engaging 74% of adult residents, we identified a high burden of undiagnosed HIV, hypertension and diabetes. Improving male attendance and optimizing linkage to care require new approaches. The campaign demonstrates the feasibility of integrating hypertension, diabetes and communicable diseases into HIV initiatives.

Background: Recently the use of indoor residual spraying of insecticide (IRS) has greatly increased in Africa; however, limited data exist on the quantitative impacts of IRS on health outcomes in highly malaria endemic areas., Methodology/principal Findings: Routine data were collected on more than 90,000 patient visits at a single health facility over a 56 month period covering five rounds of IRS using three different insecticides. Temporal associations between the timing of IRS and the probability of a patient referred for microscopy having laboratory confirmed malaria were estimated controlling for seasonality and age. Considering patients less than five years of age there was a modest decrease in the odds of malaria following the 1(st) round of IRS using DDT (OR = 0.76, p<0.001) and the 2(nd) round using alpha-cypermethrin (OR = 0.83, p = 0.002). Following rounds 3-5 using bendiocarb there was a much greater decrease in the odds of malaria (ORs 0.34, 0.16, 0.17 respectively, p<0.001 for all comparisons). Overall, the impact of IRS was less pronounced among patients 5 years or older., Conclusions/significance: IRS was associated with a reduction in malaria morbidity in an area of high transmission intensity in Uganda and the benefits appeared to be greatest after switching to a carbamate class of insecticide.

Background: Modelling is widely used to inform decisions about management of malaria and acute febrile illnesses. Most models depend on estimates of the probability that untreated patients with malaria or bacterial illnesses will progress to severe disease or death. However, data on these key parameters are lacking and assumptions are frequently made based on expert opinion. Widely diverse opinions can lead to conflicting outcomes in models they inform., Methods and Findings: A Delphi survey was conducted with malaria experts aiming to reach consensus on key parameters for public health and economic models, relating to the outcome of untreated febrile illnesses. Survey questions were stratified by malaria transmission intensity, patient age, and HIV prevalence. The impact of the variability in opinion on decision models is illustrated with a model previously used to assess the cost-effectiveness of malaria rapid diagnostic tests. Some consensus was reached around the probability that patients from higher transmission settings with untreated malaria would progress to severe disease (median 3%, inter-quartile range (IQR) 1-5%), and the probability that a non-malaria illness required antibiotics in areas of low HIV prevalence (median 20%). Children living in low transmission areas were considered to be at higher risk of progressing to severe malaria (median 30%, IQR 10-58%) than those from higher transmission areas (median 13%, IQR 7-30%). Estimates of the probability of dying from severe malaria were high in all settings (medians 60-73%). However, opinions varied widely for most parameters, and did not converge on resurveying., Conclusions: This study highlights the uncertainty around potential consequences of untreated malaria and bacterial illnesses. The lack of consensus on most parameters, the wide range of estimates, and the impact of variability in estimates on model outputs, demonstrate the importance of sensitivity analysis for decision models employing expert opinion. Results of such models should be interpreted cautiously. The diversity of expert opinion should be recognised when policy options are debated.

Background: Heath facility-based sentinel site surveillance has been proposed as a means of monitoring trends in malaria morbidity but may also provide an opportunity to improve malaria case management. Here we described the impact of a sentinel site malaria surveillance system on promoting laboratory testing and rational antimalarial drug use., Methodology/principal Findings: Sentinel site malaria surveillance was established at six health facilities in Uganda between September 2006 and January 2007. Data were collected from all patients presenting to the outpatient departments including demographics, laboratory results, diagnoses, and treatments prescribed. Between the start of surveillance and March 2010, a total 424,701 patients were seen of which 229,375 (54%) were suspected of having malaria. Comparing the first three months with the last three months of surveillance, the proportion of patients with suspected malaria who underwent diagnostic testing increased from 39% to 97% (p<0.001). The proportion of patients with an appropriate decision to prescribe antimalarial therapy (positive test result prescribed, negative test result not prescribed) increased from 64% to 95% (p<0.001). The proportion of patients appropriately prescribed antimalarial therapy who were prescribed the recommended first-line regimen artemether-lumefantrine increased from 48% to 69% (p<0.001)., Conclusions/significance: The establishment of a sentinel site malaria surveillance system in Uganda achieved almost universal utilization of diagnostic testing in patients with suspected malaria and appropriate decisions to prescribed antimalarial based on test results. Less success was achieved in promoting prescribing practice for the recommended first-line therapy. This system could provide a model for improving malaria case management in other health facilities in Africa.

Background: Late diagnosis of HIV infection is a major challenge to the scale-up of HIV prevention and treatment. In 2005 Uganda adopted provider-initiated HIV testing in the health care setting to ensure earlier HIV diagnosis and linkage to care. We provided HIV testing to patients at Mulago hospital in Uganda, and performed CD4 tests to assess disease stage at diagnosis., Methods: Patients who had never tested for HIV or tested negative over one year prior to recruitment were enrolled between May 2008 and March 2010. Participants who tested HIV positive had a blood draw for CD4. Late HIV diagnosis was defined as CD4≤250 cells/mm. Predictors of late HIV diagnosis were analyzed using multi-variable logistic regression., Results: Of 1966 participants, 616 (31.3%) were HIV infected; 47.6% of these (291) had CD4 counts ≤250. Overall, 66.7% (408) of the HIV infected participants had never received care in a medical clinic. Receiving care in a non-medical setting (home, traditional healer and drug stores) had a threefold increase in the odds of late diagnosis (OR = 3.2; 95%CI: 2.1-4.9) compared to receiving no health care., Conclusions: Late HIV diagnosis remains prevalent five years after introducing provider-initiated HIV testing in Uganda. Many individuals diagnosed with advanced HIV did not have prior exposure to medical clinics and could not have benefitted from the expansion of provider initiated HIV testing within health facilities. In addition to provider-initiated testing, approaches that reach individuals using non-hospital based encounters should be expanded to ensure early HIV diagnosis.

Background: Combination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda., Methodology/principal Findings: Children aged 1-10 years were enrolled from randomly selected households in 2004-05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs) were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP), artesunate/amodiaquine (AS/AQ), or artemether/lumefantrine (AL). Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL) decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria) and no deaths were seen., Conclusions/significance: With ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time., Trial Registration: isrctn.org ISRCTN37517549.

Background: Uganda recently adopted artemether-lumefantrine (AL) as the recommended first-line treatment for uncomplicated malaria. However, AL has several limitations, including a twice-daily dosing regimen, recommendation for administration with fatty food, and a high risk of reinfection soon after therapy in high transmission areas. Dihydroartemisinin-piperaquine (DP) is a new alternative artemisinin-based combination therapy that is dosed once daily and has a long post-treatment prophylactic effect. We compared the efficacy and safety of AL with DP in Kanungu, an area of moderate malaria transmission., Methodology/principal Findings: Patients aged 6 months to 10 years with uncomplicated falciparum malaria were randomized to therapy and followed for 42 days. Genotyping was used to distinguish recrudescence from new infection. Of 414 patients enrolled, 408 completed follow-up. Compared to patients treated with artemether-lumefantrine, patients treated with dihydroartemisinin-piperaquine had a significantly lower risk of recurrent parasitaemia (33.2% vs. 12.2%; risk difference = 20.9%, 95% CI 13.0-28.8%) but no statistically significant difference in the risk of treatment failure due to recrudescence (5.8% vs. 2.0%; risk difference = 3.8%, 95% CI -0.2-7.8%). Patients treated with dihydroartemisinin-piperaquine also had a lower risk of developing gametocytaemia after therapy (4.2% vs. 10.6%, p = 0.01). Both drugs were safe and well tolerated., Conclusions/significance: DP is highly efficacious, and operationally preferable to AL because of a less intensive dosing schedule and requirements. Dihydroartemisinin-piperaquine should be considered for a role in the antimalarial treatment policy of Uganda., Trial Registration: Controlled-Trials.com ISRCTN75606663.