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Background Malaria in pregnancy has been associated with worse cognitive outcomes in children, but its association with behavioral outcomes and the effectiveness of malaria chemoprevention on child neurodevelopment are not well characterized. Methods To determine if more effective malaria chemoprevention in mothers and their children results in better neurodevelopment, 305 pregnant women were randomly assigned to 3 doses of sulfadoxine-pyrimethamine, 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP during pregnancy, and their 293 children were assigned to DP every 3 months or monthly DP from 2 to 24 months of age. Cognition, language, and motor function were assessed at 12, 24. and 36 months of age, and attention, memory, behavior, and executive function were assessed at 24 and 36 months of age. Results Children of mothers with versus without malaria in pregnancy had worse scores on cognitive, behavioral, and executive function outcomes at 24 months. Clinical malaria in children within the first 12 months was similarly associated with poorer scores in behavior and executive function at 24 months, language at 24 and 36 months, and motor function scores at 36 months. However, more effective malaria chemoprevention in the mothers and children was not associated with better outcomes. Conclusions Malaria in pregnancy was associated with worse cognitive, behavioral, and executive function scores in affected children, but more effective malaria chemoprevention measures did not result in better outcomes. Malaria chemoprevention prior to and early in gestation and with even higher efficacy in mothers and children may be required to prevent neurodevelopmental impairment in children. Clinical Trials Registration. NCT02557425.

Background Social network analysis can elucidate tuberculosis transmission dynamics outside the home and may inform novel network-based case-finding strategies. Methods We assessed the association between social network characteristics and prevalent tuberculosis infection among residents (aged ≥15 years) of 9 rural communities in Eastern Uganda. Social contacts named during a census were used to create community-specific nonhousehold social networks. We evaluated whether social network structure and characteristics of first-degree contacts (sex, human immunodeficiency virus [HIV] status, tuberculosis infection) were associated with revalent tuberculosis infection (positive tuberculin skin test [TST] result) after adjusting for individual-level risk factors (age, sex, HIV status, tuberculosis contact, wealth, occupation, and Bacillus Calmette–Guérin [BCG] vaccination) with targeted maximum likelihood estimation. Results Among 3 335 residents sampled for TST, 32% had a positive TST results and 4% reported a tuberculosis contact. The social network contained 15 328 first-degree contacts. Persons with the most network centrality (top 10%) (adjusted risk ratio, 1.3 [95% confidence interval, 1.1–1.1]) and the most (top 10%) male contacts (1.5 [1.3–1.9]) had a higher risk of prevalent tuberculosis, than those in the remaining 90%. People with ≥1 contact with HIV (adjusted risk ratio, 1.3 [95% confidence interval, 1.1–1.6]) and ≥2 contacts with tuberculosis infection were more likely to have tuberculosis themselves (2.6 [ 95% confidence interval: 2.2–2.9]). Conclusions Social networks with higher centrality, more men, contacts with HIV, and tuberculosis infection were positively associated with tuberculosis infection. Tuberculosis transmission within measurable social networks may explain prevalent tuberculosis not associated with a household contact. Further study on network-informed tuberculosis case finding interventions is warranted.

Background We tested the hypothesis that patient-centered, streamlined human immunodeficiency virus (HIV) care would achieve lower mortality than the standard treatment model for persons with HIV and CD4 ≤ 350/uL in the setting of population-wide HIV testing. Methods In the SEARCH (Sustainable East Africa Research in Community Health) Study (NCT01864603), 32 communities in rural Uganda and Kenya were randomized to country-guided antiretroviral therapy (ART) versus streamlined ART care that included rapid ART start, visit spacing, flexible clinic hours, and welcoming environment. We assessed persons with HIV and CD4 ≤ 350/uL, ART eligible in both arms, and estimated the effect of streamlined care on ART initiation and mortality at 3 years. Comparisons between study arms used a cluster-level analysis with survival estimates from Kaplan-Meier; estimates of ART start among ART-naive persons treated death as a competing risk. Results Among 13 266 adults with HIV, 2973 (22.4%) had CD4 ≤ 350/uL. Of these, 33% were new diagnoses, and 10% were diagnosed but ART-naive. Men with HIV were almost twice as likely as women with HIV to have CD4 ≤ 350/uL and be untreated (15% vs 8%, respectively). Streamlined care reduced mortality by 28% versus control (risk ratio [RR] = 0.72; 95% confidence interval [CI]: .56, .93; P = .02). Despite eligibility in both arms, persons with CD4 ≤ 350/uL started ART faster under streamlined care versus control (76% vs 43% by 12 months, respectively; P Conclusions After population-based HIV testing, streamlined care reduced population-level mortality among persons with HIV and CD4 ≤ 350/uL, particularly among men. Streamlined HIV care models may play a key role in global efforts to reduce AIDS deaths.

Background In generalized epidemic settings, strategies are needed to prioritize individuals at higher risk of human immunodeficiency virus (HIV) acquisition for prevention services. We used population-level HIV testing data from rural Kenya and Uganda to construct HIV risk scores and assessed their ability to identify seroconversions. Methods During 2013–2017, >75% of residents in 16 communities in the SEARCH study were tested annually for HIV. In this population, we evaluated 3 strategies for using demographic factors to predict the 1-year risk of HIV seroconversion: membership in ≥1 known “risk group” (eg, having a spouse living with HIV), a “model-based” risk score constructed with logistic regression, and a “machine learning” risk score constructed with the Super Learner algorithm. We hypothesized machine learning would identify high-risk individuals more efficiently (fewer persons targeted for a fixed sensitivity) and with higher sensitivity (for a fixed number targeted) than either other approach. Results A total of 75 558 persons contributed 166 723 person-years of follow-up; 519 seroconverted. Machine learning improved efficiency. To achieve a fixed sensitivity of 50%, the risk-group strategy targeted 42% of the population, the model-based strategy targeted 27%, and machine learning targeted 18%. Machine learning also improved sensitivity. With an upper limit of 45% targeted, the risk-group strategy correctly classified 58% of seroconversions, the model-based strategy 68%, and machine learning 78%. Conclusions Machine learning improved classification of individuals at risk of HIV acquisition compared with a model-based approach or reliance on known risk groups and could inform targeting of prevention strategies in generalized epidemic settings. Clinical Trials Registration NCT01864603.

BACKGROUND: Gene-expression profiles have been reported to distinguish between patients with and without active tuberculosis (TB), but no prior study has been conducted in the context of TB screening. METHODS: We included all the patients (n = 40) with culture-confirmed TB and time-matched controls (n = 80) enrolled between July 2013 and April 2015 in a TB screening study among people living with human immunodeficiency virus (PLHIV) in Kampala, Uganda. We randomly split the patients into training (n = 80) and test (n = 40) datasets. We used the training dataset to derive candidate signatures that consisted of 1 to 5 differentially-expressed transcripts (P ≤ .10) and compared the performance of our candidate signatures with 4 published TB gene-expression signatures, both on the independent test dataset and in 2 external datasets. RESULTS: We identified a novel, 5-transcript signature that met the accuracy thresholds recommended for a TB screening test. On the independent test dataset, our signature had an area under the curve (AUC) of 0.87 (95% confidence interval [CI] 0.72–0.98), with sensitivity of 94% and specificity of 75%. None of the 4 published TB signatures achieved desired accuracy thresholds. Our novel signature performed well in external datasets from both high (AUC 0.81, 95% CI 0.74–0.88) and low (0.81, 95% CI 0.77–0.85) TB burden settings. CONCLUSIONS: We identified the first gene-expression signature for TB screening. Our signature has the potential to be translated into a point-of-care test to facilitate systematic TB screening among PLHIV and other high-risk populations.

BACKGROUND: The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs. METHODS: We enrolled HIV-infected Ugandans with pulmonary tuberculosis. Estimation of first-line antituberculosis drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of tuberculosis treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion. RESULTS: We enrolled 268 HIV-infected patients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of tuberculosis treatment (hazard ratio, 0.54; 95% confidence interval, .37–.77; P = .001) or by the end of follow-up (0.61; .44–.85; P = .003). Patients in the highest quartile for area under the rifampicin and isoniazid concentration-time curves for were twice as likely to experience sputum conversion than those in the lowest quartile. Rifampicin and isoniazid concentrations below the thresholds and weight

Dihydroartemisinin-piperaquine administered at monthly intervals, but not that dosed once a school term, is a remarkably effective measure for the prevention of incidence of malaria, prevalence of parasitemia, and prevalence of anemia in schoolchildren living in a high-transmission setting., Background. Intermittent preventive treatment (IPT) in schoolchildren offers a promising option for malaria control. However, the optimal drug and dosing regimens for IPT remain to be determined. Methods. We conducted a randomized, double-blind, placebo-controlled trial in 740 schoolchildren aged 6–14 years living in a setting of high malaria transmission in Uganda. Enrolled children were randomized to dihydroartemisinin-piperaquine (DP) given once a month (IPTm), DP given once a school term (4 treatments over 12 months, IPTst), or placebo and followed for 12 months. The primary outcome was the incidence of malaria over 12 months. Secondary outcomes included parasite prevalence and anemia over 12 months. Analyses were conducted on an intention-to-treat basis. Results. In the placebo arm, the incidence of malaria was 0.34 episodes per person-year and the prevalence of parasitemia and anemia was 38% and 20%, respectively. IPTm reduced the incidence of malaria by 96% (95% confidence interval [CI], 88%–99%, P < .0001), the prevalence of asymptomatic parasitemia by 94% (95% CI, 92%–96%, P < .0001), and the prevalence of anemia by 40% (95% CI, 19%–56%, P < .0001). IPTst had no significant effect on the incidence of symptomatic malaria or the prevalence of anemia, but reduced the prevalence of asymptomatic parasitemia by 54% (95% CI, 47%–60%, P < .0001). Conclusions. Monthly IPT with DP offered remarkable protection against clinical malaria, parasitemia, and anemia in schoolchildren living in a high-malaria-transmission setting. Clinical Trials Registration. NCT01231880.

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

BACKGROUND: HIV-infected women have lower HIV RNA levels and higher CD4-cell counts than do men. This observation has been attributed to the immunomodulatory effects of sex steroid hormones such as estrogen and progesterone. Limited data exist regarding potential sex differences in HIV RNA level and CD4 parameters among prepubertal children with untreated HIV infection. METHODS: We examined the relationship of sex to HIV RNA level and CD4 parameters among 670 perinatally HIV-infected antiretroviral therapy-naive African children aged

Background Artemisinin-based combination therapies are now widely recommended as first-line treatment for uncomplicated malaria. However, which therapies are optimal is a matter of debate. We aimed to compare the short- and longer-term efficacy of 2 leading therapies in a cohort of young Ugandan children. Methods A total of 351 children aged 6 weeks to 12 months were enrolled and followed up for up to 1 year. Children who were at least 4 months of age, weighted at least 5 kg, and had been diagnosed as having their first episode of uncomplicated malaria were randomized to receive artemether-lumefantrine or dihydroartemisinin-piperaquine. The same treatment was given for all subsequent episodes of uncomplicated malaria. Recrudescent and new infections were distinguished by polymerase chain reaction genotyping. Outcomes included the risk of recurrent malaria after individual treatments and the incidence of malaria treatments for individual children after randomization. Results A total of 113 children were randomized to artemether-lumefantrine and 119 to dihydroartemisinin-piperaquine, resulting in 320 and 351 treatments for uncomplicated falciparum malaria, respectively. Artemether-lumefantrine was associated with a higher risk of recurrent malaria after 28 days (35% vs 11%; P = .001]). When the duration of follow-up was extended, differences in the risk of recurrent malaria decreased such that the overall incidence of malaria treatments was similar for children randomized to artemether-lumefantrine, compared with those randomized to dihydroartemisinin-piperaquine (4.82 vs 4.61 treatments per person-year; P = .63). The risk of recurrent malaria due to recrudescent parasites was similarly low in both treatment arms. Conclusions Artemether-lumefantrine and dihydroartemisinin-piperaquine were both efficacious and had similar long-term effects on the risk of recurrent malaria. Clinical trials registration. NCT00527800.

Background. Although many studies have reported high early mortality among patients enrolled in antiretroviral therapy (ART) programs in sub-Saharan Africa―particularly among those individuals with advanced immunodeficiency―few studies have reported the most common causes of these early deaths Methods. We determined cause-specific mortality and the contribution of immune reconstitution inflammatory syndrome (IRIS) in a well-characterized patient cohort in Kampala, Uganda, over a 36-month period of ART. Results. In a cohort of patients who initiated antiretroviral therapy in Uganda, we observed a high early mortality rate among patients with advanced disease. The most common causes of death were tuberculosis and cryptococcal meningitis. The contribution of immune reconstitution inflammatory syndrome to mortality was limited. Conclusions. We show a significant early mortality in our ART cohort in resource-limited settings that is driven by advanced human immunodeficiency virus disease and characterized by low CD4 cell counts. In our experience, the contribution of IRIS to this observed early mortality is limited.

Cryptococcal meningitis (CM) is the proximate cause of death in 20%-30% of persons with acquired immunodeficiency syndrome in Africa. Two prospective observational cohorts enrolled human immunodeficiency virus (HIV)-infected antiretroviral-naive persons with CM in Kampala Uganda. The first cohort was enrolled in 2001-2002 (n = 92) prior to the availability of highly active antiretroviral therapy (HAART) and the second was enrolled in 2006-2007 (n = 44) when HAART was available. Ugandans presented with prolonged CM symptoms (median duration 14 days; interquartile range 7-21 days). The 14-day survival rates were 49% in 2001-2002 and 80% in 2006 (P less than .001). HAART was started 35_13 days after CM diagnosis and does not explain the improved 14-day survival rate in 2006. In 2006-2007 the survival rate continued to decrease after hospitalization with only 55% surviving to initiate HAART as an outpatient. Probable cryptococcal-related immune reconstitution inflammatory syndrome occurred in 42% of patients with 4 deaths. At 6 months after CM diagnosis 18 persons (41%) were alive and receiving HAART in 2007. The median cerebral spinal fluid (CSF) opening pressure was 330 mm H2O; 81% of patients had elevated pressure (greater than 200 mm H2O). Only 5 patients consented to therapeutic lumbar puncture. There was a trend for higher mortality for pressures greater than 250 mm H2O (odds ratio [OR] 2.1; 95% confidence interval [CI] 0.9-5.2; P = .09). Initial CSF WBC counts of less than 5 cells/mL were associated with failure of CSF sterilization (OR 17.3; 95% CI 3.1-94.3; P less than .001) and protein levels less than 35 mg/dL were associated with higher mortality (OR 2.0; 95% CI 1.2-3.3; P = .007). Significant CM-associated mortality persists despite the administration of amphotericin B and HIV therapy because of the high mortality rate before receipt of HAART and because of immune reconstitution inflammatory syndrome-related complications after HAART initiation. Approaches to increase acceptance of therapeutic lumbar punctures are needed. (authors)