Targeted newborn metabolomics: prediction of gestational age from cord blood.

OBJECTIVE: Our study sought to determine whether metabolites from a retrospective collection of banked cord blood specimens could accurately estimate gestational age and to validate these findings in cord blood samples from Busia, Uganda. STUDY DESIGN: Forty-seven metabolites were measured by tandem mass spectrometry or enzymatic assays from 942 banked cord blood samples. Multiple linear regression was performed, and the best model was used to predict gestational age, in weeks, for 150 newborns from Busia, Uganda. RESULTS: The model including metabolites and birthweight, predicted the gestational ages within 2 weeks for 76.7% of the Ugandan cohort. Importantly, this model estimated the prevalence of preterm birth <34 weeks closer to the actual prevalence (4.67% and 4.00%, respectively) than a model with only birthweight which overestimates the prevalence by 283%. CONCLUSION: Models that include cord blood metabolites and birth weight appear to offer improvement in gestational age estimation over birth weight alone.

Piperaquine-Induced QTc Prolongation Decreases With Repeated Monthly Dihydroartemisinin-Piperaquine Dosing in Pregnant Ugandan Women.

BACKGROUND: Intermittent preventive treatment with monthly dihydroartemisinin-piperaquine (DHA-PQ) is highly effective at preventing both malaria during pregnancy and placental malaria. Piperaquine prolongs the corrected QT interval (QTc), and it is possible that repeated monthly dosing could lead to progressive QTc prolongation. Intensive characterization of the relationship between piperaquine concentration and QTc interval throughout pregnancy can inform effective, safe prevention guidelines. METHODS: Data were collected from a randomized controlled trial, where pregnant Ugandan women received malaria chemoprevention with monthly DHA-PQ (120/960 mg DHA/PQ; n = 373) or sulfadoxine-pyrimethamine (SP; 1500/75 mg; n = 375) during the second and third trimesters of pregnancy. Monthly trough piperaquine samples were collected throughout pregnancy, and pre- and postdose electrocardiograms were recorded at 20, 28, and 36 weeks' gestation in each woman. The pharmacokinetics-QTc relationship for piperaquine and QTc for SP were assessed using nonlinear mixed-effects modeling. RESULTS: A positive linear relationship between piperaquine concentration and Fridericia corrected QTc interval was identified. This relationship progressively decreased from a 4.42 to 3.28 to 2.13 millisecond increase per 100 ng/mL increase in piperaquine concentration at 20, 28, and 36 weeks' gestation, respectively. Furthermore, 61% (n = 183) of women had a smaller change in QTc at week 36 than week 20. Nine women given DHA-PQ had grade 3-4 cardiac adverse events. SP was not associated with any change in QTc. CONCLUSIONS: Repeated DHA-PQ dosing did not result in increased risk of QTc prolongation and the postdose QTc intervals progressively decreased. Monthly dosing of DHA-PQ in pregnant women carries minimal risk of QTc prolongation. CLINICAL TRIALS REGISTRATION: NCT02793622.

Effect of universal HIV testing and treatment on socioeconomic wellbeing in rural Kenya and Uganda: a cluster-randomised controlled trial.

BACKGROUND: Universal testing and treatment for HIV has shown promise as an approach to reduce mortality and lower HIV incidence. Evidence on the economic effects of this approach on individuals and households in low-resource settings is scarce. We aimed to examine the effect of universal HIV testing and treatment on a range of economic outcomes. METHODS: We collected data in household surveys done over a 3-year period in a sample of HIV-positive and HIV-negative adults participating in a cluster-randomised trial of universal HIV testing and treatment in 32 rural communities in Kenya and Uganda. Communities of approximately 10 000 people were pair-matched on the basis of geographical and population characteristics, with the best-matching 16 pairs randomly assigned (1:1) to intervention or control groups. Participants in intervention communities received annual HIV and multidisease testing, universal antiretroviral therapy (ART) eligibility, and patient-centred care. Participants in control communities received baseline testing and medical care according to national guidelines. We analysed employment and health-care utilisation outcomes for working-age adults (age 18-65 years) and education outcomes for school-age children (6-17 years) using data from 3 years after the intervention. This trial is now complete, and is registered with ClinicalTrials.gov, NCT01864603. FINDINGS: Between July 9, 2013, and June 15, 2017, we collected survey data on 8198 working-age adults and 6755 school-age children. Compared with adults living with HIV in control communities, adults living with HIV in intervention communities were more likely to be employed (difference 9·7% [95% CI 2·1 to 18·3]), less likely to seek health care (-10·3% [-22·0 to 0·1]), and less likely to spend money on health care (-12·7% [-22·4 to 0·6]) 3 years after the intervention. We found no significant differences in outcomes between HIV-negative adults in intervention and control communities. Among children in households with HIV-positive adults, the intervention led to a 7·3% (95% CI 1·0 to 15·1) increase in primary school completion after 3 years in intervention communities compared with control communities. INTERPRETATION: Universal HIV testing and treatment improved employment outcomes and other indicators of socioeconomic wellbeing for HIV-positive adults and children in their households, but had no effect on HIV-negative adults. Our findings suggest that the considerable investments needed to expand ART access might have substantial short-term and long-term economic returns. FUNDING: National Institutes of Health.

Provider and Patient Perspectives of Rapid ART Initiation and Streamlined HIV Care: Qualitative Insights From Eastern African Communities.

The Sustainable East Africa Research in Community Health (SEARCH), a universal test and treat (UTT) trial, implemented 'Streamlined Care'-a multicomponent strategy including rapid linkage to care and antiretroviral therapy (ART) start, 3-monthly refills, viral load counseling, and accessible, patient-centered care provision. To understand patient and provider experiences of Streamlined Care to inform future care innovations, we conducted in-depth interviews with patients (n = 18) and providers (n = 28) at baseline (2014) and follow-up (2015) (n = 17 patients; n = 21 providers). Audio recordings were transcribed, translated, and deductively and inductively coded. Streamlined Care helped to decongest clinic spaces and de-stigmatize human immunodeficiency virus (HIV) care. Patients credited the individualized counselling, provider-assisted HIV status disclosure, and providers' knowledge of patient's drug schedules, availability, and phone call reminders for their care engagement. However, for some, denial (repeated testing to disprove HIV+ results), feeling healthy, limited understanding of the benefits of early ART, and anticipated side-effects, and mistrust of researchers hindered rapid ART initiation. Patients' short and long-term mobility proved challenging for both patients and providers. Providers viewed viral load counselling as a powerful tool to convince otherwise healthy and high-CD4 patients to initiate ART. Patient-centered HIV care models should build on the successes of Streamlined Care, while addressing persistent barriers.#NCT01864683-https://clinicaltrials.gov/ct2/show/NCT01864603.

Dimensions of HIV-related stigma in rural communities in Kenya and Uganda at the start of a large HIV 'test and treat' trial.

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.

Costs of integrating hypertension care into HIV care in rural East African clinics.

OBJECTIVE: Sub-Saharan Africa faces twin epidemics of HIV and noncommunicable diseases including hypertension. Integrating hypertension care into chronic HIV care is a global priority, but cost estimates are lacking. In the SEARCH Study, we performed population-level HIV/hypertension testing, and offered integrated streamlined chronic care. Here, we estimate costs for integrated hypertension/HIV care for HIV-positive individuals, and costs for hypertension care for HIV-negative individuals in the same clinics. DESIGN: Microcosting analysis of healthcare expenditures within Ugandan HIV clinics. METHODS: SEARCH (NCT: 01864603) conducted community health campaigns for diagnosis and linkage to care for both HIV and hypertension. HIV-positive patients received hypertension/HIV care jointly including blood pressure monitoring and medications; HIV-negative patients received hypertension care at the same clinics. Within 10 Ugandan study communities during 2015-2016, we estimated incremental annual per-patient hypertension care costs using micro-costing techniques, time-and-motion personnel studies, and administrative/clinical records review. RESULTS: Overall, 70 HIV-positive and 2355 HIV-negative participants received hypertension care. For HIV-positive participants, average incremental cost of hypertension care was $6.29 per person per year, a 2.1% marginal increase over prior estimates for HIV care alone. For HIV-negative participants, hypertension care cost $11.39 per person per year, a 3.8% marginal increase over HIV care costs. Key costs for HIV-positive patients included hypertension medications ($6.19 per patient per year; 98% of total) and laboratory testing ($0.10 per patient per year; 2%). Key costs for HIV-negative patients included medications ($5.09 per patient per year; 45%) and clinic staff salaries ($3.66 per patient per year; 32%). CONCLUSION: For only 2-4% estimated additional costs, hypertension care was added to HIV care, and also expanded to all HIV-negative patients in prototypic Ugandan clinics, demonstrating substantial synergy. Our results should encourage accelerated scale-up of hypertension care into existing clinics.

SEARCH Human Immunodeficiency Virus (HIV) Streamlined Treatment Intervention Reduces Mortality at a Population Level in Men With Low CD4 Counts.

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 < .001). Mortality was reduced substantially more among men (RR = 0.61; 95% CI: .43, .86; P = .01) than among women (RR = 0.90; 95% CI: .62, 1.32; P = .58). 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.

Predicting HIV Incidence in the SEARCH Trial: A Mathematical Modeling Study.

BACKGROUND: The SEARCH study provided community-based HIV and multidisease testing and antiretroviral therapy (ART) to 32 communities in East Africa and reported no statistically significant difference in 3-year HIV incidence. We used mathematical modeling to estimate the effect of control arm viral suppression and community mixing on SEARCH trial outcomes. SETTING: Uganda and Kenya. METHODS: Using the individual-based HIV modeling software EMOD-HIV, we configured a new model of SEARCH communities. The model was parameterized using demographic, HIV prevalence, male circumcision, and viral suppression data and calibrated to HIV prevalence, ART coverage, and population size. Using assumptions about ART scale-up in the control arm, degree of community mixing, and effect of baseline testing, we estimated comparative HIV incidence under multiple scenarios. RESULTS: Before the trial results, we predicted that SEARCH would report a 4%-40% reduction between arms, depending on control arm ART linkage rates and community mixing. With universal baseline testing followed by rapidly expanded ART eligibility and uptake, modeled effect sizes were smaller than the study was powered to detect. Using interim viral suppression data, we estimated 3-year cumulative incidence would have been reduced by up to 27% in the control arm and 43% in the intervention arm compared with a counterfactual without universal baseline testing. CONCLUSIONS: Our model suggests that the active control arm substantially reduced expected effect size and power of the SEARCH study. However, compared with a counterfactual "true control" without increased ART linkage because of baseline testing, SEARCH reduced HIV incidence by up to 43%.

Age-Related Changes in Malaria Clinical Phenotypes During Infancy Are Modified by Sickle Cell Trait.

BACKGROUND: Infants are protected against Plasmodium falciparum malaria. Mechanisms that drive this protection remain unclear due to a poor understanding of malaria clinical phenotypes during infancy. METHODS: We enrolled a birth cohort of 678 infants in Busia, Uganda, an area of high malaria transmission. We followed infants through 12 months of age and quantified protection against parasitemia and clinical disease. RESULTS: Symptomatic malaria incidence increased from 1.2 to 2.6 episodes per person-year between 0 and <6 months and between 6 and 12 months of age, while the monthly probability of asymptomatic parasitemia given infection decreased from 32% to 21%. Sickle cell trait (HbAS) was protective against symptomatic malaria (incidence rate ratio  = 0.57 comparing HbAS vs hemoglobin AA (HbAA); 95% confidence interval, 0.44-0.74; P < .001), but age modified this relationship (Pint = <0.001), with nonlinear protection that waned between 0 and 9 months of age before increasing. Increasing age was associated with higher parasite densities at the time of infection and, in infants with HbAS, a reduced ability to tolerate high parasite densities without fever. CONCLUSIONS: Age-dependent changes in HbAS protective efficacy in infancy were accompanied by differential loss of antiparasite and antidisease protection among HbAS and HbAA infants. This provides a framework for investigating the mechanisms that underlie infant protection against malaria. CLINICAL TRIALS REGISTRATION: NCT02793622.

Characteristics of HIV seroconverters in the setting of universal test and treat: Results from the SEARCH trial in rural Uganda and Kenya.

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.

HIV incidence after pre-exposure prophylaxis initiation among women and men at elevated HIV risk: A population-based study in rural Kenya and Uganda.

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, but data are limited on HIV incidence among PrEP users in generalized epidemic settings, particularly outside of selected risk groups. We performed a population-based PrEP study in rural Kenya and Uganda and sought to evaluate both changes in HIV incidence and clinical and virologic outcomes following seroconversion on PrEP. METHODS AND FINDINGS: During population-level HIV testing of individuals ≥15 years in 16 communities in the Sustainable East Africa Research in Community Health (SEARCH) study (NCT01864603), we offered universal access to PrEP with enhanced counseling for persons at elevated HIV risk (based on serodifferent partnership, machine learning-based risk score, or self-identified HIV risk). We offered rapid or same-day PrEP initiation and flexible service delivery with follow-up visits at facilities or community-based sites at 4, 12, and every 12 weeks up to week 144. Among participants with incident HIV infection after PrEP initiation, we offered same-day antiretroviral therapy (ART) initiation and analyzed HIV RNA, tenofovir hair concentrations, drug resistance, and viral suppression (<1,000 c/ml based on available assays) after ART start. Using Poisson regression with cluster-robust standard errors, we compared HIV incidence among PrEP initiators to incidence among propensity score-matched recent historical controls (from the year before PrEP availability) in 8 of the 16 communities, adjusted for risk group. Among 74,541 individuals who tested negative for HIV, 15,632/74,541 (21%) were assessed to be at elevated HIV risk; 5,447/15,632 (35%) initiated PrEP (49% female; 29% 15-24 years; 19% in serodifferent partnerships), of whom 79% engaged in ≥1 follow-up visit and 61% self-reported PrEP adherence at ≥1 visit. Over 7,150 person-years of follow-up, HIV incidence was 0.35 per 100 person-years (95% confidence interval [CI] 0.22-0.49) among PrEP initiators. Among matched controls, HIV incidence was 0.92 per 100 person-years (95% CI 0.49-1.41), corresponding to 74% lower incidence among PrEP initiators compared to matched controls (adjusted incidence rate ratio [aIRR] 0.26, 95% CI 0.09-0.75; p = 0.013). Among women, HIV incidence was 76% lower among PrEP initiators versus matched controls (aIRR 0.24, 95% CI 0.07-0.79; p = 0.019); among men, HIV incidence was 40% lower, but not significantly so (aIRR 0.60, 95% CI 0.12-3.05; p = 0.54). Of 25 participants with incident HIV infection (68% women), 7/25 (28%) reported taking PrEP ≤30 days before HIV diagnosis, and 24/25 (96%) started ART. Of those with repeat HIV RNA after ART start, 18/19 (95%) had <1,000 c/ml. One participant with viral non-suppression was found to have transmitted viral resistance, as well as emtricitabine resistance possibly related to PrEP use. Limitations include the lack of contemporaneous controls to assess HIV incidence without PrEP and that plasma samples were not archived to assess for baseline acute infection. CONCLUSIONS: Population-level offer of PrEP with rapid start and flexible service delivery was associated with 74% lower HIV incidence among PrEP initiators compared to matched recent controls prior to PrEP availability. HIV infections were significantly lower among women who started PrEP. Universal HIV testing with linkage to treatment and prevention, including PrEP, is a promising approach to accelerate reductions in new infections in generalized epidemic settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01864603.

Infant sex modifies associations between placental malaria and risk of malaria in infancy.

BACKGROUND: Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM. METHODS: Data from a birth cohort of 656 infants born to HIV-uninfected mothers randomised to IPTp with dihydroartemisinin-piperaquine (DP) or Sulfadoxine-pyrimethamine (SP) was analysed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (> 0-20% high powered fields [HPFs] with pigment), or severe past PM (> 20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. RESULTS: There were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p = 0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p = 0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p < 0.001), but not female infants (aIRR 0.74, 95% CI 0.46-1.20, p = 0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM. CONCLUSION: PM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk. Trial registration ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622.

Pathways for reduction of HIV-related stigma: a model derived from longitudinal qualitative research in Kenya and Uganda.

INTRODUCTION: The rollout of antiretroviral therapy (ART) has been associated with reductions in HIV-related stigma, but pathways through which this reduction occurs are poorly understood. In the newer context of universal test and treat (UTT) interventions, where rapid diffusion of ART uptake takes place, there is an opportunity to understand the processes through which HIV-related stigma can decline, and how UTT strategies may precipitate more rapid and widespread changes in stigma. This qualitative study sought to evaluate how a UTT intervention influenced changes in beliefs, attitudes and behaviours related to HIV. METHODS: Longitudinal qualitative in-depth semi-structured interview data were collected within a community-cluster randomized UTT trial, the Sustainable East Africa Research in Community Health (SEARCH) study, annually over three rounds (2014 to 2016) from two cohorts of adults (n = 32 community leaders, and n = 112 community members) in eight rural communities in Uganda and Kenya. Data were inductively analysed to develop new theory for understanding the pathways of stigma decline. RESULTS: We present an emergent theoretical model of pathways through which HIV-related stigma may decline: internalized stigma may be reduced by two processes accelerated through the uptake and successful usage of ART: first, a reduced fear of dying and increased optimism for prolonged and healthy years of life; second, a restoration of perceived social value and fulfilment of subjective role expectations via restored physical strength and productivity. Anticipated stigma may be reduced in response to widespread engagement in HIV testing, leading to an increasing number of HIV status disclosures in a community, "normalizing" disclosure and reducing fears. Improvements in the perceived quality of HIV care lead to people living with HIV (PLHIV) seeking care in nearby facilities, seeing other known community members living with HIV, reducing isolation and facilitating opportunities for social support and "solidarity." Finally, enacted stigma may be reduced in response to the community viewing the healthy bodies of PLHIV successfully engaged in treatment, which lessens the fears that trigger enacted stigma; it becomes no longer socially normative to stigmatize PLHIV. This process may be reinforced through public health messaging and anti-discrimination laws. CONCLUSIONS: Declines in HIV-related stigma appear to underway and explained by social processes accelerated by UTT efforts. Widespread implementation of UTT shows promise for reducing multiple dimensions of stigma, which is critical for improving health outcomes among PLHIV.

Piperaquine Exposure Is Altered by Pregnancy, HIV, and Nutritional Status in Ugandan Women.

Dihydroartemisinin-piperaquine (DHA-PQ) provides highly effective therapy and chemoprevention for malaria in pregnant African women. PQ concentrations of >10.3 ng/ml have been associated with reduced maternal parasitemia, placental malaria, and improved birth outcomes. We characterized the population pharmacokinetics (PK) of PQ in a post hoc analysis of human immunodeficiency virus (HIV)-infected and -uninfected pregnant women receiving DHA-PQ as chemoprevention every 4 or 8 weeks. The effects of covariates such as pregnancy, nutritional status (body mass index [BMI]), and efavirenz (EFV)-based antiretroviral therapy were investigated. PQ concentrations from two chemoprevention trials were pooled to create a population PK database from 274 women and 2,218 PK observations. A three-compartment model with an absorption lag best fit the data. Consistent with our prior intensive PK evaluation, pregnancy and EFV use resulted in a 72% and 61% increased PQ clearance, compared to postpartum and HIV-uninfected pregnant women, respectively. Low BMI at 28 weeks of gestation was associated with increased clearance (2% increase per unit decrease in BMI). Low-BMI women given DHA-PQ every 8 weeks had a higher prevalence of parasitemia, malaria infection, and placental malaria compared to women with higher BMIs. The reduced piperaquine exposure in women with low BMI as well as during EFV coadministration, compared to pregnant women with higher BMIs and not taking EFV, suggests that these populations could benefit from weekly instead of monthly dosing for prevention of malaria parasitemia. Simulations indicated that because of the BMI-clearance relationship, weight-based regimens would not improve protection compared to a 2,880 mg fixed-dose regimen when provided monthly. (The clinical trials described in this paper have been registered at ClinicalTrials.gov under identifiers NCT02163447 and NCT02282293.).

Impact of intermittent preventive treatment of malaria in pregnancy with dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine on the incidence of malaria in infancy: a randomized controlled trial.

BACKGROUND: Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) significantly reduces the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (SP), the current standard of care, but its impact on the incidence of malaria during infancy is unknown. METHODS: We conducted a double-blind randomized trial to compare the incidence of malaria during infancy among infants born to HIV-uninfected pregnant women who were randomized to monthly IPTp with either DP or SP. Infants were followed for all their medical care in a dedicated study clinic, and routine assessments were conducted every 4 weeks. At all visits, infants with fever and a positive thick blood smear were diagnosed and treated for malaria. The primary outcome was malaria incidence during the first 12 months of life. All analyses were done by modified intention to treat. RESULTS: Of the 782 women enrolled, 687 were followed through delivery from December 9, 2016, to December 5, 2017, resulting in 678 live births: 339 born to mothers randomized to SP and 339 born to those randomized to DP. Of these, 581 infants (85.7%) were followed up to 12 months of age. Overall, the incidence of malaria was lower among infants born to mothers randomized to DP compared to SP, but the difference was not statistically significant (1.71 vs 1.98 episodes per person-year, incidence rate ratio (IRR) 0.87, 95% confidence interval (CI) 0.73-1.03, p = 0.11). Stratifying by infant sex, IPTp with DP was associated with a lower incidence of malaria among male infants (IRR 0.75, 95% CI 0.58-0.98, p = 0.03) but not female infants (IRR 0.99, 95% CI 0.79-1.24, p = 0.93). CONCLUSION: Despite the superiority of DP for IPTp, there was no evidence of a difference in malaria incidence during infancy in infants born to mothers who received DP compared to those born to mothers who received SP. Only male infants appeared to benefit from IPTp-DP suggesting that IPTp-DP may provide additional benefits beyond birth. Further research is needed to further explore the benefits of DP versus SP for IPTp on the health outcomes of infants. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02793622 . Registered on June 8, 2016.

Anemia and Micronutrient Status during Pregnancy, and Their Associations with Obstetric and Infant Outcomes among HIV-Infected Ugandan Women Receiving Antiretroviral Therapy.

BACKGROUND: Women living with HIV (WLHIV) are at higher risk of micronutrient deficiencies and adverse health outcomes. There are limited data on the burden or sequelae of micronutrient deficiencies among pregnant WLHIV receiving antiretroviral therapy (ART). OBJECTIVES: We aimed to examine anemia and vitamin B-12, folate, and vitamin D deficiencies, and their associations with obstetric and infant outcomes, among pregnant WLHIV initiating combination antiretroviral therapy (cART) in rural Uganda. METHODS: This was a prospective analysis among pregnant WLHIV (12-28 weeks of gestation) in PROMOTE-Pregnant Women and Infants (PIs), a randomized trial comparing the effects of protease inhibitor (PI)-based ART with those of a non-PI-based ART on placental malaria risk. We conducted a substudy on the burden of anemia [trimester 1/3: hemoglobin (Hb) <11.0 g/dL; trimester 2: Hb <10.5 g/dL; n = 367] and micronutrient deficiencies (n = 127) in pregnant WLHIV and their associations with obstetric and infant outcomes. Hb was measured by cyanmethemoglobin, vitamin B-12 and folate were measured via electrochemiluminescence, and vitamin D was measured by ELISA. Linear and binomial regression were used to evaluate associations between micronutrient status during pregnancy and perinatal outcomes. RESULTS: 26.8% women were anemic, 30.2% were vitamin B-12 insufficient (<221.0 pmol/L), 66.1% were folate insufficient (<13.5 nmol/L), and 65.4% were vitamin D insufficient (<30.0 ng/mL) at enrollment. Anemia during pregnancy was associated with a greater risk of small for gestational age (SGA) (RR: 1.88; 95% CI: 1.28, 2.77; P = 0.001); each 1-g/dL decrease in Hb was associated with greater risk of SGA (RR: 0.76; 95% CI: 0.65, 0.90; P = 0.001). Multivariate models showed that increased vitamin D concentrations predicted lower risk of infant wasting (WLZ < -2; RR: 0.94; 95% CI: 0.89, 0.99; P = 0.04). Multivariate models also indicated that maternal vitamin B-12 and folate concentrations at enrollment predicted maternal (P < 0.001) and infant (P = 0.02) concentrations postpartum. CONCLUSIONS: Anemia and micronutrient deficiencies are associated with a variety of adverse obstetric and infant outcomes and are an important public health concern in perinatal WLHIV on cART and their children.This trial was registered at clinicaltrials.gov as NCT00993031.

Population-level viral suppression among pregnant and postpartum women in a universal test and treat trial.

OBJECTIVE(S): We sought to determine whether universal 'test and treat' (UTT) can achieve gains in viral suppression beyond universal antiretroviral treatment (ART) eligibility during pregnancy and postpartum, among women living with HIV. DESIGN: A community cluster randomized trial. METHODS: The SEARCH UTT trial compared an intervention of annual population testing and universal ART with a control of baseline population testing with ART by country standard, including ART eligibility for all pregnant/postpartum women, in 32 communities in Kenya and Uganda. When testing, women were asked about current pregnancy and live births over the prior year and, if HIV-infected, had their viral load measured. Between arms, we compared population-level viral suppression (HIV RNA <500 copies/ml) among all pregnant/postpartum HIV-infected women at study close (year 3). We also compared year-3 population-level viral suppression and predictors of viral suppression among all 15 to 45-year-old women by arm. RESULTS: At baseline, 92 and 93% of 15 to 45-year-old women tested for HIV: HIV prevalence was 12.6 and 12.3%, in intervention and control communities, respectively. Among HIV-infected women self-reporting pregnancy/live birth, prevalence of viral suppression was 42 and 44% at baseline, and 81 and 76% (P = 0.02) at year 3, respectively. Among all 15 to 45-year-old HIV-infected women, year-3 population-level viral suppression was higher in intervention (77%) versus control (68%; P < 0.001). Pregnancy/live birth was a predictor of year-3 viral suppression in control (P = 0.016) but not intervention (P = 0.43). Younger age was a risk factor for nonsuppression in both arms. CONCLUSION: The SEARCH intervention resulted in higher population viral suppression among pregnant/postpartum women than a control of baseline universal testing with ART eligibility for pregnant/postpartum women.

Uptake, engagement, and adherence to pre-exposure prophylaxis offered after population HIV testing in rural Kenya and Uganda: 72-week interim analysis of observational data from the SEARCH study.

BACKGROUND: Optimal strategies for pre-exposure prophylaxis (PrEP) engagement in generalised HIV epidemics are unknown. We aimed to assess PrEP uptake and engagement after population-level HIV testing and universal PrEP access to characterise gaps in the PrEP cascade in rural Kenya and Uganda. METHODS: We did a 72-week interim analysis of observational data from the ongoing SEARCH (Sustainable East Africa Research in Community Health) study. Following community sensitisation and PrEP education, we did HIV testing and offered PrEP at health fairs and facilities in 16 rural communities in western Kenya, eastern Uganda, and western Uganda. We provided enhanced PrEP counselling to individuals 15 years and older who were assessed as having an elevated HIV risk on the basis of serodifferent partnership or empirical risk score, or who otherwise self-identified as being at high risk but were not in serodifferent partnerships or identified by the risk score. PrEP follow-up visits were done at facilities, homes, or community locations. We assessed PrEP uptake within 90 days of HIV testing, programme engagement (follow-up visit attendance at week 4, week 12, and every 12 weeks thereafter), refills, self-reported adherence up to 72 weeks, and concentrations of tenofovir in hair samples from individuals reporting HIV risk and adherence during follow-up, and analysed factors associated with uptake and adherence. This study is registered with ClinicalTrials.gov, NCT01864603. FINDINGS: Between June 6, 2016, and June 23, 2017, 70 379 community residents 15 years or older who had not previously been diagnosed with HIV were tested during population-level HIV testing. Of these individuals, 69 121 tested HIV-negative, 12 935 of whom had elevated HIV risk (1353 [10%] serodifferent partnership, 6938 [54%] risk score, 4644 [36%] otherwise self-identified risk). 3489 (27%) initiated PrEP, 2865 (82%) of whom did so on the same day as HIV testing and 1733 (50%) of whom were men. PrEP uptake was lower among individuals aged 15-24 years (adjusted odds ratio 0·55, 95% CI 0·45-0·68) and mobile individuals (0·61, 0·41-0·91). At week 4, among 3466 individuals who initiated PrEP and did not withdraw or die before the first visit, 2215 (64%) were engaged in the programme, 1701 (49%) received medication refills, and 1388 (40%) self-reported adherence. At week 72, 1832 (56%) of 3274 were engaged, 1070 (33%) received a refill, and 900 (27%) self-reported adherence. Among participants reporting HIV risk at weeks 4-72, refills (89-93%) and self-reported adherence (70-76%) were high. Among sampled participants self-reporting adherence at week 24, the proportion with tenofovir concentrations in the hair reflecting at least four doses taken per week was 66%, and reflecting seven doses per week was 44%. Participants who stopped PrEP accepted HIV testing at 4274 (83%) of 5140 subsequent visits; half of these participants later restarted PrEP. 29 participants of 3489 who initiated PrEP had serious adverse events, including seven deaths. Five adverse events (all grade 3) were assessed as being possibly related to the study drug. INTERPRETATION: During population-level HIV testing, inclusive risk assessment (combining serodifferent partnership, an empirical risk score, and self-identification of HIV risk) was feasible and identified individuals who could benefit from PrEP. The biggest gap in the PrEP cascade was PrEP uptake, particularly for young and mobile individuals. Participants who initiated PrEP and had perceived HIV risk during follow-up reported taking PrEP, but one-third had drug concentrations consistent with poor adherence, highlighting the need for novel approaches and long-acting formulations as PrEP roll-out expands. FUNDING: National Institutes of Health, President's Emergency Plan for AIDS Relief, Bill & Melinda Gates Foundation, and Gilead Sciences.

Hypertension testing and treatment in Uganda and Kenya through the SEARCH study: An implementation fidelity and outcome evaluation.

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.