Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth.

BACKGROUND: The use of azithromycin reduces maternal infection in women during unplanned cesarean delivery, but its effect on those with planned vaginal delivery is unknown. Data are needed on whether an intrapartum oral dose of azithromycin would reduce maternal and offspring sepsis or death. METHODS: In this multicountry, placebo-controlled, randomized trial, we assigned women who were in labor at 28 weeks' gestation or more and who were planning a vaginal delivery to receive a single 2-g oral dose of azithromycin or placebo. The two primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. During an interim analysis, the data and safety monitoring committee recommended stopping the trial for maternal benefit. RESULTS: A total of 29,278 women underwent randomization. The incidence of maternal sepsis or death was lower in the azithromycin group than in the placebo group (1.6% vs. 2.4%), with a relative risk of 0.67 (95% confidence interval [CI], 0.56 to 0.79; P<0.001), but the incidence of stillbirth or neonatal death or sepsis was similar (10.5% vs. 10.3%), with a relative risk of 1.02 (95% CI, 0.95 to 1.09; P = 0.56). The difference in the maternal primary outcome appeared to be driven mainly by the incidence of sepsis (1.5% in the azithromycin group and 2.3% in the placebo group), with a relative risk of 0.65 (95% CI, 0.55 to 0.77); the incidence of death from any cause was 0.1% in the two groups (relative risk, 1.23; 95% CI, 0.51 to 2.97). Neonatal sepsis occurred in 9.8% and 9.6% of the infants, respectively (relative risk, 1.03; 95% CI, 0.96 to 1.10). The incidence of stillbirth was 0.4% in the two groups (relative risk, 1.06; 95% CI, 0.74 to 1.53); neonatal death within 4 weeks after birth occurred in 1.5% in both groups (relative risk, 1.03; 95% CI, 0.86 to 1.24). Azithromycin was not associated with a higher incidence in adverse events. CONCLUSIONS: Among women planning a vaginal delivery, a single oral dose of azithromycin resulted in a significantly lower risk of maternal sepsis or death than placebo but had little effect on newborn sepsis or death. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; A-PLUS ClinicalTrials.gov number, NCT03871491.).

Predictors of Plasmodium falciparum Infection in the First Trimester Among Nulliparous Women From Kenya, Zambia, and the Democratic Republic of the Congo.

BACKGROUND: Malaria can have deleterious effects early in pregnancy, during placentation. However, malaria testing and treatment are rarely initiated until the second trimester, leaving pregnancies unprotected in the first trimester. To inform potential early intervention approaches, we sought to identify clinical and demographic predictors of first-trimester malaria. METHODS: We prospectively recruited women from sites in the Democratic Republic of the Congo (DRC), Kenya, and Zambia who participated in the ASPIRIN (Aspirin Supplementation for Pregnancy Indicated risk Reduction In Nulliparas) trial. Nulliparous women were tested for first-trimester Plasmodium falciparum infection by quantitative polymerase chain reaction. We evaluated predictors using descriptive statistics. RESULTS: First-trimester malaria prevalence among 1513 nulliparous pregnant women was 6.3% (95% confidence interval [CI], 3.7%-8.8%] in the Zambian site, 37.8% (95% CI, 34.2%-41.5%) in the Kenyan site, and 62.9% (95% CI, 58.6%-67.2%) in the DRC site. First-trimester malaria was associated with shorter height and younger age in Kenyan women in site-stratified analyses, and with lower educational attainment in analyses combining all 3 sites. No other predictors were identified. CONCLUSIONS: First-trimester malaria prevalence varied by study site in sub-Saharan Africa. The absence of consistent predictors suggests that routine parasite screening in early pregnancy may be needed to mitigate first-trimester malaria in high-prevalence settings.

Systematic analysis of Kaposi's sarcoma (KS)-associated herpesvirus genomes from a KS case-control study in Cameroon: Evidence of dual infections but no association between viral sequence variation and KS risk.

In sub-Saharan Africa, Kaposi's sarcoma-associated herpesvirus (KSHV) is endemic, and Kaposi's sarcoma (KS) is a significant public health problem. Until recently, KSHV genotype analysis was performed using variable gene regions, representing a small fraction of the genome, and thus the contribution of sequence variation to viral transmission or pathogenesis are understudied. We performed near full-length KSHV genome sequence analysis on samples from 43 individuals selected from a large Cameroonian KS case-control study. KSHV genomes were obtained from 21 KS patients and 22 control participants. Phylogenetic analysis of the K1 region indicated the majority of sequences were A5 or B1 subtypes and all three K15 alleles were represented. Unique polymorphisms in the KSHV genome were observed including large gene deletions. We found evidence of multiple distinct KSHV genotypes in three individuals. Additionally, our analyses indicate that recombination is prevalent suggesting that multiple KSHV infections may not be uncommon overall. Most importantly, a detailed analysis of KSHV genomes from KS patients and control participants did not find a correlation between viral sequence variations and disease. Our study is the first to systematically compare near full-length KSHV genome sequences between KS cases and controls in the same endemic region to identify possible sequence variations associated with disease risk.

The efficacy of low-dose aspirin in pregnancy among women in malaria-endemic countries.

BACKGROUND: Low dose aspirin (LDA) is an effective strategy to reduce preterm birth. However, LDA might have differential effects globally, based on the etiology of preterm birth. In some regions, malaria in pregnancy could be an important modifier of LDA on birth outcomes and anemia. METHODS: This is a sub-study of the ASPIRIN trial, a multi-national, randomized, placebo controlled trial evaluating LDA effect on preterm birth. We enrolled a convenience sample of women in the ASPIRIN trial from the Democratic Republic of Congo (DRC), Kenya and Zambia. We used quantitative polymerase chain reaction to detect malaria. We calculated crude prevalence proportion ratios (PRs) for LDA by malaria for outcomes, and regression modelling to evaluate effect measure modification. We evaluated hemoglobin in late pregnancy based on malaria infection in early pregnancy. RESULTS: One thousand four hundred forty-six women were analyzed, with a malaria prevalence of 63% in the DRC site, 38% in the Kenya site, and 6% in the Zambia site. Preterm birth occurred in 83 (LDA) and 90 (placebo) women, (PR 0.92, 95% CI 0.70, 1.22), without interaction between LDA and malaria (p = 0.75). Perinatal mortality occurred in 41 (LDA) and 43 (placebo) pregnancies, (PR 0.95, 95% CI 0.63, 1.44), with an interaction between malaria and LDA (p = 0.014). Hemoglobin was similar by malaria and LDA status. CONCLUSIONS: Malaria in early pregnancy did not modify the effects of LDA on preterm birth, but modified the effect of LDA on perinatal mortality. This effect measure modification deserves continued study as LDA is used in malaria endemic regions.

Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Preterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation. METHODS: ASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks' gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970. FINDINGS: From March 23, 2016 to June 30, 2018, 14 361 women were screened for inclusion and 11 976 women aged 14-40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73-1·00], p=0·048), fetal loss (infant death after 16 weeks' gestation and before 7 days post partum; 0·86 [0·74-1·00], p=0·039), early preterm delivery (<34 weeks; 0·75 [0·61-0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17-0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups. INTERPRETATION: In populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Relationship between human leukocyte antigen alleles and risk of Kaposi's sarcoma in Cameroon.

Several studies published to date report associations between human leukocyte antigen (HLA) alleles and different types of Kaposi's Sarcoma (KS). However, there is little concordance between the HLA alleles identified and the populations studied. To test whether HLA alleles associate with KS in a Cameroonian case-control study, we performed high-resolution HLA typing in KSHV seropositive individuals. Among HIV-positive individuals, carriers of HLA-B*14:01 were at a significantly higher risk of AIDS-KS (p = 0.033). For HIV-negative patients, a gene-wise comparison of allele frequencies identified the HLA-B (p = 0.008) and -DQA1 (p = 0.002) loci as possible risk factors for endemic KS. Our study provides additional understanding of genetic determinants of KS and their implications in disease pathogenesis. Further validation of these findings is needed to define the functional relevance of these associations.

Mutual detection of Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus in blood and saliva of Cameroonians with and without Kaposi's sarcoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are prevalent in sub-Saharan Africa, together with HIV; the consequent burden of disease is grave. The cofactors driving transmission of the two viruses and pathogenesis of associated malignancies are not well understood. We measured KSHV and EBV DNA in whole blood and saliva as well as serum antibodies levels in 175 Cameroonians with Kaposi's sarcoma and 1,002 age- and sex-matched controls with and without HIV. KSHV seroprevalence was very high (81%) in controls, while EBV seroprevalence was 100% overall. KSHV DNA was detectable in the blood of 36-46% of cases and 6-12% of controls; EBV DNA was detected in most participants (72-89%). In saliva, more cases (50-58%) than controls (25-28%) shed KSHV, regardless of HIV infection. EBV shedding was common (75-100%); more HIV+ than HIV- controls shed EBV. Cases had higher KSHV and EBV VL in blood and saliva then controls, only among HIV+ participants. KSHV and EBV VL were also higher in HIV+ than in HIV- controls. Cases (but not controls) were more likely to have detectable KSHV in blood if they also had EBV, whereas shedding of each virus in saliva was independent. While EBV VL in saliva and blood were modestly correlated, no correlation existed for KSHV. Numerous factors, several related to parasitic coinfections, were associated with detection of either virus or with VL. These findings may help better understand the interplay between the two gammaherpesviruses and generally among copathogens contributing to cancer burden in sub-Saharan Africa.

Self-disclosure of HIV status, disclosure counseling, and retention in HIV care in Cameroon.

Poor retention in care is common among HIV-positive adults in sub-Saharan Africa settings and remains a key barrier to HIV management. We quantify the associations of disclosure of HIV status and referral to disclosure counseling with successful retention in care using data from three Cameroon clinics participating in the Phase 1 International epidemiologic Databases to Evaluate AIDS Central Africa cohort. Of 1646 patients newly initiating antiretroviral therapy between January 2008 and January 2011, 43% were retained in care following treatment initiation. Self-disclosure of HIV status to at least one person prior to treatment initiation was associated with a minimal increase in the likelihood of being retained in care (risk ratio [RR] = 1.14; 95% confidence interval (CI): 0.94, 1.38). However, referral to disclosure counseling was associated with a moderate increase in retention (RR = 1.37; 95% CI: 1.21, 1.55) and was not significantly modified by prior disclosure status (p = .3). Our results suggest that while self-disclosure may not significantly improve retention among patients receiving care at these Cameroon sites, counseling services may play an important role regardless of prior disclosure status.

A description of the methods of the aspirin supplementation for pregnancy indicated risk reduction in nulliparas (ASPIRIN) study.

BACKGROUND: Preterm birth (PTB) remains the leading cause of neonatal mortality and long term disability throughout the world. Though complex in its origins, a growing body of evidence suggests that first trimester administration of low dose aspirin (LDA) may substantially reduce the rate of PTB. METHODS: Hypothesis: LDA initiated in the first trimester reduces the risk of preterm birth. Study Design Type: Prospective randomized, placebo-controlled, double-blinded multi-national clinical trial conducted in seven low and middle income countries. Trial will be individually randomized with one-to-one ratio (intervention/control) Population: Nulliparous women between the ages of 14 and 40, with a singleton pregnancy between 6 0/7 weeks and 13 6/7 weeks gestational age (GA) confirmed by ultrasound prior to enrollment, no more than two previous first trimester pregnancy losses, and no contraindications to aspirin. INTERVENTION: Daily administration of low dose (81 mg) aspirin, initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA, compared to an identical appearing placebo. Compliance and outcomes will be assessed biweekly. OUTCOMES: Primary outcome: Incidence of PTB (birth prior to 37 0/7 weeks GA). Secondary outcomes Incidence of preeclampsia/eclampsia, small for gestational age and perinatal mortality. DISCUSSION: This study is unique as it will examine the impact of LDA early in pregnancy in low-middle income countries with preterm birth as a primary outcome. The importance of developing low-cost, high impact interventions in low-middle income countries is magnified as they are often unable to bear the financial costs of treating illness. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02409680 Date: March 30, 2015.

A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial.

BACKGROUND: Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries. METHODS: In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096. FINDINGS: The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47,394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50,743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0·0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0·96, 95% CI 0·87-1·06, p=0·65) and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1·67, 1·33-2·09, p<0·0001). Among the whole population, 28-day neonatal mortality was 27·4 per 1000 livebirths for the intervention group and 23·9 per 1000 livebirths for the control group (RR 1·12, 1·02-1·22, p=0·0127) and suspected maternal infection was reported in 1207 (3%) of 48,219 women in the intervention group and 867 (2%) of 51,523 in the control group (OR 1·45, 1·33-1·58, p<0·0001). INTERPRETATION: Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Characteristics of antiretroviral therapy-naïve patients lost-to-care in HIV clinics in Democratic Republic of Congo, Cameroon, and Burundi.

Antiretroviral therapy (ART)-naïve patients are vulnerable to becoming lost-to-care (LTC) because they are not monitored as often as patients on treatment. We examined data from 19,461 HIV positive adults at 10 HIV clinics in Democratic Republic of Congo (DRC), Cameroon, and Burundi participating in the Phase 1 International epidemiologic Databases to Evaluate AIDS Central Africa (IeDEA-CA) study. Patients were LTC if they were ART-naïve and did not return within 7 months of the end of data collection. Logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with LTC. Of 5353 ART-naïve patients, 4420 (83%) were LTC and 933 (17%) were in-care. The odds of being LTC were greatest among patients from DRC (OR = 2.16, CI: 1.64-2.84, p < .0001), males (OR = 1.39, CI: 1.15-1.69, p = .0009), and ages 18-49 (OR = 1.45, CI: 1.16-1.82, p = .001). The odds of being LTC were least among patients with a WHO Clinical Stage of 1 or 2 (OR = 0.65, CI: 0.55-0.77, p < .0001) and in a perceived concordant relationship (OR = 0.61, CI: 0.43-0.87, p < .0001). LTC patients were more likely to have characteristics associated with higher risk for HIV transmission and progression. Many entered care at advanced stages and were less likely to know their partner's serostatus. Greater efforts to retain ART-naïve patients may increase earlier initiation of ART.

Use of antenatal corticosteroids at health facilities and communities in low-and-middle income countries.

BACKGROUND: Antenatal corticosteroids (ACS) for women at high risk of preterm birth is an effective intervention to reduce neonatal mortality among preterm babies delivered in hospital settings, but has not been widely used in low-middle resource settings. We sought to assess the rates of ACS use at all levels of health care in low and middle income countries (LMIC). METHODS: We assessed rates of ACS in 7 sites in 6 LMIC participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Global Network for Women and Children's Health Research Antenatal Corticosteroids Trial (ACT), a cluster-randomized trial to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of ACS. We conducted this analysis using data from the control clusters, which did not receive any components of the intervention and intended to follow usual care. We included women who delivered an infant with a birth weight <5th percentile, a proxy for preterm birth, and were enrolled in the Maternal Newborn Health (MNH) Registry between October 2011 and March 2014 in all clusters. A survey of the site investigators regarding existing policies on ACS in health facilities and for health workers in the community was part of pre-trial activities. RESULTS: Overall, of 51,523 women delivered in control clusters across all sites, the percentage of <5th percentile babies ranged from 3.5 % in Kenya to 10.7 % in Pakistan. There was variation among the sites in the use of ACS at all hospitals and among those hospitals having cesarean section and neonatal care capabilities (bag and mask and oxygen or mechanical ventilation). Rates of ACS use for <5th percentile babies in all hospitals ranged from 3.8 % in the Kenya sites to 44.5 % in the Argentina site, and in hospitals with cesarean section and neonatal care capabilities from 0 % in Zambia to 43.5 % in Argentina. ACS were rarely used in clinic or home deliveries at any site. Guidelines for ACS use at all levels of the health system were available for most of the sites. CONCLUSION: Our study reports an overall low utilization of ACS among mothers of <5th percentile infants in hospital and clinic deliveries in LMIC. TRIAL REGISTRATION: clinicaltrials.gov ( NCT01084096 ).

Patient outcomes in Lubumbashi, Democratic Republic of Congo after a disruption in HIV care due to decreased global fund appropriations.

This study examines care seeking behaviors, clinical outcomes, and satisfaction with care of HIV-positive adults in Lubumbashi, DRC, one year after a disruption in care due to decreased global fund appropriations. We describe outcomes before and after the disruption. We compared characteristics of those who completed the survey and those who did not using the Wald F test. Most patients sought care after the disruption and continued antiretroviral therapy (ART), though use of cotrimoxizole prophylaxis declined. Though there was little change in WHO clinical stage at the new site of care, the majority of participants lost weight, adherence decreased, support group participation dropped, and satisfaction with care worsened. Patients were more likely to participate in the study if they were taking ART. This study highlights the importance of provider-patient communication during a transfer and the vulnerability of pre-ART patients to becoming lost to follow-up.

A case-control study of risk factors for incident hepatitis B virus infection in South African blood donors.

OBJECTIVES: Hepatitis B virus (HBV) infection remains a global health problem. Risk factors for HBV infection are usually assessed in prevalent rather than incident infections. To identify demographic and behavioral risks associated with incident HBV among South African blood donors. METHODS: A case-control study was performed between November 2014 and January 2018. Cases were blood donors testing positive for HBV DNA with or without hepatitis B surface antigen but negative for antibody to hepatitis B core antigen. Participants completed an audio computer-assisted structured interview on exposures during the previous 6 months. Sex-specific multivariable logistic regression yielded independent associations between risks and HBV infection. RESULTS: 56 females and 37 males with incident HBV were compared to 438 female and 439 male controls, respectively. For females, risk factors were accepting money or goods for sex, using agents to prepare one's anus prior to anal sex, penetrating injury, non-Black race, and lower educational status. Men reporting homosexual or bisexual orientation or sex with other men, previous injury, referral for HBV testing, or lack of medical insurance were at increased risk. For both sexes, having more than two male sexual partners increased risk. CONCLUSIONS: Sexual behaviors predominated over parenteral exposures as risks for incident HBV in both female and male blood donors.

Prevention of maternal and neonatal death/infections with a single oral dose of azithromycin in women in labour in low-income and middle-income countries (A-PLUS): a study protocol for a multinational, randomised placebo-controlled clinical trial.

INTRODUCTION: Maternal and neonatal infections are among the most frequent causes of maternal and neonatal mortality, and current antibiotic strategies have been ineffective in preventing many of these deaths. A randomised clinical trial conducted in a single site in The Gambia showed that treatment with an oral dose of 2 g azithromycin versus placebo for all women in labour reduced certain maternal and neonatal infections. However, it is unknown if this therapy reduces maternal and neonatal sepsis and mortality. In a large, multinational randomised trial, we will evaluate the impact of azithromycin given in labour to improve maternal and newborn outcomes. METHODS AND ANALYSIS: This randomised, placebo-controlled, multicentre clinical trial includes two primary hypotheses, one maternal and one neonatal. The maternal hypothesis is to test whether a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labour will reduce maternal death or sepsis. The neonatal hypothesis will test whether this intervention will reduce intrapartum/neonatal death or sepsis. The intervention is a single, prophylactic intrapartum oral dose of 2 g azithromycin, compared with a single intrapartum oral dose of an identical appearing placebo. A total of 34 000 labouring women from 8 research sites in sub-Saharan Africa, South Asia and Latin America will be randomised with a one-to-one ratio to intervention/placebo. In addition, we will assess antimicrobial resistance in a sample of women and their newborns. ETHICS AND DISSEMINATION: The study protocol has been reviewed and ethics approval obtained from all the relevant ethical review boards at each research site. The results will be disseminated via peer-reviewed journals and national and international scientific forums. TRIAL REGISTRATION NUMBER: NCT03871491 (https://clinicaltrials.gov/ct2/show/NCT03871491?term=NCT03871491&draw=2&rank=1).

The impact of risk factors on aspirin's efficacy for the prevention of preterm birth.

BACKGROUND: The Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas trial was a landmark study that demonstrated a reduction in preterm birth and hypertensive disorders of pregnancy in nulliparous women who received low-dose aspirin. All women in the study had at least 1 moderate-risk factor for preeclampsia (nulliparity). Unlike current US Preventative Service Task Force guidelines, which recommend low-dose aspirin for ≥2 moderate-risk factors, women in this study were randomized to receive low-dose aspirin regardless of the presence or absence of an additional risk factor. OBJECTIVE: This study aimed to compare how low-dose aspirin differentially benefits nulliparous women with and without additional preeclampsia risk factors for the prevention of preterm birth and hypertensive disorders of pregnancy. STUDY DESIGN: This was a non-prespecified secondary analysis of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas trial that randomized nulliparous women with singleton pregnancies from 6 low-middle-income countries to receive low-dose aspirin or placebo. Our primary exposure was having an additional preeclampsia risk factor beyond nulliparity. Our primary outcome was preterm birth before 37 weeks of gestation, and our secondary outcomes included preterm birth before 34 weeks of gestation, preterm birth before 28 weeks of gestation, hypertensive disorders of pregnancy, and perinatal mortality. RESULTS: Among 11,558 nulliparous women who met the inclusion criteria, 66.8% had no additional risk factors. Low-dose aspirin similarly reduced the risk of preterm birth at <37 weeks of gestation in women with and without additional risk factors (relative risk: 0.75 vs 0.85; P=.35). Additionally for our secondary outcomes, low-dose aspirin similarly reduced the risk of preterm birth at <28 weeks of gestation, hypertensive disorders of pregnancy, and perinatal mortality in women with and without additional risk factors. The reduction of preterm birth at <34 weeks of gestation with low-dose aspirin was significantly greater in women without additional risk factors than those with an additional risk factor (relative risk: 0.69 vs 1.04; P=.04). CONCLUSION: Low-dose aspirin's ability to prevent preterm birth, hypertensive disorders of pregnancy, and perinatal mortality was similar in nulliparous women with and without additional risk factors. Professional societies should consider recommending low-dose aspirin to all nulliparous women.

Lessons learned for surveillance system strengthening through capacity building and partnership engagement in post-Ebola Guinea, 2015-2019.

The 2014-2016 Ebola outbreak in Guinea revealed systematic weaknesses in the existing disease surveillance system, which contributed to delayed detection, underreporting of cases, widespread transmission in Guinea and cross-border transmission to neighboring Sierra Leone and Liberia, leading to the largest Ebola epidemic ever recorded. Efforts to understand the epidemic's scale and distribution were hindered by problems with data completeness, accuracy, and reliability. In 2017, recognizing the importance and usefulness of surveillance data in making evidence-based decisions for the control of epidemic-prone diseases, the Guinean Ministry of Health (MoH) included surveillance strengthening as a priority activity in their post-Ebola transition plan and requested the support of partners to attain its objectives. The U.S. Centers for Disease Control and Prevention (US CDC) and four of its implementing partners-International Medical Corps, the International Organization for Migration, RTI International, and the World Health Organization-worked in collaboration with the Government of Guinea to strengthen the country's surveillance capacity, in alignment with the Global Health Security Agenda and International Health Regulations 2005 objectives for surveillance and reporting. This paper describes the main surveillance activities supported by US CDC and its partners between 2015 and 2019 and provides information on the strategies used and the impact of activities. It also discusses lessons learned for building sustainable capacity and infrastructure for disease surveillance and reporting in similar resource-limited settings.

Pharmacokinetics and pharmacodynamics of artesunate and dihydroartemisinin following oral treatment in pregnant women with asymptomatic Plasmodium falciparum infections in Kinshasa DRC.

BACKGROUND: In many malaria-endemic countries, increasing resistance may soon compromise the efficacy of sulphadoxine-pyrimethamine (SP) for intermittent preventative treatment (IPT) of malaria in pregnancy. Artemisinin-based IPT regimens represent a promising potential alternative to SP. Pharmacokinetic and safety data supporting the use of artemisinin derivatives in pregnancy are urgently needed. METHODS: Subjects included pregnant women with asymptomatic falciparum parasitaemia between 22-26 weeks (n = 13) or 32-36 weeks gestation (n = 13), the same women at three months postpartum, and 25 non-pregnant parasitaemic controls. All subjects received 200 mg orally administered AS. Plasma total and free levels of AS and its active metabolite DHA were determined using a validated LC-MS method. Non-compartmental pharmacokinetic analysis was performed using standard methods. RESULTS: All pregnant women delivered live babies. The median birth weight was 3025 grams [range 2130, 3620]; 2 of 26 babies had birth weights less than 2500 grams. Rates of parasite clearance by 12 hours post-dose were high and comparable among the groups. Rapid elimination of AS was observed in all three groups. The 90% CI for the pregnancy:postpartum ratio of geometric means for total and free AUC fell within the pre-specified 0.66 - 1.50 therapeutic equivalence interval. However, more pronounced pharmacokinetic differences were observed between the pregnancy and control subjects, with the 90% CI for the pregnancy:control ratio of geometric means for both total 0.68 (90% CI 0.57-0.81) and free AUC 0.78 (90% CI 0.63-0.95) not fully contained within the 0.66 - 1.50 interval. All subjects cleared parasites rapidly, and there was no difference in the percentage of women who were parasitaemic 12 hours after dosing. CONCLUSIONS: A single dose of orally administered AS was found to be both effective and without adverse effects in this study of second and third trimester pregnant women in the DRC. Although DHA AUC during pregnancy and postpartum were similar, the AUC for the pregnant group was less than the non-pregnant controls. The findings of this study suggest that additional studies on the pharmacokinetics of AS in pregnant women are needed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00538382.

Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria.

BACKGROUND: The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS), are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA), were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC. METHODS: Data were obtained from 26 pregnant women in the second (22-26 weeks) or the third (32-36 weeks) trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling. RESULTS: A simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F) and volume of distribution (V/F) estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L) for AS V/F, 895 L/h (788-1045 L/h) for AS CL/F, 91.4 L (78.5-109 L) for DHA V/F, and 64.0 L/h (55.1-75.2 L/h) for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7-72.3%). CONCLUSIONS: In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that higher AS doses would be required to maintain similar DHA levels in pregnant women as achieved in non-pregnant controls.

Implementation of DHIS2 for Disease Surveillance in Guinea: 2015-2020.

A robust epidemic-prone disease surveillance system is a critical component of public health infrastructure and supports compliance with the International Health Regulations (IHR). One digital health platform that has been implemented in numerous low- and middle-income countries is the District Health Information System Version 2 (DHIS2). In 2015, in the wake of the Ebola epidemic, the Ministry of Health in Guinea established a strategic plan to strengthen its surveillance system, including adoption of DHIS2 as a health information system that could also capture surveillance data. In 2017, the DHIS2 platform for disease surveillance was piloted in two regions, with the aim of ensuring the timely availability of quality surveillance data for better prevention, detection, and response to epidemic-prone diseases. The success of the pilot prompted the national roll-out of DHIS2 for weekly aggregate disease surveillance starting in January 2018. In 2019, the country started to also use the DHIS2 Tracker to capture individual cases of epidemic-prone diseases. As of February 2020, for aggregate data, the national average timeliness of reporting was 72.2%, and average completeness 98.5%; however, the proportion of individual case reports filed was overall low and varied widely between diseases. While substantial progress has been made in implementation of DHIS2 in Guinea for use in surveillance of epidemic-prone diseases, much remains to be done to ensure long-term sustainability of the system. This paper describes the implementation and outcomes of DHIS2 as a digital health platform for disease surveillance in Guinea between 2015 and early 2020, highlighting lessons learned and recommendations related to the processes of planning and adoption, pilot testing in two regions, and scale up to national level.