Safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnant women with HIV from Gabon and Mozambique: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The cornerstone of malaria prevention in pregnancy, intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine, is contraindicated in women with HIV who are receiving co-trimoxazole prophylaxis. We assessed whether IPTp with dihydroartemisinin-piperaquine is safe and effective in reducing the risk of malaria infection in women with HIV receiving co-trimoxazole prophylaxis and antiretroviral drugs. METHODS: For this randomised, double-blind, placebo-controlled clinical trial, women with HIV attending the first antenatal care clinic visit, resident in the study area, and with a gestational age up to 28 weeks were enrolled at five sites in Gabon and Mozambique. Participants were randomly assigned (1:1) to receive either IPTp with dihydroartemisinin-piperaquine at each scheduled antenatal care visit plus daily co-trimoxazole (intervention group) or placebo at each scheduled antenatal care visit plus daily co-trimoxazole (control group). Randomisation was done centrally via block randomisation (block sizes of eight), stratified by country. IPTp was given over 3 days under direct observation by masked study personnel. The number of daily IPTp tablets was based on bodyweight and according to the treatment guidelines set by WHO (target dose of 4 mg/kg per day [range 2-10 mg/kg per day] of dihydroartemisinin and 18 mg/kg per day [range 16-27 mg/kg per day] of piperaquine given once a day for 3 days). At enrolment, all participants received co-trimoxazole (fixed combination drug containing 800 mg trimethoprim and 160 mg sulfamethoxazole) for daily intake. The primary study outcome was prevalence of peripheral parasitaemia detected by microscopy at delivery. The modified intention-to-treat population included all randomly assigned women who had data for the primary outcome. Secondary outcomes included frequency of adverse events, incidence of clinical malaria during pregnancy, and frequency of poor pregnancy outcomes. All study personnel, investigators, outcome assessors, data analysts, and participants were masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT03671109. FINDINGS: From Sept 18, 2019, to Nov 26, 2021, 666 women (mean age 28·5 years [SD 6·4]) were enrolled and randomly assigned to the intervention (n=332) and control (n=334) groups. 294 women in the intervention group and 308 women in the control group had peripheral blood samples taken at delivery and were included in the primary analysis. Peripheral parasitaemia at delivery was detected in one (<1%) of 294 women in the intervention group and none of 308 women in the control group. The incidence of clinical malaria during pregnancy was lower in the intervention group than in the control group (one episode in the intervention group vs six in the control group; relative risk [RR] 0·12, 95% CI 0·03-0·52, p=0·045). In a post-hoc analysis, the composite outcome of overall malaria infection (detected by any diagnostic test during pregnancy or delivery) was lower in the intervention group than in the control group (14 [5%] of 311 women vs 31 [10%] of 320 women; RR 0·48, 95% CI 0·27-0·84, p=0·010). The frequency of serious adverse events and poor pregnancy outcomes (such as miscarriages, stillbirths, premature births, and congenital malformations) did not differ between groups. The most frequently reported drug-related adverse events were gastrointestinal disorder (reported in less than 4% of participants) and headache (reported in less than 2% of participants), with no differences between study groups. INTERPRETATION: In the context of low malaria transmission, the addition of IPTp with dihydroartemisinin-piperaquine to co-trimoxazole prophylaxis in pregnant women with HIV did not reduce peripheral parasitaemia at delivery. However, the intervention was safe and associated with a decreased risk of clinical malaria and overall Plasmodium falciparum infection, so it should be considered as a strategy to protect pregnant women with HIV from malaria. FUNDING: European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) and Medicines for Malaria Venture. TRANSLATIONS: For the Portuguese and French translations of the abstract see Supplementary Materials section.

Transitioning from the "Three Delays" to a focus on continuity of care: a qualitative analysis of maternal deaths in rural Pakistan and Mozambique.

BACKGROUND: The Three Delays Framework was instrumental in the reduction of maternal mortality leading up to, and during the Millennium Development Goals. However, this paper suggests the original framework might be reconsidered, now that most mothers give birth in facilities, the quality and continuity of the clinical care is of growing importance. METHODS: The paper explores the factors that contributed to maternal deaths in rural Pakistan and Mozambique, using 76 verbal autopsy narratives from the Community Level Interventions for Pre-eclampsia (CLIP) Trial. RESULTS: Qualitative analysis of these maternal death narratives in both countries reveals an interplay of various influences, such as, underlying risks and comorbidities, temporary improvements after seeking care, gaps in quality care in emergencies, convoluted referral systems, and arrival at the final facility in critical condition. Evaluation of these narratives helps to reframe the pathways of maternal mortality beyond a single journey of care-seeking, to update the categories of seeking, reaching and receiving care. CONCLUSIONS: There is a need to supplement the pioneering "Three Delays Framework" to include focusing on continuity of care and the "Four Critical Connection Points": (1) between the stages of pregnancy, (2) between families and health care workers, (3) between health care facilities and (4) between multiple care-seeking journeys. TRIAL REGISTRATION: NCT01911494, Date Registered 30/07/2013.

Efficacy and safety of pyronaridine-artesunate (PYRAMAX) for the treatment of P. falciparum uncomplicated malaria in African pregnant women (PYRAPREG): study protocol for a phase 3, non-inferiority, randomised open-label clinical trial.

INTRODUCTION: Malaria infection during pregnancy increases the risk of low birth weight and infant mortality and should be prevented and treated. Artemisinin-based combination treatments are generally well tolerated, safe and effective; the most used being artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Pyronaridine-artesunate (PA) is a new artemisinin-based combination. The main objective of this study is to determine the efficacy and safety of PA versus AL or DP when administered to pregnant women with confirmed Plasmodium falciparum infection in the second or third trimester. The primary hypothesis is the pairwise non-inferiority of PA as compared with either AL or DP. METHODS AND ANALYSIS: A phase 3, non-inferiority, randomised, open-label clinical trial to determine the safety and efficacy of AL, DP and PA in pregnant women with malaria in five sub-Saharan, malaria-endemic countries (Burkina Faso, Democratic Republic of the Congo, Mali, Mozambique and the Gambia). A total of 1875 pregnant women will be randomised to one of the treatment arms. Women will be actively monitored until Day 63 post-treatment, at delivery and 4-6 weeks after delivery, and infants' health will be checked on their first birthday. The primary endpoint is the PCR-adjusted rate of adequate clinical and parasitological response at Day 42 in the per-protocol population. ETHICS AND DISSEMINATION: This protocol has been approved by the Ethics Committee for Health Research in Burkina Faso, the National Health Ethics Committee in the Democratic Republic of Congo, the Ethics Committee of the Faculty of Medicine and Odontostomatology/Faculty of Pharmacy in Mali, the Gambia Government/MRCG Joint Ethics Committee and the National Bioethics Committee for Health in Mozambique. Written informed consent will be obtained from each individual prior to her participation in the study. The results will be published in peer-reviewed open access journals and presented at (inter)national conferences and meetings. TRIAL REGISTRATION NUMBER: PACTR202011812241529.

Is this pill an antibiotic or a painkiller? Improving the identification of oral antibiotics for better use.

In this Viewpoint, we discuss how the identification of oral antibiotics and their distinction from other commonly used medicines can be challenging for consumers, suppliers, and health-care professionals. There is a large variation in the names that people use to refer to antibiotics and these often relate to their physical appearance, although antibiotics come in many different physical presentations. We also reflect on how the physical appearance of medicine influences health care and public health by affecting communication between patients and health-care professionals, dispensing , medicine use, and the public understanding of health campaigns. Furthermore, we report expert and stakeholder consultations on improving the identification of oral antibiotics and discuss next steps towards a new identification system for antibiotics. We propose to use the physical appearance as a tool to support and nudge awareness about antibiotics and their responsible use.

Choosing blood pressure thresholds to inform pregnancy care in the community: An analysis of cluster trials.

OBJECTIVE: To inform digital health design by evaluating diagnostic test properties of antenatal blood pressure (BP) outputs and levels to identify women at risk of adverse outcomes. DESIGN: Planned secondary analysis of cluster randomised trials. SETTING: India, Pakistan, Mozambique. POPULATION: Women with in-community BP measurements and known pregnancy outcomes. METHODS: Blood pressure was defined by its outputs (systolic and/or diastolic, systolic only, diastolic only or mean arterial pressure [calculated]) and level: normotension-1 (<135/85 mmHg), normotension-2 (135-139/85-89 mmHg), non-severe hypertension (140-149/90-99 mmHg; 150-154/100-104 mmHg; 155-159/105-109 mmHg) and severe hypertension (≥160/110 mmHg). Dose-response (adjusted risk ratio [aRR]) and diagnostic test properties (negative [-LR] and positive [+LR] likelihood ratios) were estimated. MAIN OUTCOME MEASURES: Maternal/perinatal composites of mortality/morbidity. RESULTS: Among 21 069 pregnancies, different BP outputs had similar aRR, -LR, and +LR for adverse outcomes. No BP level (even normotension-1) was associated with low risk (all -LR ≥0.20). Across outcomes, risks rose progressively with higher BP levels above normotension-1. For each of maternal central nervous system events and stillbirth, BP ≥155/105 mmHg showed at least good diagnostic test performance (+LR ≥5.0) and BP ≥135/85 mmHg at least fair performance, similar to BP ≥140/90 mmHg (+LR 2.0-4.99). CONCLUSIONS: In the community, normal BP values do not provide reassurance about subsequent adverse outcomes. Given the similar performance of BP cut-offs of 135/85 and 140/90 mmHg for hypertension, and 155/105 and 160/110 mmHg for severe hypertension, digital decision support for women in the community should consider using these lower thresholds.

The development and implementation of a community engagement strategy to improve maternal health in southern Mozambique.

Delays to seek medical help can contribute to maternal deaths particularly in community settings at home or on the road to a health facility. Community engagement (CE) can improve care-seeking behaviours and complements community-based interventions strengthening maternal health. The purpose of this paper is to describe the process undertaken to develop and implement a large-scale community engagement strategy in rural southern Mozambique. The CE strategy was developed within the context of the "Community-Level Interventions for Pre-eclampsia" (NCT01911494) conducted between 2015-2017 in southern Mozambique. Key CE messages included pregnancy complications and their warning signs, including pre-eclampsia and eclampsia, as well as emergency readiness, birth preparedness, decision-making mechanisms, transport options and information about the trial. CE meeting logs were used to record quantitative and qualitative information on demographic data and feedback. Quantitative data was analyzed using RStudio (RStudio Inc, Boston, United States) and community feedback was qualitatively analyzed on NVivo12 (QSR International, Melbourne, Australia). CE activities reached 19,169 participants during 4,239 meetings. CE activities were reported to be well received by community members though there was a relatively lower participation of men (3565 /18.6%). The use of recognized local leaders and personnel, such as community leaders, nurses and community health workers, allowed for greater acceptance of CE activities and maximized coverage of health messages in the community setting. Our CE strategy was effective in integrating maternal health promoting activities in routine care of community health workers and nurses in the area. Understanding district differences, engaging husbands, partners, mothers-in-law and community-level decision-makers to build local support for maternal health and flexibility to tailor messages to local needs were important in developing sustainable forms of CE. Better strategies are needed to effectively engage men in maternal health promotion who were less available due to working outside of the home or neighbourhoods.

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

SARS-CoV-2 Seropositivity and HIV Viral Load Among Mozambican Pregnant Women.

INTRODUCTION: Prevalence estimates of SARS-CoV-2 infection in Africa are limited, particularly among pregnant women and in those living with HIV. This study assessed the seroprevalence of SARS-CoV-2 antibodies among Mozambican HIV-infected pregnant women during the first year of the pandemic, before COVID-19 vaccines were deployed in the country. SETTING: The study was conducted in Manhiça district, a semirural area in southern Mozambique. METHODS: A prospective cohort study including pregnant women living with HIV was conducted from November 2019 to June 2021. Women were enrolled at the first antenatal care clinic visit and followed until postpartum. HIV viral load and IgM/IgG antibodies against SARS-CoV-2 were determined in blood samples at first antenatal care clinic visit and at delivery. Associations between SARS-CoV-2 serostatus and maternal characteristics at enrolment were analyzed. RESULTS: A total of 397 women were enrolled. SARS-CoV-2 IgG/IgM antibodies were detected in 7.1% of women at enrolment and in 8.5% of women at delivery. Overall, SARS-CoV-2 antibodies were detected in 45 women (11.3%; 95% confidence interval 8.4 to 14.9%) during the study period; the first seropositive sample was identified in September 2020. Having undetectable HIV viral load was associated with seropositivity of SARS-CoV-2 IgG/IgM [odds ratio 3.35 (1.10 to 11.29); P = 0.039]. CONCLUSION: Seroprevalence of SARS-CoV-2 antibodies in this cohort of Mozambican unvaccinated pregnant women was similar to reported global estimates of approximately 10% in pregnancy for 2021. The findings also suggest that pregnant women with high HIV viral load may have an impaired immune response against SARS-CoV-2 and might need to be carefully managed in case of COVID-19.

Burden, clinical presentation and risk factors of advanced HIV disease in pregnant Mozambican women.

BACKGROUND: Information on the frequency and clinical features of advanced HIV disease (AHD) in pregnancy and its effects on maternal and perinatal outcomes is limited. The objective of this study was to describe the prevalence and clinical presentation of AHD in pregnancy, and to assess the impact of AHD in maternal and perinatal outcomes in Mozambican pregnant women. METHODS: This is a prospective and retrospective cohort study including HIV-infected pregnant women who attended the antenatal care (ANC) clinic at the Manhiça District Hospital between 2015 and 2020. Women were followed up for 36 months. Levels of CD4 + cell count were determined to assess AHD immune-suppressive changes. Risk factors for AHD were analyzed and the immune-suppressive changes over time and the effect of AHD on pregnancy outcomes were assessed. RESULTS: A total of 2458 HIV-infected pregnant women were enrolled. The prevalence of AHD at first ANC visit was 14.2% (349/2458). Among women with AHD at enrolment, 76.2% (260/341) were on antiretroviral therapy (ART). The proportion of women with AHD increased with age reaching 20.5% in those older than 35 years of age (p < 0.001). Tuberculosis was the only opportunistic infection diagnosed in women with AHD [4.9% (17/349)]. There was a trend for increased CD4 + cell count in women without AHD during the follow up period; however, in women with AHD the CD4 + cell count remained below 200 cells/mm3 (p < 0.001). Forty-two out of 2458 (1.7%) of the women were severely immunosuppressed (CD4 + cell count < 50 cells/mm3). No significant differences were detected between women with and without AHD in the frequency of maternal mortality, preterm birth, low birth weight and neonatal HIV infection. CONCLUSIONS: After more than two decades of roll out of ART in Mozambique, over 14% and nearly 2% of HIV-infected pregnant women present at first ANC clinic visit with AHD and severe immunosuppression, respectively. Prompt HIV diagnosis in women of childbearing age, effective linkage to HIV care with an optimal ART regimen and close monitoring after ART initiation may contribute to reduce this burden and improve maternal and child survival.

Lay HIV counselors' knowledge and attitudes toward depression: A mixed-methods cross-sectional study at primary healthcare centers in Mozambique.

Introduction: Depression is the most common mental disorder among people living with HIV/AIDS and has a negative impact on HIV treatment outcomes. Training lay HIV counselors to identify and manage depression may contribute to improved patient access and adherence to treatment, and reduce stigma and discrimination among lay health workers toward both HIV and depression. The purpose of this study was to assess the current knowledge and attitudes of lay HIV counselors toward managing depression in primary care in Mozambique. Methods: We conducted a mixed-methods cross-sectional study to assess depression-related knowledge and attitudes among lay HIV counselors in 13 primary healthcare facilities in Mozambique. We used the quantitative Depression Attitude Questionnaire (DAQ) scale, followed by open-ended questions to further explore three key DAQ domains: the nature of depression, treatment preferences, and professional attitudes or reactions. Results: The sample included 107 participants (77.6% female, mean age: 32.3 years, sd = 7.4). Most (82.2%) had less than a high/technical school education. Findings suggested that some HIV counselors had knowledge of depression and described it as a cluster of psychological symptoms (e.g., deep sadness, anguish, apathy, isolation, and low self-esteem) sometimes leading to suicidal thoughts, or as a consequence of life stressors such as loss of a loved one, abuse, unemployment or physical illness, including being diagnosed with HIV infection. HIV counselors identified talking to trusted people about their problems, including family and/or counseling with a psychotherapist, as the best way for patients to deal with depression. While acknowledging challenges, counselors found working with patients with depression to be rewarding. Conclusion: Lay health counselors identified HIV and psychosocial issues as key risk factors for depression. They believed that the treatment approach should focus on social support and psychotherapy.

Burden of malaria in pregnancy among adolescent girls compared to adult women in 5 sub-Saharan African countries: A secondary individual participant data meta-analysis of 2 clinical trials.

BACKGROUND: Malaria is among the top causes of death in adolescent girls (10 to 19 years) globally. Adolescent motherhood is associated with increased risk of adverse maternal and neonatal outcomes. The interaction of malaria, adolescence, and pregnancy is especially relevant in malaria endemic areas, where rates of adolescent pregnancy are high. However, data on burden of malaria among adolescent girls are limited. This study aimed at investigating whether adolescent girls were at a greater risk of experiencing malaria-related outcomes in pregnancy-parasitaemia and clinical disease-than adult women. METHODS AND FINDINGS: An individual secondary participant-level meta-analysis was conducted using data from 5,804 pregnant women participating in 2 malaria prevention clinical trials in Benin, Gabon, Kenya, Mozambique, and Tanzania between 2009 and 2014. Of the sample, 1,201 participants were adolescent girls with a mean age of 17.5 years (standard deviation (SD) 1.3) and 886 (73.8%) of them primigravidae. Among the 4,603 adult women with mean age of 27.0 years (SD 5.4), 595 (12.9%) were primigravidae. Mean gestational age at enrolment was 20.2 weeks (SD 5.2) and 1,069 (18.4%) participants were HIV-infected. Women were followed monthly until the postpartum visit (1 month to 6 weeks after delivery). This study considered outcomes including clinical episodes during pregnancy, peripheral parasitaemia at delivery, and placental malaria. A 2-stage meta-analysis approach was followed by pooling single multivariable regression results into standard DerSimonian-Laird random-effects models. Adolescent girls were more likely than adult women to present with clinical malaria during pregnancy (incidence risk ratio (IRR) 1.70, 95% confidence interval (CI) 1.20; 2.39, p-value = 0.003, I2 = 0.0%, N = 4,092), peripheral parasitaemia at delivery (odds ratio (OR) 2.28, 95% CI 1.46; 3.55, p-value < 0.001, I2 = 0.0%, N = 3,977), and placental infection (OR 1.97, 95% CI 1.31; 2.98, p-value = 0.001, I2 = 1.4%, N = 4,797). Similar associations were observed among the subgroup of HIV-uninfected participants: IRR 1.72 (95% CI 1.22; 2.45, p-value = 0.002, I2 = 0.0%, N = 3,531) for clinical malaria episodes, OR 2.39 (95% CI 1.49; 3.86, p-value < 0.001, I2 = 0.0%, N = 3,053) for peripheral parasitaemia, and OR 1.88 (95% CI 1.06 to 3.33, p-value = 0.03, I2 = 34.9%, N = 3,847) for placental malaria. Among HIV-infected subgroups statistically significant associations were not observed. Similar associations were found in the subgroup analysis by gravidity. The small sample size and outcome prevalence in specific countries limited the inclusion of some countries in the meta-analysis. Furthermore, peripheral parasitaemia and placental malaria presented a considerable level of missing data-12.6% and 18.2% of participants had missing data on those outcomes, respectively. Given the original scope of the clinical trials, asymptomatic malaria infection was only assessed at the end of pregnancy through peripheral and placental parasitaemia. CONCLUSIONS: In this study, we observed that adolescent girls in sub-Saharan Africa (SSA) are more prone to experience clinical malaria episodes during pregnancy and have peripheral malaria and placental infection at delivery than adult women. Moreover, to the best of our knowledge, for the first time this study disaggregates figures and stratifies analyses by HIV infection. Similar associations were found for both HIV-infected and uninfected women, although those for HIV-infected participants were not statistically significant. Our finding suggests that adolescent girls may benefit from targeted malaria prevention strategies even before they become pregnant.

Preparing for Disease X: Ensuring Vaccine Equity for Pregnant Women in Future Pandemics.

Disease X represents a yet unknown human pathogen which has potential to cause a serious international epidemic or pandemic. The COVID-19 pandemic has illustrated that despite being at increased risk of severe disease compared with the general population, pregnant women were left behind in the development and implementation of vaccination, resulting in conflicting communications and changing guidance about vaccine receipt in pregnancy. Based on the COVID-19 experience, the COVAX Maternal Immunization Working Group have identified three key factors and five broad focus topics for consideration when proactively planning for a disease X pandemic, including 10 criteria for evaluating pandemic vaccines for potential use in pregnant women. Prior to any disease X pandemic, collaboration and coordination are needed to close the pregnancy data gap which is currently a barrier to gender equity in health innovation, which will aid in allowing timely access to life-saving interventions including vaccines for pregnant women and their infants.

Antibiotic prescription for HIV-positive patients in primary health care in Mozambique: A cross-sectional study.

Background: Antibiotic overuse is a major public health challenge worldwide and it can result in the emergence and spread of drug resistance. In Mozambique, there are limited data related to primary care physicians' antibiotic prescription patterns. The aim of this study was to assess the antibiotic prescription patterns for HIV- positive patients in primary health care. Methods: A prospective cross-sectional quantitative study was conducted in eight primary health care units in Southern Mozambique. The study was based on recording outpatient prescriptions using a structured questionnaire. Three hundred and sixty-nine prescriptions and clinical records of HIV-positive patients from 31 prescribers were assessed. A total of eight general practitioners, 13 medical technicians and 10 nurses participated. Results: Antibiotics were used in 65.9% of prescriptions, with an average of 0.9 antibiotics per prescription. Of a total of 334 prescribed antibiotics, 69.8% were for the treatment of infections and 30.2% for prophylaxis. Penicillin (29.2%), sulphonamides (19.7%), and quinolones (16.3%) were the most prescribed classes of antibiotics for treatment. For prophylaxis, only sulphonamides (93.1%) and macrolides (6.9%) were prescribed. The diagnosis was the only variable that had a significant association with antibiotic prescription (p < 0.001). Most of penicillins (68.0%) and sulphonamides (21.4%) were prescribed to treat infections related to the respiratory tract. Conclusion: The prescription of antibiotics was high and influenced by patient clinical conditions. Antibiotics were prescribed either for treatment or prophylaxis of infections, mostly to treat respiratory tract infections. Prescribers should be encouraged to adopt a rational use of antibiotics to reduce unnecessary prescriptions.

How Gender Influenced the Experience of Using a mHealth Intervention in Rural Mozambique: Secondary Qualitative Analysis of Community Health Worker Survey Data.

Background: The mixed-gender community health worker (CHW) program in Mozambique is a window into the different experiences that male and female CHWs may face in their work. The objective of this study is to investigate how gender influenced the experiences of community health workers using the PIERS on the Move (POM) mHealth app in Mozambique. Methods: This is a secondary analysis by gender of health care workers involved in the Mozambique Community Level Intervention for Pre-eclampsia (CLIP) cluster randomized trial (NCT01911494). A structured survey with 10 open-ended questions was used to elicit CHW experiences using the POM app. Data collection took place in 2017 after completion of the CLIP trial. This analysis examined emergent themes to consider how experiences may have been shaped by health worker gender. Results: Of the 43 CHWs who used the POM app, there were 31 (72%) women and 12 (28%) men. Gender differences emerged in descriptions of how using POM increased their value and respect by pregnant women and community members. Fifty-eight percent of female CHWs (18/31) said that POM positively influenced their status in the community in comparison to 33% of their male counterparts (4/12). While the small sample sizes, particularly of male CHWs who used POM, preclude conclusions, these findings were supported by qualitative results. Female CHWs tended to elaborate more about community perceptions of their increased value and status as health care providers than male CHWs. Conclusion: CHWs work within existing gender norms. While gender norms are perceived to support the comfort of women to speak to another woman about their maternal and child health issues, gender norms also work against female CHWs as their professionalism may be questioned more than for their male counterparts. CHW's narratives suggested that the mHealth intervention was valued beyond the technology itself because it also added symbolic clinical value and demonstrated a tangible investment in their professional capacities, which may have been especially appreciated by the female CHWs.

Nevirapine hair and plasma concentrations and HIV-1 viral suppression among HIV infected ante-partum and post-partum women attended in a mother and child prevention program in Maputo city, Mozambique.

INTRODUCTION: Prevention of mother to child transmission of HIV (PMTCT) is frequently challenged by irregular access to more effective anti-retroviral therapy. Nevirapine single dose (sdNVP), sdNVP+AZT+3TC for MTCT prophylaxis and NVP+ AZT+3TC for treatment and PMTCT were withdrawn due to low genetic resistance barrier and low efficacy. However current PMTCT lines in Mozambique include DTG+3TC+TDF, TDF+3TC+EFV, DTG +ABC+3TC, and AZT + NVP syrup prophylaxis for exposed babies. We assessed NVP hair and plasma concentrations and association with HIV-1RNA suppression among HIV+ ante-partum and post-partum women under PMTCT in Maputo, Mozambique. METHODS: From December 2013 to November 2014, prospectively were enrolled 200 HIV+ ante-partum women on 200mg nevirapine and zidovudine 300 plus lamivudine 150mg twice daily at least with 3 months treatment and seen again at 24 weeks post-partum. Self-reported pill-taking adherence, NVP concentrations in hair, plasma, hemoglobin, CD4 cell count, HIV-1 RNA load was evaluated. NVP concentration in hair and plasma was analyzed as categorical quartile variable based on better data fit. NVP concentration was set between ≤3.77 ng/ml in plasma and ≤17,20 ng/mg in hair in quartile one to ≥5.36 ng/ml in plasma and ≥53.21 ng/mg in hair in quartile four. Logistic regression models for repeated measures were calculated. Following the World Health Organization (WHO) guidelines we set viral suppression at HIV-1RNA < 1000 c/mL. Outcome was HIV-1 RNA<1000 copies/ml. Predictor was NVP concentration in hair categorized in quartiles. RESULTS: In total 369 person-visits (median of 1.85) were recorded. Self-reported adherence was 98% (IQR 97-100%) at ante-partum. In 25% person visits, NVP concentrations were within therapeutic levels (3.77 ng/ml to 5.35 ng/ml) in plasma and (17.20 ng/mg to 53.20 ng/mg) in hair. In 50% person visits NVP concentrations were above 5.36 ng/ml in plasm and 53.21 ng/mg in hair. HIV-1 RNA suppression was found in 34.7% of women with two viral loads, one at enrollment and another in post-partum. Odds of HIV-1 RNA suppression in quartile 4, was about 6 times higher than in quartile 1 (p-value = 0.006) for NVP hair concentration and 7 times for NVP plasma concentration (p-value = 0.012). CONCLUSIONS: The study results alert for potential low efficacy of current PMTCT drug regimens in use in Mozambique. Affordable means for individual monitoring adherence, ART plasma and hair levels, drug resistant and HIV-1 RNA levels monitoring are recommended for prompt identification of inadequate drug regimens exposure patterns and adjust accordingly.

Evaluation of the safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in HIV-infected pregnant women: protocol of a multicentre, two-arm, randomised, placebo-controlled, superiority clinical trial (MAMAH project).

INTRODUCTION: Malaria infection during pregnancy is an important driver of maternal and neonatal health especially among HIV-infected women. Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine is recommended for malaria prevention in HIV-uninfected women, but it is contraindicated in those HIV-infected on cotrimoxazole prophylaxis (CTXp) due to potential adverse effects. Dihydroartemisinin-piperaquine (DHA-PPQ) has been shown to improve antimalarial protection, constituting a promising IPTp candidate. This trial's objective is to determine if monthly 3-day IPTp courses of DHA-PPQ added to daily CTXp are safe and superior to CTXp alone in decreasing the proportion of peripheral malaria parasitaemia at the end of pregnancy. METHODS AND ANALYSIS: This is a multicentre, two-arm, placebo-controlled, individually randomised trial in HIV-infected pregnant women receiving CTXp and antiretroviral treatment. A total of 664 women will be enrolled at the first antenatal care clinic visit in sites from Gabon and Mozambique. Participants will receive an insecticide-treated net, and they will be administered monthly IPTp with DHA-PPQ or placebo (1:1 ratio) as directly observed therapy from the second trimester of pregnancy. Primary study outcome is the prevalence of maternal parasitaemia at delivery. Secondary outcomes include prevalence of malaria-related maternal and infant outcomes and proportion of adverse perinatal outcomes. Participants will be followed until 6 weeks after the end of pregnancy and their infants until 1 year of age to also evaluate the impact of DHA-PPQ on mother-to-child transmission of HIV. The analysis will be done in the intention to treat and according to protocol cohorts, adjusted by gravidity, country, seasonality and other variables associated with malaria. ETHICS AND DISSEMINATION: The protocol was reviewed and approved by the institutional and national ethics committees of Gabon and Mozambique and the Hospital Clinic of Barcelona. Project results will be presented to all stakeholders and published in open-access journals. TRIAL REGISTRATION NUMBER: NCT03671109.

Implementation of the PIERS on the Move mHealth Application From the Perspective of Community Health Workers and Nurses in Rural Mozambique.

Background:mHealth is increasingly regarded as having the potential to support service delivery by health workers in low-resource settings. PIERS on the Move (POM) is a mobile health application developed to support community health workers identification and management of women at risk of adverse outcomes from pre-eclampsia. The objective of this study was to evaluate the impact of using POM in Mozambique on community health care workers' knowledge and self-efficacy related to caring for women with pre-eclampsia, and their perception of usefulness of the tool to inform implementation. Method: An evaluation was conducted for health care workers in the Mozambique Community Level Intervention for Pre-eclampsia (CLIP) cluster randomized trial from 2014 to 2016 in Maputo and Gaza provinces (NCT01911494). A structured survey was designed using themes from the Technology Acceptance Model, which describes the likelihood of adopting the technology based on perceived usefulness and perceived ease of use. Surveys were conducted in Portuguese and translated verbatim to English for analysis. Preliminary analysis of open-ended responses was conducted to develop a coding framework for full qualitative analysis, which was completed using NVivo12 (QSR International, Melbourne, Australia). Results: Overall, 118 community health workers (44 intervention; 74 control) and 55 nurses (23 intervention; 32 control) were surveyed regarding their experiences. Many community health workers found the POM app easy to use (80%; 35/44), useful in guiding their activities (68%; 30/44) and pregnant women received their counseling more seriously because of the POM app (75%; 33/44). Almost a third CHWs reported some challenges using the POM app (30%; 13/44), including battery depletion after a full day's activity. Community health workers reported increases in knowledge about pre-eclampsia and other pregnancy complications and increases in confidence, comfort and capacity to advise women on health conditions and deliver services. Nurses recognized the increased capacity of community health workers and were more confident in their clinical and technological skills to identify women at risk of obstetric complications. Conclusions: Many of the community health workers reported that POM improved knowledge, self-efficacy and strengthened relationships with the communities they serve and local nurses. This helped to strengthen the link between community and health facility. However, findings highlight the need to consider program and systematic challenges to implementation.

Causes and circumstances of maternal death: a secondary analysis of the Community-Level Interventions for Pre-eclampsia (CLIP) trials cohort.

BACKGROUND: Incomplete vital registration systems mean that causes of death during pregnancy and childbirth are poorly understood in low-income and middle-income countries. To inform global efforts to reduce maternal mortality, we compared physician review and computerised analysis of verbal autopsies (interpreting verbal autopsies [InterVA] software), to understand their agreement on maternal cause of death and circumstances of mortality categories (COMCATs) in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials. METHODS: The CLIP trials took place in India, Pakistan, and Mozambique, enrolling pregnant women aged 12-49 years between Nov 1, 2014, and Feb 28, 2017. 69 330 pregnant women were enrolled in 44 clusters (36 008 in the 22 intervention clusters and 33 322 in the 22 control clusters). In this secondary analysis of maternal deaths in CLIP, we included women who died in any of the 22 intervention clusters or 22 control clusters. Trained staff administered the WHO 2012 verbal autopsy after maternal deaths. Two physicians (and a third for consensus, if needed) reviewed trial surveillance data and verbal autopsies, and, in intervention clusters, community health worker-led visit data. They determined cause of death according to the WHO International Classification of Diseases-Maternal Mortality (ICD-MM). Verbal autopsies were also analysed by InterVA computer models (versions 4 and 5) to generate cause of death. COMCAT analysis was provided by InterVA-5 and, in India, by physician review of Maternal Newborn Health Registry data. Causes of death and COMCATs assigned by physician review, Inter-VA-4, and InterVA-5 were compared, with agreement assessed with Cohen's κ coefficient. FINDINGS: Of 61 988 pregnancies with successful follow-up in the CLIP trials, 143 maternal deaths were reported (16 deaths in India, 105 in Pakistan, and 22 in Mozambique). The maternal death rate was 231 (95% CI 193-268) per 100 000 identified pregnancies. Most deaths were attributed to direct maternal causes (rather than indirect or undetermined causes as per ICD-MM classification), with fair to good agreement between physician review and InterVA-4 (κ=0·56 [95% CI 0·43-0·66]) or InterVA-5 (κ=0·44 [0·30-0·57]), and InterVA-4 and InterVA-5 (κ=0·72 [0·60-0·84]). The top three causes of death were the same by physician review, InterVA-4, and InterVA-5 (ICD-MM categories obstetric haemorrhage, non-obstetric complications, and hypertensive disorders); however, attribution of individual patient deaths to obstetric haemorrhage varied more between methods (physician review, 38 [27%] deaths; InterVA-4, 69 [48%] deaths; and InterVA-5, 82 [57%] deaths), than did attribution to non-obstetric causes (physician review, 39 [27%] deaths; InterVA-4, 37 [26%] deaths; and InterVA-5, 28 [20%] deaths) or hypertensive disorders (physician review, 23 [16%] deaths; InterVA-4, 25 [17%] deaths; and InterVA-5, 24 [17%] deaths). Agreement for all nine ICD-MM categories was fair for physician review versus InterVA-4 (κ=0·48 [0·38-0·58]), poor for physician review versus InterVA-5 (κ=0·36 [0·27-0·46]), and good for InterVA-4 versus InterVA-5 (κ=0·69 [0·59-0·79]). The most commonly assigned COMCATs by InterVA-5 were emergencies (68 [48%] of 143 deaths) and health systems (62 [43%] deaths), and by physician review (India only) were health systems (seven [44%] of 16 deaths) and inevitability (five [31%] deaths); agreement between InterVA-5 and physician review (India data only) was poor (κ=0·04 [0·00-0·15]). INTERPRETATION: Our findings indicate that InterVA-5 is less accurate than InterVA-4 at ascertaining causes and circumstances of maternal death, when compared with physician review. Our results suggest a need to improve the next iteration of InterVA, and for researchers and clinicians to preferentially use InterVA-4 when recording maternal deaths. FUNDING: University of British Columbia (grantee of the Bill & Melinda Gates Foundation).

Blood pressure thresholds in pregnancy for identifying maternal and infant risk: a secondary analysis of Community-Level Interventions for Pre-eclampsia (CLIP) trial data.

BACKGROUND: Blood pressure measurement is a marker of antenatal care quality. In well resourced settings, lower blood pressure cutoffs for hypertension are associated with adverse pregnancy outcomes. We aimed to study the associations between blood pressure thresholds and adverse outcomes and the diagnostic test properties of these blood pressure cutoffs in low-resource settings. METHODS: We did a secondary analysis of data from 22 intervention clusters in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials (NCT01911494) in India (n=6), Mozambique (n=6), and Pakistan (n=10). We included pregnant women aged 15-49 years (12-49 years in Mozambique), identified in their community by trained community health workers, who had data on blood pressure measurements and outcomes. The trial was unmasked. Maximum blood pressure was categorised as: normal blood pressure (systolic blood pressure [sBP] <120 mm Hg and diastolic blood pressure [dBP] <80 mm Hg), elevated blood pressure (sBP 120-129 mm Hg and dBP <80 mm Hg), stage 1 hypertension (sBP 130-139 mm Hg or dBP 80-89 mm Hg, or both), non-severe stage 2 hypertension (sBP 140-159 mm Hg or dBP 90-109 mm Hg, or both), or severe stage 2 hypertension (sBP ≥160 mm Hg or dBP ≥110 mm Hg, or both). We classified women according to the maximum blood pressure category reached across all visits for the primary analyses. The primary outcome was a maternal, fetal, or neonatal mortality or morbidity composite. We estimated dose-response relationships between blood pressure category and adverse outcomes, as well as diagnostic test properties. FINDINGS: Between Nov 1, 2014, and Feb 28, 2017, 21 069 women (6067 in India, 4163 in Mozambique, and 10 839 in Pakistan) contributed 103 679 blood pressure measurements across the three CLIP trials. Only women with non-severe or severe stage 2 hypertension, as discrete diagnostic categories, experienced more adverse outcomes than women with normal blood pressure (risk ratios 1·29-5·88). Using blood pressure categories as diagnostic thresholds (women with blood pressure within the category or any higher category vs those with blood pressure in any lower category), dose-response relationships were observed between increasing thresholds and adverse outcomes, but likelihood ratios were informative only for severe stage 2 hypertension and maternal CNS events (likelihood ratio 6·36 [95% CI 3·65-11·07]) and perinatal death (5·07 [3·64-7·07]), particularly stillbirth (8·53 [5·63-12·92]). INTERPRETATION: In low-resource settings, neither elevated blood pressure nor stage 1 hypertension were associated with maternal, fetal, or neonatal mortality or morbidity adverse composite outcomes. Only the threshold for severe stage 2 hypertension met diagnostic test performance standards. Current diagnostic thresholds for hypertension in pregnancy should be retained. FUNDING: University of British Columbia, the Bill & Melinda Gates Foundation.