Climatic drivers of melioidosis in Laos and Cambodia: a 16-year case series analysis

Background: Burkholderia pseudomallei is the cause of melioidosis, a serious and difficult to treat infection that is endemic throughout the tropics. Melioidosis incidence is highly seasonal. We aimed to identify the climatic drivers of infection and to shed light on modes of transmission and potential preventive strategies. Methods: We examined the records of patients diagnosed with melioidosis at the Microbiology Laboratory of Mahosot Hospital in Vientiane, Laos, between October, 1999, and August, 2015, and all patients with culture-confirmed melioidosis presenting to the Angkor Hospital for Children in Siem Reap, Cambodia, between February, 2009, and December, 2013. We also examined local temperature, humidity, precipitation, visibility, and wind data for the corresponding time periods. We estimated the B pseudomallei incubation period by examining profile likelihoods for hypothetical exposure-to-presentation delays. Findings: 870 patients were diagnosed with melioidosis in Laos and 173 patients were diagnosed with melioidosis in Cambodia during the study periods. Melioidosis cases were significantly associated with humidity (p<0·0001), low visibility (p<0·0001), and maximum wind speeds (p<0·0001) in Laos, and humidity (p=0·010), rainy days (p=0·015), and maximum wind speed (p=0·0070) in Cambodia. Compared with adults, children were at significantly higher odds of infection during highly humid months (odds ratio 2·79, 95% CI 1·83–4·26). Lung and disseminated infections were more common during windy months. The maximum likelihood estimate of the incubation period was 1 week (95% CI 0–2). Interpretation: The results of this study demonstrate a significant seasonal burden of melioidosis among adults and children in Laos and Cambodia. Our findings highlight the risks of infection during highly humid and windy conditions, and suggest a need for increased awareness among at-risk individuals, such as children

Climatic drivers of melioidosis in Laos and Cambodia: a 16-year case series analysis.

BACKGROUND: Burkholderia pseudomallei is the cause of melioidosis, a serious and difficult to treat infection that is endemic throughout the tropics. Melioidosis incidence is highly seasonal. We aimed to identify the climatic drivers of infection and to shed light on modes of transmission and potential preventive strategies. METHODS: We examined the records of patients diagnosed with melioidosis at the Microbiology Laboratory of Mahosot Hospital in Vientiane, Laos, between October, 1999, and August, 2015, and all patients with culture-confirmed melioidosis presenting to the Angkor Hospital for Children in Siem Reap, Cambodia, between February, 2009, and December, 2013. We also examined local temperature, humidity, precipitation, visibility, and wind data for the corresponding time periods. We estimated the B pseudomallei incubation period by examining profile likelihoods for hypothetical exposure-to-presentation delays. FINDINGS: 870 patients were diagnosed with melioidosis in Laos and 173 patients were diagnosed with melioidosis in Cambodia during the study periods. Melioidosis cases were significantly associated with humidity (p<0·0001), low visibility (p<0·0001), and maximum wind speeds (p<0·0001) in Laos, and humidity (p=0·010), rainy days (p=0·015), and maximum wind speed (p=0·0070) in Cambodia. Compared with adults, children were at significantly higher odds of infection during highly humid months (odds ratio 2·79, 95% CI 1·83-4·26). Lung and disseminated infections were more common during windy months. The maximum likelihood estimate of the incubation period was 1 week (95% CI 0-2). INTERPRETATION: The results of this study demonstrate a significant seasonal burden of melioidosis among adults and children in Laos and Cambodia. Our findings highlight the risks of infection during highly humid and windy conditions, and suggest a need for increased awareness among at-risk individuals, such as children. FUNDING: Wellcome Trust

Climatic drivers of melioidosis in Laos and Cambodia: a 16-year case series analysis

Background: Burkholderia pseudomallei is the cause of melioidosis, a serious and difficult to treat infection that is endemic throughout the tropics. Melioidosis incidence is highly seasonal. We aimed to identify the climatic drivers of infection and to shed light on modes of transmission and potential preventive strategies. Methods: We examined the records of patients diagnosed with melioidosis at the Microbiology Laboratory of Mahosot Hospital in Vientiane, Laos, between October, 1999, and August, 2015, and all patients with culture-confirmed melioidosis presenting to the Angkor Hospital for Children in Siem Reap, Cambodia, between February, 2009, and December, 2013. We also examined local temperature, humidity, precipitation, visibility, and wind data for the corresponding time periods. We estimated the B pseudomallei incubation period by examining profile likelihoods for hypothetical exposure-to-presentation delays. Findings: 870 patients were diagnosed with melioidosis in Laos and 173 patients were diagnosed with melioidosis in Cambodia during the study periods. Melioidosis cases were significantly associated with humidity (p<0·0001), low visibility (p<0·0001), and maximum wind speeds (p<0·0001) in Laos, and humidity (p=0·010), rainy days (p=0·015), and maximum wind speed (p=0·0070) in Cambodia. Compared with adults, children were at significantly higher odds of infection during highly humid months (odds ratio 2·79, 95% CI 1·83–4·26). Lung and disseminated infections were more common during windy months. The maximum likelihood estimate of the incubation period was 1 week (95% CI 0–2). Interpretation: The results of this study demonstrate a significant seasonal burden of melioidosis among adults and children in Laos and Cambodia. Our findings highlight the risks of infection during highly humid and windy conditions, and suggest a need for increased awareness among at-risk individuals, such as children

Effectiveness of Non-nucleoside Reverse-Transcriptase Inhibitor-Based Antiretroviral Therapy in Women Previously Exposed to a Single Intrapartum Dose of Nevirapine: A Multi-country, Prospective Cohort Study

In a comparative cohort study, Jeffrey Stringer and colleagues investigate the risk of ART failure in women who received single-dose nevirapine for PMTCT, and assess the duration of increased risk

Correlates of HIV status non-disclosure by pregnant women living with HIV to their male partners in Uganda: a cross-sectional study

Thesis (Master's)--University of Washington, 2020Background: HIV status disclosure by pregnant women living with HIV (PWLHIV) to their male partners is associated with improved maternal and infant outcomes. Understanding relationship factors associated with non-disclosure of HIV status by PWLHIV to their partners can inform the design of interventions to facilitate status disclosure. Methods: We conducted a cross-sectional study using enrollment data from 500 PWLHIV participating in a randomized controlled trial assessing secondary distribution of HIV self-testing kits in Kampala, Uganda. HIV status non-disclosure was the primary outcome of interest. We conducted univariate and multivariate binomial regressions to assess the association between socio-demographic, HIV history, and relationship characteristics and non-disclosure of HIV status. Results: Overall, 68.2% of women in our sample had not disclosed their HIV status to their partners. Factors that increased the likelihood of non-disclosure included shorter relationship duration <1 year (adjusted prevalence ratio (aPR=1.25); 95% CI: 1.02-1.54), being in a polygamous relationship (aPR=1.21; 95% CI: 1.07-1.36), not married (aPR=1.20; 95% CI: 1.07-1.35), reporting uncertainty about whether their partner had ever HIV-tested (aPR=1.55; 95% CI: 1.28-1.88), and reporting lack of social support from people aware of their status (aPR=1.32; 95% CI: 1.18-1.49). Conclusion: Relationship factors, including shorter-term, unmarried, and polygamous relationships, and uncertainty about the partner’s HIV testing history, were associated with increased likelihood of non-disclosure of HIV status by pregnant women to their partner. Interventions that facilitate couples’ disclosure, provide counseling messaging to reduce relationship dissolution in sero-discordant couples, and provide opportunities for women to benefit from peer support may help improve disclosure. Clinicaltrials.gov ID number: NCT0348453

FAMILY MATTERS: Relationship dynamics among couples affected by HIV during pregnancy, and neurodevelopment of HIV-exposed uninfected infants in sub-Saharan Africa

Thesis (Ph.D.)--University of Washington, 2023University of Washington Abstract Family Matters:Relationship dynamics among couples affected by HIV during pregnancy, and neurodevelopment of HIV-exposed uninfected infants in sub-Saharan Africa Michelle A Bulterys Chair of the Supervisory Committee:Dr. Grace John-Stewart Departments of Epidemiology, Global Health and Pediatrics Introduction: Caregiver wellbeing is closely linked to child health and neurodevelopmental outcomes. Families affected by HIV in sub-Saharan Africa (SSA) may face increased risk of poverty, parental relationship dissolution, and poorer child neurodevelopment, but these associations are poorly understood. Pregnant women living with HIV (PWLHIV) in sub-Saharan Africa (SSA) are especially vulnerable to adverse consequences of disclosure of their HIV serostatus, including separation, financial hardship, and poor mental and physical health outcomes. The integration of quantitative and qualitative research methods is urgently needed to better understand the predictors and consequences of separation among couples affected by HIV. Perinatal HIV exposure can increase risk of neurodevelopmental delay in children, irrespective of child HIV acquisition. Thanks to remarkable strides in prevention of mother-to-child transmission (PMTCT), there are now nearly 16 million children who are HIV-exposed uninfected (CHEU), with an additional one million CHEU born every year in SSA. It is crucial to identify caregiver-related factors associated with child neurodevelopment to ensure CHEU thrive in a manner comparable to their HIV-unexposed peers. Methods: This dissertation aimed (Chapter I) to identify factors associated with relationship dissolution between Ugandan PWLHIV and their male partners among couples enrolled in a randomized clinical trial and recommend strategies to increase male partner testing and knowledge of HIV serostatus, employing mixed methods using a convergent parallel design, (Chapter II) to compare one-year neurodevelopment between Kenyan children with and without perinatal HIV exposure in a prospective longitudinal cohort, and identify caregiver factors associated with poor child neurodevelopment using multivariate linear mixed effects models, and (Chapter III) to synthesize latest literature in a commentary about the biologic and social mechanisms through which maternal HIV could impact child neurodevelopment, and to suggest research and advocacy directions to fill knowledge gaps for CHEU. Results: (Chapter I) Separation during pregnancy and postpartum was frequent (23%) among the 500 pregnant Ugandan women living with HIV, and was associated with being in unmarried, non-cohabitating, shorter relationship duration (<1 year), polygamous relationships, as well as HIV non-disclosure and experience of verbal abuse. Participants discussed how HIV serodifferent status, financial burdens, and strong gender expectations led to relationship conflict. Separation was discussed as both a negative and positive outcome depending on couples’ circumstances, in terms of mental health, treatment continuation, financial security, and experience with IPV. (Chapter II) At one-year evaluation among Kenyan infants, CHUU (N=715) and CHEU (N=416) had comparable neurodevelopment scores across all tested domains. Among all children, after adjusting for confounders selected a priori and clustering by site, lower child neurodevelopment scores were significantly associated with male sex, having a deceased or absent father, and maternal report of IPV. Among CHEU, in utero exposure to efavirenz (EFV)-based regimens during pregnancy was associated with lower gross motor scores compared to DTG-based regimens. (Chapter III) Latest evidence from a scoping literature review suggests that perinatal HIV and ART exposure can biologically influence child neurodevelopment through altered immune function, structural brain integrity, systemic inflammation, and growth faltering. There are limited data on the roles that social and behavioral factors play in promoting child neurodevelopment among families affected by HIV in SSA. Conclusion: Relationship dissolution commonly occurs among couples affected by HIV, for a myriad of reasons. It is imperative to improve counseling messaging and better support people living with HIV who may experience IPV, relationship conflict, and separation from their partners, particularly during the vulnerable periods of pregnancy and postpartum. Additionally, IPV and paternal absence in the first year of life were significantly associated with poorer child neurodevelopment, regardless of maternal HIV status, and will require harmonized approaches to address and mitigate risk of delays. Despite evidence that CHEU have unique biologic and social factors that may influence their brain maturation, immune system, and overall health and wellbeing, we did not find a statistically significant difference in 1-year neurodevelopment between CHEU and CHUU. The lack of neurodevelopmental difference between CHEU and CHUU in this cohort, despite several sociodemographic differences, could be potentially attributable to the wider spread and more prolonged use of newer maternal DTG-based ART regimens during pregnancy and breastfeeding; prior studies have been unable to assess these improved regimens which are better able to sustain viral suppression and improve maternal health, so additional research is needed to validate this finding. There is an urgent need for rigorous, multidisciplinary research to identify modifiable aspects of biologic and household exposures that impact child neurodevelopment, as well as clear referral pathways for children, caregivers, and providers in need of additional support

Costs of Providing HIV Self-Test Kits to Pregnant Women Living with HIV for Secondary Distribution to Male Partners in Uganda

Background: Secondary distribution of HIV self-testing kits (HIVST) to pregnant women attending antenatal care (ANC) clinics to give to their male partners is a promising strategy to increase testing coverage among men, but its costs are unknown. Methods: We conducted micro-costing of a trial evaluating secondary distribution of HIVST on pregnant women living with HIV (PWLHIV) in an ANC in Kampala, Uganda. Costs (2019 USD) were collected from program budgets, expenditure records, time and motion observations, and staff interviews and estimated for three scenarios: as-studied, reflecting full costs of the research intervention, Ministry of Health (MOH) implementation, reflecting the research intervention if implemented by the MOH, and MOH roll-out, the current strategy being used to roll out HIVST distribution. Results: In the as-studied scenario, cost of HIVST provision was $13.96/PWLHIV reached, and$11.89 and $10.55 per HIV-positive and HIV-negative male partner, respectively, who linked to a clinic for facility-based testing. In the MOH implementation scenario, costs were$9.45/PWLHIV, and $7.87 and$6.99, respectively, per HIV-positive and HIV-negative male partner linking to the clinic. In the MOH roll-out scenario, the cost of HIVST provision to pregnant women regardless of HIV status was $3.70/woman, and$6.65/HIV-positive male partner. Conclusion: Secondary distribution of HIVST from pregnant women can be implemented at reasonable cost to increase testing among men in Uganda and similar settings in Africa

Neurodevelopment among children exposed to HIV and uninfected in sub‐Saharan Africa

Abstract Introduction The population of 16 million children exposed to HIV and uninfected (CHEU) under 15 years of age continues to expand rapidly, and the estimated prevalence of CHEU exceeds 20% in several countries in sub‐Saharan Africa with high HIV prevalence. Some evidence suggests that CHEU experience suboptimal neurodevelopmental outcomes compared to children born to women without HIV. In this commentary, we discuss the latest research on biologic and socio‐behavioural factors associated with neurodevelopmental outcomes among CHEU. Discussion Some but not all studies have noted that CHEU are at risk of poorer neurodevelopment across multiple cognitive domains, most notably in language and motor skills, in diverse settings, ages and using varied assessment tools. Foetal HIV exposure can adversely influence infant immune function, structural brain integrity and growth trajectories. Foetal exposure to antiretrovirals may also influence outcomes. Moreover, general, non‐CHEU‐specific risk factors for poor neurodevelopment, such as preterm birth, food insecurity, growth faltering and household violence, are amplified among CHEU; addressing these factors will require multi‐factorial solutions. There is a need for rigorous harmonised approaches to identify children at the highest risk of delay. In high‐burden HIV settings, existing maternal child health programmes serving the general population could adopt structured early child development programmes that educate healthcare workers on CHEU‐specific risk factors and train them to conduct rapid neurodevelopmental screening tests. Community‐based interventions targeting parent knowledge of optimal caregiving practices have shown to be successful in improving neurodevelopmental outcomes in children and should be adapted for CHEU. Conclusions CHEU in sub‐Saharan Africa have biologic and socio‐behavioural factors that may influence their neurodevelopment, brain maturation, immune system and overall health and wellbeing. Multidisciplinary research is needed to disentangle complex interactions between contributing factors. Common environmental and social risk factors for suboptimal neurodevelopment in the general population are disproportionately magnified within the CHEU population, and it is, therefore, important to draw on existing knowledge when considering the socio‐behavioural pathways through which HIV exposure could impact CHEU neurodevelopment. Approaches to identify children at greatest risk for poor outcomes and multisectoral interventions are needed to ensure optimal outcomes for CHEU in sub‐Saharan Africa

Guidance for the Evaluation of Tuberculosis Diagnostics That Meet the World Health Organization (WHO) Target Product Profiles: An Introduction to WHO Process and Study Design Principles

Existing high-priority target product profiles (TPPs) of the World Health Organization (WHO) establish important needs for tuberculosis (TB) diagnostic development. Building on this earlier work, this guidance series aims to provide study guidance for performing accuracy studies of novel diagnostic products that may meet the 4 high-priority WHO TPPs and thus enable adequate evidence generation to inform a WHO evidence review process. Diagnostic accuracy studies represent a fundamental step in the validation of all tests. Unfortunately, such studies often have limitations in design, execution, and reporting, leading to low certainty of the evidence about true test performance, which can delay or impede policy and scale-up decisions. This introductory paper outlines the following: (1) the purpose of this series of papers on study guidance; (2) WHO evidence needs and process for the development of policy guidelines for new TB diagnostic tests; and (3) study design considerations, ie, general diagnostic study considerations, intended use of test and role in the clinical pathway, choice of population and setting, index-test specific issues, suitable reference standard and comparators, study flow and specimen issues, and finally key issues beyond accuracy that should be considered. The other 4 papers in this series will provide more detailed guidance for each of the 4 WHO high-priority TPPs. By increasing the clarity around the clinical evaluation needs for tests that have the potential to meet the TPP specifications, we hope to support harmonized evidence generation and enable the WHO review process towards meeting the WHO End TB Strategy targets for reducing the incidence and mortality associated with TB

Guidance for the Evaluation of Tuberculosis Diagnostics That Meet the World Health Organization (WHO) Target Product Profiles: An Introduction to WHO Process and Study Design Principles

Existing high-priority target product profiles (TPPs) of the World Health Organization (WHO) establish important needs for tuberculosis (TB) diagnostic development. Building on this earlier work, this guidance series aims to provide study guidance for performing accuracy studies of novel diagnostic products that may meet the 4 high-priority WHO TPPs and thus enable adequate evidence generation to inform a WHO evidence review process. Diagnostic accuracy studies represent a fundamental step in the validation of all tests. Unfortunately, such studies often have limitations in design, execution, and reporting, leading to low certainty of the evidence about true test performance, which can delay or impede policy and scale-up decisions. This introductory paper outlines the following: (1) the purpose of this series of papers on study guidance; (2) WHO evidence needs and process for the development of policy guidelines for new TB diagnostic tests; and (3) study design considerations, ie, general diagnostic study considerations, intended use of test and role in the clinical pathway, choice of population and setting, index-test specific issues, suitable reference standard and comparators, study flow and specimen issues, and finally key issues beyond accuracy that should be considered. The other 4 papers in this series will provide more detailed guidance for each of the 4 WHO high-priority TPPs. By increasing the clarity around the clinical evaluation needs for tests that have the potential to meet the TPP specifications, we hope to support harmonized evidence generation and enable the WHO review process towards meeting the WHO End TB Strategy targets for reducing the incidence and mortality associated with TB