Optimization of pediatrics antiretroviral treatment outcomes among HIV infected children in Ethiopia

Ending the HIV/AIDS epidemic by 2030 is a global agenda. To meet this global goal, having safe and effective antiretroviral therapy is a key requirement. In Ethiopia, the safety and efficacy of combination antiretroviral therapy in HIV infected pediatric population is poorly studied. In this thesis, I aimed at understanding the short- and long-term safety and efficacy of antiretroviral therapy among HIV infected children in Ethiopia. Clinical and laboratory data were recorded for a total of 870 HIV infected children in two parallel cohorts – EPDOS and EPHIC projects. We first investigated the burden and correlates of pretreatment drug resistance (PDR) in Paper I. We observed that the overall rate of PDR was 14%. All cases with PDR had resistance to NNRTIs while ~9% harbored resistance solely to NNRTIs and ~5% harbored resistance to both NNRTIs and NRTIs. No resistance was observed to protease inhibitors. In Paper II, among children who were followed for 48 weeks following initiation of treatment, we assessed virologic outcome of children at one year of cART initiation using Cox Proportional Hazards Model. In total, 94/110 (85.5%) achieved virological suppression to undetectable levels during the first year of treatment. Thirty-six (31.9%) experienced virologic rebound. Tenofovir-containing cART regimen and absence of PDR were associated with higher virologic suppression. In Paper III, we explored burden and correlates of HIV drug resistance among children who failed treatment. Overall, 81% (73/90) of successfully genotyped participants had resistant mutations. From these, 69% (62/90) harbored dual drug class resistance. Strikingly, 42% of the participants harbored resistance to all four NRTIs recommended for second line use in the setting. Longer duration of cART and any regimen changes were associated with occurrence of drug resistance mutations. In Paper IV, we investigated the long term renal and hepatic toxicities associated with antiretroviral therapy among cART experienced children. At study enrolment, 177(25.1%) and 83(11.8%) had high aspartate aminotransferase and alanine aminotransferase (ALT), respectively. Zidovudine or nevirapine containing regimens and viral load >1000 copies/mL were associated with elevated ALT. Twenty-four (3.4%) and 84(12.1%) of the children had elevated creatinine and blood urea nitrogen (BUN), respectively. A progressive increment in BUN and decrement in GFR were observed during the follow up period. Both AST and ALT exhibited a decreasing trend. In Paper V, we compared the prevalence and correlates of dyslipidemia between cART naïve and experienced HIV infected children. Dyslipidemia was more common among cART experienced (70.2%) than naïve (58.1%) HIV infected children (p=0.03). Higher proportion of low HDLc (40.2% versus 23.4%, p=0.006) and hypertriglyceridemia (47.2% versus 35.8%, p= 0.02) was observed among cART experienced HIV infected children as compared to naïve. No difference was observed in the proportion of total hypercholesterolemia and high LDLc levels between the groups. Undernutrition was associated with more dyslipidemia in the cART naïve group (p=0.01). In conclusion, we showed that a high proportion of children with HIV infection in resource-limited settings do achieve virologic suppression during the first year of treatment initiation. We also confirmed that HIV drug resistance is a major cause of virologic treatment failure in children with limited virologic monitoring. On the other hand, the burden of PDR is low but predicts virologic outcome. Adverse events associated with cART are the major challenges for meeting the global UNAIDS targets in 2020 and 2030. The findings call for targeted monitoring and treatment of children in resource-limited settings

Pediatric urinary tract infection as a cause of outpatient clinic visits in southern Ethiopia: a cross sectional study

Background: Failure to timely diagnose and treat urinary tract infections is associated with grave long term consequences. The objectives of this study included assessing the proportion and predictors of Urinary Tract Infection (UTI) as a cause of pediatric outpatient department (OPD) visits and determining common uropathogens with antimicrobial susceptibility pattern.Methods: A cross sectional study was conducted from May to September 2015 among children of less than 15 years old at a tertiary center in Hawassa, Ethiopia. Children who fulfilled predefined eligibility criteria were recruited to undergo urine culture and urine analysis.Results: A total of 863 children visited the OPD during the study period among which 269(31.2%) fulfilled the predefined eligibility criteria. Urine culture was positive for 74/269(27.5%) of the clinically suspected children. Male uncircumcision (adjusted odds ratio (aOR) 3.70; 95% CI 1.34-10.16) and under nutrition (aOR 5.41; 95%CI 2.64-11.07) were independent predictors of culture positivity. More than 5 WBC per high power field (aOR 4.7, 95% CI 1.8-12.7) on microscopy, urine PH > 5.0 (aOR 2.6, 95%CI 1.2-5.8), and positive leukocyte esterase (aOR 9.9, 95%CI 4.1-25.7) independently predicted positive growth on urine culture. Escherichia coli (34/74, 45.9%) and Klebsiella spp (18/74, 24.3%) were the most frequent isolates. High resistance was noted against amoxicillin (70.6%) and cotrimoxazole (97.1%) by E. coli.Conclusion: UTI accounted for a tenth of total OPD visits. Commonly used first line antibiotics showed high level resistance to common etiologies of UTI. UTI should be suspected in febrile children, and antibiograms should be done to tailor prescription of antibiotics.Keywords: Bacterial profile, antibiotic resistance, children, urinary tract infectio

Empiric treatment of acute meningitis syndrome in a resource-limited setting: Clinical outcomes and predictors of survival or death

Background: Bacterial meningitis is a significant cause of morbidity and mortality in the developing world. However, limited research has focused on the diagnosis and management of meningitis in resource-limited settings.Methods: We designed a prospective case series of children admitted to a large, academic referral hospital with acute meningitis syndrome. Data were collected on age, time of presentation, prior antibiotics, cerebrospinal fluid (CSF) parameters, antibiotic and steroid prescription, and clinical outcome.Results: Data on 99 patients were collected and analyzed. Most of the patients were males, n=69 (70%), and were from a rural area, n=83 (84%). Incomplete  vaccination was common, n=36 (36%) and many have evidence of malnutrition, n=25 (38%). Most patients, n=64 (72%), had received antibiotics prior to admission with a mean duration of symptoms of 4.9 days prior to admission. The CSF white blood cell (WBC) count was higher in those who had not received prior antibiotics though it was elevated in both groups. The CSF WBC count was not associated with survival; malnutrition and length of symptoms prior to admission were both associated with decreased survival.Conclusions: While use of antibiotics prior to obtaining CSF in patients with acute meningitis syndrome may decrease their CSF WBC count, it is not clinically significant. Many patients had a significant delay in presentation that had an effect on survival, This is a potentially modifiable risk factor despite the resource-limited setting.Keywords: bacterial meningitis, children, antibiotics, glucocorticoid

Associations of water, sanitation, and hygiene with typhoid fever in case–control studies: a systematic review and meta-analysis

This work was supported, in whole or in part, by Gavi, the Vaccine Alliance, Bowdoin College, and the Bill & Melinda Gates Foundation, via the Vaccine Impact Modelling Consortium (Grant Number OPP1157270 / INV-009125). The funders were not involved in the study design, data analysis, data interpretation, and writing of the manuscript. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of their affiliated organisationsBackground Water, sanitation, and hygiene (WASH) play a pivotal role in controlling typhoid fever, as it is primarily transmitted through oral-fecal pathways. Given our constrained resources, staying current with the most recent research is crucial. This ensures we remain informed about practical insights regarding effective typhoid fever control strategies across various WASH components. We conducted a systematic review and meta-analysis of case-control studies to estimate the associations of water, sanitation, and hygiene exposures with typhoid fever. Methods We updated the previous review conducted by Brockett et al. We included new findings published between June 2018 and October 2022 in Web of Science, Embase, and PubMed. We used the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for risk of bias (ROB) assessment. We classified WASH exposures according to the classification provided by the WHO/UNICEF Joint Monitoring Programme for Water Supply, Sanitation, and Hygiene (JMP) update in 2015. We conducted the meta-analyses by only including studies that did not have a critical ROB in both Bayesian and frequentist random-effects models. Results We identified 8 new studies and analyzed 27 studies in total. Our analyses showed that while the general insights on the protective (or harmful) impact of improved (or unimproved) WASH remain the same, the pooled estimates of OR differed. Pooled estimates of limited hygiene (OR = 2.26, 95% CrI: 1.38 to 3.64), untreated water (OR = 1.96, 95% CrI: 1.28 to 3.27) and surface water (OR = 2.14, 95% CrI: 1.03 to 4.06) showed 3% increase, 18% decrease, and 16% increase, respectively, from the existing estimates. On the other hand, improved WASH reduced the odds of typhoid fever with pooled estimates for improved water source (OR = 0.54, 95% CrI: 0.31 to 1.08), basic hygiene (OR = 0.6, 95% CrI: 0.38 to 0.97) and treated water (OR = 0.54, 95% CrI: 0.36 to 0.8) showing 26% decrease, 15% increase, and 8% decrease, respectively, from the existing estimates. Conclusions The updated pooled estimates of ORs for the association of WASH with typhoid fever showed clear changes from the existing estimates. Our study affirms that relatively low-cost WASH strategies such as basic hygiene or water treatment can be an effective tool to provide protection against typhoid fever in addition to other resource-intensive ways to improve WASH

Associations of water, sanitation, and hygiene with typhoid fever in case–control studies: a systematic review and meta-analysis

Background: Water, sanitation, and hygiene (WASH) play a pivotal role in controlling typhoid fever, as it is primarily transmitted through oral-fecal pathways. Given our constrained resources, staying current with the most recent research is crucial. This ensures we remain informed about practical insights regarding effective typhoid fever control strategies across various WASH components. We conducted a systematic review and meta-analysis of case-control studies to estimate the associations of water, sanitation, and hygiene exposures with typhoid fever. Methods: We updated the previous review conducted by Brockett et al. We included new findings published between June 2018 and October 2022 in Web of Science, Embase, and PubMed. We used the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for risk of bias (ROB) assessment. We classified WASH exposures according to the classification provided by the WHO/UNICEF Joint Monitoring Programme for Water Supply, Sanitation, and Hygiene (JMP) update in 2015. We conducted the meta-analyses by only including studies that did not have a critical ROB in both Bayesian and frequentist random-effects models. Results: We identified 8 new studies and analyzed 27 studies in total. Our analyses showed that while the general insights on the protective (or harmful) impact of improved (or unimproved) WASH remain the same, the pooled estimates of OR differed. Pooled estimates of limited hygiene (OR = 2.26, 95% CrI: 1.38 to 3.64), untreated water (OR = 1.96, 95% CrI: 1.28 to 3.27) and surface water (OR = 2.14, 95% CrI: 1.03 to 4.06) showed 3% increase, 18% decrease, and 16% increase, respectively, from the existing estimates. On the other hand, improved WASH reduced the odds of typhoid fever with pooled estimates for improved water source (OR = 0.54, 95% CrI: 0.31 to 1.08), basic hygiene (OR = 0.6, 95% CrI: 0.38 to 0.97) and treated water (OR = 0.54, 95% CrI: 0.36 to 0.8) showing 26% decrease, 15% increase, and 8% decrease, respectively, from the existing estimates. Conclusions: The updated pooled estimates of ORs for the association of WASH with typhoid fever showed clear changes from the existing estimates. Our study affirms that relatively low-cost WASH strategies such as basic hygiene or water treatment can be an effective tool to provide protection against typhoid fever in addition to other resource-intensive ways to improve WASH. Trial registration PROSPERO 2021 CRD42021271881

Challenges to the Fight against Rabies-The Landscape of Policy and Prevention Strategies in Africa.

Nearly 59,000 human deaths worldwide are attributable to rabies annually, of which more than a third occur in Africa. In recent years, progress has been made in both action and collaboration including implementation of surveillance and prevention measures. In this review we assess the scale of surveillance, preventive, and control efforts of canine-transmitted human rabies in African countries. We reviewed literature published from 2014 to 2018, retrieved from electronic databases including MEDLINE, Global Index Medicus, BIOSIS, Science Citation Index, and EMBASE. WHO reports, national disease control program reports, and conference proceedings were also reviewed. The database search was conducted using keywords including rabies, control, and prevention. In forty countries (40/54), some level of rabies control and prevention strategy was available while in fourteen (14/54) countries, no specific national control and prevention strategy for human rabies could be retrieved. Thirty-four (34/54) countries utilized the Stepwise Approach towards Rabies Elimination (SARE) tool to monitor the national rabies control efforts-five of these countries were at the lowest tier (0/5) of the SARE scoring system while no country had achieved the highest score (5/5). High burden countries need to step up the implementation of context specific national rabies control, prevention, and monitoring strategies. As a zoonosis, rabies control and elimination require coordination between human and veterinarian health sectors under the "One Health" umbrella and with national master plans on the prevention and control of neglected tropical diseases ending in 2020, the time to act is now

Evaluation of Typhoid Conjugate Vaccine Effectiveness in Ghana (TyVEGHA) Using a Cluster-Randomized Controlled Phase IV Trial: Trial Design and Population Baseline Characteristics.

Typhoid fever remains a significant health problem in sub-Saharan Africa, with incidence rates of >100 cases per 100,000 person-years of observation. Despite the prequalification of safe and effective typhoid conjugate vaccines (TCV), some uncertainties remain around future demand. Real-life effectiveness data, which inform public health programs on the impact of TCVs in reducing typhoid-related mortality and morbidity, from an African setting may help encourage the introduction of TCVs in high-burden settings. Here, we describe a cluster-randomized trial to investigate population-level protection of TYPBAR-TCV®, a Vi-polysaccharide conjugated to a tetanus-toxoid protein carrier (Vi-TT) against blood-culture-confirmed typhoid fever, and the synthesis of health economic evidence to inform policy decisions. A total of 80 geographically distinct clusters are delineated within the Agogo district of the Asante Akim region in Ghana. Clusters are randomized to the intervention arm receiving Vi-TT or a control arm receiving the meningococcal A conjugate vaccine. The primary study endpoint is the total protection of Vi-TT against blood-culture-confirmed typhoid fever. Total, direct, and indirect protection are measured as secondary outcomes. Blood-culture-based enhanced surveillance enables the estimation of incidence rates in the intervention and control clusters. Evaluation of the real-world impact of TCVs and evidence synthesis improve the uptake of prequalified/licensed safe and effective typhoid vaccines in public health programs of high burden settings. This trial is registered at the Pan African Clinical Trial Registry, accessible at Pan African Clinical Trials Registry (ID: PACTR202011804563392)

Evaluation of Typhoid Conjugate Vaccine Effectiveness in Ghana (TyVEGHA) Using a Cluster-Randomized Controlled Phase IV Trial: Trial Design and Population Baseline Characteristics.

Typhoid fever remains a significant health problem in sub-Saharan Africa, with incidence rates of >100 cases per 100,000 person-years of observation. Despite the prequalification of safe and effective typhoid conjugate vaccines (TCV), some uncertainties remain around future demand. Real-life effectiveness data, which inform public health programs on the impact of TCVs in reducing typhoid-related mortality and morbidity, from an African setting may help encourage the introduction of TCVs in high-burden settings. Here, we describe a cluster-randomized trial to investigate population-level protection of TYPBAR-TCV®, a Vi-polysaccharide conjugated to a tetanus-toxoid protein carrier (Vi-TT) against blood-culture-confirmed typhoid fever, and the synthesis of health economic evidence to inform policy decisions. A total of 80 geographically distinct clusters are delineated within the Agogo district of the Asante Akim region in Ghana. Clusters are randomized to the intervention arm receiving Vi-TT or a control arm receiving the meningococcal A conjugate vaccine. The primary study endpoint is the total protection of Vi-TT against blood-culture-confirmed typhoid fever. Total, direct, and indirect protection are measured as secondary outcomes. Blood-culture-based enhanced surveillance enables the estimation of incidence rates in the intervention and control clusters. Evaluation of the real-world impact of TCVs and evidence synthesis improve the uptake of prequalified/licensed safe and effective typhoid vaccines in public health programs of high burden settings. This trial is registered at the Pan African Clinical Trial Registry, accessible at Pan African Clinical Trials Registry (ID: PACTR202011804563392)

Mapping child growth failure across low- and middle-income countries

Child growth failure (CGF), manifested as stunting, wasting, and underweight, is associated with high 5 mortality and increased risks of cognitive, physical, and metabolic impairments. Children in low- and middle-income countries (LMICs) face the highest levels of CGF globally. Here we illustrate national and subnational variation of under-5 CGF indicators across LMICs, providing 2000–2017 annual estimates mapped at a high spatial resolution and aggregated to policy-relevant administrative units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the World Health 10 Organization’s ambitious Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and rates of progress exist across regions, countries, and within countries; our maps identify areas where high prevalence persists even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where subnational disparities exist and the highest-need populations reside, these geospatial estimates can support policy-makers in planning locally 15 tailored interventions and efficient directing of resources to accelerate progress in reducing CGF and its health implications

Mapping disparities in education across low- and middle-income countries

Analyses of the proportions of individuals who have completed key levels of schooling across all low- and middle-income countries from 2000 to 2017 reveal inequalities across countries as well as within populations. Educational attainment is an important social determinant of maternal, newborn, and child health(1-3). As a tool for promoting gender equity, it has gained increasing traction in popular media, international aid strategies, and global agenda-setting(4-6). The global health agenda is increasingly focused on evidence of precision public health, which illustrates the subnational distribution of disease and illness(7,8); however, an agenda focused on future equity must integrate comparable evidence on the distribution of social determinants of health(9-11). Here we expand on the available precision SDG evidence by estimating the subnational distribution of educational attainment, including the proportions of individuals who have completed key levels of schooling, across all low- and middle-income countries from 2000 to 2017. Previous analyses have focused on geographical disparities in average attainment across Africa or for specific countries, but-to our knowledge-no analysis has examined the subnational proportions of individuals who completed specific levels of education across all low- and middle-income countries(12-14). By geolocating subnational data for more than 184 million person-years across 528 data sources, we precisely identify inequalities across geography as well as within populations.Peer reviewe