BACKGROUND: Case identification remains a challenge to reaching the United Nations 95-95-95 targets for children with HIV. While the World Health Organization approved oral mucosal HIV self-testing (HIVST) for children over 2 years in 2019, there is little information on HIVST for pediatric case identification in Ethiopia. SETTING: Nine health facilities across Ethiopia. METHODS: We implemented a pilot program from November 2021-April 2022 to assess acceptability and feasibility of using HIVST to screen children 2-14 years of adult index clients, (i.e., parents/caregivers living with HIV and on antiretroviral therapy). HIV-positive adults who had children with unknown HIV status were given HIVST kits (OraQuick®) to screen their children at home. Parents/caregivers were asked to report results telephonically and bring children screening positive to the health facility for confirmatory HIV testing. We defined HIVST acceptability as ≥50% of parents/caregivers accepting testing and ≥50% reporting results within seven days of receiving a test kit. Feasibility was defined as ≥60% of children with a reactive HIVST receiving confirmatory testing and <5 serious social harms reported per 1000 kits distributed. RESULTS: Overall, 1496 of 1651 (91%) parents/caregivers accepted HIVST kits to test their children at home and 1204 (71%) reported results within seven days. Of 17 children (1%) with reactive results, 13 (76%) received confirmatory testing; of which 7 (54%) were confirmed to be HIV-positive. One serious social harm was reported. CONCLUSION: Providing adult parents/caregivers with HIVST kits to screen their children at home is an acceptable and feasible strategy to reach untested children and improve pediatric case finding in a low prevalence setting.

Introduction Food insecurity has a bidirectional relationship with HIV infection, with hunger driving compensatory risk behaviors, while infection can increase poverty. We used a laboratory recency assay to estimate the timing of HIV infection vis-à-vis the timing of severe food insecurity (SFI).Methods Data from population-based surveys in Zambia, Eswatini, Lesotho, Uganda, and Tanzania and Namibia were used. We defined SFI as having no food ≥three times in the past month. Recent HIV infection was identified using the HIV-1 LAg avidity assay, with a viral load (&gt;1000 copies/ml) and no detectable antiretrovirals indicating an infection in the past 6 months. Logistic regression was conducted to assess correlates of SFI. Poisson regression was conducted on pooled data, adjusted by country to determine the association of SFI with recent HIV infection and risk behaviors, with effect heterogeneity evaluated for each country. All analyses were done using weighted data.Results Of 112,955 participants aged 15-59, 10.3% lived in households reporting SFI. SFI was most common in urban, woman-headed households. Among women and not men, SFI was associated with a two-fold increase in risk of recent HIV infection (adjusted relative risk [aRR] 2.08, 95% CI 1.09-3.97), with lower risk in high prevalence countries (Eswatini and Lesotho). SFI was associated with transactional sex (aRR 1.28, 95% CI 1.17-1.41), a history of forced sex (aRR 1.36, 95% CI 1.11-1.66), and condom-less sex with a partner of unknown or positive HIV status (aRR 1.08, 95% CI 1.02-1.14) in all women, and intergenerational sex (partner ≥10 years older) in women aged 15-24 (aRR 1.23, 95% CI 1.03-1.46), although this was heterogeneous. Recent receipt of food support was protective (aRR 0.36, 95% CI 0.14-0.88).Conclusion SFI increased risk for HIV acquisition in women by two-fold. Worsening food scarcity due to climactic extremes could imperil HIV epidemic control.What is already knownThe link between food insecurity and the adoption of high-risk sexual behaviors as a coping mechanism has been shown in several settings.HIV infection can also drive food insecurity due to debilitating illness reducing productivity, the costs of treatment diverting money from supplies, and potentially reduced labor migration.Food insecurity has been associated with chronic HIV infection, but it has not been linked with HIV acquisition.What are the new findingsThis study of 112,955 adults across six countries in sub-Saharan Africa provides unique information on the association between acute food insecurity and recent HIV infection in women, as well as the potential behavioral and biological mediators, including community viremia as a measure of infectiousness.The data enabled a comprehensive analysis of factors associated with risk of infection, and how these factors differed by country and gender. Women living in food insecure households had a two-fold higher risk of recent HIV acquisition, and reported higher rates of transactional sex, early sexual debut, forced sex, intergenerational sex and sex without a condom with someone of unknown or positive HIV status. This pattern was not seen in men.This study is also the first to demonstrate a protective association for food support, which was associated with a lower risk of recent HIV infection in women.What do the new findings implyIn light of worsening food insecurity due to climate change and the recent COVID-19 pandemic, our results support further exploration of gender-specific pathways of response to acute food insecurity, particularly how women’s changes in sexual behavior heighten their risk of HIV acquisition.These and other data support the inclusion of food insecurity in HIV risk assessments for women, as well as the exploration of provision of food support to those households at highest risk based on geographic and individual factors.Competing Interest StatementThe authors have declared no competing interest.Clinical Protocols https://phia.icap.columbia.edu/ Funding StatementThis project has been supported by the Presid nt Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of cooperative agreement #U2GGH001226.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The PHIA protocol and data collection tools were approved by national ethics committees for each country, and the institutional review boards at Columbia University Irving Medical Center, the US Centers for Disease Control and Prevention (CDC) and the University of California, San Francisco in the case of Namibia. Due to the inclusion of six countries and the multiple ethical boards involved, we are providing the protocol numbers for the Columbia University Irving Medical Center, which approved all protocols (AAAQ0753, AAAQ7860, AAAQ8408, AAAQ8537, AAAR2051, AAAQ889). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data used in this manuscript are publicly available at https://phia-data.icap.columbia.edu/. https://phia-data.icap.columbia.edu/

BACKGROUND: Successful linkage to HIV services and initiation of antiretroviral treatment (ART) for children living with HIV (CLHIV) is critical to improve pediatric ART coverage. We aimed to assess confirmatory testing, linkage, and rapid ART initiation among newly diagnosed CLHIV in Ethiopia from the perspectives of caregivers and healthcare workers (HCWs). METHODS: We conducted standardized surveys with HCWs and caregivers of children 2-14 years who were diagnosed with HIV but not yet on ART who had been identified during a cross-sectional study in Ethiopia from May 2017-March 2018. Eight health facilities based on their HIV caseload and testing volume and 21 extension sites were included. Forty-one children, 34 care givers and 40 healthcare workers were included in this study. Three months after study enrollment, caregivers were surveyed about timing and experiences with HIV service enrollment, confirmatory testing, and ART initiation. Data collected from HCWs included perceptions of confirmatory testing in CLHIV before ART initiation. SPSS was used to conduct descriptive statistics. RESULTS: The majority of the 41 CLHIV were enrolled to HIV services (n = 34, 83%) and initiated ART by three months (n = 32, 94%). Median time from diagnosis to ART initiation was 12 days (interquartile range 5-18). Five children died before the follow-up interview. Confirmatory HIV testing was conducted in 34 children and found no discordant results; the majority (n = 23, 68%) received it within one week of HIV diagnosis. Almost all HCWs (n = 39/40, 98%) and caregivers (n = 31/34, 91%) felt better/the same about test results after conducting confirmatory testing. CONCLUSION: Opportunities remain to strengthen linkage for newly diagnosed CLHIV in Ethiopia through intensifying early follow-up to ensure prompt confirmatory testing and rapid ART initiation. Additional services could help caregivers with decision-making around treatment initiation for their children.

OBJECTIVE: To assess the potential bidirectional relationship between food insecurity and HIV infection in sub-Saharan Africa. DESIGN: Nationally representative HIV impact assessment household-based surveys. SETTING: Zambia, Eswatini, Lesotho, Uganda and Tanzania and Namibia. PARTICIPANTS: 112 955 survey participants aged 15-59 years with HIV and recency test results. MEASURES: Recent HIV infection (within 6 months) classified using the HIV-1 limited antigen avidity assay, in participants with an unsuppressed viral load (>1000 copies/mL) and no detectable antiretrovirals; severe food insecurity (SFI) defined as having no food in the house ≥three times in the past month. RESULTS: Overall, 10.3% of participants lived in households reporting SFI. SFI was most common in urban, woman-headed households, and in people with chronic HIV infection. Among women, SFI was associated with a twofold increase in risk of recent HIV infection (adjusted relative risk (aRR) 2.08, 95% CI 1.09 to 3.97). SFI was also associated with transactional sex (aRR 1.28, 95% CI 1.17 to 1.41), a history of forced sex (aRR 1.36, 95% CI 1.11 to 1.66) and condom-less sex with a partner of unknown or positive HIV status (aRR 1.08, 95% CI 1.02 to 1.14) in all women, and intergenerational sex (partner ≥10 years older) in women aged 15-24 years (aRR 1.23, 95% CI 1.03 to 1.46). Recent receipt of food support was protective against HIV acquisition (aRR 0.36, 95% CI 0.14 to 0.88). CONCLUSION: SFI increased risk for HIV acquisition in women by twofold. Heightened food insecurity during climactic extremes could imperil HIV epidemic control, and food support to women with SFI during these events could reduce HIV transmission.

During 2020, an estimated 150,000 persons aged 0-14 years acquired HIV globally (1). Case identification is the first step to ensure children living with HIV are linked to life-saving treatment, achieve viral suppression, and live long, healthy lives. Successful interventions to optimize pediatric HIV testing during the COVID-19 pandemic are needed to sustain progress toward achieving Joint United Nations Programme on HIV/AIDS (UNAIDS) 95-95-95 targets.* Changes in HIV testing and diagnoses among persons aged 1-14 years (children) were assessed in 22 U.S. President's Emergency Plan for AIDS Relief (PEPFAR)-supported countries during October 1, 2019-September 30, 2020. This period corresponds to the two fiscal quarters before the COVID-19 pandemic (i.e., Q1 and Q2) and the two quarters after the pandemic began (i.e., Q3 and Q4). Testing was disaggregated by age group, testing strategy, and fiscal year quarter. During October 2019-September 2020, PEPFAR supported 4,312,343 HIV tests and identified 74,658 children living with HIV (CLHIV). The number of HIV tests performed was similar during Q1 and Q2, decreased 40.1% from Q2 to Q3, and increased 19.7% from Q3 to Q4. The number of HIV cases identified among children aged 1-14 years (cases identified) increased 7.4% from Q1 to Q2, decreased 29.4% from Q2 to Q3, and increased 3.3% from Q3 to Q4. Although testing in outpatient departments decreased 21% from Q1 to Q4, testing from other strategies increased during the same period, including mobile testing by 38%, facility-based index testing (offering an HIV test to partners and biological children of persons living with HIV) by 8%, and testing children with signs or symptoms of malnutrition within health facilities by 7%. In addition, most tests (61.3%) and cases identified (60.9%) were among children aged 5-14 years (school-aged children), highlighting the need to continue offering HIV testing to older children. These findings provide important information on the most effective strategies for identifying CLHIV during the COVID-19 pandemic. HIV testing programs should continue to use programmatic, surveillance, and financial data at both national and subnational levels to determine the optimal mix of testing strategies to minimize disruptions in pediatric case identification during the COVID-19 pandemic.

BACKGROUND: Implementing effective and efficient case-finding strategies is crucial to increasing pediatric antiretroviral therapy coverage. In Ethiopia, universal HIV testing is conducted for children presenting at high-risk entry points including malnutrition treatment, inpatient wards, tuberculosis (TB) clinics, index testing for children of positive adults, and referral of orphans and vulnerable children (OVC); however, low positivity rates observed at inpatient, malnutrition and OVC entry points warrant re-assessing current case-finding strategies. The aim of this study is to develop HIV risk screening tool applicable for testing children presenting at inpatient, malnutrition and OVC entry points in low-HIV prevalence settings. METHODS: The study was conducted from May 2017-March 2018 at 29 public health facilities in Amhara and Addis Ababa regions of Ethiopia. All children 2-14years presenting to five high-risk entry points including malnutrition treatment, inpatient wards, tuberculosis (TB) clinics, index testing for children of positive adults, and referral of orphans and vulnerable children (OVC) were enrolled after consent. Data were collected from registers, medical records, and caregiver interviews. Screening tools were constructed using predictors of HIV positivity as screening items by applying both logistic regression and an unweighted method. Sensitivity, specificity and number needed to test (NNT) to identify one new child living with HIV (CLHIV) were estimated for each tool. RESULTS: The screening tools had similar sensitivity of 95%. However, the specificities of tools produced by logistic regression methods (61.4 and 65.6%) which are practically applicable were higher than those achieved by the unweighted method (53.6). Applying these tools could result in 5863% reduction in the NNT compared to universal testing approach while maintaining the overall number of CLHIV identified. CONCLUSION: The screening tools developed using logistic regression method could significantly improve HIV testing efficiency among children presenting to malnutrition, inpatient, and OVC entry points in Ethiopia while maintaining case identification. These tools are simplified to practically implement and can potentially be validated for use at various entry points. HIV programs in low-prevalence countries can also further investigate and optimize these tools in their settings.

BACKGROUND: Limited data in low HIV prevalence settings such as Ethiopia limit policy development and implementation of optimized pediatric testing approaches to close the treatment gap. This study aimed to determine HIV prevalence, testing yield and factors associated with HIV among children at 5 entry points. METHODS: We conducted a cross-sectional study from May 2017 to March 2018 in 29 public health facilities in Amhara and Addis Ababa regions in Ethiopia. Children 2-14 years were enrolled through 5 entry points. Data were obtained from registers, medical records and interviews with caregivers. HIV prevalence and testing yields were calculated for each entry point. Mixed-effects logistic regression analysis identified factors associated with undiagnosed HIV. RESULTS: The study enrolled 2166 children, of whom 94 were HIV positive (40 newly diagnosed). HIV prevalence and testing yield were the highest among children of HIV-positive adults (index testing; 8.2% and 8.2%, respectively) and children presenting to tuberculosis clinics (7.9% and 1.8%) or with severe malnutrition (6.5% and 1.4%). Factors associated with undiagnosed HIV included tuberculosis or index entry point [adjusted odds ratio (aOR), 11.97; 95% CI 5.06-28.36], deceased mother (aOR 4.55; 95% CI 1.30-15.92), recurrent skin problems (aOR 17.71; 95% CI 7.75-40.43), severe malnutrition (aOR 4.56; 95% CI 2.04-10.19) and urban residence (aOR 3.47; 95% CI 1.03-11.66). CONCLUSIONS: Index testing is a critical strategy for pediatric case finding in Ethiopia. Strategies and resources can prioritize minimizing missed opportunities in implementing universal testing for very sick children (tuberculosis, severe malnutrition) and implementing targeted testing in other entry points through use of factors associated with HIV.

BACKGROUND: Invasive non-typhoidal Salmonella (iNTS) is one of the leading causes of bacteraemia in sub-Saharan Africa. We aimed to provide a better understanding of the genetic characteristics and transmission patterns associated with multi-drug resistant (MDR) iNTS serovars across the continent. METHODS: A total of 166 iNTS isolates collected from a multi-centre surveillance in 10 African countries (2010-2014) and a fever study in Ghana (2007-2009) were genome sequenced to investigate the geographical distribution, antimicrobial genetic determinants and population structure of iNTS serotypes-genotypes. Phylogenetic analyses were conducted in the context of the existing genomic frameworks for various iNTS serovars. Population-based incidence of MDR-iNTS disease was estimated in each study site. RESULTS: Salmonella Typhimurium sequence-type (ST) 313 and Salmonella Enteritidis ST11 were predominant, and both exhibited high frequencies of MDR; Salmonella Dublin ST10 was identified in West Africa only. Mutations in the gyrA gene (fluoroquinolone resistance) were identified in S. Enteritidis and S. Typhimurium in Ghana; an ST313 isolate carrying bla (CTX-M-15) was found in Kenya. International transmission of MDR ST313 (lineage II) and MDR ST11 (West African clade) was observed between Ghana and neighbouring West African countries. The incidence of MDR-iNTS disease exceeded 100/100 000 person-years-of-observation in children aged <5 years in several West African countries. CONCLUSIONS: We identified the circulation of multiple MDR iNTS serovar STs in the sampled sub-Saharan African countries. Investment in the development and deployment of iNTS vaccines coupled with intensified antimicrobial resistance surveillance are essential to limit the impact of these pathogens in Africa.

BACKGROUND: Invasive salmonellosis is a common community-acquired bacteremia in persons residing in sub-Saharan Africa. However, there is a paucity of data on severe typhoid fever and its associated acute and chronic host immune response and carriage. The Severe Typhoid Fever in Africa (SETA) program, a multicountry surveillance study, aimed to address these research gaps and contribute to the control and prevention of invasive salmonellosis. METHODS: A prospective healthcare facility-based surveillance with active screening of enteric fever and clinically suspected severe typhoid fever with complications was performed using a standardized protocol across the study sites in Burkina Faso, the Democratic Republic of Congo (DRC), Ethiopia, Ghana, Madagascar, and Nigeria. Defined inclusion criteria were used for screening of eligible patients for enrollment into the study. Enrolled patients with confirmed invasive salmonellosis by blood culture or patients with clinically suspected severe typhoid fever with perforation were eligible for clinical follow-up. Asymptomatic neighborhood controls and immediate household contacts of each case were enrolled as a comparison group to assess the level of Salmonella-specific antibodies and shedding patterns. Healthcare utilization surveys were performed to permit adjustment of incidence estimations. Postmortem questionnaires were conducted in medically underserved areas to assess death attributed to invasive Salmonella infections in selected sites. RESULTS: Research data generated through SETA aimed to address scientific knowledge gaps concerning the severe typhoid fever and mortality, long-term host immune responses, and bacterial shedding and carriage associated with natural infection by invasive salmonellae. CONCLUSIONS: SETA supports public health policy on typhoid immunization strategy in Africa.

BACKGROUND: Antimicrobial resistance (AMR) is a major global health concern, yet, there are noticeable gaps in AMR surveillance data in regions such as sub-Saharan Africa. We aimed to measure the prevalence of extended-spectrum beta-lactamase (ESBL) producing Gram-negative bacteria in bloodstream infections from 12 sentinel sites in sub-Saharan Africa. METHODS: Data were generated during the Typhoid Fever Surveillance in Africa Program (TSAP), in which standardized blood cultures were performed on febrile patients attending 12 health facilities in 9 sub-Saharan African countries between 2010 and 2014. Pathogenic bloodstream isolates were identified at the sites and then subsequently confirmed at a central reference laboratory. Antimicrobial susceptibility testing, detection of ESBL production, and conventional multiplex polymerase chain reaction (PCR) testing for genes encoding for beta-lactamase were performed on all pathogens. RESULTS: Five hundred and five pathogenic Gram-negative bloodstream isolates were isolated during the study period and available for further characterization. This included 423 Enterobacteriaceae. Phenotypically, 61 (12.1%) isolates exhibited ESBL activity, and genotypically, 47 (9.3%) yielded a PCR amplicon for at least one of the screened ESBL genes. Among specific Gram-negative isolates, 40 (45.5%) of 88 Klebsiella spp., 7 (5.7%) of 122 Escherichia coli, 6 (16.2%) of 37 Acinetobacter spp., and 2 (1.3%) of 159 of nontyphoidal Salmonella (NTS) showed phenotypic ESBL activity. CONCLUSIONS: Our findings confirm the presence of ESBL production among pathogens causing bloodstream infections in sub-Saharan Africa. With few alternatives for managing ESBL-producing pathogens in the African setting, measures to control the development and proliferation of AMR organisms are urgently needed.

There is paucity of data regarding the geographical distribution, incidence, and phylogenetics of multi-drug resistant (MDR) Salmonella Typhi in sub-Saharan Africa. Here we present a phylogenetic reconstruction of whole genome sequenced 249 contemporaneous S. Typhi isolated between 2008-2015 in 11 sub-Saharan African countries, in context of the 2,057 global S. Typhi genomic framework. Despite the broad genetic diversity, the majority of organisms (225/249; 90%) belong to only three genotypes, 4.3.1 (H58) (99/249; 40%), 3.1.1 (97/249; 39%), and 2.3.2 (29/249; 12%). Genotypes 4.3.1 and 3.1.1 are confined within East and West Africa, respectively. MDR phenotype is found in over 50% of organisms restricted within these dominant genotypes. High incidences of MDR S. Typhi are calculated in locations with a high burden of typhoid, specifically in children aged <15 years. Antimicrobial stewardship, MDR surveillance, and the introduction of typhoid conjugate vaccines will be critical for the control of MDR typhoid in Africa.

Rapid disease progression and associated opportunistic infections contribute to high mortality rates among children aged <15 years with human immunodeficiency virus (HIV) infection (1). Antiretroviral therapy (ART) has decreased childhood HIV-associated morbidity and mortality rates over the past decade (2). As accumulating evidence revealed lower HIV-associated mortality with early ART initiation, the World Health Organization (WHO) guidelines broadened ART eligibility for children with HIV infection (2). Age at ART initiation for children with HIV infection expanded sequentially in the 2010, 2013, and 2016 WHO guidelines to include children aged <2, <5, and <15 years, respectively, regardless of clinical or immunologic status (3-5). The United States President's Emergency Plan for AIDS Relief (PEPFAR) has supported ART for children with HIV infection since 2003 and, informed by the WHO guidelines and a growing evidence base, PEPFAR-supported countries have adjusted their national pediatric guidelines. To understand the lag between guideline development and implementation, as well as the ART coverage gap, CDC assessed national pediatric HIV guidelines and analyzed Joint United Nations Programme on HIV and AIDS (acquired immunodeficiency syndrome; UNAIDS) data on children aged <15 years with HIV infection and the numbers of these children on ART. Timeliness of WHO pediatric ART guideline adoption varied by country; >50% of children with HIV infection are not receiving ART, underscoring the importance of strengthening case finding and linkage to HIV treatment in pediatric ART programs.

BACKGROUND: Available incidence data for invasive salmonella disease in sub-Saharan Africa are scarce. Standardised, multicountry data are required to better understand the nature and burden of disease in Africa. We aimed to measure the adjusted incidence estimates of typhoid fever and invasive non-typhoidal salmonella (iNTS) disease in sub-Saharan Africa, and the antimicrobial susceptibility profiles of the causative agents. METHODS: We established a systematic, standardised surveillance of blood culture-based febrile illness in 13 African sentinel sites with previous reports of typhoid fever: Burkina Faso (two sites), Ethiopia, Ghana, Guinea-Bissau, Kenya, Madagascar (two sites), Senegal, South Africa, Sudan, and Tanzania (two sites). We used census data and health-care records to define study catchment areas and populations. Eligible participants were either inpatients or outpatients who resided within the catchment area and presented with tympanic (≥38.0 degrees C) or axillary temperature (≥37.5 degrees C). Inpatients with a reported history of fever for 72 h or longer were excluded. We also implemented a health-care utilisation survey in a sample of households randomly selected from each study area to investigate health-seeking behaviour in cases of self-reported fever lasting less than 3 days. Typhoid fever and iNTS disease incidences were corrected for health-care-seeking behaviour and recruitment. FINDINGS: Between March 1, 2010, and Jan 31, 2014, 135 Salmonella enterica serotype Typhi (S Typhi) and 94 iNTS isolates were cultured from the blood of 13 431 febrile patients. Salmonella spp accounted for 33% or more of all bacterial pathogens at nine sites. The adjusted incidence rate (AIR) of S Typhi per 100 000 person-years of observation ranged from 0 (95% CI 0-0) in Sudan to 383 (274-535) at one site in Burkina Faso; the AIR of iNTS ranged from 0 in Sudan, Ethiopia, Madagascar (Isotry site), and South Africa to 237 (178-316) at the second site in Burkina Faso. The AIR of iNTS and typhoid fever in individuals younger than 15 years old was typically higher than in those aged 15 years or older. Multidrug-resistant S Typhi was isolated in Ghana, Kenya, and Tanzania (both sites combined), and multidrug-resistant iNTS was isolated in Burkina Faso (both sites combined), Ghana, Kenya, and Guinea-Bissau. INTERPRETATION: Typhoid fever and iNTS disease are major causes of invasive bacterial febrile illness in the sampled locations, most commonly affecting children in both low and high population density settings. The development of iNTS vaccines and the introduction of S Typhi conjugate vaccines should be considered for high-incidence settings, such as those identified in this study. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: Country-specific studies in Africa have indicated that Plasmodium falciparum is associated with invasive nontyphoidal Salmonella (iNTS) disease. We conducted a multicenter study in 13 sites in Burkina Faso, Ethiopia, Ghana, Guinea-Bissau, Kenya, Madagascar, Senegal, South Africa, Sudan, and Tanzania to investigate the relationship between the occurrence of iNTS disease, other systemic bacterial infections, and malaria. METHODS: Febrile patients received a blood culture and a malaria test. Isolated bacteria underwent antimicrobial susceptibility testing, and the association between iNTS disease and malaria was assessed. RESULTS: A positive correlation between frequency proportions of malaria and iNTS was observed (P = .01; r = 0.70). Areas with higher burden of malaria exhibited higher odds of iNTS disease compared to other bacterial infections (odds ratio [OR], 4.89; 95% CI, 1.61-14.90; P = .005) than areas with lower malaria burden. Malaria parasite positivity was associated with iNTS disease (OR, 2.44; P = .031) and gram-positive bacteremias, particularly Staphylococcus aureus, exhibited a high proportion of coinfection with Plasmodium malaria. Salmonella Typhimurium and Salmonella Enteritidis were the predominant NTS serovars (53/73; 73%). Both moderate (OR, 6.05; P = .0001) and severe (OR, 14.62; P < .0001) anemia were associated with iNTS disease. CONCLUSIONS: A positive correlation between iNTS disease and malaria endemicity, and the association between Plasmodium parasite positivity and iNTS disease across sub-Saharan Africa, indicates the necessity to consider iNTS as a major cause of febrile illness in malaria-holoendemic areas. Prevention of iNTS disease through iNTS vaccines for areas of high malaria endemicity, targeting high-risk groups for Plasmodium parasitic infection, should be considered.

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001: were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.