Predictors of Clinical Outcomes among People with HIV and Tuberculosis Symptoms after Rapid Treatment Initiation in Haiti.

Introduction: Few studies have evaluated baseline predictors of clinical outcomes among people with HIV starting antiretroviral therapy (ART) in the modern era of rapid ART initiation. Methods: We conducted a secondary analysis of a randomized controlled trial of two rapid treatment initiation strategies for people with treatment-naïve HIV and tuberculosis symptoms at an urban clinic in Haiti. We used logistic regression models to assess associations between baseline characteristics and (1) retention in care at 48 weeks, (2) HIV viral load suppression at 48 weeks (among participants who underwent viral load testing), and (3) all-cause mortality. Results: 500 participants were enrolled in the study 11/2017-1/2020. Eighty-eight (18%) participants were diagnosed with tuberculosis, and ART was started in 494 (99%). After adjustment, less than secondary education (adjusted odds ratio [AOR] 0.21, 95% CI 0.10-0.46), dolutegravir initiation (AOR 2.57, 95% CI 1.22-5.43), age (AOR 1.42 per 10-year increase, 95% CI 1.01-1.99), and tuberculosis diagnosis (AOR 3.92, 95% CI 1.36-11.28) were significantly associated with retention. Age (AOR 1.36, 95% CI 1.05-1.75), dolutegravir initiation (AOR 1.75, 95% CI 1.07-2.85), and tuberculosis diagnosis (AOR 0.50, 95% CI 0.28-0.89) were associated with viral suppression. Higher CD4 cell count at enrollment (unadjusted odds ratio [OR] 0.69, 95% CI 0.55-0.87) and anemia (OR 4.86, 95% CI 1.71-13.81) were associated with mortality. Conclusions: We identified sociodemographic, treatment-related, clinical, and laboratory-based predictors of clinical outcomes. These characteristics may serve as markers of sub-populations that could benefit from additional interventions to support treatment success after rapid treatment initiation.

Neighborhood Social Vulnerability and Premature Cardiovascular Disease in Haiti.

Importance: Higher social vulnerability is associated with premature cardiovascular disease (CVD) and mortality but is understudied in low-income countries that have both the highest magnitude of social vulnerability and a growing CVD epidemic. Objective: To evaluate the association between social vulnerability and hypertension, CVD, and CVD subtypes in Haiti as a model for similar low-income countries. Design, Setting, and Participants: This population-based cohort study used enrollment data from adults participating in the Haiti Cardiovascular Disease Cohort Study. Recruitment occurred via multistage random sampling throughout slum and urban neighborhoods in Port-au-Prince, Haiti, from March 2019 to August 2021. Data were analyzed from May 2022 to December 2023. Exposures: A modified Haitian Social Vulnerability Index (SVI-H) was created following the US Centers for Disease Control and Prevention Social Vulnerability Index method. Twelve variables across the domains of socioeconomic status, household characteristics, and social and community context were included. The SVI-H was calculated for each study neighborhood block and then stratified into SVI-H quartiles (quartile 1 was the least vulnerable; quartile 4, the most vulnerable). Main Outcomes and Measures: Prevalent hypertension and total CVD, defined as heart failure (HF), stroke, transient ischemic attack (TIA), angina, or myocardial infarction (MI). Age-adjusted Poisson regression analysis yielded prevalence ratios (PRs) comparing the prevalence of hypertension, total CVD, and CVD subtypes across SVI-H quartiles. Results: Among 2925 adults (1704 [58.3%] female; mean [SD] age, 41.9 [15.9] years), the prevalence of hypertension was 32.8% (95% CI, 31.1%-34.5%) and the prevalence of CVD was 14.7% (95% CI, 13.5%-16.0%). Hypertension prevalence ranged from 26.2% (95% CI, 23.1%-29.3%) to 38.4% (95% CI, 34.8%-42.0%) between quartiles 1 and 4, while CVD prevalence ranged from 11.1% (95% CI, 8.8%-13.3%) to 19.7% (95% CI, 16.8%-22.6%). SVI-H quartile 4 vs 1 was associated with a greater prevalence of hypertension (PR, 1.17; 95% CI, 1.02-1.34) and CVD (PR, 1.48; 95% CI, 1.16-1.89). Among CVD subtypes, SVI-H was significantly associated with HF (PR, 1.64; 95% CI, 1.23-2.18) but not with combined stroke and TIA or combined angina and MI. Conclusions and Relevance: In urban Haiti, individuals living in neighborhoods with the highest social vulnerability had greater prevalence of hypertension and HF. Understanding CVD disparities in low-income countries is essential for targeting prevention and treatment interventions toward populations at highest risk globally.

High variance in quantification of Mycobacterium tuberculosis at low bacterial loads and with differentially detectable mycobacteria.

We examined the correlation between three different methods of Mycobacterium tuberculosis quantification: time to positivity (TTP), log10 CFU, and an assay to detect differentially detectable M. tuberculosis (DD Mtb) from three different prospective studies. Participants with DD Mtb have significantly more variation in the CFU/TTP correlation than participants with no DD Mtb (P < 0.001). This may impact the design of early bactericidal activity studies that use TTP as the primary outcome.

Spectrum of prevalent cardiovascular diseases in urban Port-au-Prince, Haiti: a population-based cross-sectional study.

Background: Eighty percent of global cardiovascular disease (CVD) is projected to occur in low- and middle -income countries (LMICs), yet local epidemiological data are scarce. We provide the first population-based, adjudicated CVD prevalence estimates in Port-au-Prince, Haiti to describe the spectrum of heart disease and investigate associated risk factors. Methods: Demographic, medical history, clinical, imaging and laboratory data were collected among adults recruited using multistage random sampling from 2019 to 2021. Prevalent CVD (heart failure, stroke, ischemic disease) were adjudicated using epidemiological criteria similar to international cohorts. Multivariable Poisson regressions assessed relationships between risk factors and prevalent CVD. Findings: Among 3003 participants, median age was 40 years, 58.1% were female, 70.2% reported income <1 USD/day, and all identified as Black Haitian. CVD age-adjusted prevalence was 14.7% (95% CI 13.3%, 16.5%), including heart failure (11.9% [95% CI 10.5%, 13.5%]), stroke (2.4% [95% CI 1.9%, 3.3%]), angina (2.1% [95% CI 1.6%, 2.9%]), myocardial infarction (1.0% [95% CI 0.6%, 1.8%]), and transient ischemic attack (0.4% [95% CI 0.2%, 1.0%]). Among participants with heart failure, median age was 57 years and 68.5% of cases were among women. The most common subtype was heart failure with preserved ejection fraction (80.4%). Heart failure was associated with hypertension, obesity, chronic kidney disease, depression, and stress. Interpretation: Early-onset heart failure prevalence is alarmingly high in urban Haiti and challenge modelling assumptions that ischemic heart disease and stroke dominate CVDs in LMICs. These data underscore the importance of local population-based epidemiologic data within LMICs to expedite the selection and implementation of evidence-based cardiovascular health policies targeting each country's spectrum of heart disease. Funding: This study was funded by NIH grants R01HL143788, D43TW011972, and K24HL163393, clinicaltrials.govNCT03892265.

Circulating CD4+ T cells in people with HIV and history of pulmonary tuberculosis have more intact HIV DNA.

Background: The primary barrier to curing HIV infection is the pool of intact HIV proviruses integrated into host cell DNA throughout the bodies of people living with HIV (PLHIV), called the HIV reservoir. Reservoir size is impacted by the duration of HIV infection, delay in starting antiretroviral therapy (ART), and breakthrough viremia during ART. The leading infectious cause of death worldwide for PLHIV is TB, but we don't know how TB impacts the HIV reservoir. Methods: We designed a case-control study to compare HIV provirus-containing CD4 in PLHIV with vs. without a history of active TB disease. Study participants in the pilot and confirmatory cohort were enrolled at GHESKIO Centers in Port au Prince, Haiti. Intact and non-intact proviral DNA were quantified using droplet digital PCR of PBMC-derived CD4 cells. For a subset, Th1 and Th2 cytokines were assayed in plasma. Kruskal-Wallis tests were used to compare medians with tobit regression for censoring. Results: In the pilot cohort, we found that PLHIV with history of active pulmonary TB (n=20) had higher intact provirus than PLHIV without history of active TB (n=47) (794 vs 117 copies per million CD4, respectively; p<0.0001). In the confirmatory cohort, the quantity of intact provirus was higher in the TB group (n=13) compared with the non-TB group (n=18) (median 102 vs. 0 intact provirus per million CD4, respectively p=0.03). Additionally, we found that the frequencies of CD4+ T cells with any detectable proviral fragment was directly proportional to the levels of IL1B (p= 0.0025) and IL2 (p=0.0002). Conclusions: This is the first assessment of HIV provirus using IPDA in a clinical cohort from a resource limited setting, and the finding of larger reservoir in PLHIV with history of TB has significant implications for our understanding of TB-HIV coinfection and HIV cure efforts in TB-endemic settings.

A bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine second line regimen for tuberculosis displays similar early bactericidal activity as the standard rifampin based first line regimen.

BACKGROUND: In 2018 the World Health Organization (WHO) recommended a switch to an all oral bedaquiline based second line regimen for treatment of drug resistant (DR) tuberculosis (TB). How these new second line regimens fare in comparison to first line regimens for treatment of drug sensitive (DS) tuberculosis is not well known. METHODS: In this study, we contemporaneously enrolled subjects with DS (n = 31) and DR (n = 23) TB and assessed their response to therapy with first-line (rifampin, isoniazid, ethambutol, pyrazinamide) or second-line (bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine) regimens, respectively. RESULTS: We found that the early bactericidal activity of first and second line regimens was similar during the first two weeks of therapy as determined by BACTEC MGIT, colony forming units (CFU), and a liquid limiting dilution (LD) assays capable of detecting differentially detectable/culturable Mtb (DD Mtb). Further, an identical percentage (77.8%) of subjects from the DS and DR cohorts converted to culture negative after two months of therapy. CONCLUSIONS: Despite presenting with more advanced disease at time of treatment, subjects with DR TB receiving an all oral bedaquiline based second line treatment regimen displayed a similar microbiological response to therapy as subjects with DS TB receiving a first-line treatment regimen.

Successful outcomes for patients with drug-resistant tuberculosis despite civil unrest and COVID-19 in Haiti.

Globally, treatment outcomes for people with multi-drug/rifampin-resistant tuberculosis (MDR/RR-TB) are sub-optimal, with MDR/RR-TB programs further weakened due to the COVID-19 pandemic, and in Haiti, by severe civil unrest. We assessed the impact of these disruptions on treatment outcomes at GHESKIO, in Port-au-Prince, Haiti. We conducted a retrospective analysis including all adults (age ≥18 years) who initiated MDR/RR-TB treatment at GHESKIO from 2010 to 2020. We assessed predictors of poor treatment outcome using multivariable logistic regression, adjusting for baseline characteristics and year of treatment. 453 patients initiated treatment for MDR/RR-TB at GHESKIO. Median age was 31 (IQR: 25, 40), 233 (51.4%) were male, and 100 (22.1%) were living with HIV. Three hundred sixty-nine patients (81.5%) achieved cure, 42 (9.3%) died, 40 (8.8%) were lost to follow-up and 2 (<1%) failed treatment. HIV status was associated with poor treatment outcome (aRR: 1.65 (95% CI: 1.09, 2.48)) but there was no difference by year of treatment initiation. Outcomes for patients with MDR/RR-TB remained outstanding, even during the COVID-19 pandemic and severe civil unrest in Haiti. We attribute this resilience in care to the adaptability of program staff and provision of economic and psychosocial support.

Ancestral Origin and Dissemination Dynamics of Reemerging Toxigenic Vibrio cholerae, Haiti.

The 2010 cholera epidemic in Haiti was thought to have ended in 2019, and the Prime Minister of Haiti declared the country cholera-free in February 2022. On September 25, 2022, cholera cases were again identified in Port-au-Prince. We compared genomic data from 42 clinical Vibrio cholerae strains from 2022 with data from 327 other strains from Haiti and 1,824 strains collected worldwide. The 2022 isolates were homogeneous and closely related to clinical and environmental strains circulating in Haiti during 2012-2019. Bayesian hypothesis testing indicated that the 2022 clinical isolates shared their most recent common ancestor with an environmental lineage circulating in Haiti in July 2018. Our findings strongly suggest that toxigenic V. cholerae O1 can persist for years in aquatic environmental reservoirs and ignite new outbreaks. These results highlight the urgent need for improved public health infrastructure and possible periodic vaccination campaigns to maintain population immunity against V. cholerae.

Same-day testing with initiation of antiretroviral therapy or tuberculosis treatment versus standard care for persons presenting with tuberculosis symptoms at HIV diagnosis: A randomized open-label trial from Haiti.

BACKGROUND: Same-day HIV testing and antiretroviral therapy (ART) initiation is being widely implemented. However, the optimal timing of ART among patients with tuberculosis (TB) symptoms is unknown. We hypothesized that same-day treatment (TB treatment for those diagnosed with TB; ART for those not diagnosed with TB) would be superior to standard care in this population. METHODS AND FINDINGS: We conducted an open-label trial among adults with TB symptoms at initial HIV diagnosis at GHESKIO in Haiti; participants were recruited and randomized on the same day. Participants were randomized in a 1:1 ratio to same-day treatment (same-day TB testing with same-day TB treatment if TB diagnosed; same-day ART if TB not diagnosed) versus standard care (initiating TB treatment within 7 days and delaying ART to day 7 if TB not diagnosed). In both groups, ART was initiated 2 weeks after TB treatment. The primary outcome was retention in care with 48-week HIV-1 RNA <200 copies/mL, with intention to treat (ITT) analysis. From November 6, 2017 to January 16, 2020, 500 participants were randomized (250/group); the final study visit occurred on March 1, 2021. Baseline TB was diagnosed in 40 (16.0%) in the standard and 48 (19.2%) in the same-day group; all initiated TB treatment. In the standard group, 245 (98.0%) initiated ART at median of 9 days; 6 (2.4%) died, 15 (6.0%) missed the 48-week visit, and 229 (91.6%) attended the 48-week visit. Among all who were randomized, 220 (88.0%) received 48-week HIV-1 RNA testing; 168 had <200 copies/mL (among randomized: 67.2%; among tested: 76.4%). In the same-day group, 249 (99.6%) initiated ART at median of 0 days; 9 (3.6%) died, 23 (9.2%) missed the 48-week visit, and 218 (87.2%) attended the 48-week visit. Among all who were randomized, 211 (84.4%) received 48-week HIV-1 RNA; 152 had <200 copies/mL (among randomized: 60.8%; among tested: 72.0%). There was no difference between groups in the primary outcome (60.8% versus 67.2%; risk difference: -0.06; 95% CI [-0.15, 0.02]; p = 0.14). Two new grade 3 or 4 events were reported per group; none were judged to be related to the intervention. The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain. CONCLUSIONS: In patients with TB symptoms at HIV diagnosis, we found that same-day treatment was not associated with superior retention and viral suppression. In this study, a short delay in ART initiation did not appear to compromise outcomes. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov NCT03154320.

Prevalence and Severity of Chronic Kidney Disease in Haiti.

BACKGROUND: CKD is a major cause of morbidity and mortality in lower-income countries. However, population-based studies characterizing the epidemiology of CKD in these settings are lacking. The study objective was to describe the epidemiology of CKD in a population-based cohort in urban Haiti, including estimates of the prevalence by CKD stage, the magnitude of associated factors with CKD, and the proportion on guideline-recommended treatment. METHODS: We assessed the prevalence of CKD and associated risk factors in the population-based Haiti Cardiovascular Disease Cohort. We analyzed cross-sectional data from 2424 adults who completed a clinical examination, risk factor surveys, and laboratory measurements for serum creatinine, urinary albumin, and urinary creatinine. We compared our results with US estimates from the National Health and Nutrition Examination Survey. CKD was defined as either a reduced eGFR <60 ml/min per 1.73 m 2 or urinary albumin-to-creatinine ratio ≥30 mg/g according to the Kidney Disease Improving Global Outcomes guidelines. Multivariable logistic regression identified associated factors with CKD. RESULTS: The mean age was 42 years, 57% of participants were female, and 69% lived in extreme poverty on ≤1 US dollar per day. The age-standardized prevalence of CKD was 14% (95% confidence interval [CI], 12% to 15%). The age-standardized prevalence of reduced eGFR and elevated urinary albumin-to-creatinine ratio was 3% (95% CI, 2% to 4%) and 11% (95% CI, 10% to 13%), respectively. Diabetes (adjusted odds ratio, 4.1; 95% CI, 2.7 to 6.2) and hypertension (adjusted odds ratio, 2.9; 95% CI, 2.0 to 4.2) were significantly associated with CKD. Only 12% of participants with CKD and albuminuria were on guideline-recommended agents, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. CONCLUSIONS: In a large population-based cohort of Haitian adults, CKD was highly associated with both diabetes and hypertension. The proportion of participants with CKD on treatment was low, underscoring the need for strengthening clinical management and nephrology care health infrastructure in Haiti. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Longitudinal Cohort Study to Evaluate Cardiovascular Risk Factors and Disease in Haiti, NCT03892265 .

An Adapted Self-screening Tool for Peripartum Cardiomyopathy in Haiti.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is considered rare in the United States; however, the literature notes that the disease has a higher prevalence in developing countries such as Haiti. Dr. James D. Fett, a US cardiologist, developed and validated a self-assessment measure for PPCM in the United States to aid women to easily differentiate the signs and symptoms of heart failure from those related to a normal pregnancy. Although this instrument was validated, it lacks the adaptation necessary to account for the language, culture, and education of the Haitian population. OBJECTIVE: The aim of this study was to translate and culturally adapt the Fett PPCM self-assessment measure for use among a Haitian Creole speaking population. METHODS: A preliminary Haitian Creole direct translation was developed from the original English Fett self-test. A total of four focus groups with medical professionals and 16 cognitive interviews with members of a community advisory board were conducted to refine the preliminary Haitian Creole translation and adaptation. RESULTS: The adaptation focused on incorporating cues that would be tangible and connected to the reality of the Haitian population while maintaining the intended meaning of the original Fett measure. CONCLUSIONS: The final adaptation provides an instrument suitable for administration by auxiliary health providers and community health workers to help patients distinguish symptoms of heart failure from symptoms related to normal pregnancy and further quantify the severity of signs and symptoms that might be indicative of heart failure.

In-hospital mortality risk stratification in children aged under 5 years with pneumonia with or without pulse oximetry: A secondary analysis of the Pneumonia REsearch Partnership to Assess WHO REcommendations (PREPARE) dataset.

OBJECTIVES: We determined the pulse oximetry benefit in pediatric pneumonia mortality risk stratification and chest-indrawing pneumonia in-hospital mortality risk factors. METHODS: We report the characteristics and in-hospital pneumonia-related mortality of children aged 2-59 months who were included in the Pneumonia Research Partnership to Assess WHO Recommendations dataset. We developed multivariable logistic regression models of chest-indrawing pneumonia to identify mortality risk factors. RESULTS: Among 285,839 children, 164,244 (57.5%) from hospital-based studies were included. Pneumonia case fatality risk (CFR) without pulse oximetry measurement was higher than with measurement (5.8%, 95% confidence interval [CI] 5.6-5.9% vs 2.1%, 95% CI 1.9-2.4%). One in five children with chest-indrawing pneumonia was hypoxemic (19.7%, 95% CI 19.0-20.4%), and the hypoxemic CFR was 10.3% (95% CI 9.1-11.5%). Other mortality risk factors were younger age (either 2-5 months [adjusted odds ratio (aOR) 9.94, 95% CI 6.67-14.84] or 6-11 months [aOR 2.67, 95% CI 1.71-4.16]), moderate malnutrition (aOR 2.41, 95% CI 1.87-3.09), and female sex (aOR 1.82, 95% CI 1.43-2.32). CONCLUSION: Children with a pulse oximetry measurement had a lower CFR. Many children hospitalized with chest-indrawing pneumonia were hypoxemic and one in 10 died. Young age and moderate malnutrition were risk factors for in-hospital chest-indrawing pneumonia-related mortality. Pulse oximetry should be integrated in pneumonia hospital care for children under 5 years.

High Dietary Sodium, Measured Using Spot Urine Samples, is Associated with Higher Blood Pressure among Young Adults in Haiti.

Background: Hypertension (HTN) is the leading cardiovascular disease (CVD) risk factor in Haiti and is likely driven by poverty-related social and dietary factors. Salt consumption in Haiti is hypothesized to be high but has never been rigorously quantified. Methods: We used spot urine samples from a subset of participants in the population-based Haiti Cardiovascular Disease Cohort to estimate population mean daily sodium intake. We compared three previously validated formulas for estimating dietary sodium intake using urine sodium, urine creatinine, age, sex, height, and weight. We explored the association between dietary sodium intake and blood pressure, stratified by age group. Results: A total of 1,240 participants had spot urine samples. Median age was 38 years (range 18-93), and 48% were female. The mean dietary sodium intake was 3.5-5.0 g/day across the three estimation methods, with 94.2%-97.9% of participants consuming above the World Health Organization (WHO) recommended maximum of 2 g/day of sodium. Among young adults aged 18-29, increasing salt intake from the lowest quartile of consumption (<3.73 g/day) to the highest quartile (>5.88 g/day) was associated with a mean 8.71 mmHg higher systolic blood pressure (SBP) (95% confidence interval: 3.35, 14.07; p = 0.001). An association was not seen in older age groups. Among participants under age 40, those with SBP ≥120 mmHg consumed 0.5 g/day more sodium than those with SBP <120 mmHg (95% confidence interval: 0.08, 0.69; p = 0.012). Conclusions: Nine out of 10 Haitian adults in our study population consumed more than the WHO recommended maximum for daily sodium intake. In young adults, higher sodium consumption was associated with higher SBP. This represents an inflection point for increased HTN risk early in the life course and points to dietary salt intake as a potential modifiable risk factor for primordial and primary CVD prevention in young adults.

Population-Based Epidemiology of Heart Failure in a Low-Income Country: The Haiti Cardiovascular Disease Cohort.

BACKGROUND: Cardiovascular disease disproportionately affects persons living in low- and middle-income countries and heart failure (HF) is thought to be a leading cause. Population-based studies characterizing the epidemiology of HF in these settings are lacking. We describe the age-standardized prevalence, survival, subtypes, risk factors, and 1-year mortality of HF in the population-based Haiti Cardiovascular Disease Cohort. METHODS: Participants were recruited using multistage cluster-area random sampling in Port-au-Prince, Haiti. A total of 2981 completed standardized history and exam, laboratory measures, and cardiac imaging. Clinical HF was defined by Framingham criteria. Kaplan-Meier and Cox proportional hazard regression assessed mortality among participants with and without HF; logistic regression identified associated factors. RESULTS: Among all participants, the median age was 40 years (interquartile range, 27-55), and 58.2% were female. Median follow-up was 15.4 months (interquartile range, 9-22). The age-standardized HF prevalence was 3.2% (93/2981 [95% CI, 2.6-3.9]). The average age of participants with HF was 57 years (interquartile range, 45-65), and 67.7% were female. The first significant increase in HF prevalence occurred between 30 to 39 and 40 to 49 years (1.1% versus 3.7%, P=0.003). HF with preserved ejection fraction was the most common HF subtype (71.0%). Age (adjusted odds ratio, 1.36 [1.12-1.66] per 10-year increase), hypertension (2.14 [1.26-3.66]), obesity (3.35 [95% CI, 1.99-5.62]), poverty (2.10 [1.18-3.72]), and renal dysfunction (5.42 [2.94-9.98]) were associated with HF. One-year HF mortality was 6.6% versus 0.8% (hazard ratio, 7.7 [95% CI, 2.9-20.6]; P<0.0001). CONCLUSIONS: The age-standardized prevalence of HF in this low-income setting was alarmingly high at 3.2%-5-fold higher than modeling estimates for low- and middle-income countries. Adults with HF were two decades younger and 7.7× more likely to die at 1 year compared with those in the community without HF. Further research characterizing the population burden of HF in low- and middle-income countries can guide resource allocation and development of pragmatic HF prevention and treatment interventions, ultimately reducing global cardiovascular disease health disparities. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03892265.

Potential Utility of C-reactive Protein for Tuberculosis Risk Stratification among Patients with Non-Meningitic Symptoms at HIV Diagnosis in Low- and Middle-Income Countries.

Article Summary: We assessed the association between C-reactive protein (CRP) and Mycobacterium tuberculosis (TB) diagnosis in symptomatic patients at HIV diagnosis. We found that CRP concentrations can improve tuberculosis risk stratification, facilitating decision making about whether (specific) tuberculosis testing is indicated before antiretroviral therapy initiation. Background: The World Health Organization recommends initiating same-day ART while tuberculosis testing is underway for patients with non-meningitic symptoms at HIV diagnosis, though safety data are limited. C-reactive protein (CRP) testing may improve tuberculosis risk stratification in this population. Methods: In this baseline analysis of 498 adults (>18 years) with tuberculosis symptoms at HIV diagnosis who were enrolled in a trial of rapid ART initiation in Haiti, we describe test characteristics of varying CRP thresholds in the diagnosis of TB. We also assessed predictors of high CRP (≥3 mg/dL) using generalized linear models. Results: Eighty-seven (17.5%) patients were diagnosed with baseline TB. The median CRP was 33.0 mg/L (IQR: 5.1, 85.5) in those with TB, and 2.6 mg/L (IQR: 0.8, 11.7) in those without TB. As the CRP threshold increased from ≥1 mg/L to ≥10 mg/L, the positive predictive value for TB increased from 22.4% to 35.4%, and negative predictive value decreased from 96.9% to 92.3%. With CRP thresholds varying from <1 to <10 mg/L, a range from 25.5% to 64.9% of the cohort would have been eligible for same-day ART, and 0.8% to 5.0% would have untreated TB at ART initiation. Conclusions: CRP concentrations can be used to improve TB risk stratification, facilitating same-day decisions about ART initiation. Depending on the CRP threshold, one-quarter to two-thirds of patients could be eligible for same-day ART, with a reduction of 3-fold to 20-fold in the proportion with untreated TB, compared with a strategy of same-day ART while awaiting TB test results.

Transcriptional Biomarkers of Differentially Detectable Mycobacterium tuberculosis in Patient Sputum.

Certain populations of Mycobacterium tuberculosis go undetected by standard diagnostics but can be enumerated using limiting dilution assays. These differentially detectable M. tuberculosis (DD M. tuberculosis) populations may have relevance for persistence due to their drug tolerance. It is unclear how well DD M. tuberculosis from patients is modeled by a recently developed in vitro model in which M. tuberculosis starved in phosphate-buffered saline is incubated with rifampin to produce DD M. tuberculosis (the PBS-RIF model). This study attempted to answer this question. We selected 14 genes that displayed differential expression in the PBS-RIF model and evaluated their expression in patient sputa containing various proportions of DD M. tuberculosis. The expression of 12/14 genes correlated with the relative abundance of DD M. tuberculosis in patient sputa. Culture filtrate (CF), which promotes recovery of DD M. tuberculosis from certain patient sputa, improved these correlations in most cases. The gene whose reduced expression relative to M. tuberculosis 16S rRNA showed the greatest association with the presence and relative abundance of DD M. tuberculosis in patient sputa, icl1, was recently shown to play a functional role in restraining DD M. tuberculosis formation in the PBS-RIF model. Expression of icl1, combined with two additional DD M. tuberculosis-related genes, showed strong performance for predicting the presence or absence of DD M. tuberculosis in patient sputa (receiver operating characteristic [ROC] area under the curve [AUC] = 0.88). Thus, the in vitro DD M. tuberculosis model developed by Saito et al. (K. Saito, T. Warrier, S. Somersan-Karakaya, L. Kaminski, et al., Proc Natl Acad Sci U S A 114:E4832-E4840, 2017, https://doi.org/10.1073/pnas.1705385114) bears a resemblance to DD M. tuberculosis found in tuberculosis (TB) patients, and DD M. tuberculosis transcriptional profiles may be useful for monitoring DD M. tuberculosis populations in patient sputum. IMPORTANCE Differentially detectable M. tuberculosis (DD M. tuberculosis), which is detectable by limiting dilution assays but not by CFU, is present and enriched for in TB patient sputum after initiation of first-line therapy. These cryptic cells may play a role in disease persistence due to their phenotypic tolerance to anti-TB drugs. A recently developed in vitro model of DD M. tuberculosis (the PBS-RIF model) has expanded our understanding of these cells, though how well it translates to DD M. tuberculosis in patients is currently unknown. To answer this question, we selected 14 genes that displayed differential expression in the PBS-RIF model and evaluated their expression in TB patient sputa. We found that 12/14 of these genes showed a similar expression profile in patient sputa that correlated with the relative abundance of DD M. tuberculosis. Further, the expression of three of these genes showed strong performance for predicting the presence or absence of DD M. tuberculosis in patient sputa. The use of DD M. tuberculosis transcriptional profiles may allow for easier monitoring of DD M. tuberculosis populations in patient sputum in comparison to limiting dilution assays.

Extreme Food Insecurity and Malnutrition in Haiti: Findings from a Population-Based Cohort in Port-au-Prince, Haiti.

Haiti is one of the most food-insecure (FIS) nations in the world, with increasing rates of overweight and obesity. This study aimed to characterize FIS among households in urban Haiti and assess the relationship between FIS and body mass index (BMI) using enrollment data from the Haiti Cardiovascular Disease Cohort Study. FIS was characterized as no/low, moderate/high, and extreme based on the Household Food Security Scale. Multinomial logistic generalized estimating equations were used to evaluate the association between FIS categories and BMI, with obesity defined as BMI ≥ 30 kg/m2. Among 2972 participants, the prevalence of moderate/high FIS was 40.1% and extreme FIS was 43.7%. Those with extreme FIS had higher median age (41 vs. 38 years) and were less educated (secondary education: 11.6% vs. 20.3%) compared to those with no/low FIS. Although all FIS categories had high obesity prevalence, those with extreme FIS compared to no/low FIS (15.3% vs. 21.6%) had the lowest prevalence. Multivariable models showed an inverse relationship between FIS and obesity: moderate/high FIS (OR: 0.77, 95% CI: 0.56, 1.08) and extreme FIS (OR: 0.58, 95% CI: 0.42, 0.81) versus no/low FIS were associated with lower adjusted odds of obesity. We found high prevalence of extreme FIS in urban Haiti in a transitioning nutrition setting. The inverse relationship between extreme FIS and obesity needs to be further studied to reduce both FIS and obesity in this population.

High prevalence of obesity among women in urban Haiti: Findings from a population-based cohort.

Introduction: Obesity is associated with increased risk of non-communicable diseases and death and is increasing rapidly in low- and middle-income countries, including Haiti. There is limited population-based data on body mass index (BMI) and waist circumference (WC) and associated risk factors in Haiti. This study describes BMI and WC, and factors associated with obesity using a population-based cohort from Port-au-Prince. Methods: Baseline sociodemographic and clinical data were collected from participants in the Haiti CVD Cohort Study between March 2019 and August 2021. Weight was categorized by BMI (kg/m2) with obesity defined as ≥30 kg/m2. Abdominal obesity was defined using WC cutoffs of ≥80 cm for women and ≥94 cm for men based on WHO guidelines. Sociodemographic and behavioral risk factors, including age, sex, educational attainment, income, smoking status, physical activity, fat/oil use, daily fruit/vegetable consumption, and frequency of fried food intake were assessed for their association with obesity using a Poisson multivariable regression. Results: Among 2,966 participants, median age was 41 years (IQR: 28-55) and 57.6% were women. Median BMI was 24.0 kg/m2 (IQR: 20.9-28.1) and 508 (17.1%) participants were obese. Women represented 89.2% of the population with BMI ≥30 kg/m2. A total of 1,167 (68.3%) women had WC ≥80 cm and 144 (11.4%) men had WC ≥94 cm. BMI ≥30 kg/m2 was significantly more prevalent among women than men [PR 5.7; 95% CI: (4.3-7.6)], those 40-49 years compared to 18-29 years [PR 3.3; 95% CI: (2.4-4.6)], and those with income >10 USD per day compared to ≤1 USD [PR 1.3; 95% CI: (1.0-1.6)]. There were no significant associations with other health and behavioral risk factors. Discussion: In Haiti, women have an alarming 6-fold higher obesity prevalence compared to men (26.5 vs. 4.3%) and 89.2% of participants with obesity were women. Abdominal obesity was high, at 44.3%. Haiti faces a paradox of an ongoing national food insecurity crises and a burgeoning obesity epidemic. Individual, social, and environmental drivers of obesity, especially among women, need to be identified.

An optimized method for purifying, detecting and quantifying Mycobacterium tuberculosis RNA from sputum for monitoring treatment response in TB patients.

Diagnostics that more accurately detect and quantify viable Mycobacterium tuberculosis (Mtb) in the sputum of patients undergoing therapy are needed. Current culture- and molecular-based tests have shown limited efficacy for monitoring treatment response in TB patients, either due to the presence of viable sub-populations of Mtb which fail to grow under standard culture conditions (termed differentially detectable/culturable Mtb, DD Mtb) or the prolonged half-life of Mtb DNA in sputum. Here, we report an optimized RNA-based method for detecting and quantifying viable Mtb from patient sputum during the course of therapy. We first empirically derived a novel RNA extraction protocol from sputum that improves recovery of Mtb RNA while almost completely eliminating contamination from Mtb DNA and host nucleic acids. Next, we identified five Mtb 16S rRNA primer sets with varying limits of detection that were capable of distinguishing between live versus dead H37Rv Mtb. This combined protocol was then tested on sputa from a longitudinal cohort of patients receiving therapy for drug sensitive (DS) or drug resistant (DR) TB with first-line or second-line regimens, respectively. Results were compared with that of culture, including CFU, BACTEC MGIT, and a limiting dilution assay capable of detecting DD Mtb. The five 16S rRNA primer sets positively identified nearly all (range 94-100%) culture positive sputa, and a portion (19-37%) of culture negative sputa. In comparison, ten highly expressed Mtb mRNAs showed positivity in 72-86% of culture positive sputa, and in 0-13% of culture negative sputa. Two of the five 16S rRNA primer sets were able to positively identify 100% of culture positive sputa, and when tested on culture negative sputa from the DS cohort at 2 months post-initiation of therapy, identified 40% of samples as positive; a percentage that is in line with expected treatment failure rates when first-line therapy is discontinued early. These two primer sets also detected 16S rRNA in 13-20% of sputa at 6 months post-initiation of therapy in the DR cohort. Cycle threshold values for 16S rRNA showed a strong correlation with Mtb numbers as determined by culture (R > 0.87), including as Mtb numbers declined during the course of treatment with first-line and second-line regimens. The optimized molecular assay outlined here may have utility for monitoring treatment response in TB patients.