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Summary: 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

Abstract 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.

Abstract Hypertension in pregnancy is a key driver of mortality and morbidity among Haitian women. HIV infection and treatment may worsen hypertension and increase cardiovascular disease risk. The authors examined blood pressure and hypertension patterns among 1965 women (2306 pregnancies ending in live births) in a prevention of maternal‐to‐child transmission (PMTCT) program in Port‐au‐Prince, Haiti, between 2007 and 2017. Hypertension was defined as blood pressure ≥140/90 mm Hg on two consecutive visits. Latent class analysis assessed trajectories of mean arterial pressure (MAP) and multinomial ordinal logistic regression examined factors associated with higher trajectories. Between 2007–2009 and 2013–2016, hypertension at PMTCT entry increased from 1.3% to 3.8% (p = .005), while incidence at any time during PMTCT follow‐up increased from 5.0 to 16.1 per 100 person‐years (p 20 weeks of gestation (possible gestational hypertension) increased from 1.1% to 3.5% (p = .003) and from 2.3% to 6.9% (p

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 (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

IntroductionWomen play an essential role in health care delivery, and it is vital that they have equal representation in health leadership for equity, innovation, and the strengthening of health systems globally. Yet women remain vastly underrepresented in global health leadership positions, providing a clear example of the deeply rooted power imbalances that are central to the calls to decolonize global health. We conducted a multi-country study in Haiti, Tanzania, India, and the USA to examine gender-based challenges to career advancement for women in the global health workforce. Quantitative data on the type and prevalence of gender-based challenges has been previously reported. In this study, we analyze qualitative data collected through focus group discussions and in-depth interviews to understand women's experiences of gender-based obstacles to career advancement, their perceptions of underlying drivers, and perspectives on effective solutions. Guided by an adaptation of the Social Action Theory, we conducted focus group discussions and in-depth interviews with women at 4 major academic centers for clinical care and research in Haiti, India, Tanzania, and the United States. In total, 85 women participated in focus groups and 15 also participated in in-depth interviews. Discussions and interviews were conducted in the local language, by an experienced local facilitator unaffiliated with the participating institution, between 2017 and 2018. Discussions were recorded, transcribed, and translated. Data were analyzed by interpretive phenomenological methods for emergent themes. Three transcendent themes on gender-based challenges were identified: 1) cultural power imbalance, referring to the prevailing norms and engrained assumptions that women are less capable than men and that women's primary responsibility should be to their families; 2) institutional power imbalance, referring to the systematic gender bias upheld by existing leadership and power structures, and ranging from exclusion from career development opportunities to sexual harassment and assault; and 3) restricted agency, referring to women's limited ability to change their circumstances because of unequal cultural and institutional structures. Participants also described local, actionable solutions to address these barriers. These included: 1) formal reporting systems for sexual harassment and assault; 2) peer support and mentorship; and 3) accessible leadership training and mandatory gender equity training. Participants proposed feasible strategies to address gender-based challenges that could improve women's retention in health careers and foster their rise to leadership. Increasing the representation of women in global health leadership positions responds directly to efforts to decolonize global health and is integral to strengthening health systems and improving health outcomes for women and children worldwide.

ABSTRACT 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.

Abstract The shell morphologies of the freshwater mussel species Pleurobema clava (federally endangered) and Pleurobema oviforme (species of concern) are similar, causing considerable taxonomic confusion between the two species over the last 100 years. While P. clava was historically widespread throughout the Ohio River basin and tributaries to the lower Laurentian Great Lakes, P. oviforme was confined to the Tennessee and the upper Cumberland River basins. We used two mitochondrial DNA (mtDNA) genes, 13 novel nuclear DNA microsatellite markers, and shell morphometrics to help resolve this taxonomic confusion. Evidence for a single species was apparent in phylogenetic analyses of each mtDNA gene, revealing monophyletic relationships with minimal differentiation and shared haplotypes. Analyses of microsatellites showed significant genetic structuring, with four main genetic clusters detected, respectively, in the upper Ohio River basin, the lower Ohio River and Great Lakes, and upper Tennessee River basin, and a fourth genetic cluster, which included geographically intermediate populations in the Ohio and Tennessee river basins. While principal components analysis (PCA) of morphometric variables (i.e., length, height, width, and weight) showed significant differences in shell shape, only 3% of the variance in shell shape was explained by nominal species. Using Linear Discriminant and Random Forest (RF) analyses, correct classification rates for the two species' shell forms were 65.5% and 83.2%, respectively. Random Forest classification rates for some populations were higher; for example, for North Fork Holston (HOLS), it was >90%. While nuclear DNA and shell morphology indicate that the HOLS population is strongly differentiated, perhaps indicative of cryptic biodiversity, we consider the presence of a single widespread species the most likely biological scenario for many of the investigated populations based on our mtDNA dataset. However, additional sampling of P. oviforme populations at nuclear loci is needed to corroborate this finding.

Abstract Multispecies risk assessments have developed within many international conservation programs, reflecting a widespread need for efficiency. Under the United States Endangered Species Act (ESA), multispecies assessments ultimately lead to species‐level listing decisions. Although this approach provides opportunities for improved efficiency, it also risks overwhelming or biasing the assessment process and would benefit from clear guidance for practitioners. We reviewed multispecies assessments conducted between 1993 and 2019 for ESA listing decisions to identify the ecological basis for combining species, the assessment approach used, and the policy factors influencing their efficacy. We identified 42 cases covering 359 species. Most assessments (81%) included two to five species, although the maximum was 82. A common theme involved grouping narrow endemics or habitat specialists based on taxonomic relatedness, similar distributions, and common threats to persistence. All assessments included a combined threats analysis, but few employed a common species' response model or expert elicitation process. Although ESA risk assessments are distinct from policy decisions, most assessments (50%) supported decisions that all species warranted endangered status. Available guidance has generally emphasized ecological similarity as the key attribute leading to successful multispecies assessments. The challenge with consistently selecting species based on qualitative proxies such as common distributions or threats to persistence is that ecological patterns and processes are scale dependent. Focusing instead on the assessment methods and their potential for bias and increased efficiency may provide a stronger basis for developing consistent and transparent guidance.

Abstract Background Environmental conditions on Earth are repeated in non-random patterns that often coincide with species from different regions and time periods having consistent combinations of morphological, physiological and behavioral traits. Observation of repeated trait combinations among species confronting similar environmental conditions suggest that adaptive trait combinations are constrained by functional tradeoffs within or across niche dimensions. In an earlier study, we assembled a high-resolution database of functional traits for 134 lizard species to explore ecological diversification in relation to five fundamental niche dimensions. Here we expand and further examine multivariate relationships in that dataset to assess the relative influence of niche dimensions on the distribution of species in 6-dimensional niche space and how these may deviate from distributions generated from null models. We then analyzed a dataset with lower functional-trait resolution for 1023 lizard species that was compiled from our dataset and a published database, representing most of the extant families and environmental conditions occupied by lizards globally. Ordinations from multivariate analysis were compared with null models to assess how ecological and historical factors have resulted in the conservation, divergence or convergence of lizard niches. Results Lizard species clustered within a functional niche volume influenced mostly by functional traits associated with diet, activity, and habitat/substrate. Consistent patterns of trait combinations within and among niche dimensions yielded 24 functional groups that occupied a total niche space significantly smaller than plausible spaces projected by null models. Null model tests indicated that several functional groups are strongly constrained by phylogeny, such as nocturnality in the Gekkota and the secondarily acquired sit-and-wait foraging strategy in Iguania. Most of the widely distributed and species-rich families contained multiple functional groups thereby contributing to high incidence of niche convergence. Conclusions Comparison of empirical patterns with those generated by null models suggests that ecological filters promote limited sets of trait combinations, especially where similar conditions occur, reflecting both niche convergence and conservatism. Widespread patterns of niche convergence following ancestral niche diversification support the idea that lizard niches are defined by trait-function relationships and interactions with environment that are, to some degree, predictable and independent of phylogeny.

Objectives: Pseudomonas aeruginosa is a leading cause of opportunistic infections worldwide, particularly in healthcare settings, and frequently demonstrates resistance to commonly prescribed antimicrobials. Carbapenem resistance is prevalent worldwide, however there are currently limited data available from Haiti. The aim of this study was to characterise and document this phenotype in Port-au-Prince, Haiti, to further inform the need for appropriate infection control, empirical treatment guidelines and laboratory screening measures, both in Haiti and globally. Methods: A total of 50 P. aeruginosa isolates were characterised by multilocus sequence typing (MLST) and antimicrobial susceptibility testing, of which 8 isolates were also subjected to whole-genome sequencing (WGS) to identify potential genetic correlations of phenotypic resistance. Results: By MLST, 23 sequence types (STs) were identified, including 13 new STs. Nineteen isolates belonged to a single, previously characterised ST (ST654), all of which demonstrated a multidrug-resistant phenotype, including resistance to meropenem, imipenem and ceftazidime; two isolates were also resistant to colistin. WGS revealed the presence of genes encoding several previously characterised resistance determinants in ST654; notably ACC(6′)-Ib3-cr and GES-7. Metallo-β-lactamase genes (blaVIM-5) were also detected in three isolates. Conclusion: These findings confirm that drug-resistant clones of P. aeruginosa are present in Haiti, supporting the need for appropriate screening and control measures and confirming that drug-resistant micro-organisms pose a global threat. Further investigations are required to guide appropriate antimicrobial prescribing in this region.

Antibiotic therapy can lead to pathogen clearance, but also to alterations in the gut microbiota and systemic immune responses. Here, the authors analyze data from patients with tuberculosis and healthy subjects to show that pathogen clearance and gut microbiota alterations are independently associated with antibiotic-induced changes of the inflammatory response of active tuberculosis.

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.

BACKGROUND Control of the tuberculosis (TB) pandemic remains hindered in part by a lack of simple and accurate measures of treatment efficacy, as current gold standard markers rely on sputum-based assays that are slow and challenging to implement. However, previous work identified urinary N1, N12-diacetylspermine (DiAcSpm), neopterin, hydroxykynurenine, N-acetylhexosamine, ureidopropionic acid, sialic acid, and mass-to-charge ratio (m/z) 241.0903 as potential biomarkers of active pulmonary TB (ATB). Here, we evaluated their ability to serve as biomarkers of TB treatment response and mycobacterial load.METHODS We analyzed urine samples prospectively collected from 2 cohorts with ATB. A total of 34 study participants from African countries treated with first-line TB therapy rifampin, isoniazid, pyrazinamide, and ethambutol (HRZE) were followed for 1 year, and 35 participants from Haiti treated with either HRZE or an experimental drug were followed for 14 days. Blinded samples were analyzed by untargeted HPLC-coupled high-resolution TOF-mass spectrometry.RESULTS Urinary levels of all 7 molecules significantly decreased by week 26 of successful treatment (P = 0.01 to P < 0.0001) and positively correlated with sputum mycobacterial load (P < 0.0001). Urinary DiAcSpm levels decreased significantly in participants treated with HRZE as early as 14 days (P < 0.0001) but remained unchanged in cases of ineffective therapy (P = 0.14).CONCLUSION Urinary DiAcSpm, neopterin, hydroxykynurenine, N-acetylhexosamine, ureidopropionic acid, sialic acid, and m/z 241.0903 reductions correlated with successful anti-TB treatment and sputum mycobacterial load. Urinary DiAcSpm levels exhibited reductions capable of differentiating treatment success from failure as early as 2 weeks after the initiation of chemotherapy, advocating its further development as a potentially simple, noninvasive biomarker for assessing treatment response and bacterial load.FUNDING This work was supported by the Clinical and Translational Science Center at Weill Cornell College of Medicine (NIH/NCATS 1 UL1 TR002384-02 and KL2TR000458), the Department of Defense (PR170782), the National Institute of Allergy and Infectious Disease grants (NIAID T32AI007613-16, K24 AI098627, and K23 AI131913), the NIH Fogarty International Center grants (R24 TW007988 and TW010062), NIH grant (R01 GM135926), the Abby and Howard P. Milstein Program in Chemical Biology and Translational Medicine, and the Tuberculosis Research Units Networks (TBRU-N, AI111143).

Introduction Adolescents living with HIV have poor antiretroviral therapy (ART) adherence and viral suppression outcomes. Viral load (VL) monitoring could reinforce adherence but standard VL testing requires strong laboratory capacity often only available in large central laboratories. Thus, coordinated transport of samples and results between the clinic and laboratory is required, presenting opportunities for delayed or misplaced results. Newly available point-of-care (POC) VL testing systems return test results the same day and could simplify VL monitoring so that adolescents receive test results faster which could strengthen adherence counselling and improve ART adherence and viral suppression.Methods and analysis This non-blinded randomised clinical trial is designed to evaluate the implementation and effectiveness of POC VL testing compared with standard laboratory-based VL testing among adolescents and youth living with HIV in Haiti. A total of 150 participants ages 10–24 who have been on ART for >6 months are randomised 1:1 to intervention or standard arms. Intervention arm participants receive a POC VL test (Cepheid Xpert HIV-1 Viral Load system) with same-day result and immediate ART adherence counselling. Standard care participants receive a laboratory-based VL test (Abbott m2000sp/m2000rt) with the result available 1 month later, at which time they receive ART adherence counselling. VL testing is repeated 6 months later for both arms. The primary objective is to describe the implementation of POC VL testing compared with standard laboratory-based VL testing. The secondary objective is to evaluate the effect of POC VL testing on VL suppression at 6 months and participant comprehension of the correlation between VL and ART adherence.Ethics and dissemination This study is approved by GHESKIO, Weill Cornell Medicine and Columbia University ethics committees. This trial will provide critical data to understand if and how POC VL testing may impact adolescent ART adherence and viral suppression. If effective, POC VL testing could routinely supplement standard laboratory-based VL testing among high-risk populations living with HIV.Trial registration number NCT03288246.

Poor diets are responsible for a large burden of noncommunicable disease (NCD). The prevalence of modifiable dietary risk factors is rising in lower-income countries such as Haiti, along with increasing urbanization and shifts to diets high in sugar, salt, and fat. We describe self-reported dietary patterns (intake of fruits, vegetables, fried food, sugar-sweetened beverages, and added salt and oil) among a population-based cohort of low-income adults in Port-au-Prince and assess for associated sociodemographic factors (age, sex, income, education, body mass index). Among 2989 participants, the median age was 40 years, and 58.0% were women. Less than 1% met the World Health Organization recommendation of at least five servings/day of fruits and vegetables. Participants consumed fried food on average 1.6 days/week and sugar-sweetened beverages on average 4.7 days/week; young males of low socioeconomic status were the most likely to consume these dietary risk factors. The vast majority of participants reported usually or often consuming salt (87.1%) and oil (86.5%) added to their meals eaten at home. Our findings underscore the need for public health campaigns, particularly those targeting young males and household cooks preparing family meals at home, to improve dietary patterns in Haiti in order to address the growing NCD burden.

Background: Tuberculosis (TB) is the leading infectious cause of death worldwide. A major barrier to control of the pandemic is a lack of clinical biomarkers with the ability to distinguish active TB from healthy and sick controls and potential for development into point-of-care diagnostics. Methods: We conducted a prospective case control study to identify candidate urine-based diagnostic biomarkers of active pulmonary TB (discovery cohort) and obtained a separate blinded “validation” cohort of confirmed cases of active pulmonary TB and controls with non-tuberculous pulmonary disease for validation. Clean-catch urine samples were collected and analyzed using high performance liquid chromatography-coupled time-of-flight mass spectrometry. Results: We discovered ten molecules from the discovery cohort with receiver-operator characteristic (ROC) area-under-the-curve (AUC) values >85%. These 10 molecules also significantly decreased after 60 days of treatment in a subset of 20 participants followed over time. Of these, a specific combination of diacetylspermine, neopterin, sialic acid, and N-acetylhexosamine exhibited ROC AUCs >80% in a blinded validation cohort of participants with active TB and non-tuberculous pulmonary disease. Conclusion: Urinary levels of diacetylspermine, neopterin, sialic acid, and N-acetylhexosamine distinguished patients with tuberculosis from healthy controls and patients with non-tuberculous pulmonary diseases, providing a potential noninvasive biosignature of active TB. Funding: This study was funded by Weill Cornell Medicine, the National Institute of Allergy and Infectious Diseases, the Clinical and Translational Science Center at Weill Cornell, the NIH Fogarty International Center grants, and the NIH Tuberculosis Research Unit (Tri-I TBRU). Keywords: Tuberculosis, Biomarker, Metabolomics, Urine

Abstract Mycobacterium tuberculosis, the cause of Tuberculosis (TB), infects one third of the world’s population and causes substantial mortality worldwide. In its shortest format, treatment of TB requires six months of multidrug therapy with a mixture of broad spectrum and mycobacterial specific antibiotics, and treatment of multidrug resistant TB is longer. The widespread use of this regimen makes this one of the largest exposures of humans to antimicrobials, yet the effects of TB treatment on intestinal microbiome composition and long-term stability are unknown. We compared the microbiome composition, assessed by both 16S rDNA and metagenomic DNA sequencing, of TB cases during antimycobacterial treatment and following cure by 6 months of antibiotics. TB treatment does not perturb overall diversity, but nonetheless dramatically depletes multiple immunologically significant commensal bacteria. The microbiomic perturbation of TB therapy can persist for at least 1.2 years, indicating that the effects of TB treatment are long lasting. These results demonstrate that TB treatment has dramatic effects on the intestinal microbiome and highlight unexpected durable consequences of treatment for the world’s most common infection on human ecology.

ABSTRACT Recent reports indicate that the sputum of 80% or more of treatment-naive subjects with tuberculosis recruited in England or South Africa contained more viable Mycobacterium tuberculosis cells detected by limiting dilution (LD) in liquid culture than detected as CFU. Efforts to generate such differentially detectable (DD) M. tuberculosis populations in vitro have been difficult to reproduce, and the LD assay is prone to artifact. Here, we applied a stringent version of the LD assay to sputum from 33 treatment-naive, HIV-negative Haitian subjects with drug-sensitive tuberculosis (TB) and to a second sputum sample after two weeks of standard treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) for 13 of these subjects. Twenty-one percent had statistically defined levels of DD M. tuberculosis in their pretreatment sputum at an average proportional excess over CFU of 3-fold. Sixty-nine percent of those who received HRZE had statistically defined levels of DD M. tuberculosis in their sputum, and of these, the mean proportionate excess over CFU was 7.9-fold. Thus, DD M. tuberculosis is detectable in pretreatment sputum from a significant proportion of subjects in the Western Hemisphere, and certain drugs or drug regimens, while reducing CFU, may at the same time increase the proportional representation of DD M. tuberculosis among the surviving bacilli. Monitoring DD M. tuberculosis may improve our ability to predict the efficacy of efforts to shorten treatment. IMPORTANCE Measurement of the reduction in CFU in sputum of patients with TB up to 2 weeks after the initiation of treatment is the gateway test for a new TB treatment. Reports have suggested that CFU assays fail to detect the majority of viable M. tuberculosis cells in sputum samples from the majority of patients when the number of M. tuberculosis is estimated by limiting dilution (LD). In an effort to avoid potential methodologic confounders, we applied a modified version of the LD assay in a study of a geographically distinct population. We confirmed that differentially detectable (DD) M. tuberculosis is often found before treatment, albeit at lower proportionate levels than in earlier reports. Strikingly, the prevalence and proportionate representation of DD M. tuberculosis increased during standard treatment. Sublethal exposure to certain antibiotics may help generate DD M. tuberculosis cells or enrich their representation among the surviving bacteria, and this may contribute to the need for prolonged treatment with those agents in order to achieve durable cures.

BACKGROUND:Over 18 million adults have initiated life-saving antiretroviral therapy (ART) in resource-poor settings; however, mortality and lost-to-follow-up rates continue to be high among patients in their first year after treatment start. Clinical decision tools are needed to identify patients at high risk for poor outcomes in order to provide individualized risk assessment and intervention. This study aimed to develop and externally validate risk prediction tools that estimate the probability of dying or of being lost to follow-up (LTF) during the year after starting ART. METHODS:We used a derivation cohort of 7,031 adults age 15-70 years initiating ART from 2007 to 2013 at 6 clinics in Haiti; 242 (3.5%) had documented death and 1,521 (21.6%) were LTF at 1 year after starting ART. The following routinely collected data were used as predictors in two logistic regression models (one to predict death and another to predict LTF): age, gender, weight, CD4 count, WHO Stage, and diagnosis of tuberculosis (TB). The validation cohort consisted of 1,835 adults initiating ART at a different HIV clinic in Haiti during 2012. We assessed model discrimination by measuring the C-statistic, and measured model calibration by how closely the predicted probabilities approximated actual probabilities of the two outcomes. We derived a nomogram and a point-based risk score from the predictive models. FINDINGS:The model predicting death within the year after starting ART had a C-statistic of 0.75 (95% CI 0.74 to 0.81). There was no evidence for significant overfitting and the predictions were well calibrated. The strongest predictors of 1-year mortality were male gender, low weight, low CD4 count, advanced WHO stage, and the absence of TB. In the validation cohort, the C-statistic was 0.69 (95% CI 0.59 to 0.77). A point-based risk score for death had a C-statistic 0.73 (95% CI 0.69 to 0.76) and categorizes patients as low risk (

Schistosomiasis affects 218 million people worldwide, with most infections in Africa. Prevalence studies suggest that people with chronic schistosomiasis may have higher risk of HIV-1 acquisition and impaired ability to control HIV-1 replication once infected. We hypothesized that: (1) pre-existing schistosome infection may increase the odds of HIV-1 acquisition and that the effects may differ between men and women, and (2) individuals with active schistosome infection at the time of HIV-1 acquisition may have impaired immune control of HIV-1, resulting in higher HIV-1 viral loads at HIV-1 seroconversion.We conducted a nested case-control study within a large population-based survey of HIV-1 transmission in Tanzania. A population of adults from seven villages was tested for HIV in 2007, 2010, and 2013 and dried blood spots were archived for future studies with participants' consent. Approximately 40% of this population has Schistosoma mansoni infection, and 2% has S. haematobium. We tested for schistosome antigens in the pre- and post-HIV-1-seroconversion blood spots of people who acquired HIV-1. We also tested blood spots of matched controls who did not acquire HIV-1 and calculated the odds that a person with schistosomiasis would become HIV-1-infected compared to these matched controls. Analysis was stratified by gender. We compared 73 HIV-1 seroconverters with 265 controls. Women with schistosome infections had a higher odds of HIV-1 acquisition than those without (adjusted OR = 2.8 [1.2-6.6], p = 0.019). Schistosome-infected men did not have an increased odds of HIV-1 acquisition (adjusted OR = 0.7 [0.3-1.8], p = 0.42). We additionally compared HIV-1 RNA levels in the post-seroconversion blood spots in HIV-1 seroconverters with schistosomiasis versus those without who became HIV-infected in 2010, before antiretroviral therapy was widely available in the region. The median whole blood HIV-1 RNA level in the 15 HIV-1 seroconverters with schistosome infection was significantly higher than in the 22 without schistosomiasis: 4.4 [3.9-4.6] log10 copies/mL versus 3.7 [3.2-4.3], p = 0.017.We confirm, in an area with endemic S. mansoni, that pre-existing schistosome infection increases odds of HIV-1 acquisition in women and raises HIV-1 viral load at the time of HIV-1 seroconversion. This is the first study to demonstrate the effect of schistosome infection on HIV-1 susceptibility and viral control, and to differentiate effects by gender. Validation studies will be needed at additional sites.

BACKGROUND:We report patient outcomes after antiretroviral therapy (ART) initiation in a network of HIV facilities in Haiti, including temporal trends and differences across clinics, during the expansion of HIV services in the country. METHODS:We assessed outcomes at 12 months after ART initiation (baseline) using routinely collected data on adults (≥15 years) in 11 HIV facilities from July 2007-December 2013. Outcomes include death (ascertained from medical records), lost to follow-up (LTF) defined as no visit > 365 days from ART initiation, and retention defined as being alive and attending care ≥ 365 days from ART initiation. Outcomes were compared across calendar year of ART initiation and across facilities. Risk factors for death and LTF were assessed using Cox proportional hazards and competing risk regression models. RESULTS:Cumulatively, 9,718 adults initiated ART with median age 37 years (IQR 30-46). Median CD4 count was 254 cells/uL (IQR 139-350). Twelve months after ART initiation, 4.4% (95% CI 4.0-4.8) of patients died, 21.7% (95% CI 20.9-22.6) were LTF, and 73.9% (95% CI 73.0-74.8) were retained in care. Twelve-month mortality decreased from 13.8% among adults who started ART in 2007 to 4.4% in 2013 (p

The baculovirus/insect cell system (BICS) is widely used in academia and industry to produce eukaryotic proteins for many applications, ranging from structure analysis to drug screening and the provision of protein biologics and therapeutics. Multi-protein complexes have emerged as vital catalysts of cellular function. In order to unlock the structure and mechanism of these essential molecular machines and decipher their function, we developed MultiBac, a BICS particularly tailored for heterologous multigene transfer and multi-protein complex production. Baculovirus is unique among common viral vectors in its capacity to accommodate very large quantities of heterologous DNA and to faithfully deliver this cargo to a host cell of choice. We exploited this beneficial feature to outfit insect cells with synthetic DNA circuitry conferring new functionality during heterologous protein expression, and developing customized MultiBac baculovirus variants in the process. By altering its tropism, recombinant baculovirions can be used for the highly efficient delivery of a customized DNA cargo in mammalian cells and tissues. Current advances in synthetic biology greatly facilitate the construction or recombinant baculoviral genomes for gene editing and genome engineering, mediated by a MultiBac baculovirus tailored to this purpose. Here, recent developments and exploits of the MultiBac system are presented and discussed.

Introduction Adolescents account for over 40% of new HIV infections in Haiti. This analysis compares outcomes among HIV‐positive adolescents before and after implementation of an adolescent HIV clinic in Port‐au‐Prince, Haiti. Methods We conducted a cohort study using programmatic data among HIV‐positive adolescents aged 13 to 19. Data from 41,218 adolescents who were HIV tested from January 2003 to December 2012 were included. Outcomes across the HIV care cascade were assessed before and after implementation of an adolescent clinic (2009), including HIV testing, enrolment in care, assessment for antiretroviral therapy (ART) eligibility, ART initiation and 12‐month retention. Pre‐ART outcomes were assessed 12 months after HIV testing. Factors associated with pre‐ART and ART attrition were identified through multivariable competing risk and Cox proportional hazards regression modelling. Results Cumulatively, 1672 (4.1%) adolescents tested HIV positive (80% female, median age 16 years). Retention by cascade step comparing pre‐ and post‐clinic included the following: 86% versus 87% of patients enrolled in care, 61% versus 79% were assessed for ART eligibility, 85% versus 92% initiated ART and 68% versus 66% were retained 12 months after ART initiation. Pre‐ART attrition decreased from 61% pre‐clinic to 50% post‐clinic (p

Oral mucosal lesions that are associated with HIV infection can play an important role in guiding the decision to initiate antiretroviral therapy (ART). The incidence of these lesions relative to the timing of ART initiation has not been well characterized. A randomized controlled clinical trial was conducted at the GHESKIO Center in Port-au-Prince, Haiti between 2004 and 2009. 816 HIV-infected ART-naïve participants with CD4 T cell counts between 200 and 350 cells/mm3 were randomized to either immediate ART initiation (early group; N = 408), or initiation when CD4 T cell count was less than or equal 200 cells/mm3 or with the development of an AIDS-defining condition (delayed group; N = 408). Every 3 months, all participants underwent an oral examination. The incidence of oral lesions was 4.10 in the early group and 17.85 in the delayed group (p-value

IntroductionMillions of HIV-infected Africans are living longer due to long-term antiretroviral therapy (ART), yet little is known about glucose metabolism disorders in this group. We aimed to compare the prevalence of glucose metabolism disorders among HIV-infected adults on long-term ART to ART-naïve adults and HIV-negative controls, hypothesizing that the odds of glucose metabolism disorders would be 2-fold greater even after adjusting for possible confounders.MethodsIn this cross-sectional study conducted between October 2012 and April 2013, consecutive adults (>18 years) attending an HIV clinic in Tanzania were enrolled in 3 groups: 153 HIV-negative controls, 151 HIV-infected, ART-naïve, and 150 HIV-infected on ART for ≥ 2 years. The primary outcome was the prevalence of glucose metabolism disorders as determined by oral glucose tolerance testing. We compared glucose metabolism disorder prevalence between each HIV group vs. the control group by Fisher's exact test and used multivariable logistic regression to determine factors associated with glucose metabolism disorders.ResultsHIV-infected adults on ART had a higher prevalence of glucose metabolism disorders (49/150 (32.7%) vs.11/153 (7.2%), pConclusionsHIV-infected adults on long-term ART had 5-fold greater odds of glucose metabolism disorders than HIV-negative controls but were rarely aware of their diagnosis. Intensive glucose metabolism disorder screening and education are needed in HIV clinics in sub-Saharan Africa. Further research should determine how glucose metabolism disorders might be related to immune reconstitution.

Schistosomiasis and HIV are both associated with kidney disease. Prevalence and factors associated with abnormal renal function among HIV-infected children in Africa compared to uninfected controls have not been well described in a schistosomiasis endemic area.This cross-sectional study was conducted at the Sekou Toure Regional Hospital HIV clinic in Mwanza, Tanzania. A total of 122 HIV-infected children and 122 HIV-uninfected siblings were consecutively enrolled. Fresh urine was obtained for measurement of albuminuria and Schistosoma circulating cathodic antigen. Blood was collected for measurement of serum creatinine. Estimated glomerular filtration rate (eGFR) was calculated using the modified Schwartz equation. Renal dysfunction was defined operationally as eGFR20 mg/L in a single sample. Among 122 HIV-infected children, 61/122 (50.0%) met our criteria for renal dysfunction: 54/122 (44.3%) had albuminuria>20 mg/L and 9/122 (7.4%) had eGFR20 mg/L and 6/122 (4.9%) had eGFR

The World Health Organization recommends diagnosing Multidrug-Resistant Tuberculosis (MDR-TB) in high burden countries by detection of mutations in Rifampin (RIF) Resistance Determining Region of Mycobacterium tuberculosis rpoB gene with rapid molecular tests GeneXpert MTB/RIF and Hain MTBDRplus. Such mutations are found in >95% of Mycobacterium tuberculosis strains resistant to RIF by conventional culture-based drug susceptibility testing (DST). However routine diagnostic screening with molecular tests uncovered specific "low level" rpoB mutations conferring resistance to RIF below the critical concentration of 1 μg/ml in some phenotypically susceptible strains. Cases with discrepant phenotypic (susceptible) and genotypic (resistant) results for resistance to RIF account for at least 10% of resistant diagnoses by molecular tests and urgently require new guidelines to inform therapeutic decision making. Eight strains with a "low level" rpoB mutation L511P were isolated by GHESKIO laboratory between 2008 and 2012 from 6 HIV-negative and 2 HIV-positive patients during routine molecular testing. Five isolates with a single L511P mutation and two isolates with double mutation L511P&M515T had MICs for RIF between 0.125 and 0.5 μg/ml and tested susceptible in culture-based DST. The eighth isolate carried a double mutation L511P&D516C and was phenotypically resistant to RIF. All eight strains shared the same spoligotype SIT 53 commonly found in Haiti but classic epidemiological investigation failed to uncover direct contacts between the patients. Whole Genome Sequencing (WGS) revealed that L511P cluster isolates resulted from a clonal expansion of an ancestral strain resistant to Isoniazid and to a very low level of RIF. Under the selective pressure of RIF-based therapy the strain acquired mutation in the M306 codon of embB followed by secondary mutations in rpoB and escalation of resistance level. This scenario highlights the importance of subcritical resistance to RIF for both clinical management of patients and public health and provides support for introducing rpoB mutations as proxy for MICs into laboratory diagnosis of RIF resistance. This study illustrates that WGS is a promising multi-purpose genotyping tool for high-burden settings as it provides both "gold standard" sequencing results for prediction of drug susceptibility and a high-resolution data for epidemiological investigation in a single assay.

Background Detection of subclinical cryptococcal disease using cryptococcal antigen screening among HIV‐positive individuals presents a potential opportunity for prevention of both clinical disease and death if patients with detectable cryptococcal antigen are identified and treated pre‐emptively. Recently developed point‐of‐care cryptococcal antigen tests may be useful for screening, particularly in resource‐limiting settings, but few studies have assessed their utility. Methodology The objectives of this study were to determine the prevalence and factors associated with cryptococcal antigenemia in HIV‐positive patients with CD4+ T‐cell counts ≤200 cells/µL who were initiating ART, and also to evaluate the utility of the point‐of‐care urine lateral flow assay (LFA) cryptococcal antigen test using two different diluents, compared to gold standard serum antigen testing, as a screening tool. Urine and serum of outpatients initiating antiretroviral therapy at two hospitals in Mwanza were tested for cryptococcal antigen, and demographic and clinical characteristics were obtained using structured questionnaires and patients’ files. Patients with asymptomatic cryptococcal antigenemia received oral fluconazole in accordance with World Health Organization recommendations. Results Among 140 patients screened, 10 (7.1%) had asymptomatic cryptococcal antigenemia with a positive serum cryptococcal antigen. Four of these ten patients had CD4 counts between 100 and 200 cells/µL. The prevalence of cryptococcal antigen detected in urine using a standard (older) and a test (newer) diluent were 44 (31.4%) and 19 (13.6%), with Kappa coefficients compared to serum of 0.28 and 0.51 (p

Data regarding the outcomes of HIV-infected adults with baseline renal dysfunction who start antiretroviral therapy are conflicting.We followed up a previously-published cohort of HIV-infected adult outpatients in northwest Tanzania who had high prevalence of renal dysfunction at the time of starting antiretroviral therapy (between November 2009 and February 2010). Patients had serum creatinine, proteinuria, microalbuminuria, and CD4(+) T-cell count measured at the time of antiretroviral therapy initiation and at follow-up. We used the adjusted Cockroft-Gault equation to calculate estimated glomerular filtration rates (eGFRs).In this cohort of 171 adults who had taken antiretroviral therapy for a median of two years, the prevalence of renal dysfunction (eGFR

The World Health Organization has recommended use of molecular-based tests MTBDRplus and GeneXpert MTB/RIF to diagnose multidrug-resistant tuberculosis in developing and high-burden countries. Both tests are based on detection of mutations in the Rifampin (RIF) Resistance-Determining Region of DNA-dependent RNA Polymerase gene (rpoB). Such mutations are found in 95-98% of Mycobacterium tuberculosis strains determined to be RIF-resistant by the "gold standard" culture-based drug susceptibility testing (DST). We report the phenotypic and genotypic characterization of 153 consecutive clinical Mycobacterium tuberculosis strains diagnosed as RIF-resistant by molecular tests in our laboratory in Port-au-Prince, Haiti. 133 isolates (86.9%) were resistant to both RIF and Isoniazid and 4 isolates (2.6%) were RIF mono-resistant in MGIT SIRE liquid culture-based DST. However the remaining 16 isolates (10.5%) tested RIF-sensitive by the assay. Five strains with discordant genotypic and phenotypic susceptibility results had RIF minimal inhibitory concentration (MIC) close to the cut-off value of 1 µg/ml used in phenotypic susceptibility assays and were confirmed as resistant by DST on solid media. Nine strains had sub-critical RIF MICs ranging from 0.063 to 0.5 µg/ml. Finally two strains were pan-susceptible and harbored a silent rpoB mutation. Our data indicate that not only detection of the presence but also identification of the nature of rpoB mutation is needed to accurately diagnose resistance to RIF in Mycobacterium tuberculosis. Observed clinical significance of low-level resistance to RIF supports the re-evaluation of the present critical concentration of the drug used in culture-based DST assays.

Clinical trials have shown that early initiation of antiretroviral therapy in HIV-infected patients with tuberculosis saves lives, but models for implementation of this new strategy have been under-studied in real-world settings.To identify the barriers and possible solutions for implementing concurrent early treatment with antiretroviral and anti-tuberculosis therapy in a large East African referral hospital where the prevalence of both infections is high.In-depth interviews among hospital administrators, laboratory technicians, nurses, pharmacists, and physicians.Twenty-six hospital staff identified six key barriers and corresponding solutions to promote rapid initiation of antiretroviral therapy in HIV-infected inpatients with tuberculosis. These include revising systems of medication delivery, integrating care between inpatient and outpatient systems, training hospital nurses to counsel and initiate medications in inpatients, and cultivating a team approach to consistent guideline implementation.Most barriers identified by hospital staff were easily surmountable with reorganization, training, and policy changes at minimal cost. Efforts to reduce mortality for HIV and tuberculosis co-infected patients in accordance with new World Health Organization guidelines are currently hampered by implementation barriers in real-world settings. Our findings suggest that these can be overcome with strategic enactment of simple, realistic interventions to promote early dual treatment for HIV/tuberculosis co-infected patients.

The ability to initiate and sustain trust is critical to health and well-being. Willingness to trust is in part determined by the reputation of the putative trustee, gained via direct interactions or indirectly through word of mouth. Few studies have examined how the reputation of others is instantiated in the brain during trust decisions. Here we use an event-related functional MRI (fMRI) design to examine what neural signals correspond to experimentally manipulated reputations acquired in direct interactions during trust decisions. We hypothesized that the caudate (dorsal striatum) and putamen (ventral striatum) and amygdala would signal differential reputations during decision-making. Twenty-nine healthy adults underwent fMRI scanning while completing an iterated Trust Game as trusters with three fictive trustee partners who had different tendencies to reciprocate (i.e., likelihood of rewarding the truster), which were learned over multiple exchanges with real-time feedback. We show that the caudate (both left and right) signals reputation during trust decisions, such that caudate is more active to partners with two types of "bad" reputations, either indifferent partners (who reciprocate 50% of the time) or unfair partners (who reciprocate 25% of the time), than to those with "good" reputations (who reciprocate 75% of the time). Further, individual differences in caudate activity related to biases in trusting behavior in the most uncertain situation, i.e. when facing an indifferent partner. We also report on other areas that were activated by reputation at p < 0.05 whole brain corrected. Our findings suggest that the caudate is involved in signaling and integrating reputations gained through experience into trust decisions, demonstrating a neural basis for this key social process.

Early, efficient and inexpensive methods for the detection of pulmonary tuberculosis are urgently needed for effective patient management as well as to interrupt transmission. These methods to detect M. tuberculosis in a timely and affordable way are not yet widely available in resource-limited settings. In a developing-country setting, we prospectively evaluated two methods for culturing and detecting M. tuberculosis in sputum. Sputum samples were cultured in liquid assay (micro broth culture) in microplate wells and growth was detected by microscopic observation, or in Löwenstein-Jensen (LJ) solid media where growth was detected by visual inspection for colonies. Sputum samples were collected from 321 tuberculosis (TB) suspects attending Bugando Medical Centre, in Mwanza, Tanzania, and were cultured in parallel. Pulmonary tuberculosis cases were diagnosed using the American Thoracic Society diagnostic standards. There were a total of 200 (62.3%) pulmonary tuberculosis cases. Liquid assay with microscopic detection detected a significantly higher proportion of cases than LJ solid culture: 89.0% (95% confidence interval [CI], 84.7% to 93.3%) versus 77.0% (95% CI, 71.2% to 82.8%) (p = 0.0007). The median turn around time to diagnose tuberculosis was significantly shorter for micro broth culture than for the LJ solid culture, 9 days (interquartile range [IQR] 7-13), versus 21 days (IQR 14-28) (p

Urogenital schistosomiasis, caused by infection with Schistosoma haematobium, is widespread and causes substantial morbidity on the African continent. The infection has been suggested as an unrecognized risk factor for incident HIV infection. Current guidelines recommend preventive chemotherapy, using praziquantel as a public health tool, to avert morbidity due to schistosomiasis. In individuals of reproductive age, urogenital schistosomiasis remains highly prevalent and, likely, underdiagnosed. This comprehensive literature review was undertaken to examine the evidence for a cause-effect relationship between urogenital schistosomiasis and HIV/AIDS. The review aims to support discussions of urogenital schistosomiasis as a neglected yet urgent public health challenge.We conducted a systematic search of the literature including online databases, clinical guidelines, and current medical textbooks. We describe plausible local and systemic mechanisms by which Schistosoma haematobium infection could increase the risk of HIV acquisition in both women and men. We also detail the effects of S. haematobium infection on the progression and transmissibility of HIV in co-infected individuals. We briefly summarize available evidence on the immunomodulatory effects of chronic schistosomiasis and the implications this might have for populations at high risk of both schistosomiasis and HIV.Studies support the hypothesis that urogenital schistosomiasis in women and men constitutes a significant risk factor for HIV acquisition due both to local genital tract and global immunological effects. In those who become HIV-infected, schistosomal co-infection may accelerate HIV disease progression and facilitate viral transmission to sexual partners. Establishing effective prevention strategies using praziquantel, including better definition of treatment age, duration, and frequency of treatment for urogenital schistosomiasis, is an important public health priority. Our findings call attention to this pressing yet neglected public health issue and the potential added benefit of scaling up coverage of schistosomal treatment for populations in whom HIV infection is prevalent.

In a randomized clinical trial of early versus standard antiretroviral therapy (ART) in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm³ in Haiti, early ART decreased mortality by 75%. We assessed the cost-effectiveness of early versus standard ART in this trial.Trial data included use of ART and other medications, laboratory tests, outpatient visits, radiographic studies, procedures, and hospital services. Medication, laboratory, radiograph, labor, and overhead costs were from the study clinic, and hospital and procedure costs were from local providers. We evaluated cost per year of life saved (YLS), including patient and caregiver costs, with a median of 21 months and maximum of 36 months of follow-up, and with costs and life expectancy discounted at 3% per annum. Between 2005 and 2008, 816 participants were enrolled and followed for a median of 21 months. Mean total costs per patient during the trial were US$1,381 for early ART and US$1,033 for standard ART. After excluding research-related laboratory tests without clinical benefit, costs were US$1,158 (early ART) and US$979 (standard ART). Early ART patients had higher mean costs for ART (US$398 versus US$81) but lower costs for non-ART medications, CD4 cell counts, clinically indicated tests, and radiographs (US$275 versus US$384). The cost-effectiveness ratio after a maximum of 3 years for early versus standard ART was US$3,975/YLS (95% CI US$2,129/YLS-US$9,979/YLS) including research-related tests, and US$2,050/YLS excluding research-related tests (95% CI US$722/YLS-US$5,537/YLS).Initiating ART in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm³ in Haiti, consistent with World Health Organization advice, was cost-effective (US$/YLS

Since 1999 GHESKIO, a large voluntary counseling and HIV testing center in Port-au-Prince, Haiti, has had an ongoing collaboration with the Haitian Ministry of Health to reduce the rate of mother to child HIV transmission. There are limited data on the ability to administer complex regimens for reducing mother to child transmission and on risk factors for continued transmission and infant mortality within programmatic settings in developing countries.We analyzed data from 551 infants born to HIV-infected mothers seen at GHESKIO, between 1999 and 2005. HIV-infected mothers and their infants were given "short-course" monotherapy with antiretrovirals for prophylaxis; and, since 2003, highly active antiretroviral therapy (HAART) when clinical or laboratory indications were met. Infected women seen in the pre-treatment era had 27% transmission rates, falling to 10% in this cohort of 551 infants, and to only 1.9% in infants of women on HAART. Mortality rate after HAART introduction (0.12 per year of follow-up [0.08-0.16]) was significantly lower than the period before the availability of such therapy (0.23 [0.16-0.30], P

New rapid syphilis tests permit simple and immediate diagnosis and treatment at a single clinic visit. We compared the cost-effectiveness, projected health outcomes, and annual cost of screening pregnant women using a rapid syphilis test as part of scaled-up prenatal testing to prevent mother-to-child HIV transmission in Haiti.A decision analytic model simulated health outcomes and costs separately for pregnant women in rural and urban areas. We compared syphilis syndromic surveillance (rural standard of care), rapid plasma reagin test with results and treatment at 1-wk follow-up (urban standard of care), and a new rapid test with immediate results and treatment. Test performance data were from a World Health Organization-Special Programme for Research and Training in Tropical Diseases field trial conducted at the GHESKIO Center Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes in Port-au-Prince. Health outcomes were projected using historical data on prenatal syphilis treatment efficacy and included disability-adjusted life years (DALYs) of newborns, congenital syphilis cases, neonatal deaths, and stillbirths. Cost-effectiveness ratios are in US dollars/DALY from a societal perspective; annual costs are in US dollars from a payer perspective. Rapid testing with immediate treatment has a cost-effectiveness ratio of $6.83/DALY in rural settings and $9.95/DALY in urban settings. Results are sensitive to regional syphilis prevalence, rapid test sensitivity, and the return rate for follow-up visits. Integrating rapid syphilis testing into a scaled-up national HIV testing and prenatal care program would prevent 1,125 congenital syphilis cases and 1,223 stillbirths or neonatal deaths annually at a cost of $525,000.In Haiti, integrating a new rapid syphilis test into prenatal care and HIV testing would prevent congenital syphilis cases and stillbirths, and is cost-effective. A similar approach may be beneficial in other resource-poor countries that are scaling up prenatal HIV testing.

OBJECTIVE: To assess outcomes after antiretroviral therapy (ART) in adolescents and youth in Haiti, a country with a generalized epidemic of infection with HIV-1. METHODS: An assessment was made of survival, plasma HIV-1 ribonucleic acid (RNA) concentrations and HIV-1 drug resistance patterns after 12 months of ART in patients aged 13-25 years who presented to a clinic in Port-au-Prince, Haiti, with AIDS between 1 March 2003 and 31 December 2005. Participants received ART in accordance with WHO guidelines. Kaplan-Meier analysis was used to estimate survival probabilities and their 95% confidence intervals (CI) for the period from ART initiation to death. FINDINGS: Of a total of 146 patients, 96 (66%) were female; the median CD4+ T-cell count at baseline was 129 cells/ml. By Kaplan-Meier analysis, 13% of the patients had died at 12 months, 17% at 24 months and 20% at 36 months. A plasma HIV-1 RNA concentration > 50 copies/ml was seen in 40 (51%) of 79 patients 12 months after treatment initiation and was associated with poor ART adherence. Among 29 patients with > 1000 copies/ml at 12 months, resistance mutations to non-nucleoside reverse transcriptase inhibitors (NNRTIs) were detected in 23 cases (79%); to both NNRTIs and lamivudine in 21 (72%) cases; and to NNRTIs, lamivudine and other nucleoside reverse transcriptase inhibitors in 10 (35%) cases. One hundred and six participants (73%) reported sexual intercourse without condoms, and 35 of the 96 women (36%) were pregnant during follow-up. CONCLUSION: Adolescents and youth with AIDS receiving ART are at risk of virologic failure and disease progression and can therefore transmit HIV-1 to sexual partners and infants. Strategies to target the special needs of this age group are urgently needed.