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1.  Use of Luminex MagPlex Magnetic Microspheres for High-Throughput Spoligotyping of Mycobacterium tuberculosis Isolates in Port-au-Prince, Haiti 
Journal of Clinical Microbiology  2013;51(7):2232-2237.
Genotyping of Mycobacterium tuberculosis strains became indispensable for understanding tuberculosis transmission dynamics and designing measures to combat the disease. Unfortunately, typing involves sophisticated laboratory analysis, is expensive, and requires a high level of technical expertise, which limited its use in the resource-poor countries where the majority of tuberculosis cases occur. Spoligotyping is a PCR-based M. tuberculosis complex genotyping method with advantages of technical simplicity, numerical output, and high reproducibility. It is based on the presence or absence of 43 distinct “spacers” separating insertion elements in the direct repeat region of the M. tuberculosis genome. The spoligotyping assay involves reverse hybridization of PCR products to the capture spacers attached to nitrocellulose membranes or to microspheres. Here we report modification of the classic 43-spacer method using the new generation of Luminex multiplexing technology with magnetic microspheres. The method was successfully established and validated on strains with known spoligotypes in our laboratory in Haiti. The distribution of spoligotypes determined in a collection of 758 recent M. tuberculosis isolates was in accordance with previous data for Haitian isolates in the SITWITWEB international database, which were obtained with the traditional membrane-based method. In the present form, spoligotyping may be suitable as a high-throughput, first-line tool for genotyping of Mycobacterium tuberculosis in countries with limited resources.
doi:10.1128/JCM.00268-13
PMCID: PMC3697689  PMID: 23658258
2.  Predictors of Disease Severity in Patients Admitted to a Cholera Treatment Center in Urban Haiti 
Cholera, previously unrecognized in Haiti, spread through the country in the fall of 2010. An analysis was performed to understand the epidemiological characteristics, clinical management, and risk factors for disease severity in a population seen at the GHESKIO Cholera Treatment Center in Port-au-Prince. A comprehensive review of the medical records of patients admitted during the period of October 28, 2010–July 10, 2011 was conducted. Disease severity on admission was directly correlated with older age, more prolonged length of stay, and presentation during the two epidemic waves seen in the observation period. Although there was a high seroprevalence of human immunodeficiency virus (HIV), severity of cholera was not greater with HIV infection. This study documents the correlation of cholera waves with rainfall and its reduction in settings with improved sanitary conditions and potable water when newly introduced cholera affects all ages equally so that interventions must be directed throughout the population.
doi:10.4269/ajtmh.13-0170
PMCID: PMC3795091  PMID: 24106188
3.  Cholera Vaccination in Urban Haiti 
Successful and sustained efforts have been made to curtail the major cholera epidemic that occurred in Haiti in 2010 with the promotion of hygiene and sanitation measures, training of health personnel and establishment of treatment centers nationwide. Oral cholera vaccine (OCV) was introduced by the Haitian Ministry of Health as a pilot project in urban and rural areas. This paper reports the successful OCV pilot project led by GHESKIO Centers in the urban slums of Port-au-Prince where 52,357 persons received dose 1 and 90.8% received dose 2; estimated coverage of the at-risk community was 75%. This pilot study demonstrated the effort, community mobilization, and organizational capacity necessary to achieve these results in a challenging setting. The OCV intervention paved the way for the recent launching of a national cholera vaccination program integrated in a long-term ambitious and comprehensive plan to address Haiti's critical need in water security and sanitation.
doi:10.4269/ajtmh.13-0171
PMCID: PMC3795097  PMID: 24106194
6.  Multidrug-resistant tuberculosis in Port-au-Prince, Haiti 
Objectives
Determine the prevalence of MDR-TB among patients with new smear-positive pulmonary TB in Port au Prince, Haiti
Methods
Sputum samples were cultured from 1006 patients diagnosed with new tuberculosis in 2008. The core region of the rpoB gene that is associated with resistance to rifampin was sequenced. All isolates with rpoB mutations were sent to the NY State reference laboratory for conventional drug susceptibility testing (DST). All isolates were also tested with the GenoType MTBDRplus line probe assay.
Results
M.tubercuosis was isolated from 906 patients. 26 (2.9%) of the isolates had mis-sense mutations or deletions in rpoB and were resistant to rifampin by DST. All 26 were also resistant to isoniazid and classified as MDR-TB. 46 control isolates without rpoB mutations were all found to be rifampin-sensitive by DST. The GenoType MTBDRplus line probe assay correctly identified 26 MDR-TB strains. It misclassified 1 pansusceptible isolate as RIF-resistant.
Conclusions
This study shows an MDR-TB prevalence of 2.9% in newly diagnosed TB patients in Haiti and also suggests that rpoB sequencing or hybridization assays are good screening tools for early detection of MDR-TB.
PMCID: PMC3676925  PMID: 22569696
Tuberculosis; Multidrug-Resistant; Haiti
7.  Long-Term Antiretroviral Treatment Outcomes in Seven Countries in the Caribbean 
Objectives
To report long-term HIV treatment outcomes in 7 Caribbean countries.
Design
Observational cohort study.
Methods
We report outcomes for all antiretroviral therapy (ART) naïve adult patients enrolled on ART from program inception until study closing for cohorts in Barbados, the Dominican Republic, Haiti, Jamaica, Martinique, Trinidad, and Puerto Rico. Incidence and predictors of mortality were analyzed by time-to-event approaches.
Results
8,203 patients started ART from 1998 to 2008. Median follow-up time was 31 months (interquartile range: 14 to 50 months). Mortality was 13% overall: 6% in Martinique, 8% in Jamaica, 11% in Trinidad, 13% in Haiti, 15% in the Dominican Republic, 15% in Barbados, and 24% in Puerto Rico. Mortality was associated with male gender (HR 1.58; 95% CI: 1.33 – 1.87), body weight (HR 0.85 per 10 pounds; 95% CI: 0.82 – 0.89), hemoglobin (HR 0.84 per g/dl; 95% CI: 0.80 – 0.88), CD4 cell count (0.90 per 50 CD4 cells; 95% CI: 0.86 – 0.93), concurrent TB (HR 1.58; 95% CI: 1.25 – 2.01) and age (HR 1.19 per 10 years; 95% CI: 1.11 – 1.28). After controlling for these variables, mortality in Martinique, Jamaica, Trinidad and Haiti was not significantly different. A total of 75% of patients remained alive and in-care at the end of the study period.
Conclusions
Long-term mortality rates vary widely across the Caribbean. Much of the difference can be explained by disease severity at ART initiation, nutritional status, and concurrent TB. Earlier ART initiation will be critical to improve outcomes.
doi:10.1097/QAI.0b013e318245d3c1
PMCID: PMC3299899  PMID: 22240464
HIV/AIDS; HIV; antiretroviral therapy; tuberculosis; low and middle-income countries; Caribbean
8.  Virologic, clinical and immunologic responses following failure of first-line antiretroviral therapy in Haiti 
Background
Since HIV-1 RNA (viral load) testing is not routinely available in Haiti, HIV-infected patients receiving antiretroviral therapy (ART) are monitored using the World Health Organization (WHO) clinical and/or immunologic criteria. Data on survival and treatment outcomes for HIV-1 infected patients who meet criteria for ART failure are limited. We conducted a retrospective study to compare survival rates for patients who experienced failure on first-line ART by clinical and/or immunologic criteria and switched to second-line ART vs. those who failed but did not switch.
Methods
Patients receiving first-line ART at the GHESKIO Center in Port-au-Prince, Haiti, who met WHO clinical and immunologic criteria for failure were identified. Survival and treatment outcomes were compared in patients who switched their ART regimen and those who did not. Cox regression analysis was used to determine predictors of mortality after failure of first-line ART.
Results
Of 3126 patients who initiated ART at the GHESKIO Center between 1 March 2003 and 31 July 2008, 482 (15%) met WHO immunologic and/or clinical criteria for failure. Among those, 195 (41%) switched to second-line ART and 287 (59%) did not. According to Kaplan–Meier survival analysis, the probability of survival to 12 months after failure of first-line ART was 93% for patients who switched to second-line ART after failure and 88% for patients who did not switch. Predictors of mortality after failure of first-line ART were weight in the lowest quartile for sex, CD4 T cell count ≤ 100, adherence < 90% at the time of failure and not switching to second-line ART.
Conclusions
Patients who failed first-line ART based on clinical and/or immunologic criteria and did not switch to second-line therapy faced a higher mortality than those who switched after failure. To decrease mortality, interventions to identify patients in whom ART may be failing earlier are needed urgently. In addition, there is a major need to optimize second-line antiretroviral regimens for improved potency, lower toxicity and greater convenience for patients.
doi:10.7448/IAS.15.2.17375
PMCID: PMC3499802  PMID: 22713258
Antiretroviral therapy; second-line therapy; virologic failure; mortality; adherence
9.  Serologic Imprint of Dengue Virus in Urban Haiti: Characterization of Humoral Immunity to Dengue in Infants and Young Children 
Dengue is endemic to Haiti but not recognized as an important illness in the autochthonous population. To evaluate the prevalence of antibodies to dengue virus (DENV), serum samples from infants and young children 7–36 months of age (n = 166) were assayed by plaque reduction neutralization assays to each DENV serotype. Dengue virus serotype 1 had infected 40% of this study population, followed by serotype 2 (12%), serotype 3 (11%), and serotype 4 (2%). Fifty-three percent of infants and young children less than 12 months of age had already experienced DENV infection, and the seroprevalence of antibody to DENV increased to 65% by 36 months. Heterotypic antibody responses were an important component of the total dengue immunity profile.
doi:10.4269/ajtmh.2011.10-0323
PMCID: PMC3062461  PMID: 21460022
10.  Risk factors for HIV infection among Haitian adolescents and young adults seeking counseling and testing in Port-au-Prince 
Many Haitian adolescents are highly vulnerable to HIV infection. Among 3,391 sexually active 13-25-year-olds in our Voluntary Counseling and Testing (VCT) Center in Port-au-Prince from October 2005 to September 2006, we assessed associations between demographic and behavioral factors and HIV status using multivariable logistic regression analyses. We diagnosed HIV infection in 6.3% of 2,533 females and 5.5% of 858 males. Age-specific prevalence was 3.4% for 13-15-year-olds, 4.7% for 16-19, and 6.8% for 20-25 (P=0.02). Poor education, not residing with parents, currently or formerly married, having a child, and being self-referred to VCT services by others were significant predictors of HIV in females. HIV infection was associated with considering oneself at higher risk, though most youth did not recognize this risk. HIV in females was also associated with suspected/confirmed sexually transmitted infection (STI), especially genital ulcers (ORadj=2.28, 95%CI:1.26-4.13), years of sexual activity (Ptrend=0.07), and suspicion that partners had other partners or an STI. Among males, HIV was associated with drug use (though uncommon), as well as sexual debut with a casual/unknown person (ORadj=3.18, 95%CI:1.58-6.42). HIV-infected young people were more likely to be RPR positive and less likely to use condoms. Young Haitians are a key target for HIV prevention and care and avail themselves readily of youth-focused VCT services.
doi:10.1097/QAI.0b013e3181ac12a8
PMCID: PMC3196358  PMID: 19738486
HIV; sexual behavior; adolescent; youth; Haiti; counseling; HIV testing
11.  Clinical Impact and Cost of Monitoring for Asymptomatic Laboratory Abnormalities among Patients Receiving Antiretroviral Therapy in a Resource-Poor Setting 
Background
Laboratory monitoring for toxicity among patients receiving antiretroviral therapy (ART) in less-developed settings is technically challenging and consumes significant resources.
Methods
We conducted a cohort study of the 1800 adult patients who initiated ART at the Haitian Study Group for Kaposi’s Sarcoma and Opportunistic Infections (GHESKIO) in Haiti from 2003 to 2006, using baseline data to establish the prevalence and using follow-up data to establish the incidence of hepatitis, renal insufficiency, hyperglycemia, anemia, neutropenia, and thrombocytopenia. We determined how frequently routine (not symptom-driven) testing detected significant laboratory abnormalities and calculated the cost per disability-adjusted life year (DALY) averted by detection of these events in the asymptomatic stage, compared with a strategy of symptom-prompted testing only.
Results
Forty-eight patients (3.5%) had severe anemia at baseline testing and consequently did not receive zidovudine. Fifty-three patients receiving zidovudine therapy developed severe anemia during follow-up (incidence, 2.5 cases/100 person-years). Monitoring for asymptomatic anemia with hematocrit testing was cost-saving at baseline and had a cost-effectiveness ratio of US$317/DALY averted during follow-up; with a complete blood count, costs increased to US$1182 and $10,781/DALY averted, respectively. With glucose monitoring, 11 patients were diagnosed with new-onset hyperglycemia during follow-up (incidence, 0.7 cases/100 person-years), resulting in a cost-effectiveness ratio of US$9845 per DALY averted. Monitoring for asymptomatic hepatitis and renal insufficiency was expensive and rarely affected care.
Conclusions
Resource-poor countries should select which laboratory tests to perform on the basis of the cost-effectiveness of each test. This will depend on the national ART drug regimen and the prevalence of other comorbidities. Routine monitoring with multitest hematological and chemistry panels is unlikely to be cost-effective.
doi:10.1086/655762
PMCID: PMC3010921  PMID: 20649436
12.  High Mortality among Patients with AIDS Who Received a Diagnosis of Tuberculosis in the First 3 Months of Antiretroviral Therapy 
We analyzed mortality among 201 patients with AIDS and tuberculosis in Haiti. Patients who received a diagnosis of tuberculosis during the first 3 months after the initiation of antiretroviral therapy were 3.25 times more likely to die than were other patients with AIDS and tuberculosis. Failure to recognize active tuberculosis at initiation of antiretroviral therapy leads to increased mortality.
doi:10.1086/597098
PMCID: PMC3010922  PMID: 19207078
13.  Rates and Reasons for Early Change of First HAART in HIV-1-Infected Patients in 7 Sites throughout the Caribbean and Latin America 
PLoS ONE  2010;5(6):e10490.
Background
HAART rollout in Latin America and the Caribbean has increased from approximately 210,000 in 2003 to 390,000 patients in 2007, covering 62% (51%–70%) of eligible patients, with considerable variation among countries. No multi-cohort study has examined rates of and reasons for change of initial HAART in this region.
Methodology
Antiretroviral-naïve patients > = 18 years who started HAART between 1996 and 2007 and had at least one follow-up visit from sites in Argentina, Brazil, Chile, Haiti, Honduras, Mexico and Peru were included. Time from HAART initiation to change (stopping or switching any antiretrovirals) was estimated using Kaplan-Meier techniques. Cox proportional hazards modeled the associations between change and demographics, initial regimen, baseline CD4 count, and clinical stage.
Principal Findings
Of 5026 HIV-infected patients, 35% were female, median age at HAART initiation was 37 years (interquartile range [IQR], 31–44), and median CD4 count was 105 cells/uL (IQR, 38–200). Estimated probabilities of changing within 3 months and one year of HAART initiation were 16% (95% confidence interval (CI) 15–17%) and 28% (95% CI 27–29%), respectively. Efavirenz-based regimens and no clinical AIDS at HAART initiation were associated with lower risk of change (hazard ratio (HR) = 1.7 (95% CI 1.1–2.6) and 2.1 (95% CI 1.7–2.5) comparing neverapine-based regimens and other regimens to efavirenz, respectively; HR = 1.3 (95% CI 1.1–1.5) for clinical AIDS at HAART initiation). The primary reason for change among HAART initiators were adverse events (14%), death (5.7%) and failure (1.3%) with specific toxicities varying among sites. After change, most patients remained in first line regimens.
Conclusions
Adverse events were the leading cause for changing initial HAART. Predictors for change due to any reason were AIDS at baseline and the use of a non-efavirenz containing regimen. Differences between participant sites were observed and require further investigation.
doi:10.1371/journal.pone.0010490
PMCID: PMC2879360  PMID: 20531956
14.  Slave Trade and Hepatitis B Virus Genotypes and Subgenotypes in Haiti and Africa 
Emerging Infectious Diseases  2009;15(8):1222-1228.
TOC Summary: The spread of genotype E in Africa occurred after the end of the transatlantic slave trade.
In Haiti, >90% of the population descended from African slaves. Of 7,147 Haitian pregnant women sampled, 44% of hepatitis B virus (HBV) infections were caused by genotype A1, which today is found mainly in eastern Africa. Twenty percent belong to a rare subgenotype, A5, which has been found only in the former Bight of Benin, a former primary slave trading post. Haitian A subgenotypes appear to have separated early from the African subgenotypes; the most prevalent genotype and subgenotype in West Africa today (E and A3, respectively) are rare in Haiti. This difference indicates that the dominant subgenotypes in Africa emerged in the general population only after the slave trade and explains the low genetic diversity of genotype E. The high prevalence of HBV genotype E in much of Africa further suggests that HBV hyperendemicity is a recent phenomenon, probably resulting from extensive use of unsafe needles.
doi:10.3201/eid1508.081642
PMCID: PMC3467954  PMID: 19751583
Hepatitis B virus; genotype; Haiti; Caribbean; Africa; viruses; transatlantic slave trade; prevalence; research
15.  HIV-1 Epidemic in the Caribbean Is Dominated by Subtype B 
PLoS ONE  2009;4(3):e4814.
Background
The molecular epidemiology of HIV-1 in the Caribbean has been described using partial genome sequencing; subtype B is the most common subtype in multiple countries. To expand our knowledge of this, nearly full genome amplification, sequencing and analysis was conducted.
Methodology/Principal Findings
Virion RNA from sera collected in Haiti, Dominican Republic, Jamaica and Trinidad and Tobago were reverse transcribed, PCR amplified, sequenced and phylogenetically analyzed. Nearly full genomes were completed for 15 strains; partial pol was done for 67 strains. All but one of the 67 strains analyzed in pol were subtype B; the exception was a unique recombinant of subtypes B and C collected in the Dominican Republic. Of the nearly full genomes of 14 strains that were subtype B in pol, all were subtype B from one end of the genome to the other and not inter-subtype recombinants. Surprisingly, the Caribbean subtype B strains clustered significantly with each other and separate from subtype B from other parts of the pandemic.
Conclusions
The more complete analysis of HIV-1 from 4 Caribbean countries confirms previous research using partial genome analysis that the predominant subtype in circulation was subtype B. The Caribbean strains are phylogenetically distinct from other subtype B strains although the biological meaning of this finding is unclear.
doi:10.1371/journal.pone.0004814
PMCID: PMC2652827  PMID: 19279683
17.  The cost of antiretroviral therapy in Haiti 
Background
We determined direct medical costs, overhead costs, societal costs, and personnel requirements for the provision of antiretroviral therapy (ART) to patients with AIDS in Haiti.
Methods
We examined data from 218 treatment-naïve adults who were consecutively initiated on ART at the GHESKIO Center in Port-au-Prince, Haiti between December 23, 2003 and May 20, 2004 and calculated costs and personnel requirements for the first year of ART.
Results
The mean total cost of treatment per patient was $US 982 including $US 846 in direct costs, $US 114 for overhead, and $US 22 for societal costs. The direct cost per patient included generic ART medications $US 355, lab tests $US 130, nutrition $US 117, hospitalizations $US 62, pre-ART evaluation $US 58, labor $US 51, non-ART medications $US 39, outside referrals $US 31, and telephone cards for patient retention $US 3. Higher treatment costs were associated with hospitalization, change in ART regimen, TB treatment, and survival for one year. We estimate that 1.5 doctors and 2.5 nurses are required to treat 1000 patients in the first year after initiating ART.
Conclusion
Initial ART treatment in Haiti costs approximately $US 1,000 per patient per year. With generic first-line antiretroviral drugs, only 36% of the cost is for medications. Patients who change regimens are significantly more expensive to treat, highlighting the need for less-expensive second-line drugs. There may be sufficient health care personnel to treat all HIV-infected patients in urban areas of Haiti, but not in rural areas. New models of HIV care are needed for rural areas using assistant medical officers and community health workers.
doi:10.1186/1478-7547-6-3
PMCID: PMC2276481  PMID: 18275615
18.  Potential of a Simplified p24 Assay for Early Diagnosis of Infant Human Immunodeficiency Virus Type 1 Infection in Haiti▿  
Journal of Clinical Microbiology  2007;45(10):3416-3418.
With global efforts to scale up the prevention of mother-to-child transmission services and pediatric antiretroviral therapy, there is an urgent need to introduce a simple, low-cost infant human immunodeficiency virus test in the field. We postulated that the p24 antigen capture enzyme-linked immunosorbent assay could be simplified by eliminating signal amplification without compromising diagnostic accuracy.
doi:10.1128/JCM.01314-07
PMCID: PMC2045325  PMID: 17670933
19.  Cost-Effectiveness of Rapid Syphilis Screening in Prenatal HIV Testing Programs in Haiti 
PLoS Medicine  2007;4(5):e183.
Background
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.
Methods and Findings
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.
Conclusions
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.
Analyzing data from Haiti, Bruce Schackman and colleagues report that scale-up of prenatal HIV testing programs provides a cost-effective opportunity to prevent congenital syphilis through rapid testing.
Editors' Summary
Background.
Congenital syphilis (syphilis that is passed on from a woman infected with the disease to her unborn baby) is a major preventable public health problem. Around half of all pregnancies among women infected with syphilis result in stillbirth or death of the baby shortly after birth. However, it should be possible to reduce the health burden of congenital syphilis if infections among pregnant women could be quickly and accurately diagnosed. In resource-poor countries, many syphilis infections go undiagnosed, because the tests that are normally used involve sending samples away to a laboratory for processing. This means that the diagnosis can only be confirmed, and treatment started, at the next available visit. As a result, there is a delay in starting antibiotic treatment, and some women may never receive their intended treatment at all if they cannot return for their follow-up visit. However, new tests are available that don't involve cold storage of reagents or electrical equipment, and these can be used to give an immediate result about syphilis infection even in rural or resource-poor settings. Currently, global initiatives are underway to ensure many more pregnant women are tested for HIV and to reduce the risk of HIV being passed on from a woman to her baby. These initiatives could provide an important opportunity for carrying out widespread immediate screening for syphilis during pregnancy as well. Such screening might then help reduce infant deaths substantially.
Why Was This Study Done?
Field trials evaluating rapid syphilis tests have already been carried out by the World Health Organization's Special Programme for Research and Training in Tropical Diseases. One such trial, carried out in Port-au-Prince, Haiti, evaluated the success of three different rapid syphilis tests as compared to two “gold standard” tests (older tests that are generally considered reliable, but which don't give an immediate result). These researchers wanted to use data from these trials to compare costs and predicted health outcomes of including different types of syphilis screening as part of scaled-up prenatal care. Specifically, the researchers wanted to find out whether including rapid syphilis testing as part of universal prenatal care would be cost-effective and whether it would reduce the rate of stillbirths and congenital syphilis.
What Did the Researchers Do and Find?
This research was based on data from the field trials previously carried out in Haiti. The data from these trials were used to create a model comparing three different strategies for screening pregnant women for syphilis infections. The three strategies were as follows: checking for the symptoms of syphilis (assumed to be the standard of care in rural areas); standard testing for antibody response to the syphilis bacterium, after which treatment can be provided at follow-up a week later (assumed to be the standard of care in urban areas); and, finally, rapid testing that gives an immediate result. For each strategy, the researchers predicted what the health outcomes would be. These outcomes are summarized in “disability-adjusted life years” (DALYs) that reflect the number of years of healthy life lost due to congenital syphilis among newborn babies, the number of stillbirths, and the number of neonatal deaths. Cost-effectiveness of each strategy was also worked out by dividing the additional costs of testing and treatment for each strategy by the number of DALYs avoided using that screening method compared to the next most expensive alternative. Under the model, urban and rural settings were looked at separately. Immediate testing was more expensive than either standard testing or checking for symptoms, but emerged as more cost-effective than standard testing in rural settings; the immediate test would cost an additional $7–$10 per disability-adjusted life year compared to the current rural or urban standard of care. The researchers predicted that if immediate syphilis testing were provided to all pregnant women in Haiti who currently have access to prenatal care, over 1,000 congenital syphilis cases would be avoided, along with over 1,000 stillbirths and neonatal deaths, at a yearly cost of $525,000.
What Do These Findings Mean?
This model suggests that including rapid syphilis testing as part of current global initiatives for preventing mother-to-child transmission of HIV could substantially reduce infant deaths. The strategy is also likely to be cost-effective.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040183.
MedlinePlus encyclopedia entry on congenital syphilis
Information from the World Health Organization about congenital syphilis, including information about screening programs and new screening tests
A report is also available from the Special Programme for Research and Training in Tropical Diseases regarding rapid syphilis tests
AVERT, an international AIDS charity, provides information about preventing mother-to-child transmission of HIV
doi:10.1371/journal.pmed.0040183
PMCID: PMC1880854  PMID: 17535105
20.  Correlation between Genotypic and Phenotypic Testing for Resistance to Rifampin in Mycobacterium tuberculosis Clinical Isolates in Haiti: Investigation of Cases with Discrepant Susceptibility Results 
PLoS ONE  2014;9(3):e90569.
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.
doi:10.1371/journal.pone.0090569
PMCID: PMC3944071  PMID: 24599230
21.  Consideration of Post-Partum Management in HIV-Positive Haitian Women: An Analysis of CD4 Decline, Mortality, and Follow-up after Delivery 
Background
A previous study at the GHESKIO HIV clinic confirmed that highly active antiretroviral therapy (HAART) prophylaxis reduced mother-to-child transmission (MTCT) and infant mortality in Haiti. This analysis looks at maternal outcomes in this cohort after delivery.
Methods
Records of 508 HIV-positive Haitian women who delivered between1999-2005 were analyzed. We examined mortality, loss to follow-up, time to death or HAART initiation, and time of decline of CD4 count to350 cells/microliter.
Results
170 women reached a CD4≤200 or developed clinical AIDS and were started on long-term HAART. The median CD4 count at HAART initiation was 178 (IQR 106-227). CD4 decline was stratified by CD4 at delivery to project the mean months to a CD4 of 350. With an initial CD4=350-499 cells/microliter it was 19 months (95% CI 14 - 28) while with a CD4>500 cells/microliter it was 71 months (95% CI 59 - 88). At study close 257 women remained in follow-up with loss to follow up three times less in those on HAART (3.2/100 person-years) than those not on HAART (9.8/100 person-years).
Conclusions
The threshold for starting treatment was often missed in HIV-infected women after delivery. Success of follow-up of women after delivery was favorably influenced by being on HAART. Women with high (>500) initial CD4 counts had a protracted time (5-7 years) before they reach a threshold CD4 count, in contrast to those with CD4<500 cells/μL. Strategies for post-partum treatment of women should be informed by the speed with which they are likely to progress.
doi:10.1097/QAI.0b013e31826abdd1
PMCID: PMC3767139  PMID: 22842846
Haiti; PMTCT; HAART
22.  Duration of Anti-Tuberculosis Therapy and Timing of Antiretroviral Therapy Initiation: Association with Mortality in HIV-Related Tuberculosis 
PLoS ONE  2013;8(9):e74057.
Background
Antiretroviral therapy (ART) decreases mortality risk in HIV-infected tuberculosis patients, but the effect of the duration of anti-tuberculosis therapy and timing of anti-tuberculosis therapy initiation in relation to ART initiation on mortality, is unclear.
Methods
We conducted a retrospective observational multi-center cohort study among HIV-infected persons concomitantly treated with Rifamycin-based anti-tuberculosis therapy and ART in Latin America. The study population included persons for whom 6 months of anti-tuberculosis therapy is recommended.
Results
Of 253 patients who met inclusion criteria, median CD4+ lymphocyte count at ART initiation was 64 cells/mm3, 171 (68%) received >180 days of anti-tuberculosis therapy, 168 (66%) initiated anti-tuberculosis therapy before ART, and 43 (17%) died. In a multivariate Cox proportional hazards model that adjusted for CD4+ lymphocytes and HIV-1 RNA, tuberculosis diagnosed after ART initiation was associated with an increased risk of death compared to tuberculosis diagnosis before ART initiation (HR 2.40; 95% CI 1.15, 5.02; P = 0.02). In a separate model among patients surviving >6 months after tuberculosis diagnosis, after adjusting for CD4+ lymphocytes, HIV-1 RNA, and timing of ART initiation relative to tuberculosis diagnosis, receipt of >6 months of anti-tuberculosis therapy was associated with a decreased risk of death (HR 0.23; 95% CI 0.08, 0.66; P=0.007).
Conclusions
The increased risk of death among persons diagnosed with tuberculosis after ART initiation highlights the importance of screening for tuberculosis before ART initiation. The decreased risk of death among persons receiving > 6 months of anti-tuberculosis therapy suggests that current anti-tuberculosis treatment duration guidelines should be re-evaluated.
doi:10.1371/journal.pone.0074057
PMCID: PMC3774609  PMID: 24066096
23.  Cost-Effectiveness of Early Versus Standard Antiretroviral Therapy in HIV-Infected Adults in Haiti 
PLoS Medicine  2011;8(9):e1001095.
This cost-effectiveness study comparing early versus standard antiretroviral treatment (ART) for HIV, based on randomized clinical trial data from Haiti, reveals that the new WHO guidelines for early ART initiation can be cost-effective in resource-poor settings.
Background
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.
Methods and Findings
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$5,537/YLS).
Conclusions
Initiating ART in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm3 in Haiti, consistent with World Health Organization advice, was cost-effective (US$/YLS <3 times gross domestic product per capita) after a maximum of 3 years, after excluding research-related laboratory tests.
Trial registration
ClinicalTrials.gov NCT00120510
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS has killed more than 25 million people since 1981, and about 33 million people (most of them living in low- and middle-income countries) are now infected with HIV, the virus that causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART) became available and, for people living in affluent countries HIV/AIDS became a chronic condition. However, ART was extremely expensive and so a diagnosis of HIV infection remained a death sentence for people living in developing countries. In 2003, this situation was declared a global health emergency, and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in developing countries. In 2009, more than a third of people in low- and middle-income countries who needed ART were receiving it, on the basis of guidelines that were in place at that time.
Why Was This Study Done?
Until recently, the World Health Organization (WHO) recommended that all HIV-positive patients with CD4 cell count below 200/mm3 blood or an AIDS-defining illness such as Kaposi's sarcoma should be given ART. Then, in 2009, the CIPRA HT-001 randomized clinical trial, which was undertaken in Haiti, reported that patients who started ART when their CD4 cell count was between 200 and 350 cells/mm3 (“early ART”) had a higher survival rate than patients who started ART according to the WHO guidelines (“standard ART”). As a result, WHO now recommends that ART is started in HIV-infected people when their CD4 cell count falls below 350 cells/mm3. But is this new recommendation cost-effective? Do its benefits outweigh its costs? Policy-makers need to know the cost-effectiveness of interventions so that they can allocate their limited resources wisely. A medical intervention is generally considered cost-effective if it costs less than three times a country's per capita gross domestic product (GDP) per year of life saved (YLS). In this study, the researchers assess the cost-effectiveness of early versus standard ART in the CIPRA HT-001 trial.
What Did the Researchers Do and Find?
The researchers used trial data on the use and costs of ART, other medications, laboratory tests, outpatient visits, radiography, procedures, and hospital services to evaluate the costs associated with early ART and standard ART among the 816 CIPRA HT-001 trial participants. The average total costs per patient after a maximum of 3 years treatment were US$1,381 for early ART and US$1,033 for standard ART. These figures dropped to US$1,158 and US$979, respectively, when the costs of research-related tests without clinical benefit were excluded. Patients who received early ART had higher average costs for ART but lower costs for other aspects of their treatment than patients who received standard ART. The incremental cost-effectiveness ratio after 3 years for early ART compared to standard ART was US$3,975/YLS if the costs of research-related tests were included in the calculation. That is, the cost of saving one year of life by starting ART early instead of when the CD4 cell count dropped below 200/mm3 was nearly US$4,000. Importantly, exclusion of the costs of research-related tests reduced the incremental cost-effectiveness ratio of early ART compared to standard ART to US$2,050/YLS.
What Do These Findings Mean?
Because the Haitian GDP per capita is US$785, these findings suggest that, in Haiti, early ART is a cost-effective intervention over a 3-year period. That is, the incremental cost per year of life saved of early ART compared to standard ART after exclusion of research-related tests is less than three times Haiti's per capita GDP. The researchers note that their incremental cost-effectiveness ratios are likely to be conservative because they did not consider the clinical benefits of early ART that continue beyond 3 years—early ART is associated with lower longer-term mortality than standard ART—or the effect of early ART on disability and quality of life. Cost-effectiveness studies now need to be undertaken at different sites to determine whether these findings are generalizable but, for now, this cost-effectiveness study suggests that the new WHO guidelines for ART initiation can be cost-effective in resource-poor settings, information that should help policy-makers in developing countries allocate their limited resources.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001095.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV/AIDS in the Caribbean, and on HIV/AIDS treatment and care (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in English, French and Spanish); its 2010 ART guidelines can be downloaded
More information about the CIPRA HT-001 clinical trial is available
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
More information about GHESKIO is available from Weill Cornell Global Health
doi:10.1371/journal.pmed.1001095
PMCID: PMC3176754  PMID: 21949643
24.  Improving Outcomes in Infants of HIV-Infected Women in a Developing Country Setting 
PLoS ONE  2008;3(11):e3723.
Background
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.
Methods and Findings
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<0.0001). The effects of maternal health, infant feeding, completeness of prophylaxis, and birth weight on mortality and transmission were determined using univariate and multivariate analysis. Infant HIV-1 infection and low birth weight were associated with infant mortality in less than 15 month olds in multivariate analysis.
Conclusions
Our findings demonstrate success in prevention of mother-to-child HIV transmission and mortality in a highly resource constrained setting. Elements contributing to programmatic success include provision of HAART in the context of a comprehensive program with pre and postnatal care for both mother and infant.
doi:10.1371/journal.pone.0003723
PMCID: PMC2580032  PMID: 19009021
25.  Application of Sensitive and Specific Molecular Methods To Uncover Global Dissemination of the Major RDRio Sublineage of the Latin American-Mediterranean Mycobacterium tuberculosis Spoligotype Family▿ ‡ 
Journal of Clinical Microbiology  2008;46(4):1259-1267.
The Latin American-Mediterranean (LAM) family of Mycobacterium tuberculosis is believed to be the cause of ∼15% of tuberculosis cases worldwide. Previously, we defined a prevalent sublineage of the LAM family in Brazil by a single characteristic genomic deletion designated RDRio. Using the Brazilian strains, we pinpoint an Ag85C103 single nucleotide polymorphism (SNP) (screened by restriction fragment length polymorphism [RFLP] analysis) that correctly identified all LAM family strains. Importantly, all RDRio strains concomitantly possessed the RD174 deletion. These genetic signatures, along with a newly developed multiplex PCR for rapid differentiation between “wild-type” and RDRio strains, were then used to analyze an international collection of M. tuberculosis strains. RDRio M. tuberculosis was identified from four continents involving 11 countries. Phylogenetic analysis of the IS6110-RFLP patterns from representative RDRio and LAM strains from Brazil, along with all representative clusters from a South African database, confirmed their genetic relatedness and transcontinental transmission. The Ag85C103 SNP RFLP, as compared to results obtained using a PCR method targeting a LAM-restricted IS6110 element, correctly identified 99.8% of LAM spoligotype strains. Together, these tests were more accurate than spoligotyping at categorizing strains with indefinable spoligotypes and segregated true LAM strains from those with convergent spoligotypes. The fact that RDRio strains were identified worldwide highlights the importance of this LAM family sublineage and suggests that this strain is a global threat that should be specifically targeted by public health resources. Our provision of simple and robust molecular methods will assist the evaluation of the LAM family and the RDRio sublineage.
doi:10.1128/JCM.02231-07
PMCID: PMC2292928  PMID: 18234868

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