The Caribbean is the region most heavily affected by HIV outside of sub-Saharan Africa, with an overall adult HIV prevalence of 1.0%, and an estimated 240,000 patients living with HIV.1 An estimated 12,000 persons die annually of AIDS-related illnesses,1 and AIDS is the leading cause of death in the Caribbean among men and women from 20 to 59 years of age.2 As in the United States, the predominant HIV-1 subtype in the Caribbean is subtype B.3 Because of its close proximity, the HIV epidemic in the Caribbean is also a major public health issue for the United States. Twenty-seven percent of new HIV diagnoses in New York City are among foreign-born persons.4 The Caribbean accounts for more HIV diagnoses in New York City than any other region (38%), and if Puerto Rico is added, the region accounts for 56% of all new HIV diagnoses.4 With frequent travel and migration between the Caribbean and the United States and Europe, the importance of HIV/AIDS in the Caribbean transcends regional boundaries.
With the global expansion of antiretroviral therapy (ART), an increasing number of studies have documented positive short-term outcomes of ART for early cohorts of patients in low- and middle-income countries, including high adherence rates and favorable virological, immunological, and clinical responses.5–10 In recent years, data on long-term outcomes of ART programs have begun to emerge, demonstrating that earlier successes can be maintained even as programs undergo rapid scale-up.11–30 However, mortality rates in the first 6 months of ART are disproportionately higher in low- and middle-income countries, compared with higher income countries,8,9,18,26 and there have been reports of high rates of program attrition after 2 years on therapy.31–33
Published data on long-term HIV treatment outcomes in the Caribbean are limited,18,34,35 although ART coverage in the region has increased dramatically in the past decade. By the end of 2009, 48% of patients with a CD4 cell count less than 350 cells/mm3 in the region were receiving ART, compared with 1% of those eligible in 2004.36,37 Countries in the Caribbean region vary widely in economic status, health infrastructure, culture, and language. Long-term data on HIV treatment outcomes across the region are critically needed.
In 2006, the Trans-Caribbean HIV/AIDS Research Initiative (TCHARI) was launched to develop a cohesive HIV/AIDS research agenda that would address the specific issues relating to HIV/AIDS in the Caribbean. This is the first study to be conducted in the TCHARI network and includes data from 7 countries: Barbados, Dominican Republic, Haiti, Jamaica, Martinique (France), Puerto Rico (United States), and Trinidad. This is the first multicohort study to present regional outcomes for ART across countries in the Caribbean, as well as the first regional outcomes paper on health in the Caribbean.
Participants and Settings
TCHARI is a collaboration among several of the largest HIV/AIDS clinical and research centers in the Caribbean and the National Institutes of Health Office of AIDS Research. The TCHARI sites include the following: (1) Ladymeade Reference Unit, St Michael's, Barbados; (2) Comprehensive Care Units of Centro Sanitario de Santo Domingo and Hospital Luis E. Aybar, Santo Domingo, Dominican Republic; (3) Haitian Study Group for Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti; (4) The University Hospital Centre for HIV/AIDS Research, Education and Services and the Comprehensive Health Centre, Kingston, Jamaica; (5) Infectious Diseases Unit/Inserm CIE 802, Centre Hospitalier Universitaire, Fort-de-France, Martinique; (6) the Medical Research Centre, Port of Spain, Trinidad and Tobago; and (7) Retrovirus Research Center of the Universidad Central del Caribe, Ramón Ruiz Arnau University Hospital, Bayamon, Puerto Rico. Institutional review board approval was obtained by all local and partner academic sites.
This study includes all ART-naive HIV-infected patients of aged 13 years or older who were consecutively enrolled on ART at these 7 sites during the study period, beginning at program inception at each site. The study dates vary among sites, but all patients initiated ART between January 1, 1998 and December 31, 2008. Table 1 describes the country and program characteristics of sites participating in TCHARI. Across the Caribbean region, HIV-infected patients consistently tend to be members of marginalized populations that experience economic disparity.
Data Collection and Measurement
At each site, de-identified data were entered into a Microsoft Access database (Microsoft, Redmond, WA) and sent to GHESKIO, where they were checked for errors, inconsistencies, and missing data. These were compiled into queries, which were addressed by each site. Baseline weight, hemoglobin, and CD4 cell count were defined as the measurement closest to the date of ART initiation, but not more than 2 weeks after ART initiation. ART was defined as a combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 non-NRTI or protease inhibitor (PI), or 3 NRTIs. Clinical stage of disease was defined according to World Health Organization (WHO) guidelines.41 Tuberculosis (TB) and ART co-treatment was defined as any overlap of treatment with these 2 therapies.
The primary outcomes were all-cause mortality and retention in care over the duration of the study. Time was measured from the date of ART initiation to the date of death, loss to follow-up (LTFU), or closing date of the study. Death was ascertained through several strategies. In Barbados, deaths were determined by chart review. In Haiti, deaths were ascertained by chart review, phone calls to next of kin, and home visits. In Jamaica and Martinique, deaths were ascertained by chart review, ART treatment database, phone calls to next of kin, and a centralized death registry. In Trinidad, Dominican Republic, and Puerto Rico, deaths were ascertained by reviewing clinical and hospital records, tracking patients who were LTFU, taking reports from family members, and reviewing death certificates, as necessary. The study closed on May 3, 2008 in Puerto Rico, February 28, 2009 in Barbados, May 15, 2009 in the Dominican Republic, June 18, 2009 in Trinidad, December 15, 2009 in Martinique, and December 31, 2009 in Haiti and Jamaica. Patients were considered alive and in care if they were not known to be dead and had at least 1 visit within 6 months of the closing date of the database. The data were analyzed by an intention-to-treat approach.
Data were entered into the Access database described above. All analyses were conducted using SAS version 9.2 (SAS Institute, Inc, Cary, NC). Kaplan–Meier survival analyses were used to estimate the time from initiation of ART to death, and results were plotted at the country cohort level. Patients who were transferred to other clinics were censored at their last visit. Cox proportional hazards models were used to assess the relationship between demographic and clinical variables, treatment site, and time to death.
We conducted univariate and multivariate analyses using the following variables: year of ART initiation, ART regimen, and country as categorical variables; gender, history of intravenous drug use, and TB and ART co-treatment as binary variables; and age, baseline weight, hemoglobin, and CD4 cell count as continuous variables. WHO stage, income, and education were not included in the analyses because they were not collected at all sites. We analyzed all variables with Cox proportional hazards models to determine predictors of time to death. In the multivariate model, we included all variables significant at the 0.05 level in univariate analyses. No sets of variables in the reported model showed signs of unacceptable colinearity.
We performed sensitivity analyses to assess the effect of LTFU on mortality rates. We reviewed the literature from tracking studies among ART patients presumed LTFU in low- and middle-income countries. We considered a scenario with the lowest and highest mortality rates (27% and 87%, respectively) among patients presumed LTFU in the published literature.42,43 We also used the combined mortality from the meta-analysis of 17 studies reported by Brinkhof et al44 (combined mortality of 40% among patients presumed LTFU). Finally, we considered the scenario where all patients who were LTFU with a CD4 cell count less than 50 cells/mm3 and less than 100 cells/mm3 had died.
A total of 8203 ART-naive HIV-infected patients aged 13 years or older who were consecutively enrolled on ART were included in this study: 560 (7%) from Barbados, 1207 (15%) from the Dominican Republic, 4717 (58%) from Haiti, 476 (6%) from Jamaica, 325 (4%) from Martinique, 725 (9%) from Trinidad, and 193 (2%) from Puerto Rico. Patient characteristics are summarized in Table 2 (note that percentages were computed using the number of patients with nonmissing values). Across all countries, 51% were women and the median age at ART initiation was 38 years. Education was measured in all sites except Jamaica; overall 42% of patients attended no school or primary school only. Income was measured in Barbados, Haiti, Trinidad, and Puerto Rico, and 57% of patients in these cohorts lived on less than $US 1 per day.
Median baseline weight varied across countries, from a low of 111 pounds for women and 125 for men in Haiti to a high of 139 pounds for women in Martinique and 152 for men in Puerto Rico. Baseline hemoglobin values were lowest in Haiti and Trinidad (10.0 g/dL for women and 11.0 g/dL for men) and highest in Puerto Rico (11.8 g/dL for women and 13.2 g/dL for men). Intravenous drug use was common only in Puerto Rico (53%), and 534 (95%) of 565 cases of TB and ART co-treatment occurred in Haiti and the Dominican Republic. Among the 565 patients with concurrent TB and ART treatment, 266 (47%) were started on TB treatment before or at the same time as ART, 177 (31%) were started on TB treatment within the first 6 months after ART initiation, and 122 (22%) were started on TB treatment after at least 6 months of ART.
Seventy-six percent of patients initiated ART with a CD4 cell count of less than 200 cells/mm3: 83% in Trinidad, 81% in the Dominican Republic, 78% in Haiti, 70% in Jamaica, 67% in Barbados, 51% in Martinique, and 46% in Puerto Rico. The median baseline CD4 cell count for the combined overall cohort was 118 cells/mm3. Baseline CD4 cell count increased only slightly with expansion of access to ART, from 114 cells/mm3 for those initiating ART in 2003–2004, to 137 cells/mm3 for those initiating ART in 2007–2008 (see Appendix, Supplemental Digital Content 1, http://links.lww.com/QAI/A251). Overall, 7384 (90%) were treated with a first-line regimen containing a non-NRTI; of these, 4382 (59%) were treated with an efavirenz-based regimen and 3002 (41%) were treated with a nevirapine-based regimen. Martinique and Puerto Rico were the exceptions, treating over 80% of patients with a PI in the first-line regimen. Among the 271 patients in Martinique who received a PI-based regimen, 158 (58%) were treated with lopinavir/ritonavir, 79 (29%) with atazanavir, 23 (8%) with fosamprenavir, 8 (3%) with indinavir, and 3 (1%) with nelfinavir. In contrast, of the 156 patients treated with a PI-based regimen in Puerto Rico, 113 (72%) were treated with nelfinavir, 27 (17%) were treated with indinavir, 9 (6%) were treated with atazanavir, 6 (4%) were treated with other PIs, and only 1 patient was treated with lopinavir/ritonavir.
The median follow-up time across sites was 31 months [interquartile range (IQR): 14–50 months], ranging from 20 months (IQR: 9–33 months) in the Dominican Republic to 52 months (IQR: 33–70 months) in Barbados (Table 3). A total of 1048 patients (13%) were known to have died during the study period. Mortality rates varied widely by country, as follows: 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.
The overall mortality rate was highest in the first 3 months [20.9 deaths per 100 person-years (PY)], and it progressively declined to 4.7 deaths per 100 PY at 5 years. Figure 1A shows the Kaplan–Meier plots of mortality over the study duration. The high early mortality was most pronounced in the Dominican Republic (34.2 deaths per 100 PY) and Haiti (21.8 deaths per 100 PY), the countries with the lowest baseline body weight and nearly all of the cases of TB and ART co-treatment, and Trinidad (17.2 deaths per 100 PY), which had the lowest median CD4 cell count at ART initiation.
Table 4 shows the univariate and adjusted hazard ratios (HRs) for mortality for the combined cohort. In the univariate analyses, older age, male gender, TB and ART co-treatment, intravenous drug use, lower baseline weight, hemoglobin, and CD4 cell count were associated with mortality. ART regimen was not associated with mortality (P = 0.3164). In the multivariate analyses, higher body weight [HR, 0.85 per 10 pounds; 95% confidence interval (CI): 0.82 to 0.89; P < 0.0001], higher hemoglobin (HR, 0.84 per g/dL; 95% CI: 0.80 to 0.88; P < 0.0001), and higher CD4 cell count (0.90 per 50 CD4 cells; 95% CI: 0.86 to 0.93; P < 0.0001) at ART initiation were associated with a lower hazard of death. Male gender (HR, 1.58; 95% CI: 1.33 to 1.87; P < 0.0001), TB and ART co-treatment (HR, 1.58; 95% CI: 1.25 to 2.01; P = 0.0002), and increased age (HR, 1.19 per 10 years; 95% CI: 1.11 to 1.28; P < 0.0001) were associated with an increased hazard of death. In the multivariate analysis, year of ART initiation and intravenous drug use were not associated with mortality.
In the univariate analysis, mortality varied by country, with HR (95% CI) at 0.43 (0.28 to 0.67; P = 0.0002) for Martinique, 0.58 (0.42 to 0.80; P = 0.0010) for Jamaica, 0.68 (0.53 to 0.86; P = 0.0013) for Trinidad, 0.91 (0.72 to 1.14; P = 0.4209) for Barbardos, 1.40 (1.18 to 1.66; P < 0.0001) for the Dominican Republic, and 1.59 (1.17 to 2.18; P = 0.0033) for Puerto Rico, compared with Haiti (reference group). These country-level differences decreased after adjusting for other variables. In the multivariate analysis (with Haiti as reference), there was no association between site and mortality for Jamaica, Martinique, and Trinidad. Higher hazard ratios persisted in the multivariate analysis for the Dominican Republic (HR, 1.72; 95% CI: 1.34 to 2.21; P < 0.0001), Barbados (HR, 1.95; 95% CI: 1.37 to 2.76; P = 0.0002), and Puerto Rico (HR, 2.25; 95% CI: 1.04 to 4.87; P = 0.0389).
Seventy-five percent of patients in the overall cohort were alive and in care at the end of the study. Figure 1B shows the Kaplan–Meier plots of retention in care over the study period. The relative positions of the countries on the retention plots are similar to those for survival, with the exception of Jamaica, which had the second lowest mortality rate (8%) but the second highest LTFU rate (16%) of the 7 countries in the study. Long-term retention in care was 89% in Martinique, 82% in Trinidad, 78% in Barbados, 76% in Jamaica, 75% in Haiti, 72% in the Dominican Republic, and 29% in Puerto Rico. A total of 13% of patients were LTFU during the study period (Table 3). The rate of LTFU was highest in the first 6 months (14 patients LTFU per 100 PY), and it progressively declined to 4.7 patients LTFU per 100 PY at 5 years.
In sensitivity analyses (Table 5), overall mortality increased from 13% to 16% with the assumption that 27% of patients presumed LTFU had died. Overall mortality increased to 18% and 24% with the assumption that 40% and 87% of patients presumed LTFU had died, respectively. With the assumption that all patients presumed LTFU with a CD4 cell count less than 50 cells/mm3 were dead, overall mortality increased from 13% to 16%; mortality increased to 18% with the assumption that those LTFU with CD4 cell count less than 100 cells/mm3 were dead.
This is the first multicohort study to describe long-term HIV treatment outcomes in the Caribbean, and the only study to directly compare long-term HIV outcomes across a region. We observed excellent outcomes, with mortality rates comparable with other long-term cohorts in low- and middle-income countries.11,13–24,30,45,46 Overall mortality was 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. Much of the mortality difference between cohorts can be explained by severity of disease at presentation, concurrent active TB, gender, and nutritional status, with no difference in mortality between Haiti and Martinique, Jamaica, and Trinidad after controlling for these variables. There is increasing pressure to measure program effectiveness by comparing mortality across sites. Our findings demonstrate that great caution is required in making such comparisons.
Patient characteristics in our Caribbean cohort are more similar to those of other low- and middle-income countries than those of the United States and Europe. Women constituted 51% of patients, and median weight and hemoglobin values were similar to those reported in African cohorts.10–16,20,45 The median CD4 cell count at ART initiation was also similar to that reported in the Antiretroviral Therapy in Lower Income Countries Cohort, with median CD4 cell count of 118 cells/mm3 versus 108 cells/mm3 in Antiretroviral Therapy in Lower Income Countries Cohort, much lower than the 234 cells/mm3 reported in the ART Collaboration groups from Europe and North America.9,47 Martinique and Puerto Rico are the exceptions. These 2 islands are among the highest income regions, and the patients in these cohorts had higher CD4 cell counts at ART initiation and were more likely to receive PIs in the first-line regimen, compared with the other countries in this study.48
Most countries in the Caribbean also had high early mortality rates as has been reported in other low- and middle-income countries,9,12–23,28 with overall mortality dropping from 20.9 deaths per 100 PY in the first 3 months to 4.7 deaths per 100 PY at 5 years. This early mortality was most pronounced in the Dominican Republic and Haiti, the 2 countries with the lowest baseline body weight and nearly all of the cases of TB and ART co-treatment, and Trinidad, which had the lowest median CD4 cell count at ART initiation. In comparison, Martinique and Puerto Rico had early mortality rates that were similar to industrialized countries.
Predictors of mortality in the Caribbean are similar to those reported in other studies from low- and middle-income countries, and included older age, male gender, concurrent TB, and lower baseline body weight, hemoglobin, and CD4 cell count.10–12,20–22,30,45,46,49 Seventy-six percent of patients in these Caribbean centers initiated ART with a CD4 cell count less than 200 cells/mm3. It is worrisome that CD4 cell counts at ART initiation are not improving substantially over time, although the number of counseling and testing centers has increased throughout the region.50 This also remains a problem in most regions of the world, including both low- and middle-income countries.30,35,49 Improved linkage between testing and treatment centers, streamlined strategies to increase ART enrollment, and widespread implementation of the 2010 guidelines of the WHO, which recommend earlier ART initiation, are necessary.51
Low weight and hemoglobin are caused by poor nutritional status and advanced AIDS. Improved nutritional supplementation will be critical to lowering mortality rates in undernourished patients. Active TB infection also remains an obstacle to HIV treatment in Haiti and the Dominican Republic. Further research is needed to evaluate the impact on mortality of newly implemented guidelines for earlier ART initiation in co-infected patients.51 More aggressive TB screening is also indicated, particularly in Haiti, as early reports suggest that TB incidence in Port-au-Prince is increasing in the aftermath of the January 12, 2010 earthquake (unpublished GHESKIO data).
The association between male gender and mortality observed in this cohort has also been reported in studies from China, Cambodia. and some countries in Africa,11,12,21–23,45 but not in Latin America.30,35 This gender difference has been attributed to lower adherence, older age, and more advanced disease in men at presentation, but 2 studies have found that mortality differences persist even after controlling for these variables.45,52 Further studies on biological, behavioral, and occupational factors that could explain the higher mortality in men are warranted to reduce this gender disparity in treatment outcomes.
Seventy-five percent of patients in the overall cohort were alive and in care at the end of the study. Retention rates generally mirrored survival rates; Jamaica was an exception, with lower mortality but higher LTFU than the overall cohort. The proportion of patients who were alive and in care was 89% in Martinique, 82% in Trinidad, 78% in Barbados, 76% in Jamaica, 75% in Haiti, 72% in the Dominican Republic, and 29% in Puerto Rico. The high mortality and high LTFU rate in Puerto Rico is probably because of high rates of intravenous drug use,53–55 high rates of hepatitis C even among patients who are not intravenous drug users, and a population that is highly migratory. With the exception of Puerto Rico, the proportion of patients who were alive and in care in the Caribbean were higher than those reported from several African countries.5,16,20,21,33,56 A systematic review of 32 publications from sub-Saharan Africa reported that African ART programs retain about 60% of patients in the first 24 months.31 A follow-up meta-analysis of 39 African cohorts found a median retention rate of 70%.32 The Caribbean sites generally retain patients at rates similar to the middle-income African countries.13,14,20,21,28,57 This is likely because the treatment programs at these Caribbean sites are well established, all ART and HIV clinic visits are provided free of charge, all sites track patients that miss visits, and most programs subsidize transportation fees.
Our study is limited by a lack of definitive outcomes for patients who are presumed LTFU. Multiple tracking studies from low- and middle-income countries have found that a significant proportion of these patients have died.32,43,44,58–62 It is possible that we may have underestimated mortality rates, but it is noteworthy that retention in care in the Caribbean is similar or superior to reported rates from other low- and middle-income countries. We also lacked data on adherence to therapy as a predictor of mortality. This and other unmeasured variables, such as incarceration or migration status, could explain the higher hazard ratios for mortality that persisted in the multivariable analysis for the Dominican Republic, Barbados, and Puerto Rico. Median follow-up times also varied between countries, with Barbados having the longest duration of follow-up. In addition, it is important to note that though we have a large sample size of patients that included from 7% to 71% of patients on ART in each country, treatment outcomes from these sites may not always be representative of whole countries, particularly as some sites are nongovernmental organizations and others are public.
In summary, this study provides the first multicohort data on long-term HIV treatment outcomes in the Caribbean. Outcomes across the region are excellent and similar to reports from other low- and middle-income countries. Mortality rates vary widely by country, but much of the difference in mortality can be explained by disease severity at ART initiation, concurrent TB, gender, and nutritional status. Earlier ART initiation and augmented nutritional supplementation for undernourished patients will be critical to improve outcomes. Further studies are necessary to identify the reasons for the gender disparities in treatment outcomes.
We thank Brendan Bain, Anthony DeMoya, Yasuhiro Yamamuro, and Carmen Zorilla, of the TCHARI Board, for their guidance and advice. We thank Stewart Smith for facilitating the collaborative process between the sites, and Jack Whitescarver of the National Institutes of Health Office of AIDS Research for his support. We thank the Global Fund to Fight AIDS, Tuberculosis, and Malaria, the US President's Emergency Plan for AIDS Relief, and the governments of Barbados, the Dominican Republic, Haiti, Jamaica, Trinidad, France, and the United States for financial support for medications and care. We acknowledge Sylvia Abel, Luis Miguel Abreu, Brendan Bain, Heejung Bang, Songee Beckles, Gisella Cestero, Graeme Crookendale, Bright Dgndy, Daniel W. Fitzgerald, Andrew Foster, Sandrine Pierre François, Celia Graham, Patrick Hochedez, Tina Hylton-Kong, Sherry-Ann Lashley, Paul Leger, Rosmund Lovell, Abdias Marcelin, Megan McLaughlin, Oris Nero-Jarvis, Glenda Ortiz, Heidy Ortiz, Charlene Sealy, Sharon Soyer-Labastide, Basil Thorpe, and Dwayne Wiltshire for their generous assistance in study development, statistical analyses, manuscript editing, and data retrieval.
Author contributions: Conceptualization of the study and manuscript: All authors were involved in the conceptualization of the study and the manuscript. Patient care: All Caribbean authors cared for the patients at their respective sites. Data collection and management: All authors were involved in data collection or management. Analysis: A. Edwards, S. Koenig, J. W. Pape. Manuscript writing and revision: S. Koenig wrote the first draft and all authors reviewed and edited the manuscript. Funding: Pape obtained funding for this study.
The authors feel that an extended author list should be justified because this study reports on long-term HIV treatment outcomes from 7 countries.
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