The estimated 1-year mortality rates and CIs for each site at specific baseline CD4 counts are shown in Figure 2. The estimated 1-year mortality probability for an individual starting HAART with CD4 count = 200 cells per microliter was quite similar between sites (1.1%-2.8%), except for GHESKIO-Haiti and IHSS/HE-Honduras, where the mortality rates were estimated as 7.5% and 7.0%, respectively (Fig. 2).
Table 3 shows adjusted HRs for mortality during the first year, for each cohort and combined across cohorts. Higher CD4 count at HAART initiation was associated with a lower hazard of death after adjusting for sex, age, clinical stage, calendar year, and type of regimen. Using CD4 count = 50 cells per microliter as a reference, the HRs were 0.79 (95% CI: 0.67 to 0.92), 0.58 (95% CI: 0.40 to 0.85), and 0.43 (95% CI: 0.22 to 0.84) for CD4 counts of 100, 200, and 350 cells per microliter, respectively. After adjusting for other variables, the hazard of death was 3.1 times higher for a person with clinical AIDS before HAART initiation than a person without (95% CI: 2.1 to 4.5), and older patients were more likely to die within 1 year of HAART initiation (HR = 1.12 per 10 years, 95% CI: 1.01 to 1.25).
Overall, there were no consistent trends between date of HAART initiation and mortality. At GHESKIO-Haiti, patients initiating HAART in later years had lower CD4 counts (P < 0.001) and were more likely to have clinical AIDS (P < 0.001) at baseline (data not shown); however, after adjusting for these and the other factors given in Table 3, initiating HAART in later years was associated with improved 1-year survival (HR = 0.64 per 1-year difference in date of HAART initiation, for example, 2005 vs. 2004, 95% CI: 0.56 to 0.84). In contrast, patients at HUCFF-Brazil and FA-Chile tended to be less immunosuppressed at HAART initiation over time (P = 0.16 and 0.007 for CD4 and clinical stage, respectively, for HUCFF-Brazil and P = 0.07 and 0.08 for FA-Chile). After adjusting for these and other predictors, there was a trend toward improved survival at HUCFF-Brazil (HR = 0.88, 95% CI: 0.71 to 1.10), and FA-Chile (HR = 0.79, 95% CI: 0.58 to 1.07).
Multivariable analyses including hemoglobin, weight, and HIV-1 RNA were also performed for sites which routinely collected this data and are shown in Table 4. Higher baseline hemoglobin was associated with a lower risk of mortality for GHESKIO-Haiti, IHSS/HE-Honduras, and INNSZ-Mexico. Higher baseline weight also was predictive of a decreased mortality risk for GHESKIO-Haiti and IMTAvH-Peru but was not statistically associated with risk of death for IHSS/HE-Honduras or INNSZ-Mexico. Baseline PVL was not an independent predictor of mortality in any of the sites, which routinely collected PVL. In FH-Argentina, the hazard of death was 2.5 times higher for subjects with history of IDU.
Loss to Follow-Up
The percentage of patients lost to follow-up during the first year shown in Table 2 was approximately 6%, ranging from less than 1% (IHSS/HE-Honduras) to 17% (FH-Argentina). The probability of being lost to follow-up or dying during the first year after HAART initiation is shown in Figure 3 for all sites. More than 6% of HAART initiators in FH-Argentina were lost after their first visit. In FH-Argentina, those lost in the first year (n = 135) had baseline characteristics more similar to those known to be alive after 1 year (n = 642) than those known to be dead (n = 17). The median CD4 count at HAART initiation for those alive, lost, and dead was 162, 190, and 33 cells per microliter, respectively (P < 0.001 comparing all 3 groups, P = 0.26 for alive vs. lost, and P < 0.001 for dead vs. lost). The percentage of patients with baseline AIDS for those alive, lost, and dead in FH-Argentina was 30%, 33%, and 98%, respectively (P < 0.001 comparing all 3 groups, P = 0.59 for alive vs. lost, and P < 0.001 for dead vs. lost). For patients who reported IDU as a risk factor for contracting HIV, the percentage of those alive, lost, and dead was 9%, 12%, and 29%, respectively (P = 0.03 comparing all 3 groups, P = 0.57 for alive vs. lost, and P = 0.12 for dead vs. lost). In FA-Chile, INNSZ-Mexico, and IMTAvH-Peru, those who were lost to follow-up tended to be intermediate between those who died and those who were alive after 1 year in terms of rates of clinical AIDS at HAART initiation and baseline CD4 count, weight (INNSZ-Mexico and IMTAvH-Peru), and hemoglobin values (INNSZ-Mexico). At GHESKIO-Haiti, those who were lost tended to be more similar at HAART initiation to those who subsequently died during the first year than to those who lived in terms of AIDS (39%, 53%, 66%, for those alive, lost, and dead, respectively), median CD4 count (110, 90, 48 cells/μL), median weight (54, 46, 47 kg), and median hemoglobin (10, 9, 9 g/dL) (P < 0.001 comparing all 3 groups for all 4 variables; P = 0.034, P = 0.065, P < 0.001, and P < 0.001 comparing lost vs. alive for AIDS, CD4, weight, and hemoglobin, respectively; and P = 0.09, 0.11, 0.72, and 0.63 comparing lost vs. dead). In most sites, the rate of loss to follow-up tended to be higher for patients initiating HAART in more recent years. The combined unadjusted hazard of being lost to follow-up during the first year after HAART initiation increased 49% per calendar year (HR = 1.49, 95% CI: 1.29 to 1.71).
Sensitivity analyses were performed to assess the extent to which loss to follow-up rates might have introduced bias in our 1-year mortality estimates. After accounting for differences in baseline characteristics between those lost and those remaining in care, resulting 1-year mortality estimates were very similar to original estimates: 2.6% (original = 2.6%) for FH-Argentina, 3.7% (original = 3.7%) for HUCFF-Brazil, 6.0% (6.0%) for FA-Chile, 13.1% (13.0%) for GHESKIO-Haiti, 3.8% (3.5%) for INNSZ-Mexico, and 9.9% (9.8%) for IMTAvH-Peru.
This is the first multicohort study to describe 1-year prognosis after HAART initiation in Latin America and the Caribbean. Overall mortality rates were similar to that of low-income countries with active follow-up, as reported by the ART-LINC Collaboration.5 However, substantial intercountry differences in mortality rates were observed, suggesting country-specific and region-specific factors may influence the effectiveness of HAART in these settings.
Consistent with reports from other large collaborations, low CD4 count at therapy initiation and more advanced disease were strong predictors of mortality in the first year.3,5 Across sites, cohorts with lower median CD4 count at HAART initiation (GHESKIO-Haiti, IHSS/HE-Honduras, and IMTAvH-Peru) tended to have higher mortality rates than clinics with higher baseline median CD4 count (FH-Argentina, HUCFF-Brazil, and FA-Chile). The one exception was the site in Mexico, where patients presented with low CD4 counts but tended to have high survival rates. Different stages of disease at HAART initiation across sites may be indicative of later presentation for care and/or different criteria for treatment initiation. Later presentation for care may reflect programmatic challenges to detect treatment candidates at earlier stages of disease. In GHESKIO-Haiti, one study showed that lower socioeconomic status and older age were associated with late access to care.12 Stigma and discrimination related to HIV/AIDS are reported reasons for refraining from seeking HIV testing among some Latin communities.13 Different disease stages at HAART initiation also could reflect local treatment guidelines. For example, GHESKIO-Haiti's treatment program followed contemporary World Health Organization recommendations to treat patients with an AIDS-defining illness or a CD4 count under 200 cells per microliter,14 whereas since 1998, HUCFF-Brazil has adopted the strategy of considering treatment for patients with CD4 counts <350 cells per microliter.
Sites located in countries with newer treatment programs tended to have patients with higher degrees of immunodeficiency and subsequent mortality. Haiti and Peru began providing free ARV treatment to HIV-infected patients in 2003 and 2004, respectively, in contrast to Brazil and Argentina, where free ARV therapy was offered as early as 1996 and 1997, respectively. Age of program, in turn, may be a proxy for infrastructure development, drug procurement and delivery systems, waiting time, and quality of clinical care.15 Indeed, the probability of death in the first year after HAART initiation tended to be lower for those starting HAART in later years in HUCFF-Brazil, FA-Chile, and GHESKIO-Haiti. Observed trends at HUCFF-Brazil and FA-Chile suggest that HAART has been initiated at less advanced disease stages in more recent years. In contrast, the opposite was observed in GHESKIO-Haiti, where patients starting HAART in later years tended to have lower CD4 counts and were more likely to have AIDS. Despite this, there was decreased mortality in later years of HAART initiation at GHESKIO-Haiti, suggesting an improvement in care over time. Structural factors, such as interruptions in drug supply16 and shortage of staff17 in Peru and bureaucracy and delays in Chile,15 may have affected program effectiveness.
The higher mortality rates in GHESKIO-Haiti and IHSS/HE-Honduras, independent of baseline CD4 count, may be a reflection of higher mortality rates in the general population. Nationwide estimates for life expectancy at birth are lower for Haiti (61.3 years) and Honduras (70.4 years) than the other 5 countries with participating sites (75.5, 72.6, 78.7, 76.4, and 71.7 years for Argentina, Brazil, Chile, Mexico, and Peru, respectively), although such data may not accurately represent background mortality in the specific locations of our clinics.18 Higher mortality rates may be indicative of chronic poverty and malnutrition. In both men and women, weight and hemoglobin at therapy initiation were consistently lower for patients in GHESKIO-Haiti than in other sites. Several previous studies, including ones conducted in Haiti, have demonstrated the deleterious effect of malnutrition on AIDS progression in resource-poor settings.14,19-22 Consistent with other studies,23,24 we observed strong associations between weight and mortality in GHESKIO-Haiti and IMTAvH-Peru and between hemoglobin and mortality in GHESKIO-Haiti, IHSS/HE-Honduras, and INNSZ-Mexico. Unfortunately, data on causes of death were not available for most sites and therefore were not examined.
The high mortality rate reported here in the first few months after HAART initiation is in agreement with other reports from resource-limited countries5,25-27 and highlights the need to determine causes of early death so that specific public health strategies may be developed.
With the exception of FH-Argentina, rates of loss to follow-up were fairly low (≤5%) across sites. The high rate of lost to follow-up in FH-Argentina raises concerns regarding its low mortality estimate. However, because those lost tended to have characteristics at HAART initiation similar to those alive after 1 year and because the mortality estimate adjusted for baseline covariates was nearly identical to the unadjusted estimate, it seems likely that the mortality rate in FH-Argentina is not significantly higher than estimated in Figure 1. The high rate of loss to follow-up in FH-Argentina may reflect patients seeking care at clinics not included in this cohort, as there are many treatment/clinic options in Buenos Aires. In contrast, patients lost to follow-up at other sites tended to have baseline characteristics intermediate between those alive and those dead after 1 year (FA-Chile, INNSZ-Mexico, and IMTAvH-Peru) or similar to those dead (GHESKIO-Haiti). Although the latter observation is consistent with recent data reported from low-income countries in Africa, Asia, and South America,28 the present study suggests that losses to follow-up may have different meanings in different settings. Similar to the findings of Brinkhof et al,28 we observed higher rates of loss to follow-up for patients initiating HAART in more recent years. This may reflect rapid scale-up paired with inability to retain patients. It should be recognized that our definition of loss to follow-up was chosen to ensure comparability with other studies that have estimated 1-year mortality in developing countries.5 Other definitions of loss to follow-up (eg, 3 months without a visit) are likely to be more meaningful when evaluating other clinical outcomes or clinic programmatic performance.
There are several limitations to this study. First, the impact of adherence to therapy, a well-known prognostic factor demonstrated in several studies,29-31 was not addressed. In contrast to developed countries, factors influencing adherence to ARV therapy have been less studied in resource-limited settings.32,33 Second, on-site data audits revealed data errors for all CCASAnet sites, although none serious enough to warrant site exclusion. Specific results of the audits, which seem to be unique among multicohort observational HIV studies, are beyond the scope of this study and will be presented elsewhere. Tendency toward overdiagnosis of AIDS was observed in HUCFF-Brazil, indicating a possible classification bias. This may reflect local practices and partially explains the imprecise hazard estimates for this variable in the multivariable model. Although we only used routinely collected variables and employed statistical techniques to account for differences between those with and without missing measurements, HRs could still be biased due to missing data. Finally, additional heterogeneity between cohorts may be present due to differences in population genetics or infecting HIV subtypes, factors which were not considered in the present analysis.
The results reported here have important public health implications. The finding of a large number of patients starting HAART at advanced stages of disease with consequent impact on mortality rates has implications for public health planning and HIV prevention. The overall rate of late diagnosis in our cohort (76%), defined as CD4 count <200 cells per microliter or AIDS at baseline, is nearly twice as high as that observed in developed countries. For example, using the same definition, studies from France and Italy reported rates of late diagnosis of 36% and 39%, respectively.34,35 In addition, the rate of patients starting HAART at advanced stages of disease did not seem to be improving with time at most CCASAnet sites. Late-presenting patients are more likely to require hospitalization and experience multiple opportunistic conditions simultaneously36 and to utilize more health care resources.37 From a prevention perspective, it is likely that late diagnosis increases risk of HIV transmission, as studies suggest that transmission is associated with lack of knowledge about HIV status38 and high PVL.39
In conclusion, in the first multicohort study to describe prognosis after HAART initiation in Latin America and the Caribbean, we found that despite considerable variability between sites, the overall mortality rate at 1 year is similar to that reported in other resource-limited settings. Differences across sites may reflect, at least in part, diverse background mortality rates, local practices, and/or national programmatic characteristics. Further operations research is necessary to elucidate this important issue.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; Caribbean; cohort; highly active; HIV; low-income population; South America; treatment outcome