This analysis from a large public antiretroviral therapy program in sub-Saharan Africa documents a substantial death rate among patients lost to follow-up soon after initiating HAART, and illustrates how deaths among patients lost to follow-up can result in both inaccurate estimates of survival and biased estimates of risk factors for death after HAART initiation.
From a clinical perspective, the fact that nearly 60% of those initially considered lost to follow-up prior to tracing were later found to have died suggests that interventions designed to decrease mortality after HAART initiation will need to include methods to identify, locate, diagnose and, if possible, treat incident illnesses in those who miss even a single clinic visit. Given the very short survival after HAART initiation among patients initially categorized as lost but who were eventually confirmed dead (i.e., 42 days), this finding also suggests that such interventions should be able to identify these patients rapidly. From a public health perspective, these results suggest that death rates after HAART initiation within antiretroviral therapy clinics may be systematically underestimated if losses to follow-up are substantial and patients with very low pre-treatment CD4 counts are presenting for care. For example, in this study, nearly 60% of all deaths within the first year would not have been detected unless patient tracing was performed. Thus, precise estimates of the actual effectiveness of global antiretroviral scale-up efforts will be difficult if not impossible to obtain unless patient tracing is undertaken, at least among those on whom outcomes are formally reported.
Since limited data on definitive outcomes among patients lost to follow-up after HAART initiation in sub-Saharan Africa exist, it is difficult to assess the scope of this problem. In particular, although patient tracing has been associated with lower survival estimates among HIV-infected patients not on HAART
, little is known about actual outcomes among patients who have initiated HAART. However, a recent report from four public sector antiretroviral therapy clinics in northern Malawi during 2004–2006 used patient tracing (including home visits) and found that 50% of those not attending clinic for 3 or more months had died, indicating that high rates of death among patients who do not return to clinic after HAART initiation are also currently being found in other settings
. Since only 5% of all patients starting HAART in the Malawi report were categorized as lost to follow-up, however, the effects of deaths among those initially considered lost on overall survival estimates would likely have been less pronounced than was shown in this study, where the initial loss to follow-up rate was approximately 17%
. This study extends findings from the Malawi study by documenting the effect of undetected deaths on overall survival estimates, and suggests that the magnitude of this effect likely relates both to the overall loss to follow-up rate and the proportion of deaths among these individuals. Since losses to follow-up in several large public antiretroviral therapy clinics in Zambia (21%)
, South Africa (14%), Cote d'Ivoire (11%)
, additional settings in Malawi (7%)
, Uganda (11%)
, Kenya (15–25%)
and in the Antiretroviral Therapy in Lower Income Countries (ART-LINC) collaboration (19% among clinics not performing tracing)
have been substantial, underestimation of deaths after HAART initiation in many reports from the region could be common.
The finding of substantial death rates among patients who are lost to follow-up also suggests that death rates after HAART initiation in the developing world may be higher than previously suspected. The ART-LINC study comparing outcomes after antiretroviral therapy initiation in low and high income countries excluded clinics that did not trace patients from survival analyses, found greater ascertainment of deaths in developed countries, and documented higher rates of losses to follow-up in developing countries
. Thus, while inability to ascertain outcomes among patients lost to follow-up could bias mortality estimates in both the ART-LINC and the ART-CC data, higher rates of losses to follow-up in the ART-LINC patients creates the possibility that deaths may have been underestimated to a greater degree in this group.
This study differs from several previous reports in that we performed prospective data collection on patients consecutively initiating HAART at a large antiretroviral therapy program in sub-Saharan Africa specifically to determine definitive outcomes on patients who were initially considered lost to follow-up and to compare survival estimates and risk factors for death before and after active tracing was performed. Although the ART-LINC collaboration documented higher rates of loss to follow-up among clinics which did not trace patients
, this analysis compared one type of clinic to another rather than comparing outcomes before and after tracing within a single group of patients. Furthermore, while the study from Malawi confirmed a high rate of death among patients who were lost
, the effect of these deaths on estimates of overall outcomes was not evaluated.
Another difference of this study from the Malawi study
is that we analyzed the effects of losses to follow-up on reported risk factors for death after HAART initiation. The tendency of losses to follow-up to bias analyses of risk factors for death, as was documented here for both baseline CD4 counts and male sex, is concerning. While this is less likely to be a problem when analyzing factors with strong biologic associations with survival (like baseline CD4 counts), factors with smaller strengths of association but with considerable public health impact may conceivably be missed if losses to follow-up are censored. Male sex is one example of such a factor. Whereas men have been shown to be at increased risk of death or loss to follow-up after HAART in this study and in several other large cohorts
, numerous other studies have not found this association
, including a large multinational analysis from ART-LINC
. This finding should be investigated prospectively. More broadly, a critical component of improving outcomes in global antiretroviral therapy scale-up efforts is accurate identification of groups at high risk of death after HAART initiation, and these data indicate the importance of patient tracing in such investigations.
This study has several important limitations. First, reasons for losses to follow-up after HAART initiation were not formally explored, and thus it is impossible to determine from these data the precise interventions capable of keeping patients alive and in care. In particular, we had limited data on social or behavioral factors that may influence adherence
to HAART in this setting. Verbal autopsies, which were not performed, may have enhanced the analysis by providing insights into likely causes of death, as has been shown in other sites
. Furthermore, while a recent report from Zambia suggested that retention rates among patients lost to follow-up were low despite multiple calls and visits
, the effectiveness of such efforts needs further prospective evaluation. Another limitation relates to the fact that approximately 5% of patients remained lost to follow-up despite patient tracing. The association between lower baseline CD4 count and being lost to follow-up among patients remaining lost after tracing, which concurs with findings from a large French database
and from ART-LINC cohorts not performing tracing
, suggests that some of these patients also died. If true, the finding of underestimation of deaths and bias due to informative censoring would likely have been more pronounced than was presented here. In addition, although the data from Malawi confirm our estimates of deaths among those lost to follow-up
, the study was conducted among only approximately 400 adults initiating HAART in 2003 and 2004. As such, results of this study do not necessarily represent the outcomes that are being experienced among patients currently enrolled in the IDCC or in other clinics in Botswana.
Providing data for comparing outcomes after HAART initiation across study settings is one way epidemiologic studies can potentially improve HIV patient care. Using such comparisons, sites with higher mortality or loss to follow-up rates can explore operational characteristics of sites or biologic or behavioral aspects of patients with lower rates in order to attempt to identify procedures or interventions capable of improving patient retention and survival. To facilitate such investigations, survival rates and risk factors for death with minimal inherent bias are needed. Uniform reporting standards have been advocated for randomized clinical trials
, for analyses of diagnostic tests
, and, more recently, for observational cohort studies
. Adoption of such standards with respect to reporting outcomes from observational cohort studies of HAART use ideally will improve reporting of the number and percent of patients lost to follow-up after HAART initiation, thereby facilitating future research efforts into ways to improve patient care.