In this analysis, we examined the relationship between mortality risk and CD4 cell counts measured at baseline and 4 monthly during ART (updated CD4 cell counts) in a large cohort. Mortality risk decreased markedly in association with ART-induced CD4 cell recovery, but patients remained at substantially greater mortality risk during person-time accrued at CD4 cell counts below a threshold of 200 cells/μl. Compared with patients with the highest updated CD4 cell counts, patients with updated CD4 cell counts of less than 200 cells/μl had a more than two-fold greater adjusted mortality risk and those with updated counts of less than 50 cells/μl had a more than 10-fold greater adjusted mortality risk. Cumulative person-time accrued within CD4 cell-strata lying below 200 cells/μl explains both the high mortality observed during the first year of ART and the high long-term cumulative mortality risk among those with the lowest baseline CD4 cell counts. Early HIV diagnosis and timely initiation of ART before CD4 cell counts fall 200 cells/μl are required.
Despite virological suppression rates of more than 90% and excellent CD4 cell count recovery in this cohort (), cumulative mortality estimates after 48 months of ART were far greater than those observed in ART cohorts in high-income countries [18
]. Similarly aged patients in the Dutch AIDS Therapy Evaluation Project (ATHENA) cohort, for example, who have sexually acquired HIV and baseline CD4 cell counts of less than 100 cells/μl have 5-year cumulative mortality estimates of 8% (AIDS patients) or 4% (non-AIDS patients) [18
]. These compare to 4-year estimates of 24.8 and 12.6%, respectively, among similarly stratified patients in our cohort. Corresponding estimates from the ATHENA cohort for patients with baseline CD4 cell counts of 100–200 cells/μl were 4% (AIDS patients) and 2% (non-AIDS patients) compared with estimates of 20.1 and 6.3% in our cohort. These findings indicate that long-term cumulative mortality estimates are over three-fold higher in our cohort.
Our data extend the findings of the Antiretroviral Treatment in Lower Income Countries (ART-LINC) collaboration, which reported that after adjustment for baseline patient characteristics, mortality risk in the first year of ART was higher among patients treated in resource-limited settings compared with those treated in high-income settings despite similar immunological and virological responses to treatment [5
]. Reasons underlying this have yet to be defined but may include differences in the spectrum of opportunistic pathogens and access to healthcare. The most common causes of early deaths in our cohort are TB, acute sepsis, cryptococcal meningitis, wasting syndrome and Kaposi's sarcoma [6
]. Immune reconstitution disease has been speculated to contribute to early mortality in this setting, and our experience is that cryptococcal disease rather than TB is more important in this regard [6
Existing studies from both high-income and resource-limited settings have largely focused on the relationship between mortality risk and baseline patient characteristics [4
]. We extended these findings, showing that mortality risk changed markedly in relationship with CD4 cell count recovery during ART () and that the absolute CD4 cell count at any given time point was the key determinant of mortality risk. However, above a threshold of 200 cells/μl, further increments in CD4 cell counts were associated with only minor additional reductions in mortality rates that did not reach statistical significance in this analysis.
Immune recovery in this cohort compares very favourably with that observed in ART cohorts in high-income countries [23
]. The proportion of patients with CD4 cell counts less than 200 cells/μl decreased steeply to reach a plateau of approximately 10% after 24–36 months of ART (). In the long term, the minority of patients with updated counts less than 200 cells/μl contributed disproportionately to overall mortality rates, and this proportion may be an important factor underlying differences in mortality rates between cohorts. Such patients may have immunological nonresponse (approximately 10% of this cohort at 48 weeks [24
]) or primary or secondary virological failure. A detectable viral load during follow-up was also an independent risk factor for death, highlighting the importance of maintaining virological suppression.
The slope of the 500 cells/μl CD4 cell count contour in indicates that substantial immune recovery was ongoing after 48 months of ART. However, as mortality risk varied relatively little above a CD4 cell count threshold of 200 cells/μl, the steadily increasing proportion of patients with counts more than 500 cells/μl is unlikely to impact overall mortality rates substantially. This may be more important, however, with regard to reducing risk of morbidity due, for example, to TB, which persists at high rates during ART in this setting [25
Cumulative mortality risk was strongly related to the proportions of person-time accrued within different CD4 cell-strata. During the first year of ART, the proportions of person-time accrued within CD4 cell-strata lying below 200 cells/μl were large, and the mortality that accrued within this period was correspondingly high. Beyond 1 year of treatment, these proportions rapidly decreased, accounting for much lower mortality rates thereafter.
In multivariate analyses, mortality risk at any given time point was associated with updated CD4 cell count rather than the baseline value. Lower baseline counts were, however, predictive of greater proportions of person-time accrued within low CD4 cell-strata with high mortality risk. Thus, cumulative mortality estimates at 48 months were much higher among patients with baseline CD4 cell counts less than 100 cells/μl compared with those with higher baseline counts (). Median baseline CD4 cell counts are low in most ART programmes in sub-Saharan Africa, and so many patients remain at high mortality risk for considerable periods.
These data indicate that patients should start ART before their CD4 cell counts fall below 200 cells/μl, though this only occurs in a small minority of patients in Africa at present. Earlier initiation of ART will require early HIV diagnosis and strengthening of longitudinal HIV care, with serial assessments of CD4 cell counts and clinical status to trigger initiation of ART at an appropriate time point. Eligibility criteria for ART in national programmes in the region need to be reconsidered. The policy in South Africa, for example, restricts ART to patients with WHO stage 4 disease (AIDS) or a CD4 cell count less than 200 cells/μl [26
], which is not in keeping with current WHO guidelines [27
]. Thus, current South African policy restricts the potential survival benefits that could be derived from ART.
Strengths of this study include the completeness of data, with less than 5% of CD4 cell count data-points missing, good ascertainment of outcomes and a low loss to follow-up rate. Previous data indicate that inadvertent misclassification of deaths as losses to follow-up in this cohort is infrequent [13
]. This analysis is novel with inclusion of updated CD4 cell counts and viral load measurements as time-dependent covariates. A much larger cohort would be needed to detect any significant differences in mortality risk in higher CD4 cell-strata, however. Baseline characteristics of patients were typical of those accessing ART in other public sector programmes across sub-Saharan Africa. However, mortality and loss to follow-up rates were lower than those observed in many other programmes, and absolute CD4 cell-stratified mortality rates may not be representative of all programmes [4
In summary, long-term cumulative mortality estimates in this South African cohort were approximately three-fold higher than those in cohorts in high-income countries despite excellent immunological and virological responses to ART. Mortality risk during ART was strongly associated with updated CD4 cell counts, and overall mortality was related to the proportions of person-time accrued within low CD4 cell-strata. Person-time accrued at CD4 cell counts less than 200 cells/μl must be minimized before and during ART. National HIV programmes should take measures to promote early diagnosis of HIV and initiation of ART before CD4 cell counts fall below 200 cells/μl.