Table 3 shows three different crude and adjusted models of the relation between baseline CD4 cell counts and virologic failure or death. We present three separate models that are identical except that they use different categorizations of CD4 cell count (models 1 and 2) or include an interaction between baseline WHO stage and CD4 cell count (model 3). Model 1, which uses the CD4 categories used previously (≤200 vs. >200 cells/μl), shows that after adjusting for age, sex and pregnancy, site, treatment arm and other indicators of immunosuppression, those with a baseline CD4 cell count of 200 cells/μl or less had twice the risk of virologic failure or death (hazard ratio, 1.94; 95% CI, 1.14–3.30). Having a baseline WHO stage IV (hazard ratio, 1.98; 95% CI, 1.18–3.33), a viral load above 100 000 vs. below 10 000 copies/ml (hazard ratio, 2.05; 95% CI, 0.71–5.89) and having a nelfinavir-based regimen (hazard ratio, 4.27; 95% CI, 1.17–15.6) were also predictive of virologic failure or death independent of CD4 cell counts.
In Model 2, we looked for a CD4 cell count dose response between decreasing baseline CD4 cell count and risk of death or virologic failure by stratifying baseline CD4 cell count into finer categories (0–99, 100–199, 200–299, and ≥300 cells/μl). After adjustment, we found those with a CD4 cell count between 100 and 199 cells/μl and those with a CD4 cell count below 100 cells/μl had a roughly three-fold increased risk of death or virologic failure as those with at least 300 cells/μl (CD4 cell count <100 vs. >300 cells/μl; hazard ratio, 3.08; 95% CI, 0.92–10.4 and CD4 cell count 100–199 vs. >300 cells/μl, hazard ratio, 3.23; 95% CI, 0.99–10.6 cells/μl), whereas those with a CD4 cell count of 200–299 cells/μl had twice the risk (hazard ratio, 2.00; 95% CI, 1.19–3.37). Thus, higher baseline CD4 cell count does appear to be associated with lower risk of virologic failure and death.
We also looked for interactions between the baseline CD4 cell count group and other markers of immunosuppression. Model 3 shows the results of a regression model that includes the only significant interaction we identified, that between baseline CD4 cell count (≤200 vs. >200 cells/μl) and baseline WHO Stage IV. Compared with the reference group of those with a baseline CD4 cell count above 200 cells/μl and no WHO Stage IV condition, those with either a WHO Stage IV condition alone or a CD4 cell count of 200 cells/μl or less alone had a two-to-three-fold increased risk of death or virologic failure (hazard ratio, 2.87; 95% CI, 0.93–8.83 and hazard ratio, 2.14; 95% CI, 1.20–3.81, respectively). However, those with both a WHO Stage IV condition and a CD4 cell count of 200 cells/μl or less at baseline had a four-fold increased risk of death or virologic failure vs. those with neither condition (hazard ratio, 3.91; 95% CI, 1.88–8.14).
Overall about 6% of all patients in the study developed incident TB over the course of follow-up with substantially more of it occurring among those initiated on ART at CD4 cell counts of 200 cells/μl or less than among those initiated above 200 cells/μl (8.0 vs. 3.1%; RR, 2.6; 95% CI, 1.3–5.2) (Table 2). In a Kaplan–Meier analysis (Fig. 1c), we note that the majority of the difference between the two groups emerged within the first 24 months on treatment. In Table 4, we present two separate models of incident TB that are identical except that they use different categorizations of CD4 cell count (Models 1 uses ≤200 vs. >200 cells/μl, whereas Model 2 uses <50, 50–199 and ≥200 cells/μl). After adjusting for site, treatment group, age, sex, use of a protease inhibitor-based regimen, baseline viral load, WHO stage and BMI, using proportional hazards regression, we found that those initiated on ART at CD4 cell counts of 200 cells/μl were twice as likely to develop TB compared with those initiated above 200 cells/μl (hazard ratio, 1.9; 95% CI, 0.89–4.0) (Table 4, Model 1). When we further stratified the lowest CD4 cell counts group into those above and below 50 cells/μl (Model 2), we found that those with a CD4 cell count below 50 vs. above 200 cells/μl were at strongly increased risk of incident TB (hazard ratio, 3.4; 95% CI, 1.4–8.5), whereas those with 50–200 vs. above 200 cells/μl were at lower increased risk (hazard ratio, 1.60; 95% CI, 0.73–3.5) (Table 4).
Loss to follow-up
Nearly 12% of the cohort were LTFU and LTFU was more common among those with a baseline CD4 cell count above 200 than 200 cells/μl or less (14.3 vs. 10.2%)(Table 2). After adjusting for age, sex, baseline WHO stage, viral load, use of a protease inhibitor, treatment arm and site (data not shown), we found a small decreased risk of being LTFU among those initiated on ART with lower CD4 cell counts (≤200 cells/μl) vs. those initiated at higher CD4 cell counts (>200 cells/μl) (hazard ratio, 0.79; 95% CI, 0.50–1.25). Figure 1(b) shows that the difference between the groups emerges only after 24 months, the minimum potential follow-up time for the cohort. Those with a baseline WHO stage IV condition also had an increased risk of LTFU (hazard ratio, 1.61; 95% CI 0.93–2.79) (data not shown).
Toxicity endpoints were experienced by about 17% of the entire cohort (Table 2). We observed small differences in rates of toxicities between CD4 count groups slightly favoring those with baseline CD4 cell counts of 200 cells/μl or less vs. above 200 cells/μl (15.6 vs. 18.0%) (Fig. 1d). After adjusting for age, sex, baseline WHO stage, viral load, treatment regimen, treatment arm and site, women (hazard ratio, 1.95; 95% CI, 1.17–3.24), those who with a BMI above 30 vs. 18.5–30 kg/m2 (hazard ratio, 2.17; 95% CI, 1.41–3.34) or a baseline WHO stage IV condition (hazard ratio, 1.91; 95% CI, 1.15–3.18) were at increased risk of toxicity failure, but we found little difference between CD4 cell count groups (hazard ratio, 0.78; 95% CI, 0.53–1.16) (data not shown). Use of lopinavir–ritonavir vs. efavirenz-based regimens decreased the risk of toxicity (hazard ratio, 0.40; 95% CI, 0.16–1.02). Nevirapine use was associated with increased risk of toxicity vs. efavirenz-based regimens in unadjusted analyses (hazard ratio, 1.46; 95% CI, 0.99–2.16), but the association disappeared after adjustment (hazard ratio, 1.01; 95% CI, 0.63–1.61).
The results of analyses of the CIPRA-SA trial data show a clearly increased risk of death or virologic failure associated with initiating ART at lower CD4 cell counts. We found that those who started ART at CD4 cell counts of 200 cells/μl or less had roughly twice the risk of death or virologic failure as those initiated at CD4 cell counts above 200 cells/μl (hazard ratio, 1.94; 95% CI, 1.14–3.30) and twice the risk of developing incident TB (hazard ratio, 1.90; 95% CI, 0.89–4.04). These findings are in line with numerous observational studies [23–27] from resource-limited settings showing low baseline CD4 cell count is a major predictor of death and LTFU. Recently, an interim analysis of the CIPRA-HT001 trial in Haiti showed a nearly four-fold increased risk of death among those starting ART with a CD4 cell count of 200 vs. 200–350 cells/μl , very similar to our five-fold increased risk (RR, 5.4; 95% CI, 1.3–23.0) . Thus, a body of evidence is beginning to emerge, showing the benefits of earlier treatment initiation in resource-limited settings. This, along with a recent analysis by Lawn et al.  showing that the longer a patient maintains a CD4 cell count of below 100 cells/μl, the higher the risk of death suggests that starting patients at higher CD4 cell counts may allow them to maintain their CD4 cell counts above the point at which they are at increased risk of death.
Our findings are also consistent with data from resource-rich environments. Observational data have shown that higher CD4 cell counts are associated with lower risk of death [7,9]. More recently, Kitahata et al.  have shown that patients initiating ART at CD4 cell counts above 500 cells/μl had substantially reduced risk of mortality vs. those below 500 cells/μl. Although our data cannot be used to comment on CD4 cell counts above 350 cells/μl, our finding of decreased mortality and virologic failure risk associated with having a starting CD4 cell count above 300 cells/μl is suggestive of a dose response with increasing baseline CD4 cell count associated with better outcomes.
Although we found a substantial association between earlier ART initiation and better treatment outcomes we also found a slightly increased risk of being LTFU among those with higher baseline CD4 cell counts, which could potentially offset some of the benefits of initiating treatment earlier. However, we urge caution in interpreting these results. Under ideal conditions, assessing the effectiveness of initiating ART at higher CD4 cell counts would come from randomizing patients to either immediate initiation of ART when the CD4 cell count falls below 350 cells/μl or follow patients and delay ART until the CD4 cell count falls below 200 cells/μl [14,29]. In both arms, patients would be followed from the time of their first CD4 cell count below 350 cells/μl. In our study, patients were initiated onto ART at enrollment as long as their CD4 cell count was below 350 cells/μl, so we do not have any follow-up time to approximate what happens to patients in the time their CD4 cell count is between 200 and 350 cells/μl; however, we anticipate some deaths and LTFU occur in this time. Although methods exist to adjust for this lead-time bias , they require pre-ART data, which we did not have.
The current analysis has several strengths. The data were from a large prospective randomized trial with excellent follow-up data at standardized intervals, which allowed the assessment of the impact of starting treatment at higher CD4 cell counts. Although the data were from a randomized trial of another intervention, because the trial showed no differences between randomization groups (i.e. nurse vs. doctor-monitored care) and because adjustment for randomization group had no impact on our current results, there is little evidence that the primary intervention had any impact on our findings.
Still, the current analysis should be considered in light of several limitations. First, as noted above, we did not have the ideal comparison group to assess death and virologic failure (i.e. a group followed from a CD4 cell count of 350 cells/μl until 200 cells/μl and then initiated on ART). Thus, any deaths occurring between 350 and 200 cells/μl would not be included in our analysis. As we are missing deaths in the high CD4 cell count group, this analysis may underestimate the treatment benefits of starting at higher CD4 cell counts. Thus, our estimates cannot be considered the true causal effect of starting treatment at higher CD4 cell counts. Second, as the data came from a randomized trial with conservative definitions of toxicity, many patients who were treatment failures for toxicity might have otherwise continued on treatment under usual practice conditions. This could have biased our toxicity results toward the null and prevented us from observing a true difference between the groups if one existed. Third, in our analysis of LTFU, we were not able to determine the final outcomes of patients lost and, therefore, we cannot say whether patients left care because they were feeling well nor could we determine how many of them have since died. Finally, as the data were from a trial, the study population may have been healthier than the general clinic population.
We found that patients initiated on standard first-line South African ART regimens were at increased risk of death and virologic failure if initiated at CD4 cell counts below 200 cells/μl compared with those initiated above 200 cells/μl. This is consistent with findings from developed areas that have shown that the benefits of starting at earlier CD4 cell counts outweigh the risks of toxicity and long-term adherence. Although the cost implications are unknown, national and international guidelines on the topic of when to initiate ART should consider our findings when deciding on whether to increase initiating CD4 cell count thresholds. If thresholds are increased, then substantial efforts will need to be made to move patients into care earlier in their disease progression in order to obtain the maximum benefit from ART.
Support for this study was provided by the US National Institute of Allergy and Infectious Diseases (NIAID) through the CIPRA network, grant #U19 AI53217. The project described was also supported by K01AI083097 and P30-AI50410 from the NIAID and 5U2RTW007373-03 from the Fogarty International Center and was also provided by the United States Agency for International Development (USAID) under the terms of agreement 674-A-00-08-00007-00 with Right to Care (RTC). The content of this publication does not necessarily reflect the views or policies of NIAID, the Fogarty Center, USAID or RTC nor does mention of trade names, commercial projects or organizations imply endorsement by the US Government. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID, the Fogarty Center, the National Institutes of Health, USAID or other parties.
M.F. performed the primary statistical analyses and drafted the manuscript. I.S., F.C. J.Z., C.O. R.I. M.R. M.D. C.v.d.H. J.M. and R.W. contributed to the design of the study and data interpretation and revising the article. All authors approved the final manuscript.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
CD4 cell count; highly active antiretroviral therapy; HIV; mortality; Sub-Saharan Africa; tuberculosis; virologic failure