In this analysis, we calculated TB incidence rates stratified by serially updated CD4 cell counts during ART and compared TB rates during early and long-term treatment. Several key findings emerged. Among patients with CD4 cell counts less than 200 cells/µl, there was a 1.7-fold excess adjusted TB rate during early ART compared with rates during long-term treatment (P = 0.026). During long-term ART, a very strong independent association between TB rates and updated CD4 cell counts was observed. At CD4 cell counts of 200–500 cells/µl, TB incidence rates remained high but were significantly lower at CD4 cell counts exceeding a threshold of 500 cells/µl. However, despite excellent immune recovery, patients spent a large majority of time at CD4 cell counts less than 500 cells/µl and overall TB rates in the cohort were, therefore, high. These data substantially extend the findings of previous studies [7
], providing important insights that will assist in the development of approaches to address the challenge of HIV-associated TB.
We suggest that the excess TB rates during early ART among those with CD4 cell counts less than 200 cells/µl may be due to ART-induced ‘unmasking’ of subclinical TB that was present but unrecognized at baseline [20
]. In patients who develop ‘unmasking’ TB, rapid immune recovery is thought to trigger host inflammatory responses and development of symptomatic disease [20
]. Although some overt cases of ‘unmasking TB’ have been described [19
], this phenomenon lacks a clear clinical case definition [27
] and has not previously been quantified.
Several lines of indirect evidence support our hypothesis. First, high rates of subclinical, culture-proven TB have been detected in patients enrolling for ART in this [32
] and in other HIV cohorts in Africa [33
]. Immune recovery in the first 4 months of ART in this cohort is very rapid, even in those with low baseline CD4 cell counts [37
]. In keeping with ‘unmasking’ TB, excess rates were restricted to those with baseline CD4 cell counts less than 200 cells/µl and were confined to early ART [19
]. Further corroboration is derived from a study of Ugandan children in whom a more than two-fold increase in TB rates during the initial months of ART was attributed to ‘unmasking’ TB [38
These data suggest that ‘unmasking’ TB may account for over one-third of TB cases presenting during the initial months of ART in this setting. CIs around this estimate are wide, however, and confirmatory studies are required. Pre-ART investigations for TB were routinely done only in those with suggestive symptoms or clinical signs. These data suggest the potential need for routine microbiological screening for TB at baseline in all patients starting ART in this setting and this approach is supported by the findings of a more recent study in this cohort [32
Although we have previously found that CD4 cell counts were strongly associated with TB incidence rates during ART [9
], the present study used a novel analytic approach to derive CD4 cell-stratified TB rates, yielding important new insights. A steep risk gradient was observed between the highest and lowest CD4 cell strata with a more than 9-fold difference in adjusted rates. We have used a similar analytic approach to examine changing mortality risk in this cohort [39
]. Whereas mortality risk was found to be largely minimized by the attainment of an updated CD4 cell count of more than 200 cells/µl, the present study shows that a threshold of more than 500 cells/µl has to be exceeded to minimize TB rates. Thus, eligibility criteria for ART initiation that aim to minimize mortality risk are not optimal for TB prevention.
Immune recovery in this cohort compared very favourably with that observed in ART cohorts in high-income countries [40
]. Approximately half of the patients achieved a CD4 cell count more than 500 cells/µl after 4 years of ART () and in these patients, TB rates (1.5 cases/100 person-years) remained approximately only two-fold higher than the rate among HIV-seronegative adults in a comparable neighbouring community (0.7 cases/100 person-years) [41
]. However, despite excellent immune recovery, the large majority of person-time in this cohort accrued at CD4 cell counts less than 500 cells/µl, with TB rates ranging between 4.2 and 16.8 cases/100 person-years. As a result, the overall TB incidence rate in the cohort was high (7.3 cases/100 person-years), approximately 10-fold higher than the rate in HIV-seronegative adults in these communities [41
Although this analysis only examined incident TB from the time of ART initiation, other factors occurring just prior to this may have influenced the findings. Many patients enrolling in this cohort had recently completed TB treatment, potentially conferring a relative protection against further TB episodes [9
]. Although all person-time accrued during TB treatment was excluded from the analysis, a similar protective effect may also have been present during the period following TB treatment in the many patients with TB diagnoses at baseline. These effects may have reduced the unadjusted TB incidence rates among those with the lowest baseline CD4 cell counts.
In multivariate analysis, baseline CD4 cell counts did not have any predictive value for TB risk over and above that provided by the current CD4 cell count at any given time-point. This does not support the hypothesis that lower baseline CD4 cell counts are associated with increased risk of clinically significant persisting defects in TB-specific immune function during long-term ART [17
]. Importantly, however, patients with low baseline CD4 cell counts accrued much greater person-time within low CD4 cell strata, thereby remaining at high TB risk for longer periods. Thus, whereas current CD4 cell counts are the key predictor of instantaneous TB risk, baseline CD4 cell counts are key predictors of cumulative long-term risk of TB during ART as was similarly found for mortality [39
Data from this study provide insight into the strategies needed to reduce the long-term burden of incident TB. Most fundamentally, the time that patients spend at low CD4 cell counts less than 500 cells/µl needs to be minimized. This requires both earlier HIV diagnosis and initiation of ART at higher CD4 cell counts. Unfortunately, the current South African national ART policy restricts eligibility to those with AIDS or a CD4 cell count of less than 200 cells/µl and therefore greatly undermines the potential benefits of ART for TB prevention. A change in this policy is needed to reduce both high mortality rates [39
] and to improve TB control.
Adjunctive TB prevention strategies such as the WHO ‘3Is policy’ [18
] are also needed to reduce TB in ART services. Within this policy, intensified case finding (ICF) might be done not only at baseline but also serially (e.g. 6-monthly) during at least the first year of ART when TB rates are highest. This approach might particularly target those with persistently low CD4 cell counts. Use of IPT concurrently with ART is likely to reduce long-term TB rates [42
] but data from randomized controlled trials are awaited [43
]. However, initiation of IPT at the same time as ART may be problematic because high rates of subclinical active TB at baseline and ‘unmasking’ TB during the first 4 months of ART may inadvertently lead to many patients with active TB receiving isoniazid monotherapy. In light of our findings, a logical approach might be to consider initiating IPT after completion of the first few months of ART.
Strengths of this study include good patient retention and ascertainment of outcomes, frequent monitoring of CD4 cell counts and the novel analytic approach. Some person-time may have been misclassified as CD4 cell counts continuously change over time. Some TB disease may have remained unascertained among those who died, leading to underestimation of TB rates particularly in those with the lowest CD4 cell counts. Not all TB cases were proven by culture of Mycobacterium tuberculosis, although the rates and proportions of pulmonary and extrapulmonary disease reported are entirely consistent with other data from this setting [6
]. The multiple lines of evidence for ‘unmasking’ TB during early ART are indirect and yet provide a coherent and biologically plausible explanation.
Baseline characteristics of the patients were typical of patients in ART roll-out programmes across Africa, but rates of loss to follow-up were comparatively low [44
]. Such losses are not related to degree of immunodeficiency in this cohort [25
] and so we do not suspect they affected the TB rates observed. The countries of southern Africa are the areas of the world hit hardest by the TB and HIV epidemics and the absolute TB rates recorded are likely to be higher than those in other regions. Nevertheless, the key relationship between TB risk and updated CD4 cell counts is likely to be applicable in other settings.
In conclusion, low baseline CD4 cell counts and ‘unmasking’ of subclinical TB are likely to explain the high burden of TB during the first 4 months of ART. This may potentially be reduced by initiation of ART at higher baseline CD4 cell counts and more effective screening for TB at baseline. The high long-term TB incidence is strongly associated with the proportion of person-time at CD4 cell counts less than 500 cells/µl and adjunctive TB prevention interventions are undoubtedly needed. However, the impact of ART on TB prevention in low-resource settings would be greatly improved by ART policies that minimize the time patients spend with CD4 cell counts less than 500 cells/µl.