In a prospective, randomized controlled trial, we found that triple nucleoside ART does not accelerate microbiologic, clinical or radiographic improvement during TB therapy in HIV/TB patients with high CD4 counts. We found a high proportion of patients with persistent AFB in sputum smear late in TB therapy despite sputum culture conversion; a finding associated with cavitation and pleural thickening on baseline chest x-ray but not ART use. Smear positive, culture negative status at month 5 was not associated with TB treatment failure or recurrence.
Few studies have evaluated the impact of ART on TB treatment response among co-infected patients with high CD4 counts. Given the central role of T cells in containing TB infection and developing TB-specific immunity [4
], we hypothesized that ART-induced immune maintenance and recovery would accelerate the clinical, radiographic and microbiologic responses to TB treatment. As new guidelines recommend ART in all TB/HIV patients, the role of ART in TB treatment response in patients with high CD4 counts is particularly relevant [1
Comparisons by HIV status in the pre-ART era suggested that HIV does not affect the likelihood of responding to TB treatment [5
], but were limited by the competing risk of non-TB death at low CD4 counts. In one post-ART era study, ART was associated with more rapid culture and smear conversion [7
], although this observational study may have been subject to selection bias and residual confounding on factors associated with ART use. Our randomized, controlled trial found no impact of ART on TB treatment response. Explanations of our findings include the possibility that the efficacy and speed of response to TB therapy are not dependent upon T cell-mediated immunity. Alternatively, ART-induced T cell recovery with subsequent TB-specific immunity may take longer than 6 months to develop. It is possible that ART containing non-nucleoside reverse transcriptase inhibitors or protease inhibitors (regimens that are more virologically potent than triple nucleoside ART [8
]) might accelerate response to TB therapy, though this seems unlikely given the high rates of virologic suppression achieved in the intervention arm. Though we found no benefit to ART in terms of TB treatment outcomes at high CD4 counts, multiple advantages to early ART initiation have been found including decreased TB incidence with CD4 cell recovery to >500 [9
] and reduced all-cause mortality [10
AFB smear positivity late in TB therapy occurred commonly in our study, despite TB culture clearance in all study participants and high rates of TB cure. TB/HIV patients with high CD4 counts tend to have a higher pulmonary bacillary load at diagnosis than patients with low CD4 counts (<350) [11
] and may be at higher risk for this phenomenon. Smear positivity with negative culture late in therapy is well-described in HIV-uninfected patients and has been attributed to the persistence of non-viable MTB, or to colonization with non-tuberculous mycobacteria (NTM) [12
]. Patients in this study were not colonized with NTM suggesting persistence of non-viable MTB. Similar to studies of HIV-uninfected TB, we found persistent smear positivity to be associated with cavitary disease, likely reflecting slow clearance of MTB bacilli from the airway due to a high baseline bacillary burden [13
]. Pleural thickening was also associated with late smear positivity, possibly due to greater parenchymal involvement in disease extending to the pleura.
In settings lacking MTB culture, WHO guidelines recommend classifying patients with positive AFB smears during the fifth month of TB therapy as treatment failures [2
]. Our results suggest that in settings where smear alone is used for follow-up during TB treatment, or where PCR-based testing may supplant culture during follow-up, there is significant potential for misclassification of patients as treatment failures despite a high likelihood of future cure. Patients in this study received a standard 6 month course of TB therapy guided by negative cultures. TB therapy was not extended even in patients with positive smears. There was no evidence of excess treatment failure or recurrence in these subjects who had close follow-up although our study was underpowered to detect small differences in the groups. Further studies are needed to determine how to utilize current TB diagnostics to monitor treatment response in settings with limited access to TB culture.