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Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial

https://doi.org/10.1016/S1473-3099(14)70733-9Get rights and content

Summary

Background

WHO guidelines recommend early initiation of antiretroviral therapy (ART) irrespective of CD4 cell count for all patients with tuberculosis who also have HIV, but evidence supporting this approach is poor quality. We assessed the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV-positive patients with CD4 counts of 220 cells per μL or more.

Methods

We did this randomised, placebo-controlled trial between Jan 1, 2008, and April 31, 2013 at 26 treatment centres in South Africa, Tanzania, Uganda, and Zambia. We enrolled HIV-positive patients with culture-confirmed tuberculosis who had tolerated 2 weeks of tuberculosis short course chemotherapy. Participants were randomly allocated (1:1) to early ART (starting after 2 weeks of tuberculosis treatment) or delayed ART (placebo, then starting ART at the end of 6 months of tuberculosis treatment). Randomisation was computer generated, with permuted blocks of size eight, and stratified by CD4 count (220–349 cells per μL vs ≥350 cells per μL). Patients and investigators were masked to treatment allocation until completion of 6-months' tuberculosis treatment, after which the study was open label. The primary endpoint was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment in the modified intention-to-treat population. Secondary endpoints included mortality. The study is registered with controlled-trials.com (ISRCTN77861053).

Findings

We screened 13 588 patients and enrolled 1675: 834 assigned early ART, 841 delayed ART. The primary endpoint was reached by 65 (8·5%) of 767 patients in the early ART group versus 71 (9·2%) of 771 in the delayed ART group (relative risk [RR] 0·91, 95% CI 0·64–1·30; p=0·9). Of patients with a CD4 cell count of 220–349 cells per μL, 26 (7·9%) of 331 patients versus 33 (9·6%) of 342 reached the primary endpoint (RR 0·80, 95% CI 0·46–1·39; p=0·6). For those with 350 cells per μL or more, 39 (8·9%) of 436 versus 38 (8·9%) of 429 reached the primary endpoint (RR 1·01, 95% CI 0·63–1·62; p=0·4). Mortality did not differ significantly between treatment groups (RR 1·4, 95% CI 0·8–2·3; p=0·23). Grade 3 and 4 adverse events occurred in 149 (18%) of 834 patients assigned early ART versus 174 (21%) of 841 assigned delayed ART (p=0·37). 87 (10%) of 834 versus 84 (10%) of 841 had immune reconstitution inflammatory syndrome (p=0·56).

Interpretation

ART can be delayed until after completion of 6 months of tuberculosis treatment for HIV-positive patients with tuberculosis who have CD4 cell counts greater than 220 cells per μL. WHO guidelines should be updated accordingly.

Funding

USAID, Zambia Ministry of Health, Tanzania Commission for Science and Technology, WHO-TDR.

Introduction

In 2012, 8·6 million incident cases of tuberculosis occurred, of which 1·1 million (13%) were in people with HIV.1 1·3 million patients with tuberculosis died, 320 000 of whom were also HIV-positive.1 Worldwide, 57% of patients with tuberculosis and HIV started antiretroviral therapy (ART) in 2008.2 The introduction and scale-up of ART has significantly improved the management and outcome of HIV infection for people who have access to ART.2, 3 However, the treatment of HIV-positive people with newly diagnosed tuberculosis is complicated by toxic effects and pharmacokinetic interactions of tuberculosis treatments and ART.4, 5 Up to 15% of co-infected patients who are receiving treatment for tuberculosis develop immune reconstitution inflammatory syndrome on starting ART.6, 7

Delaying ART until tuberculosis treatment is completed for people with HIV and active tuberculosis is associated with increased mortality across the range of immunodeficiency.8, 9, 10, 11 Although WHO recommends12 that patients should start ART as soon as possible within 8 weeks of starting tuberculosis treatment (and that those with CD4 counts <50 cells per μL should receive ART within the first 2 weeks) the same guidelines note the low-quality of evidence about the best timing of ART initiation for HIV-positive patients with tuberculosis who have CD4 counts of greater than 350 cells per μL. We did this study (TB-HAART) to assess the effect of early versus delayed initiation of ART on tuberculosis treatment outcomes for HIV-positive people with CD4 counts of at least 220 cells per μL with newly diagnosed, smear positive, culture-confirmed tuberculosis.

Section snippets

Study design and participants

This study was a randomised, placebo-controlled trial done between Jan 1, 2008, and Apr 31, 2013, at 26 HIV and tuberculosis treatment centres in South Africa (seven sites), Tanzania (six sites), Uganda (five sites), and Zambia (eight sites).

Participants had to be at least 18 years of age, HIV-positive, smear-positive and culture-positive for tuberculosis, with CD4 counts of 220 cells per μL or more, and no previous tuberculosis treatment in the preceding 2 years. Patients were excluded if they

Results

We screened 13 588 patients, of whom 11 913 were excluded. We enrolled 1675 patients in the study and data for 1538 (767 early ART, 771 late ART) were available for the primary analysis (figure 1).

Baseline characteristics were much the same in each group (table 1). 616 (40%) of 1538 patients were women and 922 (60%) were men. Median age was 32 years (IQR 27–38), median body-mass index was 19·1 kg/m2 (17·6–21·1), and baseline median CD4 count was 367 cells per μL (289–456). 674 (44%) of 1538

Discussion

Initiation of ART within 2 weeks of starting tuberculosis treatment for patients with CD4 cell counts more than 220 cells per μL does not confer any advantage on the composite outcomes of tuberculosis treatment failure, tuberculosis recurrence, and death over a 24 month follow-up period, compared with delayed ART initiation.

To date, six open-label, randomised trials of ART for patients co-infected with HIV and tuberculosis have been published, five were of patients with pulmonary tuberculosis

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