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Randomized Controlled Trial
. 2010 Mar 13;24(5):675-85.
doi: 10.1097/QAD.0b013e3283350f1b.

Prevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine

Charles F von Reyn  1 , Lillian Mtei, Robert D Arbeit, Richard Waddell, Bernard Cole, Todd Mackenzie, Mecky Matee, Muhammad Bakari, Susan Tvaroha, Lisa V Adams, Charles R Horsburgh, Kisali Pallangyo; DarDar Study Group
Collaborators, Affiliations
Randomized Controlled Trial

Prevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine

Charles F von Reyn et al. AIDS. .

Abstract

Objective: To determine whether a multiple-dose series of an inactivated whole cell mycobacterial vaccine, Mycobacterium vaccae, can prevent HIV-associated tuberculosis.

Design and methods: The DarDar trial was a randomized, placebo-controlled, double-blind trial. The study was carried in an outpatient facility in Dar es Salaam, Tanzania. HIV-infected patients with CD4 cell counts of at least 200 cells/microl and a Bacille Calmette-Guérin scar were chosen for the study. The intervention was carried out by random 1:1 assignment to five intradermal doses of M. vaccae or placebo. Tuberculin skin tests were performed, and patients with reactions of at least 5 mm were administered isoniazid for 6 months. The main outcome measures were disseminated (primary endpoint), definite, and probable tuberculosis (secondary endpoints).

Results: Two thousand thirteen individuals were randomized (1006 to M. vaccae, 1007 to placebo) and followed every 3 months for a median of 3.3 years. The trial was terminated early because of slow accrual of cases of disseminated tuberculosis and significant protection against definite tuberculosis. Hazard ratios were disseminated tuberculosis 0.52 (95% confidence interval 0.21-1.34; seven cases in M. vaccae, 13 cases in placebo; log-rank P = 0.16), definite tuberculosis 0.61 (95% confidence interval 0.39-0.96; 33 cases in M. vaccae, 52 cases in placebo; P = 0.03), and probable tuberculosis 1.17 (95% confidence interval 0.76-1.80; 48 cases in M. vaccae, 40 cases in placebo; P = 0.46). Immunization was well tolerated, with no adverse effect on CD4 cell count or HIV viral load, and no increase in the rate of serious adverse events.

Conclusion: Administration of a multiple-dose series of M. vaccae to HIV-infected adults with childhood Bacille Calmette-Guérin immunization is safe and is associated with significant protection against definite tuberculosis. These results provide evidence that immunization with a whole cell mycobacterial vaccine is a viable strategy for the prevention of HIV-associated tuberculosis.

Trial registration: ClinicalTrials.gov NCT00052195.

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Conflict of interest statement

There are no conflicts of interest reported. Dr Vuola is now with GlaxoSmithKline, Europe.

Figures

Fig. 1.
Fig. 1.. Consort diagram.
BCG, Bacille Calmette–Guérin; MV, Mycobacterium vaccae; TB, tuberculosis.
Fig. 2.
Fig. 2.. Tuberculosis study endpoints (Kaplan–Meier, intention-to-treat).
(a) Disseminated TB. (b) Definite TB. ITT, intention-to-treat; M. vaccae, Mycobacterium vaccae; TB, tuberculosis.
See this image and copyright information in PMC

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