Key Tuberculosis (TB) Drug Isoniazid Fails to Protect Infants of HIV Positive Mothers from TB Acquisition or Death

Isoniazid Tablet

Interim results from a Phase 2/3 clinical trial indicate that the anti-tuberculosis drug isoniazid is safe but ineffective in preventing tuberculosis (TB) or death in infants who had no history of TB exposure or disease at the time of enrollment and were either HIV-infected or HIV-exposed but uninfected.

An independent data and safety monitoring board (DSMB) for the trial, which was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, reached this conclusion after examining interim data from a large clinical trial in southern Africa. Consequently, the DSMB recommended that the infants in the study stop taking isoniazid or placebo, and that no additional participants be enrolled in the trial; NIAID concurred with these recommendations.

The investigators will continue to follow the enrolled infants at least through each baby's next scheduled visit, but have not yet decided whether to continue follow-up beyond that point. The parents and legal guardians of the infants are being informed of these developments as rapidly as possible.

The Phase 2/3 efficacy trial began in December 2004. The goal was to determine whether a 96-week course of isoniazid -- a key drug used to treat TB and to prevent TB disease in adults with documented TB exposure -- could protect infants born to HIV positive mothers from getting TB or dying.

The trial was conducted at 3 locations in South Africa and 1 in Botswana, where the incidence of TB and HIV are extremely high, according to UNAIDS and the World Health Organization (WHO). TB-HIV coinfection is the leading cause of HIV-related deaths in Africa, and public health experts are increasingly integrating the treatment and prevention of these diseases.

The study enrolled babies who had no history of TB exposure or disease and were either infected with HIV or exposed to the virus but uninfected. The more than 1350 infants enrolled were assigned at random to receive either isoniazid or placebo daily for 96 weeks beginning at 3 to 4 months of age and continuing at least 90 days after receiving Bacille Calmette-Guerin (BCG) vaccination, the standard TB vaccine. The study investigators do not yet know which infants received isoniazid or placebo.

As prophylaxis against Pneumocystis pneumonia, all HIV-infected infants also received cotrimoxazole (TMP-SMX) for at least 6 months. The infants had physical exams and blood drawn at the start of the study and every 12 to 24 weeks thereafter. These exams were originally scheduled to continue for more than 3.5 years.

During a regularly scheduled interim review of study data on June 26, the DSMB found no significant difference in the rates of TB or death in the infants who received isoniazid compared with those who received placebo. The DSMB also found no evidence of clinically significant differences in safety or adverse events between the 2 groups. These findings led the DSMB to conclude that it would be futile to continue the study as originally designed.

Isoniazid remains a mainstay for preventing TB in adults, TB-exposed infants and children, and other populations, even though it was ineffective at preventing TB or death in the infants in this trial. The medication also remains an essential ingredient of a multi-drug TB treatment regimen.

7/18/08

Source
NIAID/NIH. Anti-TB Drug Fails to Benefit HIV-exposed Infants Who Were Unexposed to TB at Study Enrollment. News Release. July 10, 2008.