What Is Thwarting Tuberculosis Prevention in High-Burden Settings?

Abstract

July 6, 2011 — Two studies published in this week's New England Journal of Medicine assess the efficacy of various drug regimens to prevent tuberculosis (TB) in HIV-infected patients. The results from the studies, both of which were carried out in Africa, highlight the need for more effective strategies. HIV has emerged as one of the primary factors fueling rising TB rates in many parts of the world, especially developing nations. That reality has prompted the World Health Organization to recommend administering isoniazid prophylaxis in coinfected adults and children. However, in a study published in the July 7 issue of the New England Journal of Medicine, Shabir Madhi, MD, PhD, from the Respiratory and Meningeal Pathogens Research Unit of University of the Witwatersrand in Johannesburg, South Africa, and colleagues report a surprising lack of efficacy using continuous isoniazid as primary prevention in very young children of HIV-positive mothers, regardless of the child's HIV status. Dr. Madhi's group randomly assigned a total of 1352 children from sub-Saharan Africa to receive isoniazid (10 - 20 mg/kg body weight/day) or placebo for 90 days. The authors said 548 of the children were infected with HIV; 804 were not. Treatment was initiated at 3 to 4 months of age and continued for 96 weeks. Each of the patients received bacille Calmette-Guérin vaccine during the first month of life, and nearly 99% of the children who were infected with HIV were treated with antiretroviral therapy. Among HIV-infected children, the rate of protocol-defined TB or death was nearly the same: 19.0% in the isoniazid-treated group and 19.3% in the group who received placebo (P = .93). In children not infected with HIV, there was no significant difference between the isoniazid group and the placebo group, with the TB infection rate being between 10% and 11% (P = .44). There were 121 cases of TB per 1000 child-years in children who were HIV-infected compared with 41 per 1000 child-years in children without HIV. The authors said none of the groups demonstrated significant differences in toxicities of the various treatments. They concluded: "Primary isoniazid prophylaxis did not improve [TB]-disease-free survival among HIV-infected children or [TB]-infection-free survival among HIV-uninfected children immunized with [bacille Calmette-Guérin] vaccine. Despite access to antiretroviral therapy, the burden of [TB] remained high among HIV-infected children." Another study, also published in the July 7 issue of the New England Journal of Medicine and focusing on adults, evaluated the efficacy of 3 new regimens for latent TB that some earlier research has shown may be more potent and long-lasting than standard isoniazid therapy. However, that study concluded that short-course, rifamycin-based prophylaxis had similar, but not superior, efficacy to 6-month therapy with isoniazid in tuberculin-positive adults with HIV. Neil Martinson, MB, BCh, MPH, from the Johns Hopkins University Center for Tuberculosis Research in Baltimore, Maryland, and colleagues evaluated results in more than 1100 adult patients from South Africa (median age, 30 years), using 3 different drug regimens: rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, and isoniazid (300 mg) daily for up to 6 years. A control group received isoniazid (300 mg) daily for 6 months. The authors said the incident rate of TB or death was 3.1 per 100 per-years in the rifapentine-isoniazid group, 2.9 per 100 person-years in the rifampin-isoniazid group, and 2.7 per 100 person-years in patients taking isoniazid daily for 6 years. The rate for the control group was 3.6 per 100 person-years. None of the comparisons between groups were statistically significant. More serious adverse reactions were seen in patients receiving long-term daily treatment with isoniazid (18.4/100 person years) than in any of the other groups (8.7 - 15.4/100 person-years). About 3.4% of the isolates of Mycobacterium tuberculosis were found to be multidrug resistant. The authors concluded that although all the secondary prophylactic regimens were effective, "[n]either a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid." However, they stressed that more widespread use of preventive therapy, regardless of the regimen chosen, is crucial in helping control the epidemic of HIV-related TB. Ongoing Transmission and Reinfection May Explain Limited Efficacy An editorial coauthored by Edward Nardell, MD, from the Division of Global Health Equity, Brigham and Women's Hospital and Harvard Medical School, both in Boston, Massachusetts, and Gavin Churchyard, MD, PhD, from the Aurum Institute for Health Research, Johannesburg, South Africa, and the London School of Hygiene and Tropical Medicine in the United Kingdom, accompanies the 2 studies. In the editorial, the authors highlight the reasons that prevention efforts in high-burden settings are difficult. "There are probably several factors," they write, "but a fundamental one, not fully appreciated, is ongoing transmission and reinfection." They point out that even though reinfection can be assumed to have occurred in patients after continuous isoniazid therapy has terminated, confirming reinfection is hard because genotyping of both initial and subsequent tuberculin isolates is rarely possible. "Despite immunizations at birth, by early adulthood most young adults in high-risk settings have been exposed to [TB] and infected," the editorialists note. They add that epidemiologic evidence indicates that reinfection probably routinely occurs in these settings, even in populations that are HIV-negative. Previous research has suggested that reinfection may function as an essential pathogenic mechanism in populations that have developed partial immunity from either prior vaccination or being infected with TB early in life, they say. "If that is true," the editorialists continue, "the long-term benefits of chemoprophylaxis are likely to be limited, and if natural infection is not protective, the development of a more effective vaccine will be challenging." They conclude: "Unless the force of transmission can be reduced by intensified case finding and the use of new rapid diagnostics, resulting in more effective treatment, durable benefits from prevention strategies, either chemoprophylaxis or immunization, are likely to be elusive." The study by Dr. Martinson and colleagues was supported by grants from the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the US Agency for International Development. Dr. Martinson reports receiving lecture fees from Alere. The other authors have disclosed no relevant financial relationships. Overall support for the study by Dr. Madhi and colleagues was provided by grants from the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health. This work was supported by the Statistical and Data Analysis Center at the Harvard School of Public Health, under a National Institute of Allergy and Infectious Diseases cooperative agreements with the Pediatric AIDS Clinical Trials Group and the International Maternal Pediatric Adolescent AIDS Clinical Trials Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development International and Domestic Pediatric and Maternal HIV Clinical Trials Network. The study was also supported by a grant from the Secure the Future Fund, a philanthropy program sponsored by Bristol-Myers Squibb. Several authors of the article by Dr. Madhi and colleagues report financial relationships with the following companies: Abbott, BMS, GSK, MedImmune, Novartis, Pfizer, and Tibotec. Dr. Churchyard reports receiving institutional grants from the Bill and Melinda Gates Foundation, as well as Sanofi Aventis, for a study on a related topic. Dr. Nardell has disclosed no relevant financial relationships. N Engl J Med. 2011;365:11-20, 21-31, 79-81.