Drugs and regimens for preventive therapy against tuberculosis, disseminated Mycobacterium avium complex infection and leprosy

International Journal of Leprosy and Other Mycobacterial Diseases, Dec 1999 by Ji, Baohong, Grosset, Jacques H

Preventive therapy, or chemoprophylaxis, refers to the administration of effective drugs to an individual with confirmed or suspected latent, or subclinical, infection, aiming to prevent development of overt disease. In theory, when a large number of people with latent infection exist in the community, massive application of chemoprophylaxis would lead to a rapid decline of the occurrence of the disease. However, a number of operational and technical constraints have limited its application in the control of infectious diseases; with the exception of yaws, experience with mass chemoprophylaxis for disease control has not been encouraging (43). On the other hand, significant progress has been made during the last decade in identifying effective drugs for chemoprophylaxis against infection with Mycobacterium tuberculosis and M. avium complex (MAC), and research on chemoprophylaxis against M. leprae would benefit from what has been learned with regard to chemoprophylaxis against these two infections.

In choosing an appropriate regimen for chemoprophylaxis, one should consider not only efficacy, but also a number of other elements, including tolerability, cost and the potential of drug-drug interaction. Unfortunately, a highly effective, nontoxic, lowcost and easily applicable drug for the prevention of any of the following three diseases has yet to be identified.

TUBERCULOSIS

Chemoprophylaxis with isoniazid (INH)

Experiments have clearly demonstrated that administration of INH was capable of preventing tuberculosis in guinea pigs, whether chemoprophylaxis was administered daily or every few days, as long as drug administration lasted between six and 12 months (10,45). Administration for less than six months was associated with a high relapse rate, whereas administration for longer than one year conferred no additional benefit. Subsequently, a large number of randomized, placebo-controlled, clinical trials, involving more than 100,000 participants at risk of tuberculosis, confirmed the protective effect of INH observed in guinea pigs (13,19). The effectiveness of chemoprophylaxis, in terms of reduction of the incidence of tuberculosis among those administered INH compared with that among those administered placebo, varied from 25 to 92 percent. The optimal duration of therapy was six to 12 months; administration for longer than 12 months was not associated with increased protection.

INH chemoprophylaxis is recommended by the American Thoracic Society and the U. S. Centers for Disease Control and Prevention (1) for all tuberculin-positive individuals at high risk, especially those infected with HIV and children who are close contacts of tuberculosis patients, and for some tuberculin-negative individuals, such as children who are close contacts of infectious cases and HIV-infected persons. INH is administered daily to both adults and children in a dosage of 5 mg per kg body weight, to a maximum of 300 mg. When supervised therapy is required, INH may be administered twice weekly in a dosage of 15 mg per kg, to a maximum of 900 mg. The duration of treatment is at least six months, and 12 months are required for those infected with HIV.

However, INH chemoprophylaxis is not strikingly effective, confer-ring no more than 70 percent protection (2, 10). In addition, it is difficult for people who are otherwise healthy and asymptomatic to take medication for six to 12 months to prevent an illness that may not occur in the absence of chemoprophylaxis, and is readily treatable should it occur. Consequently, noncompliance with ITSTH chemoprophylaxis is common, substantially reducing its efficacy (55). In addition, it is known that, in the course of chemoprophylaxis, INH causes toxic hepatitis in approximately 1 percent (35) , and death in fewer than 0.1 percent (31, 51) of those to whom it is administered. As a result, healthy asymptomatic people may be unwilling to accept this risk (2,55). Finally, INH is inactive against INH-resistant strains of M. tuberculosis, which are common in both developed and developing countries. Therefore, an alternative regimen of shorter duration, employing safe and more effective drugs, is needed.

"Short-course" chemoprophylaxis with rifamycins

Rifampin. Rifampin (RMP) is far more bactericidal than is M. In mice harboring small and stable populations of M. tuberculosis (8,28, 36), a situation that mimics the bacterial population of latent M. tuberculosis infection of man, we demonstrated that the administration of RMP plus pyrazinamide (PZA) for two months, or RMP alone for three months was more effective than INH alone for six months. These results suggested that the use of RMP in the chemoprophylaxis of tuberculosis may permit dramatic shortening of the duration of treatment (8, 28,36). An increasing number of clinical studies have confirmed that RMP, alone or in combination with other drugs, may be effective in chemoprophylaxis. A trial among patients with silicosis revealed RMP administered alone for 12 weeks conferred at least the same level of protection as INH administered alone for 24 weeks, and that RMP monotherapy was less hepatotoxic than INH-containing regimens (22). In another trial, 157 adolescents probably infected with strains of M. tuberculosis resistant to INH were administered chemoprophylaxis with RMP in a daily dosage of 10 mg per kg for 12 weeks (17); none of the adolescents developed tuberculosis, and the protective efficacy was calculated to be at least 56 percent. A study in Uganda demonstrated that daily administration of RMP-- INH or RMP-INH-PZA for three months conferred significant protection compared with placebo treatment, although neither regimen was superior to INH (58).