HIV-infected persons are estimated to be 100 times as likely as uninfected persons to have tuberculosis (TB). This is mainly due to reactivation of a latent infection with Mycobacterium tuberculosis. Reactivation of TB occurs in about 7% to 10% of persons who have positive tuberculin skin tests every year. Isoniazid (INH) at 300 mg/day is recommended for HIV-positive persons with positive TB test results. However, a recent study in Nairobi among 684 HIV-positive persons with positive skin tests did not show a difference between INH and placebo in prevention of TB reactivation (MP Hawken et al. AIDS. June 1997; 11(7):875-82).
Unfortunately, the TB skin test or PPD (purified protein derivative) has low sensitivity in persons infected with HIV. This is because of the high rate of anergy -- the inability to respond to tuberculin antigens due to defective delayed type hypersensitivity (DTH), an expression of cell-mediated immunity. In 1991, the CDC recommended that preventive treatment with INH be considered for high-risk HIV-positive individuals who are anergic. High-risk individuals include those who belong to groups in which the prevalence of TB is equal to, or greater than, 10%. This guideline was based on several observational studies suggesting that HIV-positive anergic homeless persons and injection drug users had increased risk of tuberculosis, similar to those with positive PPD skin tests (PA Selwyn et al. JAMA. July 22, 1992; 268(4):504-9).
In an effort to determine whether INH is effective in preventing TB, the Community Programs for Clinical Research on AIDS (CPCRA) of the National Institute of Allergy and Infectious Diseases (NIAID) conducted a randomized placebo-controlled trial to assess the effectiveness of six months of INH prophylaxis (300 mg/day) in HIV-positive patients with anergy. Trial results were recently published in The New England Journal of Medicine (F Gordin et al. July 31, 1997; 337(5):315-20). The study was conducted at 11 sites, six in the greater New York area. All patients received a PPD skin test and two anergy skin tests (mumps and tetanus toxoid) and were randomly assigned to receive INH or placebo for six months. The primary endpoint was active tuberculosis confirmed by culture from any site. Secondary endpoints were probable tuberculosis, clinical progression of HIV disease and death.
Five hundred and seventeen patients were enrolled from November 1991 and followed through June 1996. The majority of the patients were black (47%) or Latino (33%) and 32% were women. Fifty-eight percent had a previous history of injecting drug use. The mean CD4 cell count at entry was 240 and 23% of the participants had an AIDS diagnosis. Ninety percent of the patients had two or more risk factors for TB and 74% lived in the New York City area. In both groups, 63% completed six months of INH therapy; side effects led to the discontinuation of the study drug in 9% of each group. At the end of the study, 6.2% of those in the INH group and 7% of those in the placebo group had been lost to follow-up, thus their TB status could not be determined. The average duration of follow-up was 33 to 34 months for each group.
Rates of active tuberculosis were 3 of 260 patients on INH and 6 of 257 on placebo in the INH and placebo groups, respectively. This difference did not achieve statistical significance. Susceptibility tests were done in eight of the nine TB isolates, and all eight were found to be susceptible to INH. All cases of TB occurred after the six months of treatment and after the study drug had been discontinued. There were no significant differences in the death rates or rates of HIV disease progression among the two groups. There were no differences in the rates or types of side effects among the two groups; with 11.2% to 11.7% reporting side effects in each group and 9.2% to 9.3% discontinuing study medication in each group.
The authors of the study concluded that INH prophylaxis was not useful in preventing TB in this high-risk population. They further stated that the use of preventive therapy among HIV-infected persons with anergy in the United States was not warranted, except for those who have come into close contact with someone known to have active TB. These findings have led the Public Health Service/Infectious Disease Society of America (IDSA) to change the recommendation of routine evaluation of anergy in HIV-infected persons, and to discontinue recommending INH prophylaxis in cases of anergic individuals. They do, however, continue recommending PPD skin testing annually in HIV-positive persons irrespective of their CD4 count.
Skin-test reactions (a bump greater than, or equal to, 5 millimeters) warrant immediate work-up for active TB with sputum analysis and chest X-ray. Those who have evidence of latent disease should be treated with 12 months of INH at a dose of 300 mg per day, along with pyridoxine (Vitamin B6) to decrease the risk of peripheral neuropathy. In addition, HIV-positive persons who are close contacts of persons with active TB should receive preventive INH therapy, regardless of PPD skin test results or prior courses of INH.