The Hopkins HIV Report
A bimonthly newsletter for healthcare providers
Volume 8, Number 4, November 1996

TB Skin Testing, Anergy and Preventive Therapy

Jichard E. Chaisson, M.D.

While it has been clear for some time that HIV-infected, tuberculin skin test (PPD) -- positive individuals have a high risk of progression to active tuberculosis, the importance of anergy has been very controversial. Several early reports noted high rates of active tuberculosis in HIV seropositive people who were anergic by PPD testing and controls. In a report by Selwyn and associates from New York (JAMA 1992; 268:504-509), the rate of TB in HIV-infected drug users who were anergic by PPD and the CMI Multitest (Merieux Diagnostics) was 6.6 cases per 100 person-years. However, in that study the rate of TB in HIV seropositive, PPD negative nonanergic persons was not reported. Nonetheless, as a result of this report, the Centers for Disease Control and Prevention recommended that HIV-infected patients undergo routine PPD skin testing and that anergy testing be performed to aid in the interpretation of negative PPD tests. The CDC also recommended that isoniazid preventive therapy be considered for HIV seropositive anergic individuals from populations with a background prevalence of TB infection >10%.

Several important questions about these guidelines were initially unanswered, but recent studies have led to a thorough reassessment of the use of anergy tests to help identify candidates for TB prophylaxis.

How reliable is anergy testing and what do the results mean?

While the PPD skin test has been extensively studied and validated, anergy tests have not undergone similar scrutiny. The antigens used have never been standardized and the interpretation of anergy testing has not been validated. Several recent reports suggest that anergy testing has poor predictive value in HIV-infected people.

  • Markowitz et al. (Ann Intern Med 1993; 119:185-193) in the Pulmonary Complications of HIV Study found no association between PPD results and anergy results. In a study of more than 1000 HIV-infected persons, the investigators reported that the prevalence of a positive PPD (>5 mm induration) was 6% in patients with a positive control test (i.e. non-anergics) and 7% in those who were anergic. Thus, response to the anergy test did not predict response to PPD.

  • Caiaffa and associates (Arch Intern Med 1995; 155:2111-2117) performed PPD skin tests and anergy panels in a cohort of injection drug users in Baltimore. Among those individuals who were initially non-anergic, 24% of HIV seropositives and 15% of HIV seronegatives developed anergy when retested 6-12 months later. Among those who were initially anergic, however, 44% of HIV seropositives and 66% of HIV seronegatives were not anergic when retested. The authors concluded that anergy tests were unstable over time and of dubious value in individual patients.

  • Chin and associates (Am J Respir Crit Care Med 1996; 153:1982-1984) studied 491 HIV-infected individuals in the Pulmonary Complications of HIV Study, as well. They found that 30% of initially anergic individuals became non-anergic on follow-up testing. They also reported that "false positive" mumps anergy tests were found in 39% of subjects who had previous positive tuberculin skin tests that had become negative. They concluded that anergy testing could not be relied upon for helping to interpret the results of a negative PPD.

Do anergic individuals who later develop active TB have reactivation of latent infection or primary TB from a recent exposure?

  • In the study of Selwyn et al., the five HIV seropositive, anergic patients who developed active TB during follow-up had clinical features consistent with primary infection. While it is impossible to distinguish recent from remote TB infection in the HIV-infected patient without DNA fingerprinting, these cases occurred during the extraordinary epidemic of TB in New York City during the late 1980s and early 1990s.

  • In a study by Moreno and associates in Spain (Ann Intern Med 1993; 119:194-198 ), a similar situation prevailed. The rate of tuberculosis in anergic, HIV seropositive individuals was 12 per 100 person-years of follow up; the rate among HIV seropositive, PPD negative, non-anergic persons was 6 per 100 person-years. This latter rate, while significantly lower than that of anergics, is exceptionally high and represents epidemic tuberculosis.

    Thus, it is not clear that the tuberculosis that occurs in anergic individuals really is a result of reactivation of latent infection. Therefore, the value of providing routine prophylaxis with isoniazid could not be predicted based on the earlier studies.

Should anergic, HIV seropositive individuals from high TB-prevalence populations be given chemo-prophylaxis?

Two recent studies strongly suggest that the routine prescription of chemoprophylaxis to anergic patients is not efficacious or effective.

  • Graham and coworkers (Arch Intern Med 1996; 156:889-894) performed PPD and anergy skin tests on a cohort of injection drug users in Baltimore. All participants with a reactive PPD (>5 mm for HIV seropositives and >10 mm for seronegatives) were given isoniazid prophylaxis under direct supervision twice weekly for six months. HIV seropositives were also given an additional six months of self-supervised isoniazid. Anergic HIV seropositives did not receive prophylaxis. After the introduction of prophylaxis for the PPD positive drug users, cases of tuberculosis dropped dramatically (over 80% decrease in risk) in the cohort, falling to zero in the last 18 months of the study. Despite a background prevalence of tuberculin positivity that was 25%, no anergic or PPD negative individual developed tuberculosis. This ecologic study demonstrates the value of providing isoniazid prophylaxis to PPD positive, HIV seropositive patients, and suggests that prophylaxis is unnecessary for anergic individuals in a setting where tuberculosis is not epidemic.

  • Gordin and associates performed a randomized, double-blind, placebo-controlled trial of isoniazid prophylaxis for HIV seropositive, anergic individuals from populations with a background prevalence of tuberculous infection that was at least 10% (ICAAC, Late Breaker Session, 1996). Patients were treated with isoniazid 300 mg daily or placebo for six months. With an average of two years of follow up, the rate of tuberculosis in the placebo group was 0.9 cases per 100 person-years versus 0.4 cases per 100 person-years in the isoniazid group (p=not significant). This study also demonstrated a low rate of tuberculosis in anergic, HIV seropositive patients from high prevalence populations, and found no clinically or epidemiologically significant benefit to isoniazid preventive therapy in this setting.

The collective results of these recent studies indicate that anergy testing is much ado about nothing. Given the instability and lack of predictive value of anergy testing, the use of these imprecise tests in clinical practice cannot be endorsed. The results of the prospective randomized trial of Gordin and coworkers is powerful evidence that isoniazid prophylaxis is not efficacious for anergic, HIV-infected patients in the United States. Whether prophylaxis would be useful in settings where tuberculosis is more prevalent in the community, such as in many developing nations, is not now known. The United States Public Health Service/Infectious Disease Society of America Working Group on Prevention of Opportunistic Infections in HIV-infected Persons will reconvene in November 1996 to consider changes in the current recommendations for anergy testing and chemoprophylaxis. It seems likely that the data described in this article will prompt a change away from anergy testing and a greater concentration on identifying and providing prophylaxis to PPD positive persons with HIV infection.

This article is from The Johns Hopkins University AIDS Service,
The Hopkins HIV Report: A bimonthly newsletter for healthcare providers.