Correspondence

Isoniazid Prophylaxis for High-Risk Patients with Anergy and HIV Infection

N Engl J Med 1997; 337:1696-1697December 4, 1997

Article

To the Editor:

Gordin et al. (July 31 issue)1 conclude that isoniazid prophylaxis is not useful in patients with human immunodeficiency virus (HIV) infection who have anergy and multiple risk factors for latent tuberculosis. We are concerned about the validity and generalizability of this conclusion.

First, we doubt that the patients included in the study by Gordin et al. were highly representative of patients who are truly at high risk for tuberculosis. The incidence of tuberculosis in the placebo group was only 0.9 per 100 person-years, which is very close to the overall incidence of tuberculosis among HIV-infected persons in the United States who are not at high risk (0.7 per 100 person-years).2

Second, a six-month regimen of prophylaxis may have been insufficient. Only a 12-month regimen of isoniazid has proven value in HIV-infected people with positive tuberculin tests,3,4 and this is the only regimen recommended today. The lack of a benefit from a six-month regimen does not rule out a benefit from isoniazid treatment. In addition, only 63 percent of the patients assigned to the isoniazid group completed six months of treatment, and the rate may have been lower, since compliance was assessed only by interviewing the patients. This study does not have enough power to detect any decrease in the incidence of tuberculosis in a population with a basal incidence of only 0.9 per 100 patient-years.

The data reported by Gordin et al. could lead to different conclusions if applied to areas with a higher incidence of tuberculosis in HIV-positive patients. If the rate of reduction in the study by Gordin et al. were applied to our population,5 the incidence of tuberculosis in this group of patients would decrease from 12.4 to 5.5 per 100 person-years (relative risk, 0.48; 95 percent confidence interval, 0.32 to 0.69; P<0.001). In fact, the lowest rate of tuberculosis at which the benefit of isoniazid can be demonstrated is an estimated 3.2 cases per 100 patient-years (relative risk, 0.48; 95 percent confidence interval, 0.23 to 0.98; P = 0.04).

The data from the study by Gordin et al. should be applied only to populations with a very low incidence of tuberculosis and only for a six-month regimen of isoniazid. Until we can better identify the HIV-infected patients with anergy who are likely to benefit from prophylaxis, a 12-month course of isoniazid should be offered to all such patients living in areas with a high prevalence of tuberculosis.

Jose M. Aguado, M.D.
Federico Pulido, M.D.
Hospital Universitario 12 de Octubre, 28041 Madrid, Spain

Santiago Moreno, M.D.
Hospital General Morales Meseguer, 30008 Murcia, Spain

5 References

1
Gordin FM, Matts JP, Miller C, et al. A controlled trial of isoniazid in persons with anergy and human immunodeficiency virus infection who are at high risk for tuberculosis. N Engl J Med 1997;337:315-320
Full Text | Web of Science | Medline

2
Markowitz N, Hansen NI, Hopewell PC, et al. Incidence of tuberculosis in the United States among HIV-infected persons. Ann Intern Med 1997;126:123-132
Web of Science | Medline

3
Pape JW, Jean SS, Ho JL, Hafner A, Johnson WD Jr. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet 1993;342:268-272
CrossRef | Web of Science | Medline

4
Moreno S, Miralles P, Diaz MD, et al. Isoniazid preventive therapy in human immunodeficiency virus-infected persons: long-term effect on development of tuberculosis and survival. Arch Intern Med 1997;157:1729-1734
CrossRef | Web of Science | Medline

5
Moreno S, Baraia-Extaburu J, Bouza E, et al. Risk for developing tuberculosis among anergic patients infected with HIV. Ann Intern Med 1993;119:194-198
Web of Science | Medline

To the Editor:

The study by Gordin et al. has a striking lack of power. The study was designed to have 80 percent power to detect a 60 percent reduction in the incidence of tuberculosis through the use of isoniazid, assuming an incidence of tuberculosis of five cases per 100 person-years in the placebo group. In fact, the incidence of tuberculosis in the placebo group was only 0.9 per 100 person-years. At this level of incidence, the study had only 23 percent power to detect a 60 percent reduction in incidence. It is thus not surprising that the reported relative risk of 0.48, based on only nine cases of tuberculosis (six in the placebo group and three in the isoniazid group), was not statistically significant at the 0.05 level.

A second weakness of the study is the six-month duration of prophylaxis. The initial randomized trial of isoniazid prophylaxis among people with HIV infection in Haiti used a 12-month course of therapy.1 This study demonstrated more than an 80 percent reduction in the incidence of tuberculosis among people with positive purified-protein-derivative (PPD) tests and a 40 percent reduction among people with negative tests. If isoniazid prophylaxis works by preventing both reactivation of latent tuberculosis and acquisition of new infection, a longer duration of therapy should increase the chance of achieving both these objectives. The three cases of tuberculosis in the isoniazid group in the New York study occurred after the cessation of therapy.

Although improved measures to control tuberculosis in New York City in recent years may explain the relatively low incidence of tuberculosis in this study, the authors have certainly not determined whether people with HIV and anergy in areas of high background prevalence could benefit from isoniazid prophylaxis.

Gregory J. Dore, M.B., B.S., M.P.H.
Matthew G. Law, M.Sc.
John M. Kaldor, Ph.D.
University of New South Wales, Darlinghurst NSW 2010, Australia

1 References

1
Pape JW, Jean SS, Ho JL, Hafner A, Johnson WD Jr. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet 1993;342:268-272
CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We believe that our study population was highly representative of persons who contract tuberculosis in the United States. Approximately three fourths of the patients had three or more of the risk factors that the Centers for Disease Control and Prevention (CDC) reports as commonly associated with the development of tuberculosis: foreign birth, membership in a racial or ethnic minority group, residence in a high-risk geographic area, and use of alcohol or drugs.1 The lower-than-expected rate of disease in this population, as we said in our article, probably reflects a decrease in cases of primary tuberculosis as a result of improved control.

The American Thoracic Society recommends 6 months of isoniazid for HIV-negative persons and 12 months of isoniazid for HIV-positive persons,2 but there are no data to support an increased efficacy with a longer duration of use. Some researchers have therefore used a six- or nine-month isoniazid regimen — even in persons known to be both HIV-positive and PPD-positive.3,4 This six-month isoniazid regimen was recently shown by Whalen et al. to be effective in reducing the incidence of tuberculosis by 67 percent.3

Aguado et al. and Dore et al. find our study weak because, given our results, there was a lack of power. Table 5 in our report, however, shows that the assumptions underlying our study design were correct. Given the low event rate in the placebo group in our study, even if there were adequate statistical power to show a difference, we believe there would be a high risk, a high cost, and a limited benefit in providing isoniazid prophylaxis to all anergic persons in the United States. This assessment is supported by recent guidelines from the CDC, which suggest that among persons who are HIV-positive and PPD-negative, isoniazid should be given only to those with recent or ongoing exposure to active tuberculosis.5

Our study was done in the United States, and our conclusion supporting the limited use of prophylaxis for PPD-negative patients is specific to people in this country. The benefit of providing isoniazid prophylaxis to anergic, HIV-positive patients in other countries needs to be studied, but Whalen et al. found this strategy to be of no benefit in Uganda.3

Fred Gordin, M.D.
Veterans Affairs Medical Center, Washington, DC 20422

John Matts, Ph.D.
University of Minnesota, Minneapolis, MN 55414

5 References

1
Cantwell MF, Snider DE Jr, Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994;272:535-539
CrossRef | Web of Science | Medline

2
American Thoracic Society, Centers for Disease Control and Prevention. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:1359-1374
Web of Science | Medline

3
Whalen CC, Johnson JL, Okwera A, et al. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. N Engl J Med 1997;337:801-808
Full Text | Web of Science | Medline

4
Guelar A, Gatell JM, Verdejo J, et al. A prospective study of the risk of tuberculosis among HIV-infected patients. AIDS 1993;7:1345-1349
CrossRef | Web of Science | Medline