Kaplan, Jonathan E.; Spira, Thomas J.; Fishbein, Daniel B.; Lynn, Henry S.
To the Editor: In 1992, we reported a continuing risk of AIDS developing 10 years after onset of human immunodeficiency virus (HIV)-associated lymphadenopathy syndrome in a cohort of homosexual men in Atlanta (1). We now report additional follow-up of these men, two-thirds of whom now have clinical AIDS, and nearly all of whom have AIDS as defined by the revised 1993 CDC case definition.
The selection of study participants, the criteria for enrollment, and the methods of evaluation at the first and subsequent visits in our study have been described in earlier reports (1,2). Briefly, 75 homosexual or bisexual men who had lymphadenopathy in two or more extrainguinal sites for at least 3 months and were subsequently found to be seropositive for HIV were referred by physicians in the Atlanta area in 1982-1983. These men have been followed up at 3- to 6-month intervals with clinical and immunologic evaluations that include determination of T-cell subsets.
We examined the yearly and cumulative probabilities of development of clinical AIDS (according to the 1987 CDC case definition) by the Kaplan-Meier survival technique (3). The probability of AIDS developing was examined as a function of time since lymphadenopathy was first noted by the patient or by a physician. Persons were not considered at risk until they were enrolled in the study. Participants who did not have AIDS were considered at risk through July 1994 (the cutoff point in this analysis). Six men who had neither been followed up at the CDC nor been contacted by telephone within 6 months before July 1994 were considered at risk for AIDS only through the last month in which information concerning their health was obtained. An additional man who died of causes unrelated to HIV infection was considered at risk through November 1990, the month of his death.
As of July 30, 1994, clinical AIDS had developed in 51 (68%) of the 75 men 3-144 (median 69) months after enrollment in the study, and 5-157 (median 78) months after onset of lymphadenopathy. Twenty-two patients had Pneumocystis carinii pneumonia; 11 had Kaposi's sarcoma; 5 had esophageal candidiasis; 5 had disseminated Mycobacterium avium complex disease; two each had cryptococcal meningitis, cytomegalovirus retinitis, cytomegalovirus colitis, AIDS encephalopathy, and non-Hodgkin's lymphoma; and one each had cryptosporidiosis, disseminated mucocutaneous herpes simplex infection, and Toxoplasma encephalitis. (Some patients had more than one diagnosis.)
The annual incidence of clinical AIDS climbed sharply in the first 3 years after onset of lymphadenopathy and has exceeded 10% in nearly all years since the fourth year (Table 1). The 14-year cumulative incidence of AIDS was 79.1%.
Thirty men reported having received zidovudine (ZDV) at some time before clinical AIDS was diagnosed. To assess the possible impact of ZDV therapy on our analysis, we repeated the Kaplan-Meier analysis after deleting all person-months of observation since ZDV therapy was initiated. Although this diminished the number of person-months of observation and the number of AIDS cases, the cumulative incidence rates were nearly identical to those shown in Table 1. Because ZDV has been shown to delay the appearance of opportunistic infections and the development of AIDS (4), this result suggests that the number of men who received antiretroviral therapy, as well as the duration of such therapy, was insufficient to affect our analysis significantly.
In addition to the 51 men with clinical AIDS, 14 men (including 2 lost to follow-up and the man who died of unrelated causes) had AIDS as defined by the 1993 revised CDC AIDS case definition (CD4 count <200 cells/μl) (5). Of the remaining six men with follow-up information available, five have had CD4 counts decline to <500 cells/μl. One man, who first had lymphadenopathy noted in January 1982, had several CD4 measurements <500 cells/μl from 1983 to 1989, but all six determinations since that time (most recently in December 1994) have indicated >500 CD4 cells/μl.
In our study, more than two-thirds of the men originally enrolled with HIV-associated lymphadenopathy syndrome have had clinical AIDS diagnosed. Of note, the 50.6% cumulative incidence of AIDS observed in year 8 (Table 1), which approximates the median time to diagnosis of AIDS, is at the lower end of the 8-11-year incubation period of AIDS reported in nmerous studies (6-8). Although several men in our study reported illnesses consistent with the acute retroviral syndrome when lymphadenopathy was first noted, suggesting recent acquisition of HIV infection, this finding suggests that, on average, the men in our study were infected with HIV 1-2 years before lymphadenopathy was first recognized. Another possible explanation for this finding is that HIV-infected persons with lymphadenopathy progress to AIDS more rapidly than those without this manifestation. However, numerous investigators have reported no association between lymphadenopathy and rate of progression of HIV disease (9,10).
The observation that 14 men, in addition to the 51 with clinical AIDS, have AIDS as defined by the 1993 revised CDC case definition and that nearly all remaining participants with follow-up information available have experienced immunologic deterioration is sobering. Long-term survivors, most commonly defined as persons with normal CD4 counts who have been infected with HIV for at least 10 years, have generated great interest in recent studies (11,12); however, only one man in our cohort possibly meets this definition. Whether all men in this cohort will eventually have clinical AIDS is unknown.
Several limitations in our study must be noted. The number of subjects is relatively small, and the annual and cumulative incidence rates of clinical AIDS are therefore somewhat unstable. (For example, the 95% confidence intervals of the cumulative incidence rates at 8 and 14 years are 39.0-62.3%, and 66.7-91.5%, respectively—Table 1). The dates of HIV seroconversion are unknown, as are the intervals between seroconversion and onset of lymphadenopathy. Of the various medications that may affect progression to AIDS, only information on ZDV was systematically obtained; we did not collect such information on trimethoprim-sulfamethoxazole or other antiretroviral compounds. Despite these limitations, our cohort has been followed longer than most that have been assembled since recognition of the AIDS epidemic. Follow-up of these HIV-infected men continues.
Jonathan E. Kaplan; Thomas J. Spira; Daniel B. Fishbein
Center for Disease Control and Prevention; Atlanta, Georgia
Henry S. Lynn
New England Research Institute; Boston, Massachusetts, U.S.A.
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