JID 1992; 166 (November)
Concise Communications
II. Taylor JMG, Fahey JL, Detels R, Giorgi JV. CD4 percentage, CD4 number, and CD4:CD8 ratio in HIV infection: which to choose and how to use. J Acquir Immune Defic Syndr 1989;2: 114-24. 12. Cooper DA, Tindall B, Wilson EJ, Imrie AA, Penney R. Characterization ofT lymphocyte responses during primary infection with human immunodeficiency virus. J Infect Dis 1988; 157:889-96. 13.· Luft BJ, Kansas G, Engleman EG, Remington JS. Functional and
1153
quantitative alterations in T lymphocyte subpopulations in acute toxoplasmosis. J Infect Dis 1984;150:761-7. 14. Blaxhult A, Granath F, Lidman K, Giesecke J. The influence of age on the latency period to AIDS in people infected by HIV through blood transfusion. AIDS 1990;4: 125-9. 15. Phillips AN, Lee CA, Elford J, et al. More rapid progression to AIDS in older HIV-infected people: the role ofCD4+ T-cell counts. J Acquir Immune Defic Syndr 1991;4:970-5.
Herpes Zoster and Human Immunodeficiency Virus Infection AIDS Office. San Francisco Department ofPublic Health, San Francisco, California; Division of HIV/AIDS, Center for Infectious Diseases, Centers for Disease Control, Atlanta, Georgia
The interaction of herpes zoster and the human immunodeficiencyvirus (HIV) was evaluated in a cohort study of 287 homosexual men with well-defined dates of HIV seroconversion and 499 HIV-seronegative homosexual men. The incidence of herpes zoster was significantly higher among HIV-seropositive men (29.4 cases/l000 person-years) than among HIV-seronegative men (2.0 cases/lOOO person-years); the overall age-adjusted relative risk (RR) was 16.9 (95% confidence interval [CI], 8.7-32.6). When compared with that of age-matched population controls from 1945 to 1959, the incidence of zoster was significantly higher among seropositive men (RR, 26.7; 95% CI, 19.3-37.1) and slightly higher among seronegative men (RR, 1.85; 95% CI, 1.0-3.3); the latter may reflect increasing background rates over several decades. The risk of herpes zoster was not associated with duration of HIV infection and was not predictive of faster progression to AIDS. Herpes zoster occurs more frequently in older persons and those with cellular immunodeficiency from various causes [1]. In 1981, herpes zoster was noted to be associated with AIDS [2]; subsequently, herpes zoster was found to precede AIDS in persons in high-risk groups [3, 4]. Although the association of herpes zoster and the human immunodeficiency virus (HIV) has been confirmed in numerous studies, many questions remain about the interaction between HIV infection and herpes zoster. The incidence of zoster in HIV-infected persons is not known; most studies are based on referral populations [3] or relatively small case series [4]. The relationship of herpes zoster to duration of HIV infection is also unclear, being variably described as an early [3, 5-7] or a late manifestation [8] ofHIV infection. Controversy exists about the prognostic significance of herpes zoster in HIV-infected persons; while
Received 30 April 1992; 2 July 1992. Informed consent was obtained from all participants. Guidelines of the US Department of Health and Human Services and the State of California were followed. Financial support: Centers for Disease Control (U64jCCU900523-08). Reprints or correspondence: Dr. Susan P. Buchbinder, AIDS Office, 25 Van Ness Ave., Suite 500, San Francisco, CA 94102. The Journal of Infectious Diseases 1992;166:1153-6 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6605-0029$01.00
some have reported it to be a significant predictor of more rapid progression to AIDS [7, 9], others have not found this association [10]. These conflicting results may be due in part to an inability to adjust for duration ofHIV infection. Clarifying these issues is important both for clinicians counseling patients with zoster and in furthering our understanding of the pathophysiology of herpes zoster and HIV infection. We compared the incidence of herpes zoster in HIV-seropositive and -seronegative homosexual men enrolled in a prospective study of HIV and AIDS; we compared rates in both groups to expected rates based on age-matched data from a low-risk community. To investigate the relationship of herpes zoster to duration of HIV infection, we determined the cumulative incidence of herpes zoster following HIV infection. Finally, we assessed the influence of herpes zoster on progression to AIDS.
Methods Study subjects. The San Francisco City Clinic Cohort comprises 6704 homosexual men recruited from the municipal sexually transmitted disease clinic from 1978 to 1980 for studies of the incidence and prevalence of hepatitis B. Sera from these original studies were frozen and stored. In 1983, we began AIDS follow-up studies; detailed descriptions of the methodology have been published [11].
Downloaded from http://jid.oxfordjournals.org/ at New York University on July 8, 2015
Susan P. Buchbinder, Mitchell H. Katz, Nancy A. Hessol, Jennifer Y. Liu, Paul M. O'Malley, Ronald Underwood, and Scott D. Holmberg
1154
Concise Communications
risk (RR) of herpes zoster at all ages; the RR increased with increasing age (figure I). The summary age-adjusted RR was 16.9 (95% CI, 8.7-32.6). When compared with incidence data from men in a 19451959 population-based study, the age-adjusted RR of herpes zoster for Hl'V-seropositive men was 26.7 (95% CI, 19.337.1) and for HIV-seronegative men was 1.8 (95% CI, 1.0-3.4). In Kaplan-Meier analysis, the cumulative proportion of men developing herpes zoster increased in a nearly linear fashion from the time of HIV seroconversion (figure 2); by 12 years after HIV infection, 30% of the men had developed zoster. By proportional hazard analysis that controlled for age, development of herpes zoster was not significantly associated with rate of progression to AIDS (relative hazard, 1.2; 95% CI, 0.7-1.9).
Discussion We found the overall incidence of herpes zoster in HIVseropositive men to be 29.4 cases/I 000 person-years, which was significantly higher than the incidence in both HIV-seronegative men and age-matched population controls. The cumulative incidence of zoster 12 years after HIV seroconversion was 30%. These rates are considerably higher than those reported by two other cohorts. In a retrospective review of Kaposi's sarcoma patients, Friedrnan-Kien et at [3] described a rate of -- 20 cases/ I000 person-years and estimated this to be seven times higher than the rate in an age-matched population. Verroust et at. [6] described II cases of herpes zoster in HI V-seropositive subjects in a cohort of259 hemophilic men followed prospectively for 10 years. Given an HIV seroprevalence of 66% in this cohort, the proportion of Hl V-seropositive hemophilic men developing herpes zoster was II (6.4%) of 171. Our rates may have been higher for a number of reasons, including more complete ascertainment, longer follow-up, and age differences between cohorts.
Cases/1000 Person-years
Results Of the 287 Hfv-seropositive men in our cohort evaluated since 1987, 58 developed herpes zoster once, 9 developed it twice, and 4 developed it three times through their last follow-up examination. Of the 499 HIV-seronegative men evaluated since 1987, 10 developed zoster once and I man developed it twice. The incidence of index cases of zoster per 1000 personyears in Hlv-seropositive men was 29.4 cases and in HIVseronegative men, 2.0 cases. Incidence increased with increasing age for both HIV -seropositive and -seronegative men. HIV infection was associated with an increased relative
20-29
30-39
40-49
50-59
Age (Years) _
HIV Seronegative
_
HIV Seropositive
Figure 1. Incidence of herpes zoster in HIV-seronegative and -seropositive men in the San Francisco City Clinic Cohort.
Downloaded from http://jid.oxfordjournals.org/ at New York University on July 8, 2015
For men agreeing to participate in AIDS follow-up studies, we tested current and stored specimens for HIV antibodies. We enrolled in prospective studies all HIV-seropositive men with well-characterized dates of HIV seroconversion and a subsample of HIV-seronegative men, weighted toward those with extensive behavioral and serologic data. For the current study, we included all participants enrolled in these prospective studies who were interviewed after 1987, the year we first included questions about herpes zoster in the clinical interview. Definitions. For HIV-seronegative men and men who were HIV-seropositive on entry into the study in 1978-1980, we defined the study entry date as the date their first serum specimen was collected. For men whoseroconverted after entry into the cohort, we defined the study entry date as the midpoint between the collection dates of the last HIV-seronegative and first HIVseropositive specimen when this occurred with ~24 months between specimens. Men with >24 months between these specimens are excluded from analysis. As part of annual clinical evaluations, the study physician ascertained the presence and history of all episodes of herpes zoster occurring since the date of the first serum specimen (1978-1980), as well as number and dates of episodes. We defined the index zoster episode as the first episode of herpes zoster after the study entry date and used only the index case in calculating incidence. We defined AIDS on the basis of the 1987 revised Centers for Disease Control case definition. We ascertained AIDS cases and date of diagnosis by cross-matching with local and national AIDS surveillance registries. Data analysis. We compared the incidence of herpes zoster in HIV-seropositive and -seronegative men in the cohort stratified by decade. We then compared rates in these two groups with rates for men of comparable age from a population-based study (12). We calculated 95% confidence intervals (CI) using a directly weighted point estimate [13). For HIV-seropositive men, we used the Kaplan-Meier analysis to calculate the cumulative incidence of herpes zoster as a function ofduration of HIV infection. We used the Cox proportional hazard analysis, controlling for age at entry, to determine whether zoster independently predicts development of AIDS. The index zoster diagnosis was included as a time-dependent covariate to adjust for the varying lengths oftime between entry into the study and development of herpes zoster.
JID 1992; 166 (November)
110 1992: 166 (November)
Concise Communications
35 CD
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We also found recurrences of herpes zoster to occur relatively frequently in HIV-seropositive men. Of 58 men developing zoster, 13 (22%) developed at least one additional episode, comparable to rates reported in other HIV-seropositive cohorts [5]. We found that rates of herpes zoster were higher in our HIV-seronegative men than in men of comparable age from a community-based study, but the difference was of borderline statistical significance. The possibility has been raised that sexually active HIV-seronegative homosexual men may be different immunologically from other HIV-seronegative groups; such relative immunosuppression could be due to repeated antigenic exposure to sexually transmitted agents other than HIV. Alternatively, the difference in rates may have resulted from an increase in background rates of zoster since the time of the community-based study (1945-1959); data from this previous study indicated a small but statistically significant increase in incidence over this 15-year period [12]. Herpes zoster appears to be neither an early nor a late manifestation of HIV infection but occurs at a relatively constant rate following HIV infection. Prior studies of herpes zoster could infer duration ofHIV infection only on the basis of other HIV disease manifestations [3, 5, 7]. Other reports documented episodes ofzoster occurring within several years after HIV seroconversion but did not have sufficient followup to ascertain later episodes [8]. In contrast to a cohort study by Melbye et al. [7], our study did not find herpes zoster to be a harbinger of rapid progression to AIDS. The study of Melbye et al. lacked a control group of men without zoster; their reported 3-year progression rate from zoster to AIDS of 34.8% (95% CI, 20.4%49.2%) is consistent with progression rates in several other HIV-seroprevalent cohorts. A more recent study adjusting for CD4+ cell count has found herpes zoster not to be an independent predictor of AIDS [10]. This is in contrast to other clinical markers such as oral candidiasis [14] and con-
stitutional symptoms [10] that are associated with more rapid progression to AIDS, even when analyses adjust for CD4+ cell count. Several limitations of our study should be noted. Cases of herpes zoster were determined by self-report. Because information on herpes zoster was obtained retrospectively, HIVseropositive men may have been more likely to remember zoster than seronegative men. However, this is unlikely given the severity of symptoms often associated with zoster. Our results may also be affected by survival bias; men developing AIDS and dying before 1987 are not included in this study, and this may underestimate the rate of herpes zoster early after HIV infection. Finally, as this study is based on homosexual men initially recruited from a sexually transmitted disease clinic, the results may not generalize to other HIVseronegative and -seropositive groups. Nonetheless, this study has important implications for clinicians. Patients with herpes zoster should be counseled about risk factors for HIV infection and, when appropriate, offered HIV antibody testing. This recommendation applies to all patients without another cause of immunosuppression, regardless of age; the RR of herpes zoster due to HIV infection was three times higher for men aged 50-59 years than for men aged 20-29. For patients with known HIV infection, development of herpes zoster does not affect prognosis and should not signal a need to change ongoing antiviral or prophylactic regimens. Our study raises several intriguing questions about the pathophysiology of herpes zoster. Cellular immunity plays a critical role in inactivating varicella-zoster virus and maintaining its latent state [I, 15]. It appears that T lymphocytes are necessary for viral inactivation and that a relative loss of CD4+ cells and an excess of CD8+ cells accompanies acute zoster outbreaks. Humoral immunity, in contrast, does not appear to be important in viral inactivation, and antibodies to varicella-zoster may in fact block cell-mediated inactivation of the virus. HIV infection causes a gradual loss ofCD4+ cell number and function. However, our study did not find an increasing risk of zoster with increasing duration of infection, as would be expected ifCD4+ cell function was solely responsible for increased zoster risk. CD8+ cells may also play an important role in reactivating varicella-zoster and are known to increase early in HIV infection. Thus, an increase in CD8+ cells may add risk at a time when CD4+ cell function is relatively intact and distribute the risk of herpes zoster throughout the duration of HIV infection. Other sexually transmitted infections, such as cytomegalovirus, also cause a relative increase in CD8+ cell counts; exposure to such agents may explain the increased risk of zoster in HIV-seronegative men when compared with age-matched controls. In addition to providing useful clinical information, the examination of the complex interaction between herpes zoster and HIV infection provides useful insight into the patho-
Downloaded from http://jid.oxfordjournals.org/ at New York University on July 8, 2015
Figure 2. Cumulative proportion of HIV-seropositive men developing herpes zoster up to II years after HIV seroconversion.
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Concise Communications
physiology of both diseases. The role of biologic and behavioral cofactors contributing to their morbidity deserves further investigation.
6. 7.
Acknowledgments
8.
We thank L. J. Melton for providing data from his study and the following people for their invaluable assistance in this study: J. Lowell Barnhart, Torsten Bodecker, Melchor Bustamante, David Colbert, Lynda Doll, Delia Garcia, Sandra Hernandez, Elaine Hung, Robert Kono, Irene Lee, Bobby Martin, Martha Rogers, Chris Rubino, Belinda Van, Robert Wade, and the men in the San Francisco City Clinic Cohort Study.
9.
10.
II. I. Weller TH. Varicella and herpes zoster: changing concepts of the natu-
2.
3.
4.
5.
ral history. control, and importance ofa not-so-benign virus. N Engl J Med 1983;309: I 362-8. 1434-40. Masur H. Michelis MA, Greene JB, et al. An outbreak of communityacquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med 1981;305: 143 1-8. Friedman-Kien AE. Lafleur FL. Gendler E, et al. Herpes zoster: a possible early clinical sign for development of acquired immunodeficiency syndrome in high risk individuals. J Am Acad Dermatol 1986; I4: 1023-8. Sandor E. Croxson TS, Millman A, Mildvan D. Herpes zoster ophthalmicus in patients at risk for AIDS [letter]. N Engl J Med 1984;310:1 I 18-9. Colebunders R, Mann JM. Francis H, et al. Herpes zoster in African
12.
13. 14.
15.
patients: a clinical predictor of human immunodeficiency virus infection. J Infect Dis 1988; I 57:3 I 4-8. Verroust F. Lemay D. Laurian Y. High frequency of herpes zoster in young hemophiliacs [letter]. N Engl J Med 1987;3 I 6: I 66-7. Melbye M. Grossman RJ, Goedert JJ, Eyster ME, Biggar RJ. Risk of AIDS after herpes zoster. Lancet 1987; I:728-31. Melbye M. Biggar RJ. Ebbesen P. et al. Long-term seropositivity for human T-lymphotropic virus type III in homosexual men without the acquired immunodeficiency syndrome: development ofimmunologic and clinical abnormalities. Ann Intern Med 1986; I04:496500. Van Griensven GJP. de Vroome EMM. de WolfF, Goudsmit J, Roos M. Coutinho RA. Risk factors for progression of human immunodeficiency virus (HIV) infection among seroconverted and seropositive homosexual men. Am J EpidemioI1990;132:203-1O. Moss AR. Bacchetti P, Osmond D. et al. Seropositivity for HIV and the development of AIDS or AIDS related condition: three year follow up of the San Francisco General Hospital cohort. Br Med J 1988;296:745-50. Rutherford GW. Lifson AR. Hessol NA. et al. Course of HIV-I infection in a cohort of homosexual and bisexual men: an II year follow up study. BMJ 1990;30 I: II 83-8. Ragozzino MW, Melton U, Kurland LT. Chu CPo Perry HO. Population-based study of herpes zoster and its sequelae. Medicine 1982;61 :310-6. Rothman KJ. Modern epidemiology. Boston: Little. Brown, 1986: 210-3. Katz MH, Greenspan D, Westenhouse J, et al. Progression to AIDS in HIV-infected homosexual and bisexual men with hairy leukoplakia and oral candidiasis: results from three San Francisco epidemiologic cohorts. AIDS 1992;6:95-100. Arvin AM, Pollard RB. Rasmussen LE, Merigan TC. Cellular and humoral immunity in the pathogenesis of recurrent herpes viral infections in patients with lymphoma. J Clin Invest 1980;65:869-78.
Downloaded from http://jid.oxfordjournals.org/ at New York University on July 8, 2015
References
1ID 1992; I66 (November)
Concise Communications
II. Taylor JMG, Fahey JL, Detels R, Giorgi JV. CD4 percentage, CD4 number, and CD4:CD8 ratio in HIV infection: which to choose and how to use. J Acquir Immune Defic Syndr 1989;2: 114-24. 12. Cooper DA, Tindall B, Wilson EJ, Imrie AA, Penney R. Characterization ofT lymphocyte responses during primary infection with human immunodeficiency virus. J Infect Dis 1988; 157:889-96. 13.· Luft BJ, Kansas G, Engleman EG, Remington JS. Functional and
1153
quantitative alterations in T lymphocyte subpopulations in acute toxoplasmosis. J Infect Dis 1984;150:761-7. 14. Blaxhult A, Granath F, Lidman K, Giesecke J. The influence of age on the latency period to AIDS in people infected by HIV through blood transfusion. AIDS 1990;4: 125-9. 15. Phillips AN, Lee CA, Elford J, et al. More rapid progression to AIDS in older HIV-infected people: the role ofCD4+ T-cell counts. J Acquir Immune Defic Syndr 1991;4:970-5.
Herpes Zoster and Human Immunodeficiency Virus Infection AIDS Office. San Francisco Department ofPublic Health, San Francisco, California; Division of HIV/AIDS, Center for Infectious Diseases, Centers for Disease Control, Atlanta, Georgia
The interaction of herpes zoster and the human immunodeficiencyvirus (HIV) was evaluated in a cohort study of 287 homosexual men with well-defined dates of HIV seroconversion and 499 HIV-seronegative homosexual men. The incidence of herpes zoster was significantly higher among HIV-seropositive men (29.4 cases/l000 person-years) than among HIV-seronegative men (2.0 cases/lOOO person-years); the overall age-adjusted relative risk (RR) was 16.9 (95% confidence interval [CI], 8.7-32.6). When compared with that of age-matched population controls from 1945 to 1959, the incidence of zoster was significantly higher among seropositive men (RR, 26.7; 95% CI, 19.3-37.1) and slightly higher among seronegative men (RR, 1.85; 95% CI, 1.0-3.3); the latter may reflect increasing background rates over several decades. The risk of herpes zoster was not associated with duration of HIV infection and was not predictive of faster progression to AIDS. Herpes zoster occurs more frequently in older persons and those with cellular immunodeficiency from various causes [1]. In 1981, herpes zoster was noted to be associated with AIDS [2]; subsequently, herpes zoster was found to precede AIDS in persons in high-risk groups [3, 4]. Although the association of herpes zoster and the human immunodeficiency virus (HIV) has been confirmed in numerous studies, many questions remain about the interaction between HIV infection and herpes zoster. The incidence of zoster in HIV-infected persons is not known; most studies are based on referral populations [3] or relatively small case series [4]. The relationship of herpes zoster to duration of HIV infection is also unclear, being variably described as an early [3, 5-7] or a late manifestation [8] ofHIV infection. Controversy exists about the prognostic significance of herpes zoster in HIV-infected persons; while
Received 30 April 1992; 2 July 1992. Informed consent was obtained from all participants. Guidelines of the US Department of Health and Human Services and the State of California were followed. Financial support: Centers for Disease Control (U64jCCU900523-08). Reprints or correspondence: Dr. Susan P. Buchbinder, AIDS Office, 25 Van Ness Ave., Suite 500, San Francisco, CA 94102. The Journal of Infectious Diseases 1992;166:1153-6 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6605-0029$01.00
some have reported it to be a significant predictor of more rapid progression to AIDS [7, 9], others have not found this association [10]. These conflicting results may be due in part to an inability to adjust for duration ofHIV infection. Clarifying these issues is important both for clinicians counseling patients with zoster and in furthering our understanding of the pathophysiology of herpes zoster and HIV infection. We compared the incidence of herpes zoster in HIV-seropositive and -seronegative homosexual men enrolled in a prospective study of HIV and AIDS; we compared rates in both groups to expected rates based on age-matched data from a low-risk community. To investigate the relationship of herpes zoster to duration of HIV infection, we determined the cumulative incidence of herpes zoster following HIV infection. Finally, we assessed the influence of herpes zoster on progression to AIDS.
Methods Study subjects. The San Francisco City Clinic Cohort comprises 6704 homosexual men recruited from the municipal sexually transmitted disease clinic from 1978 to 1980 for studies of the incidence and prevalence of hepatitis B. Sera from these original studies were frozen and stored. In 1983, we began AIDS follow-up studies; detailed descriptions of the methodology have been published [11].
Downloaded from http://jid.oxfordjournals.org/ at New York University on July 8, 2015
Susan P. Buchbinder, Mitchell H. Katz, Nancy A. Hessol, Jennifer Y. Liu, Paul M. O'Malley, Ronald Underwood, and Scott D. Holmberg
1154
Concise Communications
risk (RR) of herpes zoster at all ages; the RR increased with increasing age (figure I). The summary age-adjusted RR was 16.9 (95% CI, 8.7-32.6). When compared with incidence data from men in a 19451959 population-based study, the age-adjusted RR of herpes zoster for Hl'V-seropositive men was 26.7 (95% CI, 19.337.1) and for HIV-seronegative men was 1.8 (95% CI, 1.0-3.4). In Kaplan-Meier analysis, the cumulative proportion of men developing herpes zoster increased in a nearly linear fashion from the time of HIV seroconversion (figure 2); by 12 years after HIV infection, 30% of the men had developed zoster. By proportional hazard analysis that controlled for age, development of herpes zoster was not significantly associated with rate of progression to AIDS (relative hazard, 1.2; 95% CI, 0.7-1.9).
Discussion We found the overall incidence of herpes zoster in HIVseropositive men to be 29.4 cases/I 000 person-years, which was significantly higher than the incidence in both HIV-seronegative men and age-matched population controls. The cumulative incidence of zoster 12 years after HIV seroconversion was 30%. These rates are considerably higher than those reported by two other cohorts. In a retrospective review of Kaposi's sarcoma patients, Friedrnan-Kien et at [3] described a rate of -- 20 cases/ I000 person-years and estimated this to be seven times higher than the rate in an age-matched population. Verroust et at. [6] described II cases of herpes zoster in HI V-seropositive subjects in a cohort of259 hemophilic men followed prospectively for 10 years. Given an HIV seroprevalence of 66% in this cohort, the proportion of Hl V-seropositive hemophilic men developing herpes zoster was II (6.4%) of 171. Our rates may have been higher for a number of reasons, including more complete ascertainment, longer follow-up, and age differences between cohorts.
Cases/1000 Person-years
Results Of the 287 Hfv-seropositive men in our cohort evaluated since 1987, 58 developed herpes zoster once, 9 developed it twice, and 4 developed it three times through their last follow-up examination. Of the 499 HIV-seronegative men evaluated since 1987, 10 developed zoster once and I man developed it twice. The incidence of index cases of zoster per 1000 personyears in Hlv-seropositive men was 29.4 cases and in HIVseronegative men, 2.0 cases. Incidence increased with increasing age for both HIV -seropositive and -seronegative men. HIV infection was associated with an increased relative
20-29
30-39
40-49
50-59
Age (Years) _
HIV Seronegative
_
HIV Seropositive
Figure 1. Incidence of herpes zoster in HIV-seronegative and -seropositive men in the San Francisco City Clinic Cohort.
Downloaded from http://jid.oxfordjournals.org/ at New York University on July 8, 2015
For men agreeing to participate in AIDS follow-up studies, we tested current and stored specimens for HIV antibodies. We enrolled in prospective studies all HIV-seropositive men with well-characterized dates of HIV seroconversion and a subsample of HIV-seronegative men, weighted toward those with extensive behavioral and serologic data. For the current study, we included all participants enrolled in these prospective studies who were interviewed after 1987, the year we first included questions about herpes zoster in the clinical interview. Definitions. For HIV-seronegative men and men who were HIV-seropositive on entry into the study in 1978-1980, we defined the study entry date as the date their first serum specimen was collected. For men whoseroconverted after entry into the cohort, we defined the study entry date as the midpoint between the collection dates of the last HIV-seronegative and first HIVseropositive specimen when this occurred with ~24 months between specimens. Men with >24 months between these specimens are excluded from analysis. As part of annual clinical evaluations, the study physician ascertained the presence and history of all episodes of herpes zoster occurring since the date of the first serum specimen (1978-1980), as well as number and dates of episodes. We defined the index zoster episode as the first episode of herpes zoster after the study entry date and used only the index case in calculating incidence. We defined AIDS on the basis of the 1987 revised Centers for Disease Control case definition. We ascertained AIDS cases and date of diagnosis by cross-matching with local and national AIDS surveillance registries. Data analysis. We compared the incidence of herpes zoster in HIV-seropositive and -seronegative men in the cohort stratified by decade. We then compared rates in these two groups with rates for men of comparable age from a population-based study (12). We calculated 95% confidence intervals (CI) using a directly weighted point estimate [13). For HIV-seropositive men, we used the Kaplan-Meier analysis to calculate the cumulative incidence of herpes zoster as a function ofduration of HIV infection. We used the Cox proportional hazard analysis, controlling for age at entry, to determine whether zoster independently predicts development of AIDS. The index zoster diagnosis was included as a time-dependent covariate to adjust for the varying lengths oftime between entry into the study and development of herpes zoster.
JID 1992; 166 (November)
110 1992: 166 (November)
Concise Communications
35 CD
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Years After HIV Seroconversion
We also found recurrences of herpes zoster to occur relatively frequently in HIV-seropositive men. Of 58 men developing zoster, 13 (22%) developed at least one additional episode, comparable to rates reported in other HIV-seropositive cohorts [5]. We found that rates of herpes zoster were higher in our HIV-seronegative men than in men of comparable age from a community-based study, but the difference was of borderline statistical significance. The possibility has been raised that sexually active HIV-seronegative homosexual men may be different immunologically from other HIV-seronegative groups; such relative immunosuppression could be due to repeated antigenic exposure to sexually transmitted agents other than HIV. Alternatively, the difference in rates may have resulted from an increase in background rates of zoster since the time of the community-based study (1945-1959); data from this previous study indicated a small but statistically significant increase in incidence over this 15-year period [12]. Herpes zoster appears to be neither an early nor a late manifestation of HIV infection but occurs at a relatively constant rate following HIV infection. Prior studies of herpes zoster could infer duration ofHIV infection only on the basis of other HIV disease manifestations [3, 5, 7]. Other reports documented episodes ofzoster occurring within several years after HIV seroconversion but did not have sufficient followup to ascertain later episodes [8]. In contrast to a cohort study by Melbye et al. [7], our study did not find herpes zoster to be a harbinger of rapid progression to AIDS. The study of Melbye et al. lacked a control group of men without zoster; their reported 3-year progression rate from zoster to AIDS of 34.8% (95% CI, 20.4%49.2%) is consistent with progression rates in several other HIV-seroprevalent cohorts. A more recent study adjusting for CD4+ cell count has found herpes zoster not to be an independent predictor of AIDS [10]. This is in contrast to other clinical markers such as oral candidiasis [14] and con-
stitutional symptoms [10] that are associated with more rapid progression to AIDS, even when analyses adjust for CD4+ cell count. Several limitations of our study should be noted. Cases of herpes zoster were determined by self-report. Because information on herpes zoster was obtained retrospectively, HIVseropositive men may have been more likely to remember zoster than seronegative men. However, this is unlikely given the severity of symptoms often associated with zoster. Our results may also be affected by survival bias; men developing AIDS and dying before 1987 are not included in this study, and this may underestimate the rate of herpes zoster early after HIV infection. Finally, as this study is based on homosexual men initially recruited from a sexually transmitted disease clinic, the results may not generalize to other HIVseronegative and -seropositive groups. Nonetheless, this study has important implications for clinicians. Patients with herpes zoster should be counseled about risk factors for HIV infection and, when appropriate, offered HIV antibody testing. This recommendation applies to all patients without another cause of immunosuppression, regardless of age; the RR of herpes zoster due to HIV infection was three times higher for men aged 50-59 years than for men aged 20-29. For patients with known HIV infection, development of herpes zoster does not affect prognosis and should not signal a need to change ongoing antiviral or prophylactic regimens. Our study raises several intriguing questions about the pathophysiology of herpes zoster. Cellular immunity plays a critical role in inactivating varicella-zoster virus and maintaining its latent state [I, 15]. It appears that T lymphocytes are necessary for viral inactivation and that a relative loss of CD4+ cells and an excess of CD8+ cells accompanies acute zoster outbreaks. Humoral immunity, in contrast, does not appear to be important in viral inactivation, and antibodies to varicella-zoster may in fact block cell-mediated inactivation of the virus. HIV infection causes a gradual loss ofCD4+ cell number and function. However, our study did not find an increasing risk of zoster with increasing duration of infection, as would be expected ifCD4+ cell function was solely responsible for increased zoster risk. CD8+ cells may also play an important role in reactivating varicella-zoster and are known to increase early in HIV infection. Thus, an increase in CD8+ cells may add risk at a time when CD4+ cell function is relatively intact and distribute the risk of herpes zoster throughout the duration of HIV infection. Other sexually transmitted infections, such as cytomegalovirus, also cause a relative increase in CD8+ cell counts; exposure to such agents may explain the increased risk of zoster in HIV-seronegative men when compared with age-matched controls. In addition to providing useful clinical information, the examination of the complex interaction between herpes zoster and HIV infection provides useful insight into the patho-
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Figure 2. Cumulative proportion of HIV-seropositive men developing herpes zoster up to II years after HIV seroconversion.
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physiology of both diseases. The role of biologic and behavioral cofactors contributing to their morbidity deserves further investigation.
6. 7.
Acknowledgments
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We thank L. J. Melton for providing data from his study and the following people for their invaluable assistance in this study: J. Lowell Barnhart, Torsten Bodecker, Melchor Bustamante, David Colbert, Lynda Doll, Delia Garcia, Sandra Hernandez, Elaine Hung, Robert Kono, Irene Lee, Bobby Martin, Martha Rogers, Chris Rubino, Belinda Van, Robert Wade, and the men in the San Francisco City Clinic Cohort Study.
9.
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II. I. Weller TH. Varicella and herpes zoster: changing concepts of the natu-
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ral history. control, and importance ofa not-so-benign virus. N Engl J Med 1983;309: I 362-8. 1434-40. Masur H. Michelis MA, Greene JB, et al. An outbreak of communityacquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med 1981;305: 143 1-8. Friedman-Kien AE. Lafleur FL. Gendler E, et al. Herpes zoster: a possible early clinical sign for development of acquired immunodeficiency syndrome in high risk individuals. J Am Acad Dermatol 1986; I4: 1023-8. Sandor E. Croxson TS, Millman A, Mildvan D. Herpes zoster ophthalmicus in patients at risk for AIDS [letter]. N Engl J Med 1984;310:1 I 18-9. Colebunders R, Mann JM. Francis H, et al. Herpes zoster in African
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patients: a clinical predictor of human immunodeficiency virus infection. J Infect Dis 1988; I 57:3 I 4-8. Verroust F. Lemay D. Laurian Y. High frequency of herpes zoster in young hemophiliacs [letter]. N Engl J Med 1987;3 I 6: I 66-7. Melbye M. Grossman RJ, Goedert JJ, Eyster ME, Biggar RJ. Risk of AIDS after herpes zoster. Lancet 1987; I:728-31. Melbye M. Biggar RJ. Ebbesen P. et al. Long-term seropositivity for human T-lymphotropic virus type III in homosexual men without the acquired immunodeficiency syndrome: development ofimmunologic and clinical abnormalities. Ann Intern Med 1986; I04:496500. Van Griensven GJP. de Vroome EMM. de WolfF, Goudsmit J, Roos M. Coutinho RA. Risk factors for progression of human immunodeficiency virus (HIV) infection among seroconverted and seropositive homosexual men. Am J EpidemioI1990;132:203-1O. Moss AR. Bacchetti P, Osmond D. et al. Seropositivity for HIV and the development of AIDS or AIDS related condition: three year follow up of the San Francisco General Hospital cohort. Br Med J 1988;296:745-50. Rutherford GW. Lifson AR. Hessol NA. et al. Course of HIV-I infection in a cohort of homosexual and bisexual men: an II year follow up study. BMJ 1990;30 I: II 83-8. Ragozzino MW, Melton U, Kurland LT. Chu CPo Perry HO. Population-based study of herpes zoster and its sequelae. Medicine 1982;61 :310-6. Rothman KJ. Modern epidemiology. Boston: Little. Brown, 1986: 210-3. Katz MH, Greenspan D, Westenhouse J, et al. Progression to AIDS in HIV-infected homosexual and bisexual men with hairy leukoplakia and oral candidiasis: results from three San Francisco epidemiologic cohorts. AIDS 1992;6:95-100. Arvin AM, Pollard RB. Rasmussen LE, Merigan TC. Cellular and humoral immunity in the pathogenesis of recurrent herpes viral infections in patients with lymphoma. J Clin Invest 1980;65:869-78.
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