Public Health Briefs
Departnent of Veterans Affairs and by the National Institute on Drug Abuse (grant R01 DA05281). The data presented here were presented, in part, as a poster exhibit at the Seventh International Conference on AIDS, Florence, Italy, June 16-21, 1991. The authors were supported in their data colection efforts by the treatment staffof the Outpatient Clinic, Addiction Treatment Center, Veterans Affairs Medical Center, Seattle, Wash.
changing their seal than their needlesharingpmce. PosterpresentedattheFifth to
Intenatimal Conference on AIDS; June4-9, 1989; Montreal, Quebec, Canada. 4. Kall KI, Olin RG. HIV status and changes in risk behavior among intravenous drug 5.
References 6.
1. Guydish JR, GoldenE, HembryK. Needle sharing, needle cleaning, and risk behavior change among injection drug users. In: Sorensen JL, Wermuth LA, Gibson DR, Choi K, Guydish JR, Batki SL, eds. PrveMg AIDS in Drug Users and 77eirSexualPatners. NewYork, NY: Guilford Press; 1991: 28-42. 2. Choi K, Wermuth LA. Unsafe sex and behavior change. In: Sorensen JL, Wermuth LA, Gibson DR, Choi K, Guydish JR, Batki SL, eds. Preventin AIDS in Dnmg Users and Their Sexual Patners. New York, NY: Guilford Press; 1991:43-61. 3. JainS, FlynnN, BaileyV, SwehaA,DingD, Sloan W. IVDU and AIDS: more resisance
..........~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.-. fS
SS. fS-;fSsf'S: SSSS:f: fs: fS f f'-^:LS::: US.::: 8ff'S :Ri: -:Ssf::ff :::S:s:...................................... fs::'S ::-: LS.Ss 5i....S......... :: :S5: ::} ::.f::': S :'}R. ::.''........:::....f.f::;:...:}f:Afe::: ::::: S'fR ff ::'CR Z ::f::::::::}:.:'f:::::'::S ..: S5.s : ................:.S...S....f f f :>; .S| :e ..............: S::S::S:: S:: ':::::': ::''S':S:': ....f:':'::'S:. S :'::........ ::}S'::S::':':S''S ::':::'::: ::: }S'::::'S' S:}S:
...
,'::,,},:,:,S.ff-:S:.. '§ f _ -,,S,:S,: S,S,:-:,S,:-.f .--.f::SS: ,, ,.;.f!
~ ~~ ~ ~ ~~ ~
8.
e..
The Progression of Untreated HIV-1 Infection Prior to AIDS Donald 1 Hoove, PhD Alfred Saa/h MD, Helena Bacellar, MA, Robert
W_,s,e....ff.......
-:-x.-f -e.:..s.:.::--:s:s: ..:::-- ::::.::.s:.:.::..:fs< .-.
7.
users in Stockholm 1987-1988.Aids. 1990; 4:153-157. van den HoekA, van Haastrecht HJA. Litdle change in sexual behavior in drug users in Amsterdam. Poster presented at the Sixth International Conference on AIDS; June 20-24, 1990; San Francisco, Calif. Calsyn DA, Saxon AJ, Freeman G Jr, Whittaker S. Ineffectiveness of AIDS education and HIV antibody testing in reducing high-risk behaviors among injection drug users. Am J Public Heakh 1992;82; 573-575. Chitwood DD, McCoy CB, McCoy HV, McKay C, McBride DC, Comerford M. Evaluation of a risk reduction program for intravenous drug users. Poster presented at the Sixth International Conference on AIDS; June 20-24, 1990; San Francisco, Calif. Watters JK, Cheng YT, Segal M, Lorvick J, Case P, Carlson J. Epidemiology and prevention of HIV in intravenous drug us-
ers in San Francisco, 1986-1989. Poster presented at the Sixth International Conference on AIDS; June 20-24, 1990; San Francisco, Calif. 9. Hjorther A, Nielsen FM, Segest E. Prevention of AIDS: free condoms to drug abusers in the municipality of Copenhagen. IntJAddict. 1990;25:745-753. 10. Stephens RC, Feucht TE, Roman SW. Effects of an intervention on AIDS-related drug and needle behavior among intravenousdrugusers.AmJPubficHealh 1991; 81:568-571. 11. Sorensen JL, London J, Morales ES. Group counseling to prevent AIDS. In: Sorensen JL, Wermuth LA, Gibson DR, Choi K, Guydish JR, Batki SL, eds. Prvenig AIDS in Dng Users and Their Sexaal Partners. NewYork, NY: Guilford Press; 1991: 99-115. 12. Meinecke C. Maximizing Effective and Reliable Use of Condoms: An HIVRiskReduction Program for Intravenos Dng Users. Cincinnati, Ohio: UniversityofCincinnati; 1991. Doctoral dissertation. 13. Prochaska JO. What causes people to change from unhealthy to health enhancing behavior? Cancer Prev. 1990;1:38-42.
S'f fs ':}"::}'::B }.}-,}-},..............:,8':''::' .fi. ........:...........,S ,,S:--
Mwuphy, MD, Barbara Vsscher, MD, DrPH, Sharon MeiZ RN, MPH, RogerAnderson, MD, and Richard A. Kaslow, MD, MPH
-°''::fS, }S',,f,: .,:,S:.: st ste -f
s-
fCs: fes:-Sf f-........f...'....'. -'e'...'.
S' sess f
In rodudion The objective of this study was to estimate the timing and impact of human immunodeficiency virus (HIV-linduced effects on homosexual men during the period immediately preceding a diagnosis of acquired immunodeficiency syndrome (AIDS). We used simple matching and data reorganization methods to distinguish any pre-AIDS HIV-1 effects from other chronological changes in the cohort.
~~~~~~~~~~~~~~.:...:.r.
.......'.:':.'.'....-..
.-SsS
ff~~~~~~~~~~ ........................
:S.:::.:SS}SS:-.SS:-.::::.:S.
'f" tf
f -SS.,:'......
.......
Mate,ial and Mehods
...................
.S..,....
:S''R.':::::':::'S: .--:: ,, S ''... :-.,.f :."., ',. !.; ''^'"'' :S 5sfSsf:':"'5s:gS5::'f:'-:RSfff'SS E f:f}ssf:ss:::}:::f::sses:2:2sssseRs::: :|:SS5S5:f5::5 2:f.B :: > , f: Sf>
ssf:fS.............Ss:s:
*.a fS . Sf. SiS f-"|; l..|#
S
:
S
-
U
3_
S
^
_!S-
:S:S:s:ss: f _-: ,S,:: S,,:f.S,::f
X
2. S f..-.-...-..-.
The Multicenter AIDS Cohort Study (MACS)1 consists of homosexual or bisexual men being seen semiannually for an interview, a physical examination, and laboratory testing. Case subjects here were 387 men diagnosedwith AIDS (using the 1987 Centers for Disease Control [CDC] definition2) before October 1988. Up to that time, pre-AIDS antiretroviral
therapy and Pneumocystis cannii pneumonia (PCP) prophylaxis were uncommon. One HIV-1 seropositive control subject who was not diagnosed with AIDS by December 1989 was matched to each case Donald R. Hoover, Alfred Saah, Helena Bacellar, and Sharon Metz are with the School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Md. Robert Murphy is with the Division of Infectious Diseases, Northwestern University Medical School, Evanston, Ill. Barbara Visscher is with the School of Public Health and Jonsson Comprehensive Cancer Center, University of California, Los Angeles. Roger Anderson is with the Graduate School of Public Health, University of Pittsburgh, Pa. Richard A. Kaslow is with the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Request for reprints should be sent to Donald R. Hoover, PhD, Departnent of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, 624 N Broadway, Room 784, Baltimore, MD 21205. This paper was submitted June 17, 1991, and accepted with revisions July 8, 1992.
November 1992, Vol. 82, No. 11
Pubfic Health Briefs
subject according to same study center and 3-month entry period. Study visits for case and matched control subjects were renumbered backwards from the date AIDS was diagnosed in the case subject: visit 0 being 0 to 182 days (0 to 6 months) after diagnosis; visit -1 being 1 to 182 days (within 6 months) before diagnosis; visit -2 being 183 to 365 days (6-12 months) before diagnosis; and so forth. Matched control subjects were AIDS-free at least one year longer beyond a renumbered visit than were case subjects. Since renumbered visits for control subjects occurred at the same chronological time as those for matched case subjects, comparisons by renumbered visit removed confounding from chronological changes in measures occurring independentlyof the disease process (i.e., changes in laboratory techniques, protocol changes, etc.). Trained interviewers documented selfreported occurrence during the 6-month period prior to each visit of2weeks or more of the following symptoms: persistent fatigue, thrush, night sweats, diarrhea, fever over 100 SF, unintentional weight loss of 10 or more lbs, remarkable headache, new skin rash, new or unusual cough, sore throat or mouth, unusual bruises or skin discoloration, and shortness of breath. We computed the "Minimum Symptom DaysiYear" as (total symptoms per 6-month period) times (14 days of symptoms) times (2 6-month periods per year). This formula probably underestimates the yearly rates ofthese symptoms, because 2 weeks in the formula represents symptoms lasting 2 to 26 weeks, and symptoms not lasting 2 weeks were omitted from our study. Nevertheless, it may be useful in obtaining a lower bound for HIV-1 impact. Reported fever during the week prior to the visit was analyzed. Employment status, Center for Epidemiological Studies Depression Score (CES-D),3 weight, temperature, hemoglobin, mean corusculr volume, and CD4+ cell counts were obtained.
Results Case and control subjects did not differ statistically by age (mean 34.0 years and 33.7 years, respectively) or ethnicity (12% and 13% non-White, respectively). Table 1 gives case-control summaries from 6 pre-AIDS visits through the visit following AIDS diagnosis. Beginning 2 to 2.5 years (5 visits) prior to an AIDS diagnosis, case subjects had more total symptoms than did their matched control subjects (0.75 vs 0.39, November 1992, Vol. 82, No. 11
P 5 .01). Mean total symptoms in case subjects rose to 1.19 (53.7% reporting at least one symptom) by 6 to 12 months prior to AIDS and to 1.93 within 6 months before AIDS (64.9% reporting at least one). Immediately following an AIDS diagnosis, case subjects had an average of 4.00 total symptoms (91.4% with at least one). Among symptoms, thrush, rash, persistent fatigue, and fever showed the largest increases with a subject's progression towards AIDS. Reported thrush and fever were specific for imminent AIDS onset, being uncommon in the control subjects and, until 6 to 12 months prior to AIDS diagnosis, in the case subjects. Rash and fatigue had high background levels (at least 5%) in the control subjects but were more prevalent in the case subjects even at 2 to 2.5 years prior to AIDS. At 12 to 18, 6 to 12, and within 6 months prior to a diagnosis of AIDS, 11.9%, 14.6%, and 25.3% of the case subjects reported fever during the week prior to the respective visit. These percentages are well above the background rate of around 5.0% for seropositive controls; the average difference was equivalent to 9.6 extra weeks in which fever was reported during the 1.5 years prior to AIDS (9.6 = [(26weeks per 6 month period) x ([11.9 5.0] + [14.6 - 5.0] + [25.3 - 5.0])]/100). Case subjects generally had higher CES-D scores. By 6 to 12 months prior to AIDS diagnosis, the difference was statistically significant (10.9 versus 9.4, P c .05). Generally, 15 to 20% of the control subjects demonstrated clinical depression (CES-D 2 16).3 At 6 to 12 months, within 6 months prior to AIDS, and at 0 to 6 months following AIDS diagnosis, depression was present in 26.7%, 34.2%, and 42.7% of case subjects, respectively. More case than control subjects were unemployed within 6 months prior to AIDS diagnosis: 9% vs 4% (P < .05). The increase in reported fever noted earlier agrees with a rise in the measured temperatures of men progressing to AIDS. Overall, only 1% of control subjects had temperatures greater than 100 OF. However, at 12 to 18, 6 to 12, and within 6 months prior to AIDS, 2%, 3%, and 7%, respectively, of case subjects had temperatures above 100 'F. At 6 to 12 and within 6 months before AIDS, case subjects had statistically higher temperatures than control subjects (P c .05 and P < .001, respectively). Hemoglobin was lower in case than in control subjects beginning 2 to 2.5 years prior to AIDS. At 18 to 12, 12 to 6, and within 6 months prior to AIDS, 9.5%, 17.1%, and 31.5%, respec-
tively, of case subjects had anemia by the World Health Organization definition, Hb < 13.0 g/dL.4 Control subjects rarely had anemia. This agrees with other reports that anemia is associated with increased risk of disease progression.5,6 Control subjects rarely had CD4+ cell counts less than 200 x 106/L. In contrast, at 18 to 12, 12 to 6, and within 6 months before AIDS diagnosis, 19.3%, 37.7%, and 64.7%, respectively, of case subjects had CD4+ counts less than 200 x 106/L. At all pre-AIDS times, weight, depression, and unemployment in case subjects did not differ between those with CD4+ counts less than and thosewith counts equal to or greater than 200 x 106/ L (data not shown). Although case subjects with CD4+ counts less than 200 x 106/L had signiificantly more symptoms, the magnitude of this difference was not great. Anemia in case subjects was strongly correlated with low CD4+ levels. At 12 to 6 and within 6 months prior to AIDS, only 12.3% and 10.4%, respectively, of case subjects with CD4+ counts equal to or greater than 200 x 10 6/L were anemic.
Diswussion In the absence of PCP prophylaxis/ antiretroviral therapy, homosexual and bisexual men in our cohort experienced an increase of, at minimum, 46.5 more days of uncomfortable symptoms (beginning 2.5 years prior to AIDS diagnosis) and 9.6 extra weeks of reported fever (beginning 1.5 years prior to AIDS). An economic impact of extra physician and hospital visits and lost workdays was certainly associated with this burden to patients. Not all individuals reported preAIDS symptoms. Within 6 months prior to AIDS, 35% reported no symptoms. Of those case subjects attending all 6 visits before AIDS diagnosis, 11% never reported symptoms, compared to 36% of control subjects with similar attendance. Some men might not have recognized or acknowledged pre-AIDS symptoms. Alternatively, some individuals might have experienced a precipitous decline in health. Other studies have found that unemployment greatly increases after a diagnosis of AIDS.7'8 Our study's higher percentage (almost 10%) of case subjects who were unemployed prior to AIDS could have implications for health insurance. Our cohort consisted predominantly of white collar workers,' who may be less influenced by fatigue or health status than other American Journal of Public Health 1539
Public Health Briefs
1540 American Journal of Public Health
November 1992, Vol. 82, No. 11
Public Health Bnfefs
workers. Those losing employment prior to AIDS may be abruptly disqualified for medical and disability coverage. The Federal Consolidated Omnibus Budget Reconciliation Act (COBRA) allows extension of work health coverage for 18 months after employment termination, if this extension is requested within 60 days of losing work. Individuals must pay to extend this health coverage and may choose not to do so in the absence of diagnosed AIDS. We excluded those subjects receiving pre-AIDS antiretoviral treatments or PCP prophylaxis, which prolong the period prior to the development of AIDS9 10,11 and produce significant side effects.9'10.12 Further research is needed to quantify the pre- and post-AIDS impact of such therapies. Should therapies prevent AIDS onset without also reducing pre-AIDS symptoms, our findings may underestimate the current pre-AIDS impact of HIV-1. Since zidovudine accelerates anemia,8.9,11 our findings of 30% pre-AIDS anemia in untreated men demonstrate the need to monitor hemoglobin levels of HIV-1 infected individuals. Recently, the CDC has considered including a measured CD4+ count less than 200 x 106/L as an AIDS-defining diagnosis.13 Because CD4+ counts less than 200 x 106/L frequently occurred in our case subjects within 18 months before a clinical AIDS diagnosis, and because anemia rarely occurred in those with CD4+ counts equal to or greater than 200 x 106/ L, such a change in definition could significantly reduce the current level of preAIDS HIV-1 effects in a regularly tested population. Other issues surrounding the implementation and effects of this proposed definitional change are more thoroughly discussed in another MACS pub-
lication.14 0]
November 1992. Vol. 82, No. 11
Acknowldgments This work was supported by National Institutes of Health contracts AI-72631, AI-72632, AI72634, AI-72676, and AI-32535 and grant DRR5MORR00722. The authors thank Lewis Schrager for substantial contributions and Edith Muth for secretarial support. Centers and investigators in the Multicenter AIDS Cohort Study: Data Coordinating Center, Johns Hopkins School of Public Health, Baltimore, Md.: A. Munioz, V. Carey, D. Hoover, L. P. Jacobson; Johns Hopkdns School of Public Heakh, Baltimore, Md.: A. Saah, H. Farzadegan, N. Graham, J. Margolick, J. McArthur, N. Odaka, J. Palenicek; Howard Brown Memonal Clinic, Northwestem University Medical School, Chicago, Ill.: J. P. Phair, J. S. Chmiel, B. Cohen, K. Sheridan, S. Wolinsky; University of Pittsburgh School ofPublic Health, Pittsburgh, Pa.: C. R. Rinaldo, J. Armstrong, P. Gupta, M. Ho, L. A. Kingsley; University of California-Los Angeles Schools ofPublic Health and Medicine: R. Detels, B. R. Visscher, J. Dudley, J. L. Fahey, J. V. Giorgi, J. Taylor; National Instiute of Allery and Infectious Diseases, Bethesda, Md.: S. H. Vermund, L. K Schrager, R. A. Kaslow, M. J. VanRaden; National CancerInstite, Bethesda, Md.: I. Obrams, D. Seminara.
References 1. Kaslow RA, Ostrow DG, Detels R, et al. The Multicenter AIDS Cohort Study: rationale, organization and selected characteristics of the participants. Am J Epide-
mioL 1987;126:310-318. 2. Centers for Disease Control. Revision of the CDC surveillance case definition for Acquired Immunodeficiency Syndrome. MMWR 1987;36(suppl no. 1S):1-15. 3. RadloffLS. The CES-D Scale: a self-report depression scale for research in the general population.ApplPsychMeas. 1977;1:385401. 4. Callender ST. Blood Disorders: The Facts. Oxford, England: Oxford University Press; 1985. 5. Kaslow RA, Phair JP, Friedman HB, et al. Infection with the Human Immunodeficiency Virus: clinical manifestations and
their relationship to immune deficiency. Ann Intem Med. 1987;107:474-480. 6. 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; 296:745-750. 7. Yelin EH, Greenblatt RM, Hollander H, et al. The impact of HIV-related illness on employment.AmJPublicHealth. 1991;81: 1990;79-84. 8. Metz S, Fox R, Odaka N, et al. Employment status of men diagnosed with AIDS in the Baltimore MACS. Proceedings of the Sixth International Conference on AIDS; Montreal, Quebec, Canada; 3:SD 813. 9. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immune deficiency virus infection: a controiled clinical trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. NEngI J MedL 1990;322:941-949. 10. Fischl MA, Richman DD, Hansen N, et al. The safety and efficacy of Zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus Type 1 (FHV) infection. Ann Intem Med. 1990;112:727-737. 11. Kovacs JA. Diagnosis, treatment and prevention of Pnewnocystis cannii pneumonia in HIV infected people.AIDS Updates. 1989;2:1-12. 12. Richman DD, Fischl MA, Greico MH, et al. The toxicity of Azydothymidine (AZT) in the treatment of patients with AIDS and AIDS-related-complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987;317:192-197. 13. Sheppard HW, Winkelstein W, Osmond D, Moss A, et al. Effect of new AIDS case definition on numbers of cases among homosexual and bisexual men in San Francisco. JAMA. 1991;226:2221. Letter. 14. Hoover DR, Graham NMH, Chen B, et al. Effect of CD4+ cell count measurement variability on staging HIV-1 infection. J Acquir Immune Defic Syndr. 1992;5:794802.
American Joumal of Public Health 1541
Departnent of Veterans Affairs and by the National Institute on Drug Abuse (grant R01 DA05281). The data presented here were presented, in part, as a poster exhibit at the Seventh International Conference on AIDS, Florence, Italy, June 16-21, 1991. The authors were supported in their data colection efforts by the treatment staffof the Outpatient Clinic, Addiction Treatment Center, Veterans Affairs Medical Center, Seattle, Wash.
changing their seal than their needlesharingpmce. PosterpresentedattheFifth to
Intenatimal Conference on AIDS; June4-9, 1989; Montreal, Quebec, Canada. 4. Kall KI, Olin RG. HIV status and changes in risk behavior among intravenous drug 5.
References 6.
1. Guydish JR, GoldenE, HembryK. Needle sharing, needle cleaning, and risk behavior change among injection drug users. In: Sorensen JL, Wermuth LA, Gibson DR, Choi K, Guydish JR, Batki SL, eds. PrveMg AIDS in Drug Users and 77eirSexualPatners. NewYork, NY: Guilford Press; 1991: 28-42. 2. Choi K, Wermuth LA. Unsafe sex and behavior change. In: Sorensen JL, Wermuth LA, Gibson DR, Choi K, Guydish JR, Batki SL, eds. Preventin AIDS in Dnmg Users and Their Sexual Patners. New York, NY: Guilford Press; 1991:43-61. 3. JainS, FlynnN, BaileyV, SwehaA,DingD, Sloan W. IVDU and AIDS: more resisance
..........~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.-. fS
SS. fS-;fSsf'S: SSSS:f: fs: fS f f'-^:LS::: US.::: 8ff'S :Ri: -:Ssf::ff :::S:s:...................................... fs::'S ::-: LS.Ss 5i....S......... :: :S5: ::} ::.f::': S :'}R. ::.''........:::....f.f::;:...:}f:Afe::: ::::: S'fR ff ::'CR Z ::f::::::::}:.:'f:::::'::S ..: S5.s : ................:.S...S....f f f :>; .S| :e ..............: S::S::S:: S:: ':::::': ::''S':S:': ....f:':'::'S:. S :'::........ ::}S'::S::':':S''S ::':::'::: ::: }S'::::'S' S:}S:
...
,'::,,},:,:,S.ff-:S:.. '§ f _ -,,S,:S,: S,S,:-:,S,:-.f .--.f::SS: ,, ,.;.f!
~ ~~ ~ ~ ~~ ~
8.
e..
The Progression of Untreated HIV-1 Infection Prior to AIDS Donald 1 Hoove, PhD Alfred Saa/h MD, Helena Bacellar, MA, Robert
W_,s,e....ff.......
-:-x.-f -e.:..s.:.::--:s:s: ..:::-- ::::.::.s:.:.::..:fs< .-.
7.
users in Stockholm 1987-1988.Aids. 1990; 4:153-157. van den HoekA, van Haastrecht HJA. Litdle change in sexual behavior in drug users in Amsterdam. Poster presented at the Sixth International Conference on AIDS; June 20-24, 1990; San Francisco, Calif. Calsyn DA, Saxon AJ, Freeman G Jr, Whittaker S. Ineffectiveness of AIDS education and HIV antibody testing in reducing high-risk behaviors among injection drug users. Am J Public Heakh 1992;82; 573-575. Chitwood DD, McCoy CB, McCoy HV, McKay C, McBride DC, Comerford M. Evaluation of a risk reduction program for intravenous drug users. Poster presented at the Sixth International Conference on AIDS; June 20-24, 1990; San Francisco, Calif. Watters JK, Cheng YT, Segal M, Lorvick J, Case P, Carlson J. Epidemiology and prevention of HIV in intravenous drug us-
ers in San Francisco, 1986-1989. Poster presented at the Sixth International Conference on AIDS; June 20-24, 1990; San Francisco, Calif. 9. Hjorther A, Nielsen FM, Segest E. Prevention of AIDS: free condoms to drug abusers in the municipality of Copenhagen. IntJAddict. 1990;25:745-753. 10. Stephens RC, Feucht TE, Roman SW. Effects of an intervention on AIDS-related drug and needle behavior among intravenousdrugusers.AmJPubficHealh 1991; 81:568-571. 11. Sorensen JL, London J, Morales ES. Group counseling to prevent AIDS. In: Sorensen JL, Wermuth LA, Gibson DR, Choi K, Guydish JR, Batki SL, eds. Prvenig AIDS in Dng Users and Their Sexaal Partners. NewYork, NY: Guilford Press; 1991: 99-115. 12. Meinecke C. Maximizing Effective and Reliable Use of Condoms: An HIVRiskReduction Program for Intravenos Dng Users. Cincinnati, Ohio: UniversityofCincinnati; 1991. Doctoral dissertation. 13. Prochaska JO. What causes people to change from unhealthy to health enhancing behavior? Cancer Prev. 1990;1:38-42.
S'f fs ':}"::}'::B }.}-,}-},..............:,8':''::' .fi. ........:...........,S ,,S:--
Mwuphy, MD, Barbara Vsscher, MD, DrPH, Sharon MeiZ RN, MPH, RogerAnderson, MD, and Richard A. Kaslow, MD, MPH
-°''::fS, }S',,f,: .,:,S:.: st ste -f
s-
fCs: fes:-Sf f-........f...'....'. -'e'...'.
S' sess f
In rodudion The objective of this study was to estimate the timing and impact of human immunodeficiency virus (HIV-linduced effects on homosexual men during the period immediately preceding a diagnosis of acquired immunodeficiency syndrome (AIDS). We used simple matching and data reorganization methods to distinguish any pre-AIDS HIV-1 effects from other chronological changes in the cohort.
~~~~~~~~~~~~~~.:...:.r.
.......'.:':.'.'....-..
.-SsS
ff~~~~~~~~~~ ........................
:S.:::.:SS}SS:-.SS:-.::::.:S.
'f" tf
f -SS.,:'......
.......
Mate,ial and Mehods
...................
.S..,....
:S''R.':::::':::'S: .--:: ,, S ''... :-.,.f :."., ',. !.; ''^'"'' :S 5sfSsf:':"'5s:gS5::'f:'-:RSfff'SS E f:f}ssf:ss:::}:::f::sses:2:2sssseRs::: :|:SS5S5:f5::5 2:f.B :: > , f: Sf>
ssf:fS.............Ss:s:
*.a fS . Sf. SiS f-"|; l..|#
S
:
S
-
U
3_
S
^
_!S-
:S:S:s:ss: f _-: ,S,:: S,,:f.S,::f
X
2. S f..-.-...-..-.
The Multicenter AIDS Cohort Study (MACS)1 consists of homosexual or bisexual men being seen semiannually for an interview, a physical examination, and laboratory testing. Case subjects here were 387 men diagnosedwith AIDS (using the 1987 Centers for Disease Control [CDC] definition2) before October 1988. Up to that time, pre-AIDS antiretroviral
therapy and Pneumocystis cannii pneumonia (PCP) prophylaxis were uncommon. One HIV-1 seropositive control subject who was not diagnosed with AIDS by December 1989 was matched to each case Donald R. Hoover, Alfred Saah, Helena Bacellar, and Sharon Metz are with the School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Md. Robert Murphy is with the Division of Infectious Diseases, Northwestern University Medical School, Evanston, Ill. Barbara Visscher is with the School of Public Health and Jonsson Comprehensive Cancer Center, University of California, Los Angeles. Roger Anderson is with the Graduate School of Public Health, University of Pittsburgh, Pa. Richard A. Kaslow is with the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Request for reprints should be sent to Donald R. Hoover, PhD, Departnent of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, 624 N Broadway, Room 784, Baltimore, MD 21205. This paper was submitted June 17, 1991, and accepted with revisions July 8, 1992.
November 1992, Vol. 82, No. 11
Pubfic Health Briefs
subject according to same study center and 3-month entry period. Study visits for case and matched control subjects were renumbered backwards from the date AIDS was diagnosed in the case subject: visit 0 being 0 to 182 days (0 to 6 months) after diagnosis; visit -1 being 1 to 182 days (within 6 months) before diagnosis; visit -2 being 183 to 365 days (6-12 months) before diagnosis; and so forth. Matched control subjects were AIDS-free at least one year longer beyond a renumbered visit than were case subjects. Since renumbered visits for control subjects occurred at the same chronological time as those for matched case subjects, comparisons by renumbered visit removed confounding from chronological changes in measures occurring independentlyof the disease process (i.e., changes in laboratory techniques, protocol changes, etc.). Trained interviewers documented selfreported occurrence during the 6-month period prior to each visit of2weeks or more of the following symptoms: persistent fatigue, thrush, night sweats, diarrhea, fever over 100 SF, unintentional weight loss of 10 or more lbs, remarkable headache, new skin rash, new or unusual cough, sore throat or mouth, unusual bruises or skin discoloration, and shortness of breath. We computed the "Minimum Symptom DaysiYear" as (total symptoms per 6-month period) times (14 days of symptoms) times (2 6-month periods per year). This formula probably underestimates the yearly rates ofthese symptoms, because 2 weeks in the formula represents symptoms lasting 2 to 26 weeks, and symptoms not lasting 2 weeks were omitted from our study. Nevertheless, it may be useful in obtaining a lower bound for HIV-1 impact. Reported fever during the week prior to the visit was analyzed. Employment status, Center for Epidemiological Studies Depression Score (CES-D),3 weight, temperature, hemoglobin, mean corusculr volume, and CD4+ cell counts were obtained.
Results Case and control subjects did not differ statistically by age (mean 34.0 years and 33.7 years, respectively) or ethnicity (12% and 13% non-White, respectively). Table 1 gives case-control summaries from 6 pre-AIDS visits through the visit following AIDS diagnosis. Beginning 2 to 2.5 years (5 visits) prior to an AIDS diagnosis, case subjects had more total symptoms than did their matched control subjects (0.75 vs 0.39, November 1992, Vol. 82, No. 11
P 5 .01). Mean total symptoms in case subjects rose to 1.19 (53.7% reporting at least one symptom) by 6 to 12 months prior to AIDS and to 1.93 within 6 months before AIDS (64.9% reporting at least one). Immediately following an AIDS diagnosis, case subjects had an average of 4.00 total symptoms (91.4% with at least one). Among symptoms, thrush, rash, persistent fatigue, and fever showed the largest increases with a subject's progression towards AIDS. Reported thrush and fever were specific for imminent AIDS onset, being uncommon in the control subjects and, until 6 to 12 months prior to AIDS diagnosis, in the case subjects. Rash and fatigue had high background levels (at least 5%) in the control subjects but were more prevalent in the case subjects even at 2 to 2.5 years prior to AIDS. At 12 to 18, 6 to 12, and within 6 months prior to a diagnosis of AIDS, 11.9%, 14.6%, and 25.3% of the case subjects reported fever during the week prior to the respective visit. These percentages are well above the background rate of around 5.0% for seropositive controls; the average difference was equivalent to 9.6 extra weeks in which fever was reported during the 1.5 years prior to AIDS (9.6 = [(26weeks per 6 month period) x ([11.9 5.0] + [14.6 - 5.0] + [25.3 - 5.0])]/100). Case subjects generally had higher CES-D scores. By 6 to 12 months prior to AIDS diagnosis, the difference was statistically significant (10.9 versus 9.4, P c .05). Generally, 15 to 20% of the control subjects demonstrated clinical depression (CES-D 2 16).3 At 6 to 12 months, within 6 months prior to AIDS, and at 0 to 6 months following AIDS diagnosis, depression was present in 26.7%, 34.2%, and 42.7% of case subjects, respectively. More case than control subjects were unemployed within 6 months prior to AIDS diagnosis: 9% vs 4% (P < .05). The increase in reported fever noted earlier agrees with a rise in the measured temperatures of men progressing to AIDS. Overall, only 1% of control subjects had temperatures greater than 100 OF. However, at 12 to 18, 6 to 12, and within 6 months prior to AIDS, 2%, 3%, and 7%, respectively, of case subjects had temperatures above 100 'F. At 6 to 12 and within 6 months before AIDS, case subjects had statistically higher temperatures than control subjects (P c .05 and P < .001, respectively). Hemoglobin was lower in case than in control subjects beginning 2 to 2.5 years prior to AIDS. At 18 to 12, 12 to 6, and within 6 months prior to AIDS, 9.5%, 17.1%, and 31.5%, respec-
tively, of case subjects had anemia by the World Health Organization definition, Hb < 13.0 g/dL.4 Control subjects rarely had anemia. This agrees with other reports that anemia is associated with increased risk of disease progression.5,6 Control subjects rarely had CD4+ cell counts less than 200 x 106/L. In contrast, at 18 to 12, 12 to 6, and within 6 months before AIDS diagnosis, 19.3%, 37.7%, and 64.7%, respectively, of case subjects had CD4+ counts less than 200 x 106/L. At all pre-AIDS times, weight, depression, and unemployment in case subjects did not differ between those with CD4+ counts less than and thosewith counts equal to or greater than 200 x 106/ L (data not shown). Although case subjects with CD4+ counts less than 200 x 106/L had signiificantly more symptoms, the magnitude of this difference was not great. Anemia in case subjects was strongly correlated with low CD4+ levels. At 12 to 6 and within 6 months prior to AIDS, only 12.3% and 10.4%, respectively, of case subjects with CD4+ counts equal to or greater than 200 x 10 6/L were anemic.
Diswussion In the absence of PCP prophylaxis/ antiretroviral therapy, homosexual and bisexual men in our cohort experienced an increase of, at minimum, 46.5 more days of uncomfortable symptoms (beginning 2.5 years prior to AIDS diagnosis) and 9.6 extra weeks of reported fever (beginning 1.5 years prior to AIDS). An economic impact of extra physician and hospital visits and lost workdays was certainly associated with this burden to patients. Not all individuals reported preAIDS symptoms. Within 6 months prior to AIDS, 35% reported no symptoms. Of those case subjects attending all 6 visits before AIDS diagnosis, 11% never reported symptoms, compared to 36% of control subjects with similar attendance. Some men might not have recognized or acknowledged pre-AIDS symptoms. Alternatively, some individuals might have experienced a precipitous decline in health. Other studies have found that unemployment greatly increases after a diagnosis of AIDS.7'8 Our study's higher percentage (almost 10%) of case subjects who were unemployed prior to AIDS could have implications for health insurance. Our cohort consisted predominantly of white collar workers,' who may be less influenced by fatigue or health status than other American Journal of Public Health 1539
Public Health Briefs
1540 American Journal of Public Health
November 1992, Vol. 82, No. 11
Public Health Bnfefs
workers. Those losing employment prior to AIDS may be abruptly disqualified for medical and disability coverage. The Federal Consolidated Omnibus Budget Reconciliation Act (COBRA) allows extension of work health coverage for 18 months after employment termination, if this extension is requested within 60 days of losing work. Individuals must pay to extend this health coverage and may choose not to do so in the absence of diagnosed AIDS. We excluded those subjects receiving pre-AIDS antiretoviral treatments or PCP prophylaxis, which prolong the period prior to the development of AIDS9 10,11 and produce significant side effects.9'10.12 Further research is needed to quantify the pre- and post-AIDS impact of such therapies. Should therapies prevent AIDS onset without also reducing pre-AIDS symptoms, our findings may underestimate the current pre-AIDS impact of HIV-1. Since zidovudine accelerates anemia,8.9,11 our findings of 30% pre-AIDS anemia in untreated men demonstrate the need to monitor hemoglobin levels of HIV-1 infected individuals. Recently, the CDC has considered including a measured CD4+ count less than 200 x 106/L as an AIDS-defining diagnosis.13 Because CD4+ counts less than 200 x 106/L frequently occurred in our case subjects within 18 months before a clinical AIDS diagnosis, and because anemia rarely occurred in those with CD4+ counts equal to or greater than 200 x 106/ L, such a change in definition could significantly reduce the current level of preAIDS HIV-1 effects in a regularly tested population. Other issues surrounding the implementation and effects of this proposed definitional change are more thoroughly discussed in another MACS pub-
lication.14 0]
November 1992. Vol. 82, No. 11
Acknowldgments This work was supported by National Institutes of Health contracts AI-72631, AI-72632, AI72634, AI-72676, and AI-32535 and grant DRR5MORR00722. The authors thank Lewis Schrager for substantial contributions and Edith Muth for secretarial support. Centers and investigators in the Multicenter AIDS Cohort Study: Data Coordinating Center, Johns Hopkins School of Public Health, Baltimore, Md.: A. Munioz, V. Carey, D. Hoover, L. P. Jacobson; Johns Hopkdns School of Public Heakh, Baltimore, Md.: A. Saah, H. Farzadegan, N. Graham, J. Margolick, J. McArthur, N. Odaka, J. Palenicek; Howard Brown Memonal Clinic, Northwestem University Medical School, Chicago, Ill.: J. P. Phair, J. S. Chmiel, B. Cohen, K. Sheridan, S. Wolinsky; University of Pittsburgh School ofPublic Health, Pittsburgh, Pa.: C. R. Rinaldo, J. Armstrong, P. Gupta, M. Ho, L. A. Kingsley; University of California-Los Angeles Schools ofPublic Health and Medicine: R. Detels, B. R. Visscher, J. Dudley, J. L. Fahey, J. V. Giorgi, J. Taylor; National Instiute of Allery and Infectious Diseases, Bethesda, Md.: S. H. Vermund, L. K Schrager, R. A. Kaslow, M. J. VanRaden; National CancerInstite, Bethesda, Md.: I. Obrams, D. Seminara.
References 1. Kaslow RA, Ostrow DG, Detels R, et al. The Multicenter AIDS Cohort Study: rationale, organization and selected characteristics of the participants. Am J Epide-
mioL 1987;126:310-318. 2. Centers for Disease Control. Revision of the CDC surveillance case definition for Acquired Immunodeficiency Syndrome. MMWR 1987;36(suppl no. 1S):1-15. 3. RadloffLS. The CES-D Scale: a self-report depression scale for research in the general population.ApplPsychMeas. 1977;1:385401. 4. Callender ST. Blood Disorders: The Facts. Oxford, England: Oxford University Press; 1985. 5. Kaslow RA, Phair JP, Friedman HB, et al. Infection with the Human Immunodeficiency Virus: clinical manifestations and
their relationship to immune deficiency. Ann Intem Med. 1987;107:474-480. 6. 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; 296:745-750. 7. Yelin EH, Greenblatt RM, Hollander H, et al. The impact of HIV-related illness on employment.AmJPublicHealth. 1991;81: 1990;79-84. 8. Metz S, Fox R, Odaka N, et al. Employment status of men diagnosed with AIDS in the Baltimore MACS. Proceedings of the Sixth International Conference on AIDS; Montreal, Quebec, Canada; 3:SD 813. 9. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immune deficiency virus infection: a controiled clinical trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. NEngI J MedL 1990;322:941-949. 10. Fischl MA, Richman DD, Hansen N, et al. The safety and efficacy of Zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus Type 1 (FHV) infection. Ann Intem Med. 1990;112:727-737. 11. Kovacs JA. Diagnosis, treatment and prevention of Pnewnocystis cannii pneumonia in HIV infected people.AIDS Updates. 1989;2:1-12. 12. Richman DD, Fischl MA, Greico MH, et al. The toxicity of Azydothymidine (AZT) in the treatment of patients with AIDS and AIDS-related-complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987;317:192-197. 13. Sheppard HW, Winkelstein W, Osmond D, Moss A, et al. Effect of new AIDS case definition on numbers of cases among homosexual and bisexual men in San Francisco. JAMA. 1991;226:2221. Letter. 14. Hoover DR, Graham NMH, Chen B, et al. Effect of CD4+ cell count measurement variability on staging HIV-1 infection. J Acquir Immune Defic Syndr. 1992;5:794802.
American Joumal of Public Health 1541
