CONCISE COMMUNICATION

611 CONCISE COMMUNICATION Risk for Preventable Opportunistic Infections in Persons with AIDS after Antiretroviral Therapy Increases CD4 + T Lymphocyte Counts above Prophylaxis Thresholds Mark S. Dworkin, 1 Debra L. Hanson, 1 Jonathan E. Kaplan, 1,2 Jeffrey L. Jones, 2 John W. Ward, 3 and the Adult/Adolescent Spectrum of HIV Disease Project a 1 Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, 2 National Center for Infectious Diseases, and 3 Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, Georgia To determine incidence and risk for preventable opportunistic infections (Pneumocystis carinii pneumonia [PCP] and disseminated Mycobacterium avium complex [MAC] infection) in persons whose CD4 + T lymphocyte counts had increased by 100 cells/ml to exceed the threshold of risk and in persons whose CD4 + counts had never dropped below the threshold of risk, we analyzed data collected during the period 1990 1998 in the Adult/Adolescent Spectrum of HIV (Human Immunodeficiency Virus) Disease Project. Using a counting-process formulation of the Cox model, we analyzed observation time in these 2 groups for persons who were prescribed antiretroviral therapy but not prophylaxis. The incidences of the infections were low for patients whose CD4 + count rose above the threshold of risk (PCP, 0.6 cases per 100 person-years [PY]; MAC, 1.0 cases per 100 PY) and not higher than in persons whose CD4 + counts had not decreased below these thresholds, which suggests that discontinuation of primary prophylaxis for opportunistic infections may be considered for some patients. Recent trends in AIDS-defining opportunistic illnesses indicate significant declines in their incidence and associated mortality [1], which have been attributed primarily to successful responses to highly active combination antiretroviral therapy in human immunodeficiency virus (HIV) infected persons [2]. Prophylaxis recommended for HIV-infected patients includes prevention of Pneumocystis carinii pneumonia (PCP) and disseminated Mycobacterium avium complex (MAC) infection [3]. These recommendations are based primarily on the observation that the risk for development of these infections is increased when the CD4 T lymphocyte counts decline to!200 cells/ml for PCP or!50 cells/ml for MAC. The number of medications taken by HIV-infected patients can be a significant burden. Adding these medications to patients drug treatment regimens adds to the cost and the risk Received 23 November 1999; revised 24 April 2000; electronically published 14 July 2000. Presented in part: 36th annual meeting of the Infectious Diseases Society of America, Denver, 12 15 November 1998, and 6th Conference on Retroviruses and Opportunistic Infections, Chicago, 31 January 4 February 1999. a A list of the Adult/Adolescent Spectrum of HIV Disease Project investigators follows the text. Reprints: National Center for HIV, STD, and TB Prevention, Office of Communications, Centers for Disease Control and Prevention, Mail Stop E-06, Atlanta, GA 30333. Correspondence: Dr. Mark S. Dworkin, Division of HIV/AIDS Prevention, Mail Stop E-47, Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30333 (mdd3@cdc.gov). The Journal of Infectious Diseases 2000;182:611 5 2000 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2000/18202-0033$02.00 for untoward effects, drug interactions, and antimicrobial resistance. Also, prophylaxis, by increasing pill burden, could increase the difficulty of adhering to complicated antiretroviral regimens. Therefore, HIV-infected patients and their physicians would benefit from information about the risk for opportunistic infections after the CD4 count rises above prophylaxis thresholds associated with increased risk in response to highly active antiretroviral therapy. If patients are at very low risk for these conditions once their CD4 counts increase, discontinuation of these medications may be reasonable. Recent published reports describe outcomes for European [4 6] and US patients [7] whose primary PCP prophylaxis was stopped after CD4 counts increased in response to highly active antiretroviral therapy. In these studies, there were no cases of PCP. A recent randomized placebo-controlled trial suggests that withdrawal of MAC prophylaxis may be safe [8]. Followup after CD4 cell count increases in these studies was limited. Also, another recently reported European study that examined the rate of disease progression after CD4 cell counts increased from very low levels to 200 cells/ml found that a low CD4 cell count nadir was associated with a higher risk for disease progression after the counts increased to 1200 cells/ml [9]. We analyzed data collected in the Adult and Adolescent Spectrum of HIV Disease Project (ASD) to compare the incidence of and risk for 2 preventable primary opportunistic infections (PCP and MAC) in patients whose CD4 count had risen above recommended CD4 prophylaxis thresholds of risk with those of patients whose counts had not been observed to decline

612 Dworkin et al. JID 2000;182 (August) below these thresholds. This study, which reflects actual practice patterns, provides information to consider, along with the emerging data from other observational data and clinical trials of discontinuation of primary prophylaxis. Subjects and Methods The methods used in ASD have been reported elsewhere [10]. ASD is a national surveillance project of the Centers for Disease Control and Prevention (CDC), in collaboration with 11 state and local health departments, in which information is abstracted from the medical records of HIV-infected patients at selected health care facilities. The initial data abstraction is a review of the 12 months before initial patient observation except for AIDS-defining conditions and HIV risk mode, which are recorded, if available, at any time before initial observation. The initial abstraction is followed by 6-month abstractions until death or loss to follow-up. Data collection began at project sites in 1990 (Atlanta, GA; Dallas, Houston, and San Antonio, TX; Denver, CO; Detroit, MI; Los Angeles, CA; New Orleans, LA; and Seattle, WA), 1991 (New York, NY), and 1992 (Bayamon, PR). More than 100 participating facilities include hospitals, outpatient offices, and emergency rooms. Patients in our analysis were observed during 1990 1999, using the September 1999 ASD data. Criteria for Group Membership Patients were considered eligible for the analysis if antiretroviral therapy had been prescribed and they met the following group membership criteria. PCP. Group PCP1 patients had a CD4 count of!200 cells/ ml, which was followed by a rise of 100 cells to 200 cells/ml. Group PCP2 patients had never had a recorded CD4 count of!200 cells/ml. In addition, group PCP2 patients did not have a history of oral candidiasis or previous prescription of PCP prophylaxis. Patients with a history of PCP were excluded. MAC. Group MAC1 patients had a CD4 count of!50 cells/ ml, which was followed by a rise of 100 cells to 100 cells/ml. Group MAC2 patients had never had a recorded CD4 count of!100 cells/ml, and prophylaxis had not been prescribed for disseminated MAC. Patients with a history of MAC were excluded. Incidence of Primary PCP and MAC among Persons Not Prescribed Primary Prophylaxis Cases of the 2 opportunistic infections met the CDC AIDS surveillance case definition for the specific infection [11]. Because the AIDS case definition and ASD combine collection of diagnosis of MAC with disseminated M. kansasi, for this analysis MAC includes both of these diagnoses. Cases included definitive and presumptive diagnoses. We calculated the incidence rates of primary PCP and MAC per 100 person-years (PY) in groups PCP1 and PCP2 and MAC1 and MAC2. To limit the analysis to the time when the patients were not taking prophylaxis against that specific opportunistic infection, for groups PCP1 and MAC1, we included only follow-up time when no prophylaxis was prescribed after the CD4 count increased above and, if it occurred, before the CD4 count decreased again to below the threshold of risk. For groups PCP2 and MAC2, only follow-up time at CD4 counts above the threshold of risk was included. More specifically, the PCP analysis included follow-up time for groups PCP1 and PCP2 before either a recorded CD4 count of!200 cells/ml or diagnosis of oral candidiasis or until diagnosis of PCP or last patient contact. The MAC analysis included follow-up time for group MAC1 or MAC2 before a CD4 count of!50 cells/ml or until diagnosis of MAC or last patient contact. Prophylactic medications were trimethoprim-sulfamethoxazole, pentamidine, and dapsone for PCP and clarithromycin, azithromycin, and rifabutin for MAC. Risk for the opportunistic infections was compared between groups PCP1 and PCP2 and MAC1 and MAC2 by use of a counting-process formulation of the Cox model [12]. The model controlled for HIV transmission mode, age, sex, race/ethnicity, city, and the time-dependent covariates CD4 cell count, calendar period, history of another AIDS opportunistic illness, and antiretroviral therapy regimen (mono, dual, or triple). Results Characteristics of the 2 groups for each opportunistic infection (PCP1 and PCP2 and MAC1 and MAC2) were similar in mode of HIV transmission, age, sex, and race (table 1). For persons who were prescribed 3-drug antiretroviral therapy, 90% of patients were prescribed a protease inhibitor. Among patients receiving any antiretroviral therapy, the incidence rates for the opportunistic infections, by group, were low and similar: 0.6 cases per 100 PY for group PCP1 versus 0.7 cases per 100 PY for group PCP2; 1.0 cases per 100 PY for group MAC1 versus 0.5 cases per 100 PY for MAC2. Among patients for whom dual or triple combination therapy had been prescribed, rates were also low (table 2). In the multivariate analysis of patients for whom any antiretroviral therapy had been prescribed (table 2), compared with patients whose CD4 counts had not fallen below the threshold of risk, patients whose counts had risen above the threshold of risk were not at significantly increased risk for PCP and MAC. We had insufficient evidence to conclude that there was an increased risk for PCP among persons prescribed triple combination therapy; the confidence limits were wide, although not statistically significant, and were based on only 3 PCP cases in group PCP1. Discussion Our findings demonstrate low incidence rates of PCP and MAC after CD4 cell counts have risen above the threshold of risk in AIDS patients treated with antiretroviral therapy. These low incidence rates also provide strong evidence of the significant effect that highly active antiretroviral therapy is having on the incidence of AIDS-associated opportunistic infections as a result of its effect on patients CD4 cell counts. The incidence of PCP and MAC in those with CD4 cell counts

JID 2000;182 (August) Risk for Opportunistic Infections 613 Table 1. Characteristics of human immunodeficiency virus (HIV) infected patients at the time of meeting group membership criteria. Characteristic PCP1 (n p 1012) PCP2 (n p 4123) MAC1 (n p 1136) MAC2 (n p 13,270) CD4 cell count/ml Median 327 414 174 320 Nadir, median 146 350 21 269 Increase from nadir, median 178 NA 146 NA Received combination antiretroviral therapy (%) a 68 37 82 35 Received protease inhibitor (%) b 44 16 70 13 Years of observation (%) 1990 1994 30 59 16 65 1995 1998 70 41 84 35 Median age (years) 37 34 37 35 Mode of HIV transmission (%) Male-male sex 51 48 49 49 Injection drug use 15 14 15 17 Male-male sex and injection drug use 7 8 7 10 Heterosexual contact 12 14 11 11 Other or unknown 15 16 18 13 Race/ethnicity (%) White 44 42 36 42 Black 34 38 41 38 Hispanic 21 18 21 18 Other or unknown 1 2 2 2 Sex (%) Male 76 75 82 78 Female 24 25 18 22 NOTE. PCP, Pneumocystis carinii pneumonia; MAC, disseminated Mycobacterium avium complex; NA, not applicable. PCP1 and MAC1 groups represent patients whose CD4 cell counts fell below prophylaxis thresholds and then rose by 100 CD4 cells/ml to 200 cells/ml for PCP and 100 cells/ml for MAC. PCP2 and MAC2 groups represent patients whose CD4 cell counts had never been observed below the prophylaxis threshold. a Recommended dual- or triple-combination antiretroviral therapy [13, 14]. b Includes saquinavir, ritonavir, indinavir, nelfinavir, or amprenavir. above the threshold of risk was low during person-time when the patients were not prescribed primary prophylaxis. For comparison, the incidence rates we present were similar to those recently published by the Swiss HIV Cohort Study (0.22 cases per 100 PY for PCP; 0.76 cases per 100 PY for nontuberculous mycobacteria), which examined rates of opportunistic illnesses within 15 months after starting potent anitretroviral therapy, although details regarding the exact changes in CD4 counts and prophylaxis of PCP and MAC were not provided [15]. In addition, multivariate analyses suggested no increased risk for PCP and MAC in persons whose CD4 count had increased, when compared with persons whose CD4 counts had not dropped below prophylaxis thresholds. Therefore, although the incidence rates below which prophylaxis might be discontinued have not been determined, these results suggest that discontinuing primary prophylaxis in these patients may be undertaken without increased risk. Although the incidence of PCP was elevated for group PCP1 in the analysis of persons receiving triple combination therapy, it was not a statistically significant finding. Even with additional statistical power, this finding would be of questionable clinical significance. One limitation of our study is that, because ASD is an observational database, patients are not randomly selected for the cessation of prophylaxis after their CD4 cell count rises above prophylaxis thresholds. Our results may have been influenced by a selection bias allowing for the healthiest patients to be included in groups PCP1 or MAC1; thus, the rates of disease in these groups may be lower than if patients had been selected randomly. Because ASD is not population based, our findings may not be generalizable to all HIV-infected patients in the United States. To our knowledge, however, this is the largest and most demographically diverse group among whom this issue has been examined. Also, ASD collects no more than 2 CD4 counts per 6-month interval, the lowest and the most recent. Therefore, although ASD will capture the CD4 nadir, it may not include every CD4 count within 6 months. Finally, virus load was not included in the multivariate model. Virus load data were not available on a large number of patients in this data set, which included many patients with follow-up prior to the widespread use of virus load monitoring. In addition to considering the risk for these opportunistic infections above the threshold of risk, other issues in stopping prophylaxis include the cost of the medication, pill burden, the ability of patients to adhere to the regimen, adverse effects, drug interactions, antimicrobial resistance, and the possible protection from other pathogens. In particular, PCP prophy-

614 Dworkin et al. JID 2000;182 (August) Table 2. Incidence and risk (hazard ratio) for Pneumocystis carinii pneumonia (PCP) and disseminated Mycobacterium avium complex (MAC) among human immunodeficiency virus infected patients prescribed antiretroviral therapy but not prophylaxis at CD4 T lymphocyte counts above prophylaxis thresholds. Treatment and group No. of patients No. of cases Personyears Incidence a (95% confidence limits) Hazard ratio b (95% confidence limits) Any antiretroviral therapy PCP1 1012 5 848 0.6 (0.1, 1.1) 0.8 (0.3, 2.2) PCP2 4123 37 5469 0.7 (0.5, 0.9) Referent MAC1 1136 11 1068 1.0 (0.4, 1.6) 1.8 (0.9, 3.5) MAC2 13,270 126 23,967 0.5 (0.4, 0.6) Referent Dual or triple antiretroviral therapy PCP1 803 4 634 0.6 (0.0, 1.3) 1.1 (0.3, 3.5) PCP2 2374 14 2752 0.5 (0.2, 0.8) Referent MAC1 1023 4 919 0.4 (0.0, 0.9) 0.6 (0.2, 1.9) MAC2 9041 53 12,473 0.4 (0.3, 0.5) Referent Triple antiretroviral therapy PCP1 602 3 437 0.7 (0.0, 1.5) 2.5 (0.5, 13.2) PCP2 1411 3 1346 0.2 (0.0, 0.5) Referent MAC1 896 2 780 0.3 (0.0, 0.6) 0.5 (0.1, 2.6) MAC2 5034 10 5695 0.2 (0.1, 0.3) Referent NOTE. PCP1 and MAC1 groups represent patients whose CD4 cell counts fell below prophylaxis thresholds and then rose by 100 CD4 cells/ml to 200 cells/ml for PCP and 100 cells/ml for MAC. PCP2 and MAC2 groups represent patients whose CD4 cell counts had never been observed below the prophylaxis threshold. a Cases per 100 person-years. b Multivariate Anderson-Gill analysis. laxis with trimethoprim-sulfamethoxazole is inexpensive, does not significantly add to the pill burden, and may provide protection against other infections, such as those caused by species of Streptococcus, Salmonella, Shigella, Nocardia, and Listeria. Many factors must be considered before deciding to discontinue prophylaxis. Our analysis provides important information in considering when and for whom primary prophylaxis may be discontinued. Results from randomized controlled clinical trials addressing discontinuation of MAC and primary PCP prophylaxis are emerging [8]. Our analysis suggests that patients whose CD4 cell counts rise above the threshold of risk are at low risk for opportunistic infections and that discontinuing primary prophylaxis may be considered in these patients. These results support the conclusions derived from other published studies [4 7]. We recommend that consideration of discontinuing primary prophylaxis be decided on an individual basis and that further study be devoted to identifying subgroups of patients whose CD4 cell counts have increased but still require prophylaxis. Houston Department of Health and Human Services, Houston, TX; Frank Sorvillo, Ph.D., and Dorothy Masters, Los Angeles County Department of Health Services, Los Angeles, CA; Anne Morse and Stephanie Broyles, M.P.H., Louisiana Office of Public Health, New Orleans; Judy Sackoff, Ph.D., and Jeffrey McFarland, M.D., The City of New York Department of Health, New York, NY; Jose Otero, M.P.H., Robert Hunter, M.D., and Maria de los Angeles Gomez, Ph.D., University Central del Caribe, Bayamon, and Sandra Miranda, M.P.H., Puerto Rico Department of Health, San Juan; Susan Buskin, Ph.D., Sharon G. Hopkins, D.V.M., and Beth Sohlberg, M.S., Seattle King County Department of Public Health, Seattle, WA. Acknowledgments We gratefully acknowledge the many medical record abstractors who have worked on the ASD project since its inception and appreciate the thoughtful review of this manuscript by Dr. Henry Masur, National Institutes of Health. Adult/Adolescent Spectrum of HIV Disease Project The Adult and Adolescent Spectrum of HIV Disease Investigators are Melanie Thompson, M.D., Julia Gable, M.S., and William McCarthy, Ph.D., AIDS Research Consortium of Atlanta, Atlanta, GA; Sylvia Odem, M.P.H., and Sharon Melville, M.D., Texas Department of Health, Austin; Arthur J. Davidson, M.D., David L. Cohn, M.D., and Cornelius A. M. Rietmeijer, M.D., Denver Department of Health and Hospitals, Denver, CO; Linda L. Wotring, Ph.D., M.P.H., and Eve D. Mokotoff, M.P.H., Michigan Department of Community Health, Detroit; Wes McNeely, M.S., and Kaye Reynolds, References 1. Jones JL, Hanson DL, Dworkin MS, Kaplan JE, Ward JW. Trends in AIDSrelated opportunistic infections among men who have sex with men and among injecting drug users 1991 1996. J Infect Dis 1998;178:114 20. 2. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med 1998;338: 853 60. 3. Centers for Disease Control and Prevention. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 1997; 46(RR-12):4 6. 4. Furrer H, Egger M, Opravil M, et al. Discontinuation of primary prophylaxis

JID 2000;182 (August) Risk for Opportunistic Infections 615 against Pneumocystis carinii pneumonia in HIV-infected adults treated with combination antiretroviral therapy. N Engl J Med 1999;340:1301 6. 5. Weverling GJ, Mocroft A, Ledergerber B, et al. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection. Lancet 1999;353:1293 8. 6. Schneider MME, Borleffs JCC, Stolk RP, Jaspes CAJJ, Hoepelman AIM. Discontinuation of Pneumocystis carinii pneumonia prophylaxis in HIV- 1 infected patients treated with highly active antiretroviral therapy. Lancet 1999; 353:201 3. 7. Yangco BG, Von Bargen JC, Moorman AC, Holmberg SD, HIV Outpatient Study (HOPS) Investigators. Discontinuation of chemoprophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection. HIV Outpatient Study (HOPS) Investigators. Ann Intern Med 2000;132: 201 5. 8. Currier JS, Williams PL, Koletar S, et al. A randomized, placebo-controlled trial of azithromycin prophylaxis for the prevention of Mycobacterium avium complex (MAC) in subjects with increases in CD4 cells on antiretroviral therapy [abstract LB-23]. In: Program and abstracts: 39th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1999. 9. Miller V, Mocroft A, Reiss P, et al. Relations among CD4 lymphocyte count nadir, antiretroviral therapy, and HIV-1 disease progression: results from the EuroSIDA study. Ann Intern Med 1999;130:570 7. 10. Farizo KM, Buehler JW, Chamberland ME, et al. Spectrum of disease in persons with human immunodeficiency virus infection in the United States. JAMA 1992;267:1798 805. 11. Centers for Disease Control and Prevention. 1993 revised classificationsystem for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992; 41(RR-17):1 19. 12. Andersen PK, Borgan O, Gill RD, Keiding N. Statistical models based on counting processes. New York: Springer, 1993. 13. Centers for Disease Control and Prevention. Report of the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR Morb Mortal Wkly Rep 1998;47(RR-5):1 82. 14. Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society USA panel. JAMA 1998;280:78 86. 15. Ledergerber B, Egger M, Erard V, et al. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy. JAMA 1999; 282:2220 6.