Discontinuation of Primary Prophylaxis against ...

BRIEF REPORT

Discontinuation of Primary Prophylaxis against Mycobacterium avium Complex Infection in HIVInfected Persons Receiving Antiretroviral Therapy: Observations from a Large National Cohort in the United States, 1992–2002

Clinical Epidemiology Section, Epidemiology Branch, 2Statistics and Data Management Branch, and 3Clinical Outcomes Section, Behavioral and Clinical Surveillance Branch, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia

1

In a large, diverse cohort of human immunodeficiency virus (HIV)–infected persons receiving routine care, the proportion of eligible persons who discontinued primary prophylaxis against Mycobacterium avium complex (MAC) infection, according to guidelines of the US Public Health Service and the Infectious Diseases Society of America, increased from 16.7% (in 1996) to 84.9% (in 2002). The discontinuation of primary prophylaxis was not associated with an increased risk of disseminated MAC infection. Multiple studies have shown that primary prophylaxis against infection with Mycobacterium avium complex (MAC) can be safely discontinued after an increase in the CD4 cell count of 1100 cells/mL that occurs in response to HAART and is maintained for at least 3 months [1–4]. Accordingly, current guidelines of the US Public Health Service and the Infectious Diseases Society of America (published in July 2002) recommend the discontinuation of primary MAC prophylaxis under these circumstances [5]. This recommendation is based on data from carefully controlled clinical trials or selected cohort studies of patients in a limited number of treatment settings that may Received 21 January 2005; accepted 25 March 2005; electronically published 7 July 2005. a Members of the study group are listed at the end of the text. Reprints or correspondence: Dr. John T. Brooks, Centers for Disease Control and Prevention, DHAP/NCHSTP, 1600 Clifton Rd. NE, Mailstop E-45, Atlanta, GA 30333 ([email protected]). Clinical Infectious Diseases 2005; 41:549–53 This article is in the public domain and no copyright is claimed 1058-4838/2005/4104-0022$15.00

limit the representativeness and the generalizabilty of findings to routine clinical practice [6, 7]. We evaluated the impact of this recommendation using data from a large, national cohort of HIV-infected patients receiving routine clinical care in the United States. Methods. We analyzed data from the Adult and Adolescent Spectrum of Disease (ASD) Project for the period January 1992–December 2002. The ASD Project conducted surveillance for opportunistic infections and other HIV-related illnesses by means of medical chart review; the project has been described elsewhere in detail [8]. As of December 2002, records had been reviewed for 46,663 HIV-infected persons 113 years of age receiving care at 1100 medical facilities in 10 major US cities. Standardized chart abstractions were conducted retrospectively for each patient’s records for the 12-month period preceding enrollment and, thereafter, prospectively at 6-month intervals until death or loss to follow-up. Data collected include demographic characteristics, mode of HIV exposure, prescription of medications (e.g., antiretrovirals and prophylaxis), CD4 cell counts, viral loads, opportunistic infections, and other medical conditions. We defined an incident case as a blood culture–confirmed disseminated infection in a person with no known prior MAC infection. We calculated the incidence rate as the number of infections among enrollees during a calendar year divided by the number of person-years of observation (PYOs) of enrollees during that same year. Individuals were excluded from the atrisk population after the date of first diagnosis of MAC infection during follow-up or if they had a history of any prior MAC infection (either culture-confirmed or reported) documented in their medical records before entry into the study. We defined primary MAC prophylaxis as a prescribed course of therapy with clarithromycin, azithromycin, or rifabutin for a person with no known prior MAC infection. In most cases, the purpose of such prescriptions was documented as either for prophylaxis or for treatment. If the purpose of a prescription during an interval was undocumented, we defined the therapy as prophylaxis if 1 of the 3 medications had also been administered during the preceding 6-month interval. We defined a person as eligible to receive primary MAC prophylaxis when his/her CD4 cell count was !50 cells/mL and if he/she had no known prior MAC infection. We defined a person as eligible to discontinue primary MAC prophylaxis when, while receiving HAART and primary MAC prophylaxis, his/her CD4 cell count increased to and maintained a level of 1100 cells/mL for ⭓3 months. HIV/AIDS • CID 2005:41 (15 August) • 549

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John T. Brooks,1 Ruiguang Song,2 Debra L. Hanson,2 Mitchell Wolfe,3 David L. Swerdlow,3 and the Adult and Adolescent Spectrum of Disease Working Groupa

HIV/AIDS

We evaluated the effect of the discontinuation of prophylaxis against primary MAC infection among persons eligible to discontinue primary prophylaxis during the period 1996–2002. We calculated incidence rates of MAC infection by dividing the number of primary infections by the total PYOs of persons who continued, discontinued, and intermittently continued primary prophylaxis while remaining eligible for discontinuation. Person-time was censored if a person’s CD4 cell count was observed to have decreased to !100 cells/mL, when a person was lost to follow-up, when a person died, or after 31 December 2002. Data were analyzed using SAS software, version 8.0 (SAS). Results. Between 1992 and 2002, 46,663 persons were observed for a total 116,167 PYOs. During this 11-year period, 2589 primary disseminated MAC infections were diagnosed, producing an overall incidence of 22.3 infections per 1000 PYOs. The overall incidence decreased 13-fold from 1992 to 2002, with the largest decline occurring after 1996, when protease inhibitors became generally available (figure 1). Persons with nadir CD4 cell counts of !50 cells/mL remained, on average, 3.7 times more likely to develop a disseminated MAC infection, compared with all other persons (i.e., persons with CD4 cell counts of all levels, including persons with nadir CD4 cell counts of !50 cells/mL). There were 962 persons who became eligible to discontinue primary MAC prophylaxis from 1 January 1996 through 31 December 2002, the period during which HAART became generally available. The proportion of these persons who discon550 • CID 2005:41 (15 August) • HIV/AIDS

tinued primary MAC prophylaxis increased from 16.7% to 84.9% (figure 2). As shown in table 1, persons who continued primary MAC prophylaxis (n p 262; 27% of persons) after immune reconstitution, who discontinued primary MAC prophylaxis (n p 592; 61% of persons), and who received primary MAC prophylaxis intermittently (n p 108 ; 11% of persons) did not differ with respect to age, sex, race, HIV infection risk

Figure 2. Proportion of Adult and Adolescent Spectrum of Disease Project enrollees who discontinued prophylaxis as a percentage of enrollees who were eligible for discontinuation, according to the guidelines of the US Public Health Service and the Infectious Diseases Society of America [5], by year, 1996–2002 (n p 962). Total number of persons contributing observation time varies annually; persons may have contributed observation time across multiple years.


Figure 1. Incidence rates per 1000 person-years of observation (PYOs) of culture-confirmed primary Mycobacterium avium complex infections among 46,663 Adult and Adolescent Spectrum of Disease Project enrollees by year, 1992–2002. The table on the x-axis indicates the number of infections per 1000 PYOs by year and by CD4 cell count stratum.

Table 1. Comparison of 962 enrollees in the Adult and Adolescent Spectrum of Disease Project after becoming eligible for the discontinuation of primary Mycobacterium avium complex (MAC) prophylaxis following HAART-associated immune reconstitution. Continued MAC prophylaxis (n p 262)

Discontinued MAC prophylaxis (n p 592)

Intermittent MAC prophylaxis (n p 108)

P

Age, median years (IQR)

39 (34–45)

39 (34–44)

39 (35–45)

.263

Female sex

18.3

20.3

22.2

.663

White

21.8

28.2

27.8

…

Black

56.9

49.0

50.9

…

Hispanic

19.5

21.8

19.4

…

1.8

1.0

1.9

…

Men who have sex with men

41.2

48.5

50.0

…

Injection drug user

12.6

10.8

13.0

…

Heterosexual

14.5

14.7

15.7

…

Other

11.9

8.3

6.5

…

Unknown

19.8

17.7

14.8

…

Variable Demographic characteristic a

Race/ethnicity

.483

Other or unknown ethnicity HIV infection risk category

.612

CD4 count, mean cells/mL (IQR) Nadir b

At initiation of HAART (IQR)

Maximum increase of CD4 cell count after initiation of HAART, mean cells/mL (IQR) Viral load at initiation of HAART, mean copies/mL (IQR)

19 (6–29)

19 (7–30)

17 (6–26)

.615

64 (15–82)

62 (13–77)

45 (10–47)

.030

176 (116–217)

217 (142–252)

230 (134–268)

242,503 (15,309–395,120)

224,516 (5170–362,016)

163,820 (6994–181,394)

!.001

.314

c

Type of HAART regimen NRTI

100

100

100

1.000

PI

84

83

90

.182

NNRTI

32

35

31

.606

Duration of HAART regimen before becoming eligible to discontinue primary MAC prophylaxis, median months (IQR)

16 (11–25)

14 (11–22)

15 (12–23)

.096

Duration of MAC prophylaxis before becoming eligible to discontinue primary MAC prophylaxis, median months (IQR)

16 (10–25)

13 (8–20)

14 (11–22)

!.001

Time parameter

Total duration of follow-up after becoming eligible to discontinue primary MAC prophylaxis, person-years Duration of follow-up per person after becoming eligible to discontinue primary MAC prophylaxis, median months (IQR)

187

6 (3–10)

1465

29 (15–41)

329

34 (24–50)

!.001

!.001

NOTE. The data are percentage of enrollees, unless otherwise indicated. The x2 test was used for categorical variables, and Kruskal-Wallis test was used for continuous variables. IQR, interquartile range; NRTI, nucleoside reverse-transcriptase inhibitor; NNRTI, nonnucleoside reversetranscriptase inhibitor; PI, protease inhibitor. a b c

Median age at the time the participant became eligible to discontinue primary MAC prophylaxis. The value measured within the preceding 6 months that was obtained closest to initiation of HAART. Percentages represent the proportion of persons whose HAART regimens included drugs from each respective class of antiretrovirals.

category, nadir CD4 count, viral load at initiation of HAART, or type of HAART regimen received. Persons who intermittently received MAC prophylaxis had significantly lower CD4 cell counts at the time that HAART was initiated but achieved significantly greater mean maximal increases in CD4 cell counts after the initiation of HAART. The length of follow-time for persons receiving MAC prophylaxis before becoming eligible to discontinue MAC prophylaxis who either continued, dis-

continued, or intermittently continued MAC prophylaxis after they were eligible for discontinuation was significantly different (median values were 16, 13, and 14 months, respectively). Persons who continued MAC prophylaxis also contributed significantly less observation time to this analysis. Among persons who, despite becoming eligible to discontinue MAC prophylaxis, continued prophylaxis after immune reconstitution, there were no MAC infections diagnosed during HIV/AIDS • CID 2005:41 (15 August) • 551


Immune and virologic parameters

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required that the person had been receiving the prophylactic medicines for at least 3 months before discontinuation. Third, some individual care providers participating in the ASD Project were aware that their records were being abstracted. Being concerned that the quality of their care might be assessed could have prompted participating providers to improve their practices. Fourth, although our data are collected from a large cohort, the length of follow-up periods for persons who continued prophylaxis after becoming eligible for discontinuation was, on average, !1 year per person. Despite these limitations, this study provides important confirmatory data. In earlier studies, strict inclusion criteria, geographic and demographic homogeneity among potential participants, and willingness to volunteer are among factors that can produce a research population from whom extrapolation of findings may be limited by representativeness [6, 7]. A strength of these study results is the insight they offer into routine medical practices following dissemination of a recommended practice guideline. The Adult and Adolescent Spectrum of Disease Working Group. M. Thompson and E. Sinclair (AIDS Research Consortium of Atlanta); D. Cohen, A. Davidson, and C. Rietmeijer (Denver Department of Health and Hospitals); J. Turner and A. Wohl (Los Angeles County Department of Health Services); A. Morse, S. Broyles, and C. Lynn Besch (Louisiana Department of Health, New Orleans); L. Worting and E. Mokotoff (Michigan Department of Health, Detroit); J. Sackoff and M. A. Bernard (New York City Department of Health); A. Amill, R. Hunter, and M. de Gomez (University Central del Caribe, Bayamon); S. Miranda (Puerto Rico Department of Health, Bayamon); S. Buskin and S. Hopkins (Seattle–King County Department of Health, Seattle); S. Odem (Texas Department of Health, Austin); P. Keiser (Parkland Hospital, Dallas); K. Reynolds and W. McNealy (Department of Health and Human Services, Houston). Acknowledgments Potential conflicts of interest.

All authors: no conflicts.

References 1. Kirk O, Lundgren JD, Pedersen C, Nielsen H, Gerstoft J. Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS 1999; 13:1647–51. 2. El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. N Engl J Med 2000; 342:1085–92. 3. Furrer H, Telenti A, Rossi M, Ledergerber B. Discontinuing or withholding primary prophylaxis against Mycobacterium avium in patients on successful antiretroviral combination therapy. The Swiss HIV Cohort Study. AIDS 2000; 14:1409–12. 4. Currier JS, Williams PL, Koletar SL, et al. Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral


187 person-years of follow-up (median duration of follow-up, 0.71 years/person). Similarly, among persons who intermittently received MAC prophylaxis after becoming eligible for discontinuation, there was no case of MAC infection diagnosed; the average individual follow-up period was 3.05 years. One case of MAC infection occurred among persons who discontinued prophylaxis (incidence, 0.68 infections per 1000 PYOs); the average individual follow-up period was 2.47 years. This infection occurred in a 38-year-old white man with a nadir CD4 cell count of 2 cells/mL. The CD4 cell count and viral load, at their last measurement 2 months before the diagnosis of disseminated MAC infection, were 148 cells/mL and !400 copies/mL, respectively. At the time of diagnosis, the man had not been receiving primary prophylaxis for 5 months. He had completed 6 months of continuous prophylaxis before discontinuation. Discussion. Between 1992 and 2002, the incidence of primary disseminated MAC infection among persons observed in the ASD Project decreased ∼13-fold, with a notable decrease that occurred after the advent of protease inhibitors and HAART in 1996. The proportion of persons eligible, according to current guidelines, for the discontinuation of primary MAC prophylaxis between 1996 and 2002 increased ∼5-fold. There was no evidence of substantially increased risk of MAC infection following the discontinuation of primary MAC prophylaxis while a CD4 cell count of 1100 cells/mL was maintained. This finding is based on the results of observational data from of a large, diverse cohort that we estimate represented ∼5% of HIVinfected persons receiving medical care in the United States during the study period (Centers for Disease Control and Prevention, unpublished data). Discontinuation of prophylaxis offers patients multiple benefits. The cost of care and the risk of an adverse drug reaction decrease. The smaller pill burden may improve compliance with antiretroviral medications. The risk of antimicrobial resistance resulting from prolonged drug pressure is reduced both for the individual and within the population. Our findings corroborate the conclusions of earlier cohort studies and prospective controlled trials [1–4]. However, our data are subject to at least 4 limitations. First, MAC infections that occurred prior to enrollment in the study may not have been captured, which may have led to the misclassification of some persons as eligible for primary prophylaxis. Dosage data for medications included in the ASD Project are inadequate to differentiate persons likely to be receiving treatment or secondary prophylaxis. Second, we were unable to definitively infer the reason for the discontinuation of prophylaxis after documentation of HAART-associated immune restoration. We cannot rule out the possibility that some persons may have discontinued prophylaxis because of an allergic reaction, drug intolerance, or poor compliance, even though our definition

therapy-induced increases in CD4+ cell count. Ann Intern Med 2000; 133:493–503. 5. Kaplan J, Masur H, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons—2002 recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep 2002; 51:1–46. 6. Moore DAJ, Goodall RL, Ives NJ, Hooker M, Gazzard BG, Easterbrook PJ. How generalizable are the results of large randomized controlled trials of antiretroviral therapy? HIV Med 2000; 1:149–54.

7. Zimmerman M, Mattia JI, Posternak MA. Are subjects in pharmacological treatment trials of depression representative of patients in routine clinical practice? Am J Psychiatry 2002; 159:469–73. 8. Farizo K, Buehler J, Chamberland M, et al. Spectrum of disease in persons with human immunodeficiency virus infection in the United States. JAMA 1992; 267:1798–805.


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