FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 342:1085-1092 April 13, 2000 Number 15 Next

Abstract PDF Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy.

Methods We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia.

Results A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome–defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002).

Conclusions Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy.

Since the studies of prophylaxis against M. avium complex disease were performed, more potent antiretroviral regimens have been introduced that suppress HIV replication and increase the CD4+ cell count.⁹ Marked decreases in the incidence of major infectious complications, especially P. carinii pneumonia and M. avium complex disease, have been reported in patients treated with these regimens.^9,10 The question now is whether patients whose CD4+ cell counts have been below the threshold for the initiation of prophylaxis against opportunistic infection should continue to receive prophylaxis once their cell counts rise above the threshold. Because of concern about the function of CD4+ cells in patients receiving antiretroviral therapy, the 1997 guidelines for the prevention of opportunistic infections recommended continued prophylaxis despite an increase in the CD4+ cell count.⁷

We performed a study to determine whether patients whose CD4+ cell counts had increased substantially in response to antiretroviral therapy should receive prophylaxis against M. avium complex disease and bacterial pneumonia.

Methods

Study Population

HIV-infected patients 13 years of age or older were eligible for the study if they had had a CD4+ cell count of less than 50 per cubic millimeter (at any time in the past), followed by a count of more than 100 cells per cubic millimeter on two consecutive occasions in response to antiretroviral therapy. Patients with a history of intolerance of azithromycin, prior or current disseminated M. avium complex disease, or a condition requiring treatment with agents that have activity against M. avium complex were excluded.

The study was approved by the institutional review board at each participating center, and written informed consent was obtained from all patients.

Study Design

The study was a randomized, double-blind clinical trial comparing the efficacy of azithromycin (Zithromax, Pfizer), given at a dose of 1200 mg once weekly, with that of a matched placebo. Patients were randomly assigned to the study groups in a 1:1 ratio, with stratification according to the clinical center and according to whether the patients had received prophylaxis for M. avium complex disease at any time before enrollment. Patients whose CD4+ cell counts fell below 50 per cubic millimeter after enrollment were offered open-label azithromycin.

The sample size (850 patients) and the duration of follow-up (27 months) were chosen to provide the study with 80 percent power to detect a 40 percent difference in the primary end point between the study groups (22.0 percent vs. 13.2 percent). We also assumed that the death rate would be 34 percent at 27 months and that 4 percent of the patients would be lost to follow-up.

End Points and Follow-Up

The primary end point of the study was the development of either confirmed M. avium complex disease or confirmed or probable bacterial pneumonia. One of two criteria had to be met for a diagnosis of confirmed M. avium complex disease: a positive culture of a blood specimen or a specimen from another normally sterile site or a positive culture of a specimen from a nonsterile site with clinical evidence of dissemination. One of three criteria had to be met for a diagnosis of confirmed bacterial pneumonia: histologic evidence of bacterial pneumonia, a positive quantitative culture of a protected-brush specimen for a likely pathogen, or clinical and radiographic abnormalities consistent with the diagnosis. The third criterion had to be accompanied by at least one of two additional types of evidence: a positive culture or Gram's stain for a likely pathogen in a blood specimen, a specimen from another normally sterile site, a bronchoalveolar-lavage specimen, or a lung aspirate or the predominance of such a pathogen in an adequate specimen of sputum, or serologic evidence of recent infection with legionella, Mycoplasma pneumoniae, or Chlamydia pneumoniae. Probable bacterial pneumonia was defined as clinical and radiographic evidence (as described above), the absence of another diagnosis, and a response to antibiotic therapy.

The secondary end points were death, the development of P. carinii pneumonia, grade IV adverse events (i.e., severe and potentially life-threatening events, as graded on a five-point scale developed by the Division of AIDS of the National Institute of Allergy and Infectious Diseases), and toxic effects requiring permanent discontinuation of azithromycin or placebo. A clinical-events committee, which was unaware of the treatment assignments, reviewed all cases of M. avium complex disease and bacterial pneumonia that were not confirmed.

Follow-up visits were scheduled for every four months. At each visit, a clinical evaluation was performed to determine whether any primary or secondary end points had occurred, and the CD4+ cell count and HIV-1 RNA level were measured (by either a polymerase-chain-reaction [PCR] assay or a branched-chain DNA assay).

Statistical Analysis

The investigators were unaware of the interim results, which were reviewed by an independent data and safety monitoring board. On July 28, 1999, the board recommended closure of the study because of the low rates of M. avium complex disease and bacterial pneumonia.

The study groups were compared with use of the chi-square test or Fisher's exact test for categorical data and with use of Student's t-test for continuous data. Time-to-event analyses were performed with proportional-hazards regression. All analyses were performed on an intention-to-treat basis, and all reported P values are two-sided. Exact 95 percent confidence intervals for incidence rates were calculated on the basis of the Poisson distribution.

Results

Characteristics of the Patients

Between October 1997 and July 1999, 520 patients at 15 centers were enrolled in the study; 258 patients were randomly assigned to azithromycin, and 262 to placebo. The median prior nadir CD4+ cell count was 23 per cubic millimeter. The median CD4+ cell count at base line was 230 per cubic millimeter. The median count was higher in the placebo group than in the azithromycin group (243 vs. 226 per cubic millimeter, P=0.02). The two groups were otherwise similar with regard to base-line characteristics (Table 1). At enrollment, 50 percent of the patients in whom HIV RNA was measured by PCR had less than 400 copies per milliliter, and 37 percent of those in whom HIV RNA was measured by a branched-chain DNA assay had less than 500 copies per milliliter. Sixty-five percent of the patients had received a clinical diagnosis of the acquired immunodeficiency syndrome (AIDS); 41 percent had a history of P. carinii pneumonia; and 14 percent had a history of bacterial pneumonia. At enrollment, 93 percent of the participants were receiving prophylaxis against P. carinii pneumonia; 69.4 percent of the patients in the azithromycin group and 68.7 percent of those in the placebo group were receiving trimethoprim–sulfamethoxazole (P=0.87). Sixty-nine percent of the patients had received prophylaxis against M. avium complex disease. Of the 242 patients (47 percent) who were receiving prophylaxis against M. avium complex disease at base line, 210 were receiving azithromycin, 26 clarithromycin, and 5 rifabutin. Similar proportions of patients in the two groups had undergone pneumococcal vaccination (64.3 percent in the azithromycin group and 69.9 percent in the placebo group, P=0.18).

View this table: [in this window] [in a new window]   Table 1. Base-Line Characteristics of the Patients.

 
All the study participants were receiving antiretroviral therapy at enrollment, with 94 percent receiving regimens that included a protease inhibitor. At 12 months, 98 percent of the patients were receiving antiretroviral therapy, with 92 percent receiving regimens that included a protease inhibitor. The antiretroviral regimens did not differ significantly between the two study groups.

Duration of Follow-Up and Study Treatment

At the time that the treatment assignments were revealed, the median duration of follow-up was 12.7 months (range, 0.5 to 21.2) in the azithromycin group and 12.0 months (range, 0.1 to 21.4) in the placebo group. Seven patients (1.3 percent) were lost to follow-up (four in the azithromycin group and three in the placebo group).

Eight of the 258 patients in the azithromycin group (3.1 percent) and 4 of the 262 patients in the placebo group (1.5 percent) received open-label azithromycin during follow-up. Fifty-one patients in the azithromycin group (19.8 percent) and 32 patients in the placebo group (12.2 percent) discontinued the assigned treatment but were not eligible for open-label azithromycin (relative risk in the azithromycin group as compared with the placebo group, 1.67; P=0.02).

Primary End Point

Confirmed or probable bacterial pneumonia developed in three patients in the azithromycin group (1.2 percent) and in five patients in the placebo group (1.9 percent; relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48) (Table 2). There were no cases of confirmed M. avium complex disease. Bacterial pneumonia was confirmed in two of the three patients in the azithromycin group and in three of the five patients in the placebo group. The 95 percent confidence interval for the rate of bacterial pneumonia was 0.2 to 3.5 episodes per 100 person-years in the azithromycin group and 0.6 to 4.7 episodes per 100 person-years in the placebo group. The 95 percent confidence interval for the rate of M. avium complex disease in each group was 0 to 1.5 episodes per 100 person-years.

View this table: [in this window] [in a new window]   Table 2. First Occurrence of Clinical Events.

 
Deaths and AIDS-Defining Events

In each group, five patients (1.9 percent) died. Three patients died from liver failure, three from cardiovascular disease, two from cancer, one from an overdose of methadone, and one from wasting. In addition, the progression of HIV disease (including death) was reported in 14 patients assigned to receive azithromycin (5.4 percent) and in 13 patients assigned to receive placebo (5.0 percent) (Table 2). None of the patients had cytomegalovirus disease, cryptococcosis, histoplasmosis, Kaposi's sarcoma, or progressive multifocal leukoencephalopathy. There were six cases of P. carinii pneumonia, four of esophageal candidiasis, and one each of tuberculosis, toxoplasmosis, AIDS-related dementia, and lymphoma. There were 47 cases of bacterial infections, which were distributed similarly in the two groups. The rates of events that could have been associated with azithromycin treatment (i.e., P. carinii pneumonia, toxoplasmosis, sinusitis, and bacteremia) were low and did not differ significantly between the two groups (Table 2).

Adverse Events and Discontinuation of Study Drugs

Grade IV adverse events occurred in 27 patients in the azithromycin group (10.5 percent) and in 36 patients in the placebo group (13.7 percent; relative risk in the azithromycin group, 0.73; P=0.22). Toxic effects required discontinuation of the assigned treatment in 19 patients in the azithromycin group (7.4 percent) and in 3 patients in the placebo group (1.1 percent; relative risk, 6.64; P=0.002) (Table 3). Most toxic effects requiring discontinuation of the study drug were grade II. In 11.6 percent of the patients assigned to receive azithromycin and in 5.3 percent of those assigned to receive placebo, the study drug was discontinued at the patient's request (relative risk, 2.30; P=0.01). The blinded study drug was discontinued because of a switch to open-label azithromycin (in patients with CD4+ cell counts that dropped below 50 per cubic millimeter) in 3.1 percent of the azithromycin group and in 1.5 percent of the placebo group, because of death in 1.6 percent of the azithromycin group and in 1.1 percent of the placebo group, and for other reasons in 6.2 percent of the azithromycin group and in 5.7 percent of the placebo group (Table 3). In some cases, there was more than one reason for discontinuation.

View this table: [in this window] [in a new window]   Table 3. Grade IV Adverse Events and Discontinuation of the Study Drug.

 
CD4+ Cell Counts and HIV RNA Levels

In both study groups, the average CD4+ cell count rose during follow-up (Figure 1). At 12 months, the average increase from base line in the CD4+ cell count was 37.6 per cubic millimeter in the azithromycin group and 40.7 per cubic millimeter in the placebo group. During follow-up, 12 patients in the azithromycin group (4.7 percent) and 10 patients in the placebo group (3.8 percent) had a CD4+ cell count of less than 50 per cubic millimeter on at least one occasion.

View larger version (7K): [in this window] [in a new window]   Figure 1. Average CD4+ Cell Count at Base Line and during Follow-up in 520 HIV-Infected Patients Assigned to Receive Azithromycin or Placebo. The bars represent 95 percent confidence intervals.

 
The HIV RNA values declined slightly in both groups. Figure 2 shows the proportions of patients with values that were below the limit of detection at base line and at months 4, 8, 12, and 16. Of the 216 patients in whom HIV RNA was measured by a PCR assay at 12 months, 53 percent of those assigned to receive azithromycin and 55 percent of those assigned to receive placebo had an HIV RNA level of less than 400 copies per milliliter. There were no significant differences in HIV RNA levels between the two groups.

View larger version (9K): [in this window] [in a new window]   Figure 2. Proportions of Patients in the Azithromycin and Placebo Groups Who Had Undetectable Levels of HIV RNA. The limit of detection was 400 copies per milliliter with the PCR assay and 500 copies per milliliter with the branched-chain DNA assay.

 
Discussion

The results of our randomized, placebo-controlled trial show that it is safe to withhold azithromycin prophylaxis in HIV-infected patients whose CD4+ cell counts have risen to more than 100 per cubic millimeter in response to antiretroviral therapy. Even though our patients had advanced AIDS, there were no cases of confirmed M. avium complex disease during approximately 500 patient-years of follow-up, and the rates of bacterial pneumonia were low in both the placebo group and the azithromycin group.

The dramatic effect of improved immune function on the rates of M. avium complex disease and bacterial pneumonia in our study can be recognized by comparing the rates of these two disorders before effective antiretroviral therapy was available. In that era, the rate of M. avium complex disease in patients with a CD4+ cell count of 20 to 30 per cubic millimeter (a value similar to the nadir count in the patients in our study) was 20 to 30 percent per year.^11,12 Even with the use of clarithromycin or azithromycin as prophylaxis, the annual risk of M. avium complex disease in patients with a base-line CD4+ cell count of less than 100 per cubic millimeter was 7 to 8 percent per year.^3,4,5 Similarly, rates of bacterial pneumonia were much higher before the introduction of effective antiretroviral therapy. For example, in one prospective study, the rate of bacterial pneumonia was 10.8 episodes per 100 person-years among patients with a base-line CD4+ cell count of less than 200 per cubic millimeter and 2.8 episodes per 100 person-years among those with a base-line count of more than 500 per cubic millimeter.¹³ Both groups in our study had lower rates of bacterial pneumonia, even though they had a median nadir CD4+ cell count of only 23 per cubic millimeter and a median base-line count of 230 per cubic millimeter.

Our finding that it is safe to withhold azithromycin prophylaxis in patients with a CD4+ cell count of more than 100 per cubic millimeter in response to antiretroviral therapy parallels the results of recent studies of the safety of withdrawing prophylaxis against P. carinii pneumonia in patients whose CD4+ cell counts have increased to more than 200 per cubic millimeter. Two observational studies,^14,15 two nonrandomized prospective studies,^16,17 and the preliminary results of one randomized trial¹⁸ all indicate that the withdrawal of primary prophylaxis against P. carinii pneumonia is safe in patients with a sufficient increase in the CD4+ cell count in response to antiretroviral therapy. The recently updated guidelines recommend the discontinuation of prophylaxis against M. avium complex and P. carinii pneumonia under these circumstances, although in the case of M. avium complex disease, the recommendation until now was based only on observational studies.¹⁹

The rates of other opportunistic conditions were also low in our study. The rate of P. carinii pneumonia was 1.0 episode per 100 person-years, as compared with 3.5 episodes per 100 person-years in the largest trial of trimethoprim–sulfamethoxazole,²⁰ the most effective prophylactic agent.²¹ The rate of cytomegalovirus disease in our study was 0 episodes per 100 person-years, as compared with 14 episodes per 100 person-years among similarly immunocompromised patients who received ganciclovir prophylaxis in the era before potent antiretroviral therapy was available.^22,23 Although some investigators have postulated that progressive HIV infection causes irreversible damage to the immune system,²⁴ the low rates of all opportunistic illnesses in our study demonstrate that effective immunity can be restored with antiretroviral therapy, even in patients with nadir CD4+ cell counts below 50 per cubic millimeter.

Despite the relative simplicity of azithromycin prophylaxis, there are a number of reasons to defer antimicrobial prophylaxis if the rate of the target opportunistic infection is low. Rates of antibiotic resistance among common bacterial pathogens, such as Streptococcus pneumoniae, have increased dramatically in the past 10 years,^25,26 and prior exposure to antibiotics is a strong risk factor for infection with antibiotic-resistant bacteria.²⁷ Patients with advanced AIDS have high rates of colonization and infection with antibiotic-resistant S. pneumoniae,^28,29 probably in part because of the use of prophylaxis against M. avium complex disease and P. carinii pneumonia.³⁰ In one study involving patients with HIV infection, both weekly treatment with azithromycin and daily treatment with clarithromycin were associated with the isolation of macrolide-resistant respiratory flora in all the study participants.³¹

In addition, polypharmacy carries the risk of drug interactions and may reduce adherence to treatment regimens.³² Finally, the risk of drug intolerance is a reason for withholding prophylaxis. In our study, side effects led to the discontinuation of the study drug in 7 percent of the patients assigned to receive azithromycin but in only 1 percent of those assigned to receive placebo.

Our study has several limitations. The patients had a marked increase in the CD4+ cell count, from a median previous nadir of 23 per cubic millimeter to a median of 230 per cubic millimeter at the time of enrollment. Furthermore, the CD4+ cell count continued to increase over the course of the study. It is unclear whether the results of this study apply to patients with less dramatic increases in the CD4+ cell count or to patients in whom the CD4+ cell count drops after an initial increase in response to antiretroviral therapy. In addition, our study cannot answer the question of whether the recommended threshold CD4+ cell count of less than 50 per cubic millimeter should be used as a criterion for restarting prophylaxis in this population. Until this question is answered, prophylaxis against M. avium complex disease is recommended for all patients with a CD4+ cell count of less than 50 per cubic millimeter, as specified by the current guidelines.¹⁹

In summary, our study shows that prophylaxis against disseminated M. avium complex disease can be safely withheld in patients with CD4+ cell counts that have increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy, because the risk of disseminated M. avium complex disease in this population is low. In addition, our study shows that azithromycin prophylaxis does not significantly affect the rates of bacterial pneumonia, progression of HIV disease, or death in such patients. These findings contribute to the efforts to simplify treatment regimens and improve adherence to them, decrease the risk of antimicrobial resistance, and avoid adverse events associated with additional medications.

Supported by a grant from the National Institute of Allergy and Infectious Diseases.

We are indebted to the patients who participated in the study; to Mira Madans, Charles Knirsch, Shari Thomas, Rita Verheggen, Reginald Caldwell, Rusty Moore, Jill Chestnut, Kerry Lecky, Sheila Flanagan, Pat Dodson, Beverly Campbell, Pat Dixon, Louis Fiol, Amanda Ferguson, Pam Gorman, Kerry Griscti, Cheryl Guity, Martha Howe, Sr. Sue Pablovich, Becky Perelli, Steven Pierson, Barbara Standridge, Beverly Weaver, and Megan Yoder for their substantial contributions; and to Pfizer for providing azithromycin and placebo for the study.

^* Other participating investigators are listed in the Appendix.

Source Information

From Harlem Hospital Center and Columbia University College of Physicians and Surgeons, New York (W.M.E.-S., S.B.M.); the Denver Public Health Department and the University of Colorado Health Sciences Center, Denver (W.J.B.); the Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis (L.B.G., J.P.M.); the Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Md. (R.H., A.M.); Wayne State University, Detroit (L.C.); the Research and Education Group, Portland, Oreg. (D.Z.); Philadelphia FIGHT, Philadelphia (B.G.); and the Department of Veterans Affairs Medical Center, Washington, D.C. (F.G.).

Address reprint requests to Dr. El-Sadr at Harlem Hospital Center, Division of Infectious Diseases, 506 Lenox Ave., Rm. 3107, New York, NY 10037, or at wme1{at}columbia.edu.

References

1. Moore RD, Chaisson RE. Natural history of opportunistic disease in an HIV-infected urban clinical cohort. Ann Intern Med 1996;124:633-642. [Free Full Text]
2. Hanson DL, Chu SY, Farizo KM, Ward JW. Distribution of CD4+ T lymphocytes at diagnosis of acquired immunodeficiency syndrome-defining and other human immunodeficiency virus-related illnesses. Arch Intern Med 1995;155:1537-1542. [Free Full Text]
3. Oldfield EC III, Fessel WJ, Dunne MW, et al. Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind, placebo-controlled multicenter trial. Clin Infect Dis 1998;26:611-619. [Medline]
4. Havlir DV, Dubé MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996;335:392-398. [Free Full Text]
5. Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome. N Engl J Med 1996;335:384-391. [Free Full Text]
6. Benson CA, Cohn DL, Williams P, ACTG 196/CPCRA 009 Study Team. A phase III prospective, randomized, double-blind study of the safety and efficacy of clarithromycin vs. rifabutin, vs. clarithromycin plus rifabutin for prevention of Mycobacterium avium complex disease in HIV+ patients with CD4 counts less than or equal to 100 cells/uL. In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28–February 1, 1996. Alexandria, Va.: IDSA Foundation for Retrovirology and Human Health, 1996:91. abstract.
7. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 1997;46:1-46. [Medline]
8. Dunne MW, Bozzette S, McCutchan JA, et al. Efficacy of azithromycin in prevention of Pneumocystis carinii pneumonia: a randomised trial. Lancet 1999;354:891-895. [CrossRef][Medline]
9. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997;337:725-733. [Free Full Text]
10. Palella FJ Jr, Delany KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853-860. [Free Full Text]
11. Nightingale SD, Byrd LT, Southern PM, Jockusch JD, Cal SX, Wynne BA. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis 1992;165:1082-1085. [Medline]
12. Mocroft A, Youle M, Phillips AN, et al. The incidence of AIDS-defining illnesses in 4883 patients with human immunodeficiency virus infection. Arch Intern Med 1998;158:491-497. [Free Full Text]
13. Hirschtick RE, Glassroth J, Jordan MC, et al. Bacterial pneumonia in persons infected with human immunodeficiency virus. N Engl J Med 1995;333:845-851. [Free Full Text]
14. 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;353:1293-1298. [CrossRef][Medline]
15. Dworkin M, Hanson D, Jones J, Kaplan J. The risk for Pneumocystis carinii pneumonia and disseminated nontuberculous mycobacteriosis after antiretroviral therapy associated increase in the CD4+ T-lymphocyte count. In: Program and abstracts of the Sixth Conference on Retroviruses and Opportunistic Infections, Chicago, January 31–February 4, 1999. Alexandria, Va.: Foundation for Human Retrovirology, 1999:198. abstract.
16. Schneider MM, Borleffs JC, Stolk RP, Jaspers CA, Hoepelman AI. Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with highly active antiretroviral therapy. Lancet 1999;353:201-203. [CrossRef][Medline]
17. Furrer H, Egger M, Opravil M, et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. N Engl J Med 1999;340:1301-1306. [Free Full Text]
18. Lopez JC, Pena JM, Miro JM, Podsamczer D. Discontinuation of PCP prophylaxis is safe in HIV-infected patients with immunological recovery with HAART: preliminary results of an open, randomized and multicentric clinical trial (GESIDA A04/98). In: Program and abstracts of the Sixth Conference on Retroviruses and Opportunistic Infections, Chicago, January 31–February 4, 1999. Alexandria, Va.: Foundation for Human Retrovirology, 1999:206. abstract.
19. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: U. S. Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA). MMWR Morb Mortal Wkly Rep 1999;48:1-66.
20. El-Sadr WM, Luskin-Hawk R, Yurik T, et al. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons: Terry Beirn Community Programs for Clinical Research on AIDS. Clin Infect Dis 1999;29:775-783. [Medline]
21. Ioannidis JPA, Cappelleri JC, Skolnik PR, Lau J, Sacks HS. A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens. Arch Intern Med 1996;156:177-188. [Free Full Text]
22. Spector SA, McKinley GF, Lalezari JP, et al. Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. N Engl J Med 1996;334:1491-1497. [Free Full Text]
23. Brosgart CL, Louis TA, Hillman DW, et al. A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of cytomegalovirus disease in HIV-infected individuals. AIDS 1998;12:269-277. [CrossRef][Medline]
24. Connors M, Kovacs JA, Krevet S, et al. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med 1997;3:533-540. [CrossRef][Medline]
25. Butler JC, Hofmann J, Cetron MS, Elliott JA, Facklam RR, Breiman RF. The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System. J Infect Dis 1996;174:986-993. [Medline]
26. Plouffe JF, Breiman RF, Facklam RR. Bacteremia with Streptococcus pneumoniae: implications for therapy and prevention. JAMA 1996;275:194-198. [Free Full Text]
27. Meynard JL, Barbut F, Blum L, et al. Risk factors for isolation of Streptococcus pneumoniae with decreased susceptibility to penicillin G from patients infected with human immunodeficiency virus. Clin Infect Dis 1996;22:437-440. [Medline]
28. Rodriguez-Barradas MC, Tharapel RA, Groover JE, et al. Colonization by Streptococcus pneumoniae among human immunodeficiency virus-infected adults: prevalence of antibiotic resistance, impact of immunization, and characterization by polymerase chain reaction with BOX primers of isolates from persistent S. pneumoniae carriers. J Infect Dis 1997;175:590-597. [Medline]
29. Crew-Brown HH, Karstaedt AS, Saunders GL, et al. Streptococcus pneumoniae blood culture isolates from patients with and without human immunodeficiency virus infection: alterations in penicillin susceptibilities and in serogroups or serotypes. Clin Infect Dis 1997;25:1165-1172. [Medline]
30. Kedree MA. High prevalence of trimethoprim-sulfamethoxazole (TMP-SMX) resistant Streptococcus pneumoniae in HIV-infected patients on TMP-SMX for Pneumocystis prophylaxis: therapeutic implications. In: Program and abstracts of the 11th International Conference on AIDS, Vancouver, B.C., July 7–12, 1996. Vancouver, B.C.: XI Conference on AIDS Society, 1996:232. abstract.
31. Aberg JA, Yajko DM, Jacobson MA, Flamm R, Notario GF. The development of macrolide resistance to respiratory flora in patients receiving either clarithromycin or azithromycin for Mycobacterium avium complex prophylaxis. In: Programs and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 26–29, 1999. Washington, D.C.: American Society for Microbiology, 1999:1164. abstract.
32. Eldred LJ, Wu AW, Chaisson RE, Moore RD. Adherence to antiretroviral and pneumocystis prophylaxis in HIV disease. J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117-125. [Medline]

The following centers and investigators participated in the study: AIDS Research Alliance, Chicago — M. Diaz-Linares, R. Luskin-Hawk, C. Peterson; AIDS Research Consortium of Atlanta, Atlanta — P. Couey, M. Thompson, B. Weaver; Community Consortium of San Francisco, San Francisco — S. Crawford, H. Lampiris, R. Scott; Denver Community Programs for Clinical Research on AIDS, Denver — B. Barber, D. Cohn, R. Fernandez; Harlem AIDS Treatment Group, New York — C. Guity, S. Barnaby, L. Fuentes; Henry Ford Hospital, Detroit — B. Braxton, B. Campbell, L. Faber; Louisiana Community AIDS Program, New Orleans — C.L. Besch, D. Mushatt, J. Osterberger; North Jersey Community Research Initiative, Newark, N.J. — P. Andrew, N. Regevik, R. Roland; Partners in Research New Mexico, Albuquerque — C. Angel, K. Hammer, J. Magill; Philadelphia FIGHT, Philadelphia — P. Cooper, B. Gallagher, P. Loynd; Richmond AIDS Consortium, Richmond, Va. — M. Britton, P. Dodson, M. Howe; Research and Education Group, Portland, Oreg. — D. Antoniskis, S. Peterson, S. Pierson; Southern New Jersey Clinical Trials, Camden — K. Casey, D. Condoluci, J. Muratore; Washington Regional AIDS Program, Washington, D.C. — B. Rashbaum, K. Shade, S. Zubairi; and Wayne State University, Detroit — R. MacArthur, P. Reitenga, M. Yoder.

Abstract PDF Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

This article has been cited by other articles:

• Griffith, D. E., Aksamit, T., Brown-Elliott, B. A., Catanzaro, A., Daley, C., Gordin, F., Holland, S. M., Horsburgh, R., Huitt, G., Iademarco, M. F., Iseman, M., Olivier, K., Ruoss, S., von Reyn, C. F., Wallace, R. J. Jr., Winthrop, K., on behalf of the ATS Mycobacterial Diseases Subcom, (2007). An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. Am. J. Respir. Crit. Care Med. 175: 367-416 [Full Text]  
• Lampe, F. C., Gatell, J. M., Staszewski, S., Johnson, M. A., Pradier, C., Gill, M. J., de Lazzari, E., Dauer, B., Youle, M., Fontas, E., Krentz, H. B., Phillips, A. N. (2006). Changes over time in risk of initial virological failure of combination antiretroviral therapy: a multicohort analysis, 1996 to 2002.. Arch Intern Med 166: 521-528 [Abstract] [Full Text]  
• Nachman, S., Gona, P., Dankner, W., Weinberg, A., Yogev, R., Gershon, A., Rathore, M., Read, J. S., Huang, S., Elgie, C., Hudgens, K., Hughes, W. (2005). The Rate of Serious Bacterial Infections Among HIV-Infected Children With Immune Reconstitution Who Have Discontinued Opportunistic Infection Prophylaxis. Pediatrics 115: e488-e494 [Abstract] [Full Text]  
• Hung, C.-C., Chang, S.-C. (2004). Impact of highly active antiretroviral therapy on incidence and management of human immunodeficiency virus-related opportunistic infections. J Antimicrob Chemother 54: 849-853 [Abstract] [Full Text]  
• Hira, S. K. (2003). Occurrence and Management of Opportunistic Infections Associated with HIV/AIDS in Asia. Journal of Health Management 5: 237-260 [Abstract]  
• Roland, M. E., Lo, B., Braff, J., Stock, P. G. (2003). Key Clinical, Ethical, and Policy Issues in the Evaluation of the Safety and Effectiveness of Solid Organ Transplantation in HIV-Infected Patients. Arch Intern Med 163: 1773-1778 [Full Text]  
• Shafran, S. D., Mashinter, L. D., Phillips, P., Lalonde, R. G., Gill, M. J., Walmsley, S. L., Toma, E., Conway, B., Fong, I. W., Rachlis, A. R., Williams, K. E., Garber, G. E., Schlech, W. F. III, Smaill, F. (2002). Successful Discontinuation of Therapy for Disseminated Mycobacterium avium Complex Infection after Effective Antiretroviral Therapy. ANN INTERN MED 137: 734-737 [Abstract] [Full Text]  
• Masur, P. b. H., Kaplan, J. E., Holmes, K. K. (2002). 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. ANN INTERN MED 137: 435-478 [Abstract] [Full Text]  
• Kirk, O., Reiss, P., Uberti-Foppa, C., Bickel, M., Gerstoft, J., Pradier, C., Wit, F. W., Ledergerber, B., Lundgren, J. D., Furrer, H., for Seven European HIV Cohorts*, (2002). Safe Interruption of Maintenance Therapy against Previous Infection with Four Common HIV-Associated Opportunistic Pathogens during Potent Antiretroviral Therapy. ANN INTERN MED 137: 239-250 [Abstract] [Full Text]  
• Kaplan, J. E., Masur, H., Holmes, K. K. (2002). Discontinuing Prophylaxis against Recurrent Opportunistic Infections in HIV-Infected Persons: A Victory in the Era of HAART. ANN INTERN MED 137: 285-287 [Full Text]  
• Weinstein, M. C., Goldie, S. J., Losina, E., Cohen, C. J., Baxter, J. D., Zhang, H., Kimmel, A. D., Freedberg, K. A. (2001). Use of Genotypic Resistance Testing To Guide HIV Therapy: Clinical Impact and Cost-Effectiveness. ANN INTERN MED 134: 440-450 [Abstract] [Full Text]  
• Girard, P.-M. (2001). Discontinuing Pneumocystis carinii Prophylaxis. NEJM 344: 222-223 [Full Text]  
• Purdy, B. D. (2000). Management and Prevention of Opportunistic Infections in the HIV-Infected Patient. Journal of Pharmacy Practice 13: 475-498 [Abstract]  
• Currier, J. S., Williams, P. L., Koletar, S. L., Cohn, S. E., Murphy, R. L., Heald, A. E., Hafner, R., Bassily, E. L., Lederman, H. M., Knirsch, C., Benson, C. A., Valdez, H., Aberg, J. A., McCutchan, J. A. (2000). Discontinuation of Mycobacterium avium Complex Prophylaxis in Patients with Antiretroviral Therapy-Induced Increases in CD4+ Cell Count: A Randomized, Double-Blind, Placebo-Controlled Trial. ANN INTERN MED 133: 493-503 [Abstract] [Full Text]  
• Lederman, M. M., Valdez, H. (2000). Immune Restoration With Antiretroviral Therapies: Implications for Clinical Management. JAMA 284: 223-228 [Abstract] [Full Text]  
• (2000). Stopping MAC Prophylaxis. AIDS Clin Care 2000: 7-7 [Full Text]  
• (2000). M. avium Prophylaxis Can Stop When CD4 Cells Increase. JWatch Infect. Diseases 2000: 14-14 [Full Text]  
• (2000). MAC Prophylaxis Is Unnecessary When CD4 Counts Rise. JWatch General 2000: 1-1 [Full Text]