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A Study of Discontinuing Maintenance Therapy in Human Immunodeficiency Virus–Infected Subjects with Disseminated Mycobacterium avium Complex: AIDS Clinical Trial Group 393 Study Team

  1. Judith A Aberg1,
  2. Paige L Williams4,
  3. Tun Liu4,
  4. Howard M Lederman5,
  5. Richard Hafner6,
  6. Francesca J Torriani2,
  7. Jeffrey L Lennox7,
  8. Michael P Dube3,
  9. Rob Roy MacGregor8 and
  10. Judith S Currier3
  1. 1 Department of Medicine, Division of Infectious Disease, University of California, San Francisco,
  2. 2 Department of Medicine, Division of Infectious Disease, University of California, San Diego, and
  3. 3 Department of Medicine, Division of Infectious Disease, University of Southern California, Los Angeles;
  4. 4 Harvard School of Public Health, Boston, Massachusetts;
  5. 5 Johns Hopkins University, Baltimore, and
  6. 6 Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;
  7. 7 Department of Medicine, Division of Infectious Disease, Emory University, Atlanta, Georgia;
  8. 8 Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia
  1. Reprints or correspondence: Dr. Judith A. Aberg, Washington University School of Medicine, AIDS Clinical Trials Unit, 4511 Forest Park Ave., Ste. 304, St. Louis, MO 63108 (jaberg{at}im.wustl.edu)
 
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Abstract

The present nonrandomized prospective study evaluated whether antimycobacterial therapy for disseminated Mycobacterium avium complex (MAC) could be withdrawn from human immunodeficiency virus–infected subjects who experienced immunologic recovery while receiving highly active antiretroviral therapy (HAART). Eligible subjects had received macrolide-based therapy for least 12 months, were asymptomatic for MAC, had received HAART for at least 16 weeks, and had CD4+ T cell counts >100 cells/μL. Forty-eight subjects were enrolled, with a median CD4+ T cell count of 240 cells/μL at the time of discontinuation of MAC therapy. Forty-seven subjects remained MAC free, whereas 1 subject developed localized MAC osteomyelitis. The median duration of follow-up while not receiving therapy was 77 weeks, and the incidence of MAC infection was 1.44/100 person-years (95% confidence interval, 0.04–8.01). Withdrawal of anti-MAC therapy appears to be safe in patients who have been treated with a macrolide-based regimen for at least 1 year and have an immunologic response on HAART

Prior to the introduction of highly active antiretroviral therapy (HAART), disseminated infection with Mycobacterium avium complex (MAC) was one of the most common life-threatening opportunistic infections in human immunodeficiency virus (HIV)–1–infected patients. Disseminated MAC (DMAC) occurred almost exclusively in patients with CD4+ T cell counts <50 cells/μL, frequently relapsed during therapy, and resulted in a median survival of only 4–8 months after diagnosis in affected patients [1 –4]. The standard of care was therefore to continue lifelong treatment, because immunologic recovery and microbiological cure were not expected

The introduction of potent antiretroviral therapy significantly decreased AIDS-related morbidity and mortality [5]. For DMAC, the median duration of survival almost doubled between 1994 and 1997 [6]. Patients who once required lifelong suppressive therapy for other opportunistic infections have now successfully discontinued both primary and secondary prophylaxis for cytomegalovirus, Pneumocystis carinii pneumonia, and toxoplasmosis [7 –18]. Several studies have shown that it is safe to withdraw primary prophylaxis given to prevent DMAC, but there are only limited reports of successful withdrawal of secondary prophylaxis, and most have been retrospective [19 –26]. Because patients who developed DMAC when their CD4+ T cell counts were <50 cells/μL may have a sustained immunologic response to HAART, we set out to determine whether secondary prophylaxis could safely be discontinued in such patients

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Subjects, Materials, and Methods

The present study was a nonrandomized, prospective clinical trial that was designed to enroll ∼50 subjects who had completed at least 12 months of macrolide-based therapy for DMAC and to monitor each subject for MAC recurrence. The primary objective was to evaluate whether antimycobacterial therapy could be withdrawn from HIV-infected subjects who had completed a course of macrolide-based therapy for DMAC and to estimate the duration of time that those subjects remained free of MAC infection. The secondary objective was to evaluate whether certain immunologic measures could predict the risk of MAC recurrence. For the latter objective, subjects who had a MAC recurrence were to be compared with those who remained MAC free with respect to T cell subsets, in vitro lymphocyte proliferation assay (LPA) responses to MAC and other recall antigens, and delayed-type hypersensitivity (DTH) skin test responses

Eligible subjects were age ⩾13 years, had documented HIV infection, had been treated for at least 12 months with macrolide-based antimycobacterial therapy for MAC infection diagnosed by blood or bone-marrow culture, had been asymptomatic for MAC for at least 16 weeks, had received HAART for at least 16 weeks, and had CD4+ T cell counts >100 cells/μL on 2 occasions, with 1 documented CD4+ T cell count at least 60 days prior to study entry. Women of childbearing age were required to have a negative pregnancy test, given the potential of developing relapsing MAC during pregnancy, which was considered to be a much greater risk to the mother/fetus than remaining on the recommended prophylaxis that was being well tolerated. Initially, all subjects who met the above criteria had blood and bone marrow cultured for MAC at study entainer; Becton-Dickinson) and shipped overnight with refrigerant packs at 20°C to a central laboratory (Non-tuberculous Mycobacterial Reference Laboratory, Childrens Hospital, Los Angeles) [27]. A core sample obtained from the bone-marrow biopsy specimen was also shipped to the central laboratory if it had been collected. After the first 17 subjects enrolled had sterile bone-marrow cultures, the bone-marrow aspirate for culture became optional, but all subjects continued to have blood cultures collected. If cultures were sterile, MAC therapy was discontinued at week 6, and the subjects were monitored for signs and symptoms of infection. Clinical evaluations were done and blood cultures obtained at weeks 6, 10, and 14 and every 8 weeks thereafter, to examine for suspected relapse until closure to study follow-up. CD4+ T cell counts were obtained at study weeks 0, 6, 10, and 14 and then every 8 weeks. HIV RNA samples were collected at various time points throughout the study and were assayed via an ultrasensitive reverse-transcription polymerase chain reaction HIV-1 RNA assay (done at Johns Hopkins Virology Laboratory, Baltimore; level of detection, <50 copies/mL) for samples collected at study entry (week 0) and at week 22. Any subject who had 2 consecutive CD4+ T cell counts <50 cells/μL was to reinitiate MAC maintenance therapy

Immunologic assays The standard 3-color flow and advanced phenotyping panel included flow-based monitoring for natural killer (CD56/16) cells and for γδT cells and was done in real time at weeks 6, 30, 62, and 110 and every 48 weeks until study closure. These assays were done using the AIDS Clinical Trial Group (ACTG) consensus methodology (available at http://aactg.s-3.com/immlab.htm)

LPA responses to tetanus toxoid (1 μg/mL; Wyeth-Lederle), Candida albicans antigen (10 μg/mL; Greer Laboratories), and 3 MAC antigen preparations ( 1–10 μg/mL MAS-Sensitin PPD, M. avium RS10/2, lot 38, Statens Seruminstitut; 5 μg/mL MAC LR114F culture filtrate of M. avium LR114F, supplied by Dr. Robert Wallis, Case Western Reserve University School of Medicine, Cleveland; and 5 μg/mL MAC 101 sonicate of M. avium complex 101, supplied by Dr. Robert Wallis, Case Western Reserve University School of Medicine) were measured at weeks 6, 30, 62, and 110. These assays were done using the ACTG consensus methodology (http://aactg.s-3.com/immmeth.htm). For each antigen, a stimulation index (SI) was calculated as the ratio of median counts per minute for stimulated wells versus the median counts per minute for control wells. A positive response was defined to be an SI ⩾10 for the mitogen phytohemagglutinin (PHA) and ⩾5 for all antigens

DTH skin test responses to mumps, candida, tetanus, and tuberculin (5 tuberculin units [TU]) were applied by standard technique at weeks 6, 62, and every 48 weeks until the last subject had completed 60 weeks in the study. Subjects who were negative for 5 TU (<5 mm skin test results) at weeks 6 and 62 were to be retested using 250 TU at weeks 10 and 70. However, during the course of the study, the manufacturer discontinued the product, and subjects were unable to continue to be tested using the 250 TU formulation

Statistical methods A sample size of 40 subjects would provide 80% power for testing the null hypothesis that the yearly rate of subjects with MAC recurrence was >25% versus the alternative that it was <10%, based on a 1-sided test and a 0.05 significance level. The total target sample size was increased to 50 subjects, to account for possible loss to follow-up. It was anticipated that these 50 subjects would be accrued over 1 year and that all subjects would be monitored until the last accrued subject had been followed for 60 weeks. Given the small number of events, the Poisson distribution was used to calculate incidence rates and confidence intervals (CIs) for MAC recurrence. Standard Kaplan-Meier survival estimates were used to estimate the distribution of MAC-free time after the discontinuation of therapy. Repeated-measures models based on generalized estimating equations [28] were used to evaluate trends in CD4+ T cell counts over time, while accounting for the correlation among the repeated measurements taken on the same subject

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Results

A total of 49 subjects were enrolled between September 1998 and September 2000 at 14 clinical centers. The study was closed to follow-up in April 2001. One subject, who enrolled with presumptive MAC, was determined to be ineligible because the MAC infection was not documented by blood or bone-marrow culture, and that subject was therefore discontinued from the study. For the 49 subjects, the median CD4+ T cell count at screening was 212 cells/μL (range, 104–592 cells/μL), and the pre-entry level was 241 cells/μL (range, 100-619 cells/μL). The first screening CD4 count was a median of 19 days prior to randomization (range, 5–52 days). The second screening CD4 count was a median of 7 days prior to randomization (range, 1–15 days). There was a median of 10 days between the 2 screening CD4 counts (range, 1–45 days). For the 48 eligible subjects, the median CD4+ T cell count at the time of MAC therapy discontinuation (week 6) was 240 cells/μL (range, 84–958 cells/μL), and 15 (31%) of 48 subjects had CD4+ T cell counts >300 cells/μL. The median time that subjects had been treated for MAC until study entry was 31 months (range, 13–87 months). Of the 42 subjects with available HIV load data, 29 (69%) had an undetectable HIV load at entry. See table 1 for a summary of these and other baseline characteristics. Note that, with the exception of virus load, these baseline parameters were assessed at study week 6, which is the time that MAC therapy was stopped. All subjects had sterile blood cultures, and all of the 17 who underwent bone-marrow biopsy had sterile bone-marrow cultures prior to the discontinuation of therapy

Table 1
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Table 1

Baseline characteristics of the study group

Forty-seven of 48 subjects remained MAC free, with a median duration of 77 weeks (range, 21–121 weeks) not receiving therapy. Only 1 subject had a MAC recurrence, yielding an estimated incidence rate of 1.44 MAC recurrences/100 person-years of follow-up (95% CI, 0.04–8.01). The 1 subject with a recurrence developed MAC osteomyelitis of the left anterior sixth rib (confirmed by bone biopsy and culture) 16 months after the discontinuation of MAC therapy [29]. Of note, his CD4+ T cell count had never decreased to <150 cells/μL after the discontinuation of MAC therapy. His HIV load decreased to <50 copies/mL by week 22 and remained below the limit of detection throughout the remainder of the study. Eighty weeks after discontinuing therapy, his CD4+ T cell count was 244 cells/μL, at which time he was definitively diagnosed with recurrent MAC and resumed MAC therapy. One other subject died of non–HIV-related liver disease during study follow-up, 21 weeks after discontinuing MAC therapy. In addition, 2 subjects developed oropharyngeal candidiasis (1 probable and 1 confirmed), and 1 developed probable Kaposi sarcoma

Although extensive immunologic data were collected on all subjects, the occurrence of a single MAC event prevented the comparison of these data between subjects with and without relapse. On the basis of fitting a repeated-measures model, the CD4+ T cell count of the cohort was estimated to rise an average of 6 cells/μL for every 8 weeks on follow-up (P=.003). The median CD4+ T cell count increased from 240 cells/μL (15%) at week 6 to 322 cells/μL (19%) at week 110. CD4+ T cell counts decreased to <100 cells/μL at some point during the study in 11 subjects, including 2 subjects whose CD4+ T cell count decreased to <50 cells/μL. The majority of these 11 subjects had only 1 transient decrease in CD4+ T cell counts, and none required the reinitiation of MAC maintenance therapy

Both the absolute numbers of naive and memory CD4+ T cells increased over time, but there were no significant changes in the percentage of naive cells over time (29.5%–24.2%). The CD8+ T cell count increased from 718 at week 6 to 914 at week 110, but the percentage (48.6%–47.3%) remained stable over time as well. Those subjects with undetectable HIV RNA tended to have higher numbers of naive CD4+ T cells. Neither the number nor percentage of activated CD4+ T cells changed significantly over time. A negative correlation was found between the number of activated CD4+ T cells and positive LPA response to all MAC antigens. Only 3 subjects had a virus load >5000 copies/mL at entry, and 5 subjects had a virus load >5000 copies/mL at week 22. Given the small sample size, we were not able to determine whether there was a statistical correlation between LPA response and virological failure

During the course of follow-up, increases in the percentage of subjects with positive LPA responses to certain stimulants were observed (table 2). For example, the percentage of subjects with a positive LPA response to PHA increased from 58% at week 6 to 86% at week 110. LPA responses to both MAS (57%–80%) and MAC LR/114F (45%–78%) also increased. In contrast, the percentage of subjects with positive LPA responses to tetanus or candida did not increase over the course of the study. At weeks 6 and 62, when both LPA and DTH responses were measured, the percentage of DTH responders was consistently lower than the percentage of LPA responders. In addition, subjects with a positive LPA response did not always maintain their response. This was especially true for candida and MAS 1.0. For candida, only 8 (25%) of 32 subjects who had ever had a positive LPA response maintained this response, whereas 12 (38%) lost this response (the remaining 12 subjects had no further LPA data). For MAS 1.0, 16 (48%) of 33 subjects maintained their positive response, whereas 13 (39%) lost the response

Table 2
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Table 2

Positive lymphocyte proliferation assay and delayed-type hypersensitivity responses by stimulant and visit week

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Discussion

After a median of 77 weeks not receiving antimycobacterial therapy, all but 1 of our subjects remained free of recurrent disease. In the initial pilot study evaluating the safety of discontinuing secondary prophylaxis for DMAC, 4 patients discontinued antimycobacterial therapy without evidence of recurrence after 8–13 months of follow-up [22]. In the present larger, prospective study, we have demonstrated that MAC relapse is rare. It, therefore, appears to be safe to withdraw anti-MAC therapy in those patients who have been treated with a macrolide-based regimen for at least 1 year and whose CD4 counts have increased to >100 cells/μL on HAART

In a retrospective study of secondary prophylaxis discontinuation conducted in France, 3 of 26 patients had a MAC relapse [23]. One patient was severely immunosuppressed, with a CD4+ T cell count <50 cells/μL at the time of relapse. However, the other 2 patients developed atypical bone infections and had CD4+ T cell counts of 126 and 160 cells/μL, respectively. It is interesting to note that, in our study, 1 patient also developed MAC osteomyelitis and had a CD4+ T cell count of 244 cells/μL, similar to those described in the French retrospective study. Furthermore, in a prospective study that evaluated whether primary prophylaxis with azithromycin could be withdrawn in subjects whose CD4+ T cell counts were >100 cells/μL on HAART, there were 2 cases of localized MAC osteomyelitis that occurred among the 321 subjects enrolled in the placebo arm [20]. No cases of MAC occurred in the 322 subjects who remained on azithromycin. Given the lack of disseminated disease and the evidence for immune reconstitution, this could be a process that is significantly facilitated by the limited ability of immune cells to gain access to a previously infected site

Overall, the present results provide additional evidence for the clinical benefit of immune restoration after HAART, even among those patients with a history of profoundly advanced HIV disease. For example, ∼50% of the subjects had positive MAC-specific responses 6 weeks after the discontinuation of MAC prophylaxis, and these significantly increased in 3 of 4 MAC antigens 1 year after stopping MAC treatment. These results suggest that, in HIV-infected patients with prior DMAC due to severe immunosuppression, the ability to mount an antigen-specific response increases in parallel to HAART-induced CD4+ T cell regeneration, along with the absence of continued suppression of mycobacterial growth. Of interest, similar responses were observed in a cohort of HIV-uninfected control subjects [30]

The present study also included extensive immunologic assays at baseline and during follow-up. In our patient population, the predictive value of immunologic tests other than measurement of CD4 counts remains uncertain. It is notable that responses to LPA assays and DTH skin tests are often negative, despite the clinically apparent immune function protecting these patients from MAC relapse. This result suggests that these immune markers have little clinical utility for predicting immune competency against MAC. One limitation of the study was that DTH responses to mycobacteria were determined for tuberculin, which may not be an adequate predictor for response to MAC. Another study has shown that the MAS DTH was positive in 11 of 26 patients with a previous DMAC infection, whereas tuberculin was negative in all 26 [31]. On the other hand, the DTH response rates to all antigens were poor, which possibly suggests that DTH responses may not be an adequate surrogate marker for measuring immune recovery

Stopping MAC therapy may be of considerable benefit to patients. Patients would no longer need to take lifelong MAC suppressive therapy. Prolonged macrolide therapy may lead to macrolide resistance, not only to MAC but also to common respiratory flora, potentially making it more difficult to treat respiratory infections [32]. All antimycobacterial agents can have significant side effects and can cause potential drug-drug interactions, particularly rifabutin, which further complicates therapeutics. Additionally, adherence to antiretroviral therapy is a critical component in maintaining virus suppression. Reducing the daily pill burden may help improve this adherence

It is also important to consider the reinitiation of MAC prophylaxis if immunologic and/or virological failure results in a decrease in the CD4+ T cell count, as recommended by the US Public Health Service/Infectious Diseases Society of America (USPHS/IDSA) guidelines [33]. At present, the threshold of CD4+ T cell count below which MAC therapy should be reinitiated is unknown. Recurrent MAC did not develop in any of the 11 patients in the present study who had transient decreases in their CD4+ T cells to <100 cells/μL. It therefore appears that the USPHS/IDSA guideline to resume secondary prophylaxis if the CD4+ T cell count decreases to <100 cells/μL may need to be tempered by considerations of the likelihood of transient decreases below this level

Although the rarity of MAC recurrences in the present study suggests that it is safe to discontinue primary and secondary prophylaxis, clinicians need to be aware that atypical manifestations of MAC may occur in patients with sustained elevations of their CD4+ T cells. The atypical presentation of MAC in this and other studies suggests that this manifestation is a focal reactivation of previous hematogenous dissemination. Our study demonstrated that the routine monitoring of blood cultures was not effective for detecting these atypical manifestations. Therefore, monitoring patients at high risk for MAC development or recurrence requires a careful examination of signs and symptoms, along with an evaluation of other normally sterile sites that could harbor MAC infection. It may be prudent to treat patients who develop atypical manifestations of MAC despite HAART-induced increases in CD4+ T cell counts for a prolonged period and consider lifelong suppressive therapy

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Acknowledgments

We thank other members of the AIDS Clinical Trial Group 393 protocol team and participating sites as follows: Adult AIDS Clinical Trial Group Operations Center, Thomas Nevin; Statistical and Data Analysis Center, Yinmei Zhou; Frontier Science and Technology Research Foundation, Susan Owens and Peter Hojczyk; field representative, Michael Conklin (Washington University); laboratory consultants, Robert S. Wallis (Case Western Reserve University School of Medicine, Cleveland) and Clark Inderlied (Childrens Hospital of Los Angeles); Pharmaceutical and Regulatory Affairs Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, Lynette Purdue; and community representative, John McFeely. Participating sites: Bellevue Hospital Center, New York, Maura Laverty and Olivia Ortiz; Emory University, Atlanta, James Bryan Thompson; Johns Hopkins, Baltimore, Ilene Wiggins; Indiana University/Wishard Memorial Hospital, Indianapolis, Jean Craft and Mitchell Goldman; Rush Presbyterian/St. Luke’s, Chicago, Mary Ann Colletti and Beverly Sha; San Francisco General Hospital, Carol Arri; Stanford University, Stanford, California, Debbie Slamowit and Stephen Lee; University of California, San Diego, Joanne Santangelo; University of Colorado Health Sciences Center, Denver, Sally Canmann and Steven Johnson; University of Hawaii School of Medicine, Honolulu; Debra Ogata-Arakaki and Bruce Shiramizu; University of North Carolina, Raleigh, Laurie Frarey and Charles van der Horst; University of Pennsylvania, Philadelphia, Doris Shank; and University of Southern California, Los Angeles, Frances Canchola

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Footnotes

  • Presented in part: 9th Conference on Retroviruses and Opportunistic Infections, Seattle, 24–28 February 2002 (abstract 634-W)

    Informed consent was obtained from patients or their parents or guardians, and human experimentation guidelines of the US Department of Health and Human Services and/or of the authors’ institution(s) were followed in the conduct of clinical research. Each participating Institutional Review Board approved the study protocol

    Financial support: National Institutes of Allergy and Infectious Disease (AIDS clinical trials grant AI38858); General Clinical Research Center Units, funded by the National Center for Research Resources; Emory University (AIDS Clinical Trials Unit [ACTU] grant AI32775); Johns Hopkins University (ACTU grant AI27668 and Genral Clinical Research Center [GCRC] grant RR-00052); San Francisco General Hospital (GCRC grant RR-00083); University of California, San Diego (ACTU grant AI 27670); University of North Carolina (ACTU grant AI25868 and GCRC grant RR00046)

  • Present affiliations: Washington University, St. Louis, Missouri (J.A.A.); Indiana University School of Medicine, Indianapolis (M.P.D.); University of California, Los Angeles (J.S.C.)

  • Received October 3, 2002.
  • Accepted December 4, 2002.
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  1. J Infect Dis. (2003) 187 (7): 1046-1052. doi: 10.1086/368413
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