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Discontinuation of Secondary Prophylaxis for Cryptococcal Meningitis in Human Immunodeficiency Virus-Infected Patients Treated with Highly Active Antiretroviral Therapy: A Prospective, Multicenter, Randomized Study

  1. Asda Vibhagool1,
  2. Somnuek Sungkanuparph1,
  3. Piroon Mootsikapun3,
  4. Ploenchan Chetchotisakd3,
  5. Somsit Tansuphaswaswadikul4,
  6. Chureeratana Bowonwatanuwong5, and
  7. Atiporn Ingsathit2
  1. 1Faculty of Medicine and Mahidol University, Bangkok
  2. 2Clinical Epidemiology Unit, Ramathibodi Hospital, Mahidol University, Bangkok
  3. 3Faculty of Medicine, Khon Kaen University, Khon Kaen
  4. 4Bamrasnaradura Hospital, Ministry of Public Health, Nonthaburi
  5. 5Chonburi Hospital, Chonburi, Thailand
  1. Reprints or correspondence: Dr. Somnuek Sungkanuparph, Div. of Infectious Diseases, Dept. of Medicine, Ramathibodi Hospital, 270 Rama 6 Rd., Bangkok, 10400, Thailand (tesuk{at}mahidol.ac.th).

  1. Presented in part: 14th International AIDS Conference, Barcelona, Spain, 7–12 July 2002 (poster ThPeB 7292).

 
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Abstract

A prospective, multicenter, randomized study was conducted with human immunodeficiency virus (HIV)-infected patients who were successfully treated for acute cryptococcal meningitis, were receiving secondary prophylaxis, and were naive for antiretroviral therapy. Patients were randomized to continue or discontinue secondary prophylaxis when the CD4 cell count had increased to >100 cells/μL and an undetectable HIV RNA level had been sustained for 3 months. At a median of 48 weeks after randomization, there were no episodes of cryptococcal meningitis in either group.

Cryptococcal meningitis is the most common fungal infection in HIV-infected patients [1]. Life-long secondary prophylaxis after completion of the initial treatment regimen is indicated [2]. However, the use of HAART has improved the survival rates and reconstituted the immune function in recipients [3]. Several studies have demonstrated that secondary prophylaxis for specific opportunistic infections can be discontinued safely in patients who have a CD4 cell count that has increased to more than certain level [4–6]. Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia (PCP) and cytomegalovirus (CMV) infection has been recommended for selected conditions [7]. Preliminary data from small studies suggest that secondary prophylaxis for cryptococcal meningitis may be discontinued safely in patients whose CD4 lymphocyte counts have increased with receipt of antiretroviral therapy [8–10]. This prospective, multicenter, randomized study was conducted to evaluate the safety of discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients who are responding to HAART.

Patients and methods. A prospective, randomized study was conducted in 4 medical centers in Thailand (Ramathibodi Hospital, Bangkok; Khon Kaen University Hospital, Khon Kaen; Bamrasnaradura Hospital, Nonthaburi; and Chonburi Hospital, Chonburi). The study protocol was approved by the institutional review board at each study site. We enrolled adult patients who had acute cryptococcal meningitis (diagnosed by CSF culture positive for Cryptococcus neoformans), who had successfully been treated (i.e., CSF culture did not yield C. neoformans), who were receiving secondary prophylaxis, and who were naive for antiretroviral therapy. A HAART regimen including zidovudine, lamivudine, and efavirenz was initiated. CD4 cell counts and HIV RNA levels were monitored every 12 weeks. If the HAART regimen could not be tolerated, indinavir and a baby dose of ritonavir (100 mg b.i.d.) were substituted for efavirenz, and stavudine or didanosine could be substituted for zidovudine or lamivudine, respectively.

Patients included in the study were randomized to continue (group A) or discontinue (group B) secondary prophylaxis when the CD4 cell count had increased to >100 cells/μL and an undetectable HIV RNA level (<50 copies/mL) was achieved and sustained for 3 months (figure 1). The patients were observed for 48 weeks after randomization.

Figure 1
Figure 1

Enrollment and randomization of patients in a study of the discontinuation of secondary prophylaxis for cryptococcal meningitis. VL, virus load; wk, weeks.

Sample size was calculated from an analysis that used a 2-sided test with an α level of 0.05 and a power of 80%; 22 patients per group, for a total of 44 patients, were required to detect a statistically significant difference. All analyses were performed on an intent-to-treat basis. Values presented as mean ± SD and median with range were used to determine the continuous variables and proportions for the categorical variables. The differences between baseline characteristics were compared using Student's t test. For proportional analysis, we compared the differences between groups by using the χ2 test. The 95% CIs for outcomes were evaluated using the binomial exact confidence method. All P values were 2 tailed. Statistical significance was accepted at the level of P ⩽ .05.

Results. Sixty patients who had successfully been treated for acute cryptococcal meningitis, who were receiving secondary prophylaxis, and who were naive for antiretroviral therapy initiated a HAART regimen. At 48 weeks of antiretroviral therapy, 42 patients (85.7%) had a CD4 cell count of >100 cells/μL and had sustained an undetectable HIV RNA level for 3 months. The other 18 patients were lost to follow-up (9 patients), died (2 patients), or had a CD4 cell count of ⩽100 cells/μL (7 patients). Of the 42 eligible patients, 22 were randomized to group A and 20 were randomized to group B. Demographic data, baseline laboratory parameters, duration of follow-up, and outcomes of the 2 groups are shown in table 1. The baseline median CD4 cell count was <50 cells/μL and the median HIV RNA level was >5.0 log10 copies/mL (100,000 copies/mL) in both groups. During the median 48-week follow-up period after randomization, there were no episodes of cryptococcal meningitis in either group.

Table 1
Table 1

Demographic data, baseline laboratory parameters, and outcomes for patients who continued (group A) or discontinued (group B) secondary prophylaxis for cryptococcal meningitis.

Discussion. Previous small studies have reported that secondary prophylaxis for cryptococcal meningitis may be discontinued safely in patients with AIDS who have immune reconstitution resulting from HAART use [8–10]. Each study described 6 patients who successfully discontinued secondary prophylaxis for cryptococcal meningitis after responding to HAART, and each proposed that the strategy of discontinuation would have considerable benefit for selected patients. However, these data are limited by the small sample sizes, and they need to be supported by a larger prospective trial before such a strategy can be considered safe.

In certain conditions, discontinuation of secondary prophylaxis for patients who have had cryptococcal meningitis, if found to be safe, can reduce the pill burden, the cost of treatment, and the risk of side effects and drug-drug interactions. The strategy of discontinuation of secondary prophylaxis for other opportunistic infections (particularly PCP and CMV disease) is safe at a certain level of immunological response and is recommended by the guidelines of the 2002 US Public Health Service/Infectious Diseases Society of America [7]. However, the discontinuation of secondary prophylaxis for cryptococcal meningitis is only optional (CIII level).

We enrolled 60 patients who had documented cryptococcal meningitis, who had been successfully treated, and who were receiving secondary prophylaxis. At 48 weeks of HAART, 42 patients had a CD4 cell count of >100 cells/μL and had sustained an undetectable HIV RNA level for 3 months. The baseline characteristics, the duration of HAART and the CD4 cell count at the time of randomization, and the duration of follow-up after randomization for 22 patients in group A and 20 patients in group B were not different (table 1). During the 48 weeks of follow-up after randomization, there were no episodes of relapse of cryptococcal meningitis in either group. The calculated power of our study to detect the difference was 79%, and the median 48-week follow-up period after the randomization was reasonable. This result could support the argument in favor of the safety of discontinuation of secondary prophylaxis for HIV-infected patients with cryptococcal meningitis who have responded to HAART.

In a prospective study from the pre-HAART era, Saag et al. [11] reported a 4% rate of relapse in patients receiving secondary prophylaxis with fluconazole, whereas the relapse rate was as high as 37%–60% in patients who did not receive prophylaxis [12, 13]. There were no relapses in our 42 patients who responded to HAART in both groups. Immunological restoration associated with HAART use may reduce the risk of clinical relapse and the need for secondary prophylaxis.

In conclusion, the results of this study indicate that secondary prophylaxis for cryptococcal meningitis can be discontinued safely in patients who have sustained immunological and virological responses (i.e., a CD4 cell count of >100 cells/μL and an undetectable HIV RNA level) to HAART for ⩾3 months.

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Acknowledgments

We thank the AIDS Division, Ministry of Public Health (Nonthaburi), for supporting this study, and the Clinical Epidemiology Unit, Ramathibodi Hospital, Mahidol University (Bangkok), for help with statistical analysis.

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Footnotes

  • Financial support: AIDS Division, Ministry of Public Health, Nonthaburi, Thailand.

  • Received January 4, 2003.
  • Accepted January 22, 2003.
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  1. Clin Infect Dis. (2003) 36 (10): 1329-1331. doi: 10.1086/374849
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