To the Editors:
Cryptococcal meningitis is a leading cause of mortality and morbidity among HIV-1-infected patients, particularly in developing countries.1,2 Most cases are observed among newly diagnosed HIV-infected patients who have CD4 T-lymphocyte counts of <50 cells/mm3.3-5 Treatment for acute disease has been well established (ie, amphotericin B, usually combined with flucytosine, for 2 weeks, followed by fluconazole for an additional 8 weeks).6 There is evidence that antiretroviral therapy (ART) improves the survival rate in HIV-1-infected patients with various opportunistic infections, including cryptococcosis.2 The risk of disease progression that leads to death from deferred initiation of ART must be weighed against the risk of adverse reactions, drug-drug interactions, and immune reconstitution syndromes (IRSs) from early ART initiation. Nevertheless, clinical data regarding the optimal timing for initiation of ART are not available. Thus, this study was conducted and attempted to define the optimal timing for ART initiation in antiretroviral-naive HIV-infected patients with newly diagnosed cryptococcal meningitis. The mortality rate was compared between early and deferred ART initiation after the diagnosis of cryptococcal meningitis.
A retrospective cohort study was conducted among HIV-1-infected patients with cryptococcal meningitis, for whom ART was subsequently initiated, at Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health (MOPH), Bangkok, Thailand, between January 2002 and December 2004. The institute is a 200-bed tertiary care HIV referral center and belongs to the MOPH. Patient inclusion criteria were as follows: (1) HIV infection at >15 years of age, (2) newly diagnosed with cryptococcal meningitis, (3) naive to ART before the diagnosis of cryptococcal meningitis, (4) initiation of ART after the diagnosis of cryptococcal meningitis, and (5) follow-up for at least 2 clinic visits. The patients were excluded if they were transferred from other hospitals. All patients were followed up until the end of October 2006. Cryptococcal meningitis was defined by cerebrospinal fluid (CSF) being positive for an India ink preparation, positive for cryptococcal antigen, and/or positive for a Cryptococcus neoformans fungal culture. The objective was to compare the mortality rate between early and deferred initiation of ART. The comparisons of mortality rate were also performed at different time points after the diagnosis of cryptococcal meningitis. We obtained the actual vital status of patients by searching the National Registration Database System and the Central Population Database of the Ministry of the Interior in October 2006.
Mean (±SD), median (interquartile range [IQR]), and frequencies were used to describe findings. A P value <0.5 was considered to be significant. A Kaplan-Meier analysis was used to determine the probability of death and the median time to death. The patients were censored in case they were lost to follow-up or were transferred to other hospitals. The log-rank test was used to compare the median time to death. The Cox proportional hazard model was used to determine the probability of death by adjusting for confounding factors. The outcome of death by different time points of ART initiation was compared between the groups by the χ2 test. All analyses were performed using SPSS program, version 11.5 (SPSS, Inc., Chicago, IL). The study was approved by the Institutional Review Board and the Ethical Committee for Research in Human Subjects, Department of Diseases Control, MOPH, Thailand.
There were 281 patients who were eligible according to the study criteria, contributing to 1050 patient-years of observation. The median (IQR) duration of follow-up was 3.7 (2.6 to 4.8) years. Baseline characteristics were as follows: mean ± SD age was 33.4 ± 6.9 years and 73.7% of patients were male. The median (IQR) CD4 cell count and percentage of CD4 cells were 20 (6 to 74) cells/mm3 and 2% (1% to 6%), respectively. Eighty-five (30%) patients had previous major opportunistic infections, including tuberculosis (58.1%), Pneumocystis pneumonia (16.2%), cytomegalovirus (CMV) retinitis (10.9%), and others (14.8%). The median (IQR) time from the diagnosis of cryptococcal meningitis to ART initiation for all patients was 2.8 (1.3 to 8.6) months. Among all patients, 209 (74.4%), 48 (17%), 18 (6.5%), and 6 (2.1%) received nevirapine-based ART, efavirenz-based ART, protease inhibitor-based ART, and other regimens, respectively. During the follow-up period, 52 (18.5%) of 281 patients died. By Kaplan-Meier analysis, the probabilities of death at 1, 2, and 3 years after the diagnosis of cryptococcal meningitis were 7.2%, 12.6%, and 14.5%, respectively. The probabilities of death at corresponding periods in the patients who had a baseline CD4 count ≤50 cells/mm3 versus those with a baseline CD4 count >50 cells/mm3 were as follows: 8.0% versus 3.4%, 15.4% versus 3.6%, and 20.0% versus 4.8%, respectively (P = 0.002, log-rank test).
Among 52 patients who died, the causes of death in 44 (84.6%) patients were associated with cryptococcal meningitis and the rest were associated with other opportunistic infections. The all-cause mortality rates with early and deferred initiation of ART at different time points are shown in Table 1. There were no differences in the mortality rate at each time point of ART initiation (P > 0.05). By multivariate analysis, a baseline CD4 count ≤50 cells/mm3 was associated with a higher probability of death (hazard ratio [HR] =3.546, 95% confidence interval [CI]: 1.056 to 11.905; P = 0.041) after adjusting for CSF opening pressure, number of white blood cells in the CSF, and timing from diagnosis of cryptococcal meningitis to initiation of ART.
Although the indication for ART in HIV-infected patients has been well established in many treatment guidelines,7,8 no information is available to guide physicians in the optimal timing of ART initiation in antiretroviral-naive HIV-infected patients with newly diagnosed cryptococcal meningitis. In resource-limited settings, HIV-infected patients usually present late with low CD4 cell counts and with comorbid opportunistic infections.5 The risk of disease progression leading to death from deferred initiation of ART must be weighed against the risk of adverse reactions, drug-drug interactions, and IRSs from early ART initiation. Therefore, the present study attempts to determine the difference in the mortality rate between early and deferred initiation of ART.
Interestingly, we found that the timing of ART initiation was not a factor associated with mortality. Several reasons may explain this finding. First, the mortality rate is relatively low, even in this population, which was considered to have advanced disease. Thus, we may not be able to detect the difference in low mortality rate between early and deferred ART initiation at different time points. Second, the distribution of mortality occurred homogeneously after initiation of ART throughout the study period. In contrast, patients with a CD4 count ≤50 cells/mm3 were 3.5 times more likely to die compared with those who had baseline CD4 count >50 cells/mm3 in univariate and multivariate analyses (P < 0.05). Our result in these particular patients are consistent with a previous pooled analysis of 13 cohorts in developed countries demonstrating that the 3-year risk of progression to AIDS or death was different between the patients who had CD4 counts <50 cells/mm3 and >50 cells/mm3.9 According to these findings, low baseline CD4 cell counts have an impact on mortality much more than the timing of ART initiation in patients with cryptococcal meningitis. Thus, early detection of HIV infection is a priority intervention required in resource-limited settings.
In conclusion, a high risk of death was found in advanced HIV-infected patients with cryptococcal meningitis with a baseline CD4 count ≤50 cells/mm3. No difference in the mortality rate between early and deferred initiation of ART was observed. A future prospective study should be conducted to confirm this result, however.
The authors thank all the study patients in this study and the attending staff. This study was supported by a grant from Bamrasnaradura Infectious Diseases Institute.
Weerawat Manosuthi, MD*†
Suthat Chottanapund, MD*
Somnuek Sungkanuparph, MD†
*Bamrasnaradura Infectious Diseases Institute Ministry of Public Health Nonthaburi, Thailand
†Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok, Thailand
1. Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS-100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev
2. Jongwutiwes U, Kiertiburanakul S, Sungkanuparph S. Impact of antiretroviral therapy on the relapse of cryptococcosis and survival of HIV-infected patients with cryptococcal infection. Curr HIV Res
3. Inverarity D, Bradshaw Q, Wright P, et al. The spectrum of HIV-related disease in rural Central Thailand. Southeast Asian J Trop Med Public Health
4. Tansuphasawadikul S, Amornkul PN, Tanchanpong C, et al. Clinical presentation of hospitalized adult patients with HIV infection and AIDS in Bangkok, Thailand. J Acquir Immune Defic Syndr
5. Ruxrungtham K, Phanuphak P. Update on HIV/AIDS in Thailand. J Med Assoc Thai
. 2001;84(Suppl 1):S1-S17.
6. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis
7. Joint United Nations Program on HIV/AIDS (UNAIDS) and World Health Organization (WHO). Scaling up Antiretroviral Therapy in Resource-Limited Settings: Treatment Guidelines for a Public Health Approach. 2006 Revision
. Geneva. Switzerland: World Health Organization; 2006.
8. US Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. October, 2006. Available at: http://AIDSinfo.nih.gov
. Accessed October 11, 2007.
9. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet