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Opportunistic infections after the initiation of highly active antiretroviral therapy in advanced AIDS patients in an area with a high prevalence of tuberculosis

Sungkanuparph, Somnueka; Vibhagool, Asdaa; Mootsikapun, Piroonb; Chetchotisakd, Ploenchanb; Tansuphaswaswadikul, Somsitc; Bowonwatanuwong, Chureeratanad

Research Letters

aFaculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; bFaculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; cBamrasnaradura Hospital, Ministry of Public Health, Nonthaburi, Thailand; and dChonburi Hospital, Chonburi, Thailand.

This study was presented as poster H-1151 at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 2002.

Sponsorship: This study was supported by a research grant from the AIDS Division, CDC, Ministry of Public Health, Thailand.

Received: 19 January 2003; accepted: 28 April 2003.

A prospective multicentre study was conducted to investigate the incidence and spectrum of opportunistic infections after the initiation of highly active antiretroviral therapy (HAART) in advanced AIDS patients with very low CD4 cell counts. Sixty patients with successful HAART treatment, which raised the median CD4 cell count from 9 to168 cells/μl at 48 weeks, were studied. Fourteen patients developed 20 episodes of opportunistic infections, including tuberculosis, Mycobacterium avium complex infection, relapsed cryptococcal meningitis, herpes zoster, toxoplasmosis, and herpes genitalis.

Highly active antiretroviral therapy (HAART) has been shown to improve survival and reconstitute immune function [1]. CD4 T-cell reactivity against opportunistic pathogens can be recovered even in severely immunosuppressed patients [2]. The exaggerated inflammatory immune response to an opportunistic pathogen during immune restoration may induce a clinical flare-up of the opportunistic infection (OI), called ‘immune reconstitution syndrome’ [3,4]. The most commonly described immune reconstitution syndromes have been responses to tuberculosis, infection with Mycobacterium avium complex or cytomegalovirus, or cryptococcosis [5–8].

In Thailand, as well as in other developing countries, HIV-infected patients often present late with advanced AIDS and major OI. Patients with low CD4 cell counts are prone to develop OI within the first few months after the initiation of HAART [9]. The spectrums of OI after the initiation of HAART, as immune reconstitution syndrome, may be varied according to the prevalence of OI in each area. The objective of our study was to investigate the incidence and spectrum of OI after the initiation of HAART in advanced AIDS patients with very low CD4 cell counts.

A prospective multicentre study was conducted in four medical centres in Thailand. We enrolled advanced AIDS patients who had had successful treatment of acute cryptococcal meningitis and were on secondary prophylaxis, and were naive for antiretroviral therapy. A HAART regimen including zidovudine, lamivudine, and efavirenz was initiated and followed up for 48 weeks. The occurrence of OI was observed.

Sixty patients (50 men) with a mean age of 33.1 ± 6.0 years were enrolled. The baseline median (range) CD4 cell count was 9 (0–147) cells/μl and the baseline median (range) HIV-RNA level was 5.18 log10 (4.45–5.95 log10) copies/ml. As treated analysis, the percentage of patients with HIV-RNA levels less than 400 copies/ml at 12, 24, 36, and 48 weeks were 96.4, 88.5, 92.0, and 87.8%, respectively. The median CD4 cell counts at 12, 24, 36, 48 weeks were 69, 96, 119, and 168 cells/μl, respectively. In the 48-week period after the initiation of HAART, 14 our of 60 patients (23.3%) had 20 episodes of OI, including tuberculosis (eight episodes), M. avium complex infection (three episodes), relapsed cryptococcal meningitis (three episodes), herpes zoster (three episodes), toxoplasmosis (two episodes), and herpes genitalis (one episode). OI occurred after the initiation of HAART for a median (range) duration of 16 (4–32) weeks. Two patients died during the OI (toxoplasmosis and relapsed cryptococcal meningitis).

We enrolled patients with cryptococcal meningitis, one of the most common OI, which usually occurred in patients with CD4 cell counts of less than 100 cells/μl, to the study. The results of our study show that HAART was effective in advanced AIDS patients with very low CD4 cell counts, high HIV-RNA levels, and recent illness from acute cryptococcal meningitis. The improvement in immune function during HAART plays an important role in prolonging the survival and disease-free period. However, rapidly effective HAART has often raised the inflammatory response to residual pathogens and induced OI [3–8]. More than 20% of our patients had an OI after the initiation of HAART, and half of them occurred in the first 16 weeks of treatment. Twenty-four episodes occurred in a 48-week follow-up period in 60 patients. This equalled 33 episodes/100 person-years. The incidence is much higher than that of previous studies [10]. The most common OI in our study was tuberculosis, which differs from that in an area with a low prevalence of tuberculosis [10]. As tuberculosis occurred despite successful HAART treatment, immune restoration and the response to Mycobacterium tuberculosis may explain this [11].

The incidence of OI after the initiation of HAART in advanced AIDS patients with very low CD4 cell counts is high. Tuberculosis is the most common OI in an area with a high prevalence of tuberculosis. An inflammatory response to latent pathogens caused by immune recovery (immune reconstitution syndrome) explains this. The initiation of HAART in patients with very low CD4 cell counts calls for an awareness of the occurrence of OI and close follow-up.

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© 2003 Lippincott Williams & Wilkins, Inc.