Penicilliosis marneffei, a systemic infection caused by the dimorphic fungus Penicillium marneffei, is most commonly found in southeast Asian countries, India, Taiwan, Hong Kong, and southern China . It is the third most common AIDS-defining opportunistic infection in northern Thailand, accounting for 15–20% of presenting AIDS-related illnesses . This disseminated fungal infection develops more commonly in HIV-infected patients who have CD4 cell counts of less than 100 cells/μl . The common clinical manifestations include fever, anaemia, weight loss, and generalized skin papules with central umbilication . A presumptive diagnosis could be made by the identification of characteristic septate yeast-like organisms under microscopic examination of the Wright's-stained samples of bone marrow aspirate, and touch smears of the skin biopsy and lymph node biopsy specimens. P. marneffei could be isolated from various clinical specimens including blood, skin, bone marrow, and lymph node. Treatment with intravenous amphotericin B for 2 weeks, followed by oral itraconazole for 10 weeks, is highly effective and safe . A study from Chiang Mai University showed that 50% of patients had a relapse of penicilliosis marneffei within 6 months after the discontinuation of antifungal therapy . A double-blind, placebo-controlled study by Supparatpinyo et al.  demonstrated that oral itraconazole 200 mg a day for secondary prophylaxis in AIDS patients reduced the relapse rate of penicilliosis marneffei from 57 to 0% (P < 0.001). A lifelong secondary prophylaxis with itraconazole has become the standard of care for this systemic fungal infection in Thailand.
Data from developed countries have shown that primary and secondary prophylaxis for several opportunistic infections can safely be discontinued when patients have received HAART and their CD4 cell counts are persistently greater than the values associated with a high risk of the development of specific opportunistic infections [7–10]. For penicilliosis marneffei, there has been only one observation by Hung et al.  in 14 HIV-infected patients who had received HAART with favourable immunological response and discontinued secondary prophylaxis. No relapse was reported after a median follow-up duration of 18 months. However, the sample size was relatively small and the level of CD4 cells at the time of antifungal discontinuation was not specified.
We conducted a retrospective cohort study at Chiang Mai University Hospital to evaluate the safety of discontinuation of secondary prophylaxis for penicilliosis marneffei in AIDS patients who were receiving HAART and had a sustained immunological response. The study was approved by the Faculty of Medicine, Chiang Mai University Ethical Committee. Inclusion criteria included: (i) patients were 15 years of age or older; (ii) had previously been documented as having culture-confirmed penicilliosis marneffei; (iii) were successfully treated with systemic antifungal therapy; (iv) had received oral itraconazole 200 mg a day for secondary prophylaxis; (v) received HAART, defined as two nucleoside reverse transcriptase inhibitors plus either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor; (vi) had a favourable immunological response to HAART, defined as having a CD4 cell count of 100 cells/μl or greater for at least 6 months; and (vii) had discontinued itraconazole secondary prophylaxis. The decision to discontinue itraconazole secondary prophylaxis was made by attending physicians with consultation from infectious disease specialists. This followed the recommendation from the Thai Ministry of Public Health that antifungal prophylaxis could be discontinued in patients who had CD4 cell counts of 100 cells/μl or greater for at least 6 months after antiretroviral therapy. All patients were scheduled for follow-up every 2 months to evaluate the evidence of relapse of penicilliosis marneffei. The relapse rate was expressed as the number of events per person-months of follow-up. Statistical analyses were performed using SPSS version 10.0 (SPSS for Windows, Rel. 13.0.1997; SPSS Inc., Chicago, Illinois, USA).
From March 2002 to December 2005, there were 33 HIV-infected patients with culture-confirmed penicilliosis marneffei who met all the eligibility criteria for the discontinuation of itraconazole secondary prophylaxis. The clinical characteristics of these patients are shown in Table 1. The median duration of antifungal secondary prophylaxis before study enrollment was 25 months (range 8–83). The median duration of HAART before the discontinuation of antifungal secondary prophylaxis was 13.0 months (range 6–49). The CD4 cell counts at the time of discontinuation of itraconazole secondary prophylaxis and the time of study completion were significantly higher than the baseline values before the initiation of HAART (P < 0.05). Plasma HIV-RNA measurement was performed in 26 patients; 24 of those (92.3%) had undetectable HIV viral loads at the end of the study. In one patient who had an HIV viral load of 53 307 copies/ml, the antiretroviral regimen was changed to lopinavir/ritonavir and saquinavir. The antiretroviral regimen was not changed in the other patient who had an HIV viral load of 2165 copies/ml.
At the time of study completion, none of the 33 patients were lost to follow-up. The median length of follow-up was 18.0 months (range 6–45), with a total follow-up of 641 person-months. Twenty-four patients (72.7%) had a follow-up duration of more than 12 months. Throughout the follow-up duration, no patients had symptoms or signs suggestive of systemic fungal infection. There was no relapse of penicilliosis marneffei; the observed incidence of relapse was zero cases per 641 person-months [95% confidence interval (CI) 0–0.6 cases per 100 person-months]. No patients died during the study period.
Our study has demonstrated the safety of the discontinuation of secondary prophylaxis in AIDS patients with a previous history of penicilliosis marneffei who had a sustained increase of the CD4 cell count to 100 cells/μl or greater after HAART. The patients were followed for a total of 641 person-months after the discontinuation of antifungal prophylaxis. There was no relapse among this group of patients, giving the relapse rate of 0.6 cases per 100 person-months at the upper limit of the 95% confidence interval. This is in marked contrast to the relapse rate of 11.5 cases per 100 person-months (95% CI 7.2–17.2) obtained in patients without secondary antifungal prophylaxis in one of our studies conducted before the HAART era . In that study, 35 HIV-infected patients with successfully treated culture-confirmed penicilliosis marneffei who were not given secondary antifungal prophylaxis were followed for a total of 174 person-months. There were 20 relapses among the 35 patients.
Our study has the drawback of using a retrospective cohort and comparing the relapse rate with that obtained from a historical control group. However, because of the magnitude of the difference between the two relapse rates and the fact that the two studies were conducted at the same university hospital drawing from the same pool of patients, we are confident to conclude that it is safe to discontinue itraconazole secondary prophylaxis in HIV-infected patients with a previous history of penicilliosis marneffei who have started HAART and have had a CD4 cell count of 100 cells/μl or greater for at least 6 months. A randomized controlled trial should, however, be conducted to address this issue more definitively.
The authors are grateful to Ms Wilai Kotarathititum and Ms Jutharat Praparatanaphan for data collection and retrieval. There is no conflict of interest among the authors.
Sponsorship: This study was partly supported by the Thailand Research Fund of the Royal Thai Government.
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