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AIDS:
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Discontinuation of secondary prophylaxis for penicilliosis marneffei in AIDS patients responding to highly active antiretroviral therapy

Hung, Chien-Chinga,b; Chen, Mao-Yuana; Hsieh, Szu-Mina; Sheng, Wang-Hweia; Hsiao, Chin-Fuc; Chang, Shan-Chwena

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aDepartment of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; bDepartment of Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan; and cNational Health Research Institutes, Taipei, Taiwan.

Received: 13 August 2001;

revised: 27 September 2001; accepted: 3 October 2001.

Invasive fungal infection caused by Penicillium marneffei has been recognized recently as an emerging opportunistic infection of HIV-infected patients residing or traveling in Southeast Asia, especially northern Thailand, and southern China [1,2]. It was ranked the third most common AIDS-defining opportunistic infection in Thailand. Most of the patients with P. marneffei infection were at the advanced stage of HIV infection [1,3,4], and disseminated infection is common at diagnosis because the organism can often be isolated from multiple sterile sites [1]. Amphotericin B 0.6 mg/kg a day for 2 weeks followed by itraconazole 400 mg a day for 10 weeks had been shown to be an effective and safe regimen [3]. Relapse is common, however, and the rate may be as high as 50% in patients without maintenance antifungal therapy [5]. Such a relapse can be prevented if maintenance therapy with itraconazole is given [4]. The optimal duration of antifungal prophylaxis to prevent relapse remains unclear, although long-term maintenance therapy has been recommended [4].

The clinical studies on antifungal treatment for penicilliosis marneffei and secondary prophylaxis to prevent relapse mainly involved HIV-infected patients without highly active antiretroviral therapy (HAART) in Thailand [3–5]. Whether antifungal prophylaxis with itraconazole can be safely discontinued in HIV-infected patients responding to HAART has not been investigated, partly because such invasive fungal infection is rare in western countries [2]. In this study, we reported the experience of the successful discontinuation of itraconazole in nine patients with penicilliosis marneffei who continued to receive HAART.

Penicilliosis marneffei is also an emerging endemic fungal infection in HIV-infected patients in Taiwan [6]. From June 1994 to June 2001, 17 out of 574 (3.0%) HIV-infected patients treated at the National Taiwan University Hospital were diagnosed with penicilliosis marneffei. Eight patients died: directly as a result of penicilliosis marneffei (four patients) or caused by other opportunistic diseases (four patients). The patients with penicilliosis marneffei were usually treated with amphotericin B at a daily dose of 0.7–1.0 mg/kg for 2 weeks, followed by itraconazole 400 mg a day for 6–8 weeks. Subsequently, those who survived penicilliosis marneffei continued to receive HAART and itraconazole 200 mg a day.

As of 31 July 2001, nine patients had discontinued their secondary prophylaxis to prevent a relapse of P. marneffei infection. The median duration of secondary prophylaxis was 14 months (range 10–37 months; mean 16 months). The median CD4 cell count at diagnosis of penicilliosis marneffei was 7 × 106/l (range 2–31 × 106/l; mean 11 × 106/l). Plasma viral load (PVL) by reverse transcriptase–polymerase chain reaction was available for only two patients: 5.78 log10 and 5.13 log10 copies/ml. The median CD4 cell count at discontinuation of antifungal prophylaxis was 83 × 106/l (range 49–120 × 106/l; mean 85 × 106/l). The median PVL at discontinuation of antifungal prophylaxis was undetectable in seven patients, whereas that for the other two patients was 2.97 log10 and 5.78 log10. The latest PVL was undetectable in eight patients and was 4.62 log10 for the ninth patient. Their latest median CD4 cell count was 170 × 106/l (range 59–424 × 106/l; mean 215 × 106/l). There was no relapse of penicilliosis marneffei in those nine patients after a median observation duration of 15 months (range 5–49 months; mean 28 months) after discontinuation of antifungal prophylaxis. No other invasive fungal infection or oro-oesophageal candidiasis was observed during the study period.

With the introduction of HAART, incidences of invasive fungal infections of AIDS, such as cryptococcosis, are declining [7], and clinicians are beginning to pursue studies to investigate the outcome of the discontinuation of secondary antifungal prophylaxis against relapse [8,9]. The findings of our study involving nine HIV-infected patients with penicilliosis marneffei, similar to those of the studies of patients with cryptococcosis [8,9], suggested that maintenance antifungal therapy to prevent the relapse of invasive fungal infection could be safely discontinued in HIV-infected patients who responded to HAART. The earlier discontinuation of itraconazole or other antifungal agents in patients with reconstitution of immunity after the initiation of HAART may reduce medical costs and the risk of adverse effects and drug–drug interactions between azoles and protease inhibitors. Such discontinuation may also have a positive psychological impact on HIV-infected patients taking HAART.

The studies of the discontinuation of antifungal prophylaxis in HIV-infected patients responding to HAART reported to date, including the present study, all involved small case numbers and short observation durations. In addition, unlike the recommendations for the discontinuation of primary or secondary prophylaxis for pneumocystosis [10], no specific cut-off value of CD4 cell count can be used as a clinical guide to discontinue secondary antifungal prophylaxis. Therefore, randomized, case–control studies are desperately needed to confirm those observations and to set the appropriate cut-off value of CD4 cell count for the discontinuation of secondary antifungal prophylaxis in HIV-infected patients who respond favourably to HAART.

Chien-Ching Hunga,b

Mao-Yuan Chena

Szu-Min Hsieha

Wang-Hwei Shenga

Chin-Fu Hsiaoc

Shan-Chwen Changa

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References

1. Supparatpinyo K, Khamwan C, Baosoung V, Nelson K, Sirisanthana T. Disseminated Penicillium marneffei infection in Southeast Asia. Lancet 1994, 344: 110–113.

2. Duong TA. Infection due to Penicillium marneffei, an emerging pathogen: review of 155 reported cases. Clin Infect Dis 1996, 23: 125–130.

3. Sirisanthana T, Supparatpinyo K, Perriens J, Nelson K. Amphotericin B and itraconazole for treatment of disseminated Penicillium marneffei infection in human immunodeficiency virus-infected patients. Clin Infect Dis 1998, 26: 1107–1110.

4. Supparatpinyo K, Perriens J, Nelson K, Sirisanthana T. A controlled trial of itraconazole to prevent relapse of Penicillium marneffei infection in patients infected with the human immunodeficiency virus. N Engl J Med 1998, 339: 1739–1743.

5. Supparatpinyo K, Chiewchanvit S, Hirunsri P. et al. An efficacy study of itraconazole in the treatment of Penicillium marneffei infection. J Med Assoc Thai 1992, 57: 688–691.

6. Hung CC, Hsueh PR, Chen MY, Hsiao CS, Chang SC, Luh KT. Invasive infections caused by Penicillium marneffei: an emerging pathogen in Taiwan. Clin Infect Dis 1998, 26: 202–203.

7. van Elden LJ, Walenkamp AM, Lipovsky MM. et al. Declining number of patients with cryptococcosis in the Netherlands in the era of highly active antiretroviral therapy. AIDS 2000, 14: 2787–2788.

8. Aberg JA, Price RW, Heeren DM, Pearce RB, Bredt B. Discontinuation of antifungal therapy for cryptococcosis after immunologic response to antiretroviral therapy. In:Proceedings of the Seventh Conference on Retroviruses and Opportunistic Infections. San Francisco, 30 January–2 February, 2000 [Abstract 250].

9. Martinez E, Garcia-Viejo MA, Marcos MA. et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy. AIDS 2000, 14: 2615–2617.

10. Kovac JA, Masur H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med 2000, 342: 1416–1429.

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© 2002 Lippincott Williams & Wilkins, Inc.

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