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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although no anti-fungal agents have received regulatory approval specifically for systemic P. marneffei infection, early diagnosis is important, and untreated infections are often fatal.5,6 Response to anti-fungal therapy is good if the treatment is started early, and amphotericin B and itraconazole are generally effective,7,8 although patients may require secondary anti-fungal prophylaxis for life after their initial treatment.2,9 Primary prophylaxis with itraconazole can prevent systemic P. marneffei infection in patients with advanced HIV infection (although there was no survival advantage when given to such patients),10 and secondary prophylaxis can prevent relapses during remission.11
Voriconazole is a new extended-spectrum triazole anti-fungal agent with potent in vitro activity against a range of molds, yeasts, and dematiaceous fungi.12,13 The in vitro activities of voriconazole against P. marneffei are superior to those of amphotericin B and comparable with those of itraconazole; voriconazole minimum inhibitory concentrations (determined using NCCLS and Etest methods) were in the range of < 0.01–0.06 µg/mL, and minimum fungicidal concentrations were 0.12–0.5 µg/mL.14
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Administration of study drugs. Route of administration (intravenous or oral) and duration (maximum of 12 weeks) of initial therapy were determined by the principal investigator, based on response to therapy. Intravenous voriconazole was administered at 4 mg/kg every 12 hours for at least 3 days (after an optional loading dose of 6 mg/kg every 12 hours for the first 24 hours), after which patients could switch to oral therapy at 200 mg twice a day. Patients starting treatment with oral voriconazole received 200 mg twice a day (with an optional 400 mg twice a day loading dose on Day 1); oral doses were halved for patients weighing < 40 kg. After the end of the study, patients could continue to receive voriconazole at the discretion of the local investigator as part of a separate, extended-treatment program.
Efficacy assessments. The primary efficacy variable was global response evaluated at Week 12 or at end of therapy (EOT), whichever was earlier. Global response was based on clinical and mycological responses, as described elsewhere.15 For the purposes of the patients included in this series, complete response was defined as resolution of all clinical signs and symptoms attributable to fungal infection present at baseline and mycological eradication (when obtainable); partial response was defined as major improvement of all clinical signs and symptoms attributable to fungal infection; stable disease was defined as minor or no clinical improvement but without deterioration; and failure was defined as clinical deterioration necessitating alternative anti-fungal therapy or resulting in death and/or persistence of fungal infection on the basis of culture, microscopic evaluation, or histopathologic testing.
When mycological assessments were undertaken, eradication was defined as the absence of the original fungal pathogen in a relevant clinical specimen. Presumed eradication was inferred in subjects with complete clinical response for whom an invasive procedure for obtaining the relevant clinical specimen was not performed. Persistence was defined by the continuing presence of any evidence for the presence of the original fungal pathogen.
For subjects with complete response, partial response, or stable disease at EOT, follow-up evaluations were performed 4 weeks after EOT. The response (findings attributable to the fungal infection) was compared with that at EOT and categorized as cured (continued resolution), improved (further improvement), stable (no improvement), or relapsed (deterioration).
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RESULTS |
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Eight patients had positive blood cultures for P. marneffei at the time of study entry. Nine patients had positive cultures from other sites, including lymph node (two), liver (five), skin (four), or bone marrow (one). Two patients had concurrent cryptococcosis (Table 1
). The mean duration of infection between diagnosis and study entry was 10 days (range, 0–25 days). Only two patients had received anti-fungal therapy/prophylaxis in the 4 weeks before entering the study (Patient 4 in Table 1 received a single dose of amphotericin B, whereas Patient 7 received 10 days of ketoconazole therapy). None of the patients in this study received concomitant anti-retroviral therapy.
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Response at end of therapy.
Two of the 11 patients (Patients 3 and 5) were not evaluable for efficacy at EOT because therapy was discontinued prematurely, owing to abnormal laboratory test results [creatinine increased > 2.5 mg/dL; alkaline phosphatase increased to > 5x upper limit of normal (ULN)]. At EOT, eight of the nine remaining evaluable patients had a favorable global response to therapy; five patients (including one with concurrent cryptococcosis) had a complete response, and three patients had partial responses. One patient (Patient 9) responded initially, but failed at EOT, owing to recurrence of cryptococcosis and P. marneffei infection, which was attributed, at least in part, to poor compliance (the patient repeatedly missed doses of study drug in the 2 weeks before EOT). Mycological responses at EOT were eradication in two patients, presumed eradication in six patients (including one patient with concurrent cryptococcosis), and persistence in one patient with concurrent cryptococcosis (Table 1
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Safety. All 11 patients were evaluable for safety and reported a total of 66 adverse events (AEs). Five patients reported serious and severe AEs, but there were no treatment discontinuations because of these events. Twenty-six AEs were considered to be related to treatment with voriconazole; two of these (abnormal vision, anemia) were severe in intensity. Treatment-related AEs reported by two or more patients included abnormal vision (eight patients), insomnia (three patients), dizziness (two patients), and dyspepsia (two patients). In one patient, administration of voriconazole was temporarily suspended to allow treatment of a mild, treatment-related maculopapular rash.
All visual AEs were reported as "blurred vision." In seven patients, these events were mild in intensity, began in the first 5 days of voriconazole therapy, and resolved without intervention by Day 8 of therapy. One patient experienced severe post-treatment blurred vision in both eyes, but this too resolved during the study after an ophthalmologic consultation.
One patient (Patient 10) with CD4 counts of 17 cells/µL, disseminated P. marneffei infection, hepatomegaly, and moderate ascites at baseline expired after 15 days of the study. Cause of death was reported as "CNS infection" and there was no autopsy performed. One patient (Patient 9) was withdrawn because of insufficient clinical response on Day 81 of therapy, and one (Patient 4) was lost to follow-up during the post-therapy period.
Follow-up assessments. Six patients (Patients 1, 2, 6, 7, 8, and 11) were available for evaluation 4 weeks after EOT. There were no relapses of P. marneffei infection, although one patient (Patient 6, with concurrent baseline P. marneffei infection and cryptococcosis) had a relapse of cryptococcosis during this period.
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DISCUSSION |
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In this study, 9 of the 11 patients with advanced HIV infection and systemic P. marneffei infection received oral voriconazole throughout the treatment period. The remaining two patients received oral therapy after 15 days of intravenous voriconazole. Favorable global response to voriconazole at EOT was recorded in eight of the nine evaluable patients with infections caused solely or in part by P. marneffei, and there were no relapses of P. marneffei infection within 4 weeks of the EOT.
Itraconazole and ketoconazole have been proposed as first-choice drugs for mild to moderately severe P. marneffei infection, with the option of parenteral amphotericin B in seriously ill patients.16 Intravenous amphotericin B for 2 weeks followed by oral itraconazole for 10 weeks has been recommended as the treatment regimen of choice for disseminated P. marneffei infection in HIV-infected patients.17 In an open-label, noncomparative study of HIV-positive patients with disseminated P. marneffei infection, 72/74 (97%) responded to this regimen (0.6 mg/kg/d amphotericin B deoxycholate for 14 days, followed by 400 mg/d oral itraconazole for 70 days).17 However, in an earlier retrospective study in HIV-infected patients, 12/40 (30%) patients who responded to initial therapy relapsed within 6 months, regardless of initial anti-fungal agent.16 Maintenance oral therapy (itraconazole 200 mg/d) is also recommended.17 Although clinical successes have been reported using itraconazole monotherapy to treat systemic P. marneffei infections, blood cultures can be relatively slow to clear, requiring 2 months of therapy.17 Consequently, initial therapy with itraconazole is not recommended.18
Voriconazole is metabolized by cytochrome P450 enzymes, including CYP2C19, which exhibits genetic polymorphism. The proportion of "poor metabolizers" is higher in many Asian populations than in whites, although the frequency of poor metabolizers in Thai subjects has been reported to be lower than in other Asian populations.19 CYP2C19 genotyping/phenotyping was not undertaken in this study, because voriconazole dosing does not need to be adjusted according to CYP2C19 status, so no information is available on the number of poor metabolizers included in this study.
The results from this study suggest that voriconazole is an effective therapeutic option for AIDS patients with systemic P. marneffei infection. Voriconazole also has the potential to be more convenient than the current recommended treatment regimen, in that it can be administered solely by the oral route or by using intravenous-to-oral stepdown therapy.
Received September 22, 2004. Accepted for publication April 5, 2006.
Disclosure: H. T. Schlamm is an employee of Pfizer Inc. This statement is made in the interest of full disclosure and not because the author considers this to be a conflict of interest.
* Address correspondence to Haran T. Schlamm, MD, Pfizer Global Research and Development, Pfizer Inc., 235 East 42nd Street, New York, NY 10017. E-mail: Haran.T.Schlamm{at}pfizer.com 
Authors’ addresses: Khuanchai Supparatpinyo, Department of Internal Medicine, Faculty of Medicine, Division of Infectious Disease, Chiang Mai University, 110 Intavaroros Road, Chiang Mai, 50200, Thailand. Haran T. Schlamm, Pfizer Global Research and Development, Pfizer Inc., 235 East 42nd Street, New York, NY 10017.
Reprint requests: Haran T. Schlamm, Pfizer Global Research and Development, Pfizer Inc., 235 East 42nd Street, New York, NY 10017. E-mail: Haran.T.Schlamm{at}pfizer.com.
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