Treatment of disseminated histoplasmosis in advanced HIV using itraconazole with increased bioavailability

Introduction

Histoplasmosis is a fungal infection caused by the thermal dimorphic fungus, Histoplasma capsulatum. ¹ It is a saprophytic fungus that exists in mold form in the soil rich in bird and bat guano, at temperatures of 25–30°C and yeast form at 37°C and is endemic in many parts of the world, particularly North and Central America, parts of South America and Africa with sporadic cases occurring elsewhere.^2,3 Initial infection involves the lung via inhalation of fungal spores and then infects other organs via the reticuloendothelial system. ² Infection in the immunocompetent host can be asymptomatic or present as a self-limiting pulmonary syndrome. ³ In immunosuppressed individuals, the primary infection or reactivation of infection can disseminate producing progressive disseminated histoplasmosis (DH). ³ Choice of antifungal treatment for DH depends on clinical and biochemical severity with guidelines recommending intravenous (IV) amphotericin B for severe and moderate-to-severe DH and oral itraconazole for mild-to-moderate DH. ⁴

Case report

A 42-year-old, antiretroviral therapy (ART)-naïve man, newly diagnosed with human immunodeficiency virus (HIV) infection, presented with a history of 18 kg weight loss, fever, cough, shortness of breath, diarrhoea with abdominal discomfort and a pruritic papular rash over his face and body. He had no other medical conditions and took no regular medications. His risk factor for HIV acquisition was unprotected sexual contact with men. He hailed from Thailand but had spent the last three years in Australia with no travel in that time.

On examination, he was febrile, hypotensive with a body mass index (BMI) of 18. He had bibasilar crepitations on respiratory exam and mild diffuse tenderness per abdomen. There was a diffuse, erythematous, indurated, violaceous, papulo-nodular rash over his face and neck (Figure 1(d)), trunk and arms.

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Figure 1.

Fungal stains of skin biopsy. (a) Methenamine silver stain showing yeast cells. (b) Gram stain showing intracellular organisms. (c) Lactophenol cotton blue stain showing septate hyphae and micro- and macroconidia. (d) and (e) are clinical photographs of the lesions taken at start of treatment and at six months after commencing treatment. (f ) shows serum itraconazole levels in µg/ml at three weeks after commencing conventional formulation and at eight weeks post commencing newer formulation.

Pertinent investigations revealed diffuse ground glass appearance with a fine nodular pattern on chest radiograph, a HIV viral load of >3 million copies/ml, and CD4+ T cell count and percentage of 14 cells/µl and 12%, respectively. Fungal, mycobacterial blood cultures and sexually transmitted infection screen were negative.

Provisional diagnoses of advanced HIV, Pneumocystis jiroveci pneumonia, gastroenteritis and Talaromyces marneffei were made. He was commenced on 2 g Ceftriaxone IV and trimethoprim/sulfamethoxazole 5 + 25 mg/kg orally three times a day. Blood cultures at 48 hours were positive for multi-resistant Salmonella choleraesuis and his antibiotic regimen was changed to meropenem 1 g IV eight-hourly. Following this he had stable haemodynamics, but continued to be febrile.

Methenamine silver stain (Figure 1(a)) and Gram stain (Figure 1(b)) of skin biopsy revealed abundant yeasts. Fungal cultures on Sabouraud’s dextrose agar grew brownish-white colonies and lactophenol cotton blue stain (Figure 1(c)) showed long thin septate hyphae with macro- and microconidia consistent with H. capsulatum. Pan-fungal nucleic acid detection was positive for H. capsulatum DNA by polymerase chain reaction.

He was commenced on itraconazole (Sporanox™, Janssen Pharmaceuticals, Titusville NJ USA) 200 mg, orally, twice daily on day 14 and co-formulated daily lamivudine 300 mg, abacavir 200 mg and dolutegravir 50 mg on day 16. Due to concerns about tolerability of itraconazole in the setting of dyspepsia and ongoing fevers, he was changed to a formulation of itraconazole with improved oral bioavailability (Lozanoc™, Mayne Pharma International Ltd.) at week 6 at a dose of 100 mg bd as per prescribing information. Serum trough levels while on conventional itraconazole at three weeks were 0.33 µg/ml compared to 1.31 µg/ml on the newer formulation at two months. Guidelines recommend levels above 1 µg/ml ⁴ (Figure 1(f )). He has been on antifungal treatment for 12 months now and has gained 18 kg of weight (BMI of 25) with improvement of rash (Figure 1(e) at six months).

Discussion

In HIV, histoplasmosis is almost always (>95%) disseminated, presenting with non-specific systemic features that can progress to a sepsis-like syndrome with multi-organ dysfunction, disseminated intravascular coagulation and death. ¹ Involvement of the central nervous system ⁵ and skin ⁶ can also occur. Cutaneous lesions in DH can appear as papules, nodules, plaques, crusts, ulcerations, umbilicated lesions and acneiform eruptions. ⁶ Although cases of histoplasmosis have been described in Australia, they are rare and pose a diagnostic challenge. ⁷ Antifungal treatment depends on severity ⁴ but clear definitions of mild, moderate and severe DH are lacking in the literature. Our patient initially presented with features that may have been consistent with moderate to severe DH; however, he improved with treatment of other co-existing infections. Consequently, he was commenced on conventional formulation oral itraconazole and ART was commenced within 48 h of antifungal treatment as per guidelines. ⁴ Absorption of conventional itraconazole is reduced in subjects with reduced gastric acidity hence the recommendation to administer after a full meal or co-administer with an acidic beverage. ⁸ The patient’s medication chart was reviewed to ensure that there were no significant drug interactions, importantly that he was not on acid-lowering therapy. Monitoring of itraconazole levels is recommended at two weeks and then 2–3 monthly, aiming for random levels >1.0 µg/ml. ⁴ A novel formulation of solid dispersion of itraconazole in a pH-dependent polymer has increased bioavailability and can be dosed without regard to food or acidic beverages. ⁸ This itraconazole formulation has increased oral bioavailability due to its pH-dependent polymeric matrix that improves intestinal absorption ⁸ and in our patient yielded serum levels above 1.0 µg/ml. This combined with ART maintained an excellent clinical response. To our knowledge this is the first report of successful treatment of DH in advanced HIV with itraconazole of increased oral bioavailability. Its use warrants further study in this population particularly those with poor oral intake.