Combination antiretroviral therapy (ART) in patients with HIV/AIDS continues to demonstrate significant reductions in morbidity and mortality [1]. Despite these advances, HIV-associated opportunistic infections remain a significant concern [2,3], with fungi accounting for a large percentage [3]. Voriconazole is an excellent choice for invasive fungal infections (e.g. Aspergillus and Candida), given its high oral bioavailability and favorable side-effect profile compared with amphotericin [4]. However, voriconazole is a substrate and inhibitor of cytochrome P450 (CYP)2C19, 2C9 and 3A4, leading to significant drug–drug interactions with ART [4]. A thorough review of the pharmacokinetics of concomitant voriconazole and antiretrovirals has been reported [5]. The authors concluded that experimental evidence with most ART regimens is unavailable or theoretical [5]. Since the 2008 review [5], eight reports have been published (Table 1) [6–13]. No data regarding the combination of atazanavir and voriconazole are available.Table 1-a: Summary of literature regarding concurrent voriconazole and antiretrovirals.Table 1-b: Summary of literature regarding concurrent voriconazole and antiretrovirals.We report the case of a 56-year-old white male with HIV [diagnosed in 2000; CD4 cell count on hospital admission = 36 cells/μl (6%); HIV PCR = 445 000 copies/ml] with a 2-month history of productive cough, 5 days of hemoptysis, reported 13.6-kg weight loss, frequent night sweats and one episode of fever. Prior to admission, the patient was nonadherent to ART, including a once-daily, fixed-dose combination tablet of efavirenz 600 mg, emtricitabine 200 mg and tenofovir 300 mg. Chest computed tomography (CT) revealed a large, right upper lobe cavitary lesion (3.8 × 5.4 × 10 cm) with dependent soft tissue density (3.0 × 2.5 × 5.0 cm) consistent with aspergilloma and endobronchial spread, suggesting a probable aspergillosis. A bronchoalveolar lavage was negative for Pneumocystis jiroveci and acid-fast bacilli, but positive for Gomori's methenamine silver stain, consistent with Candida spp. Infectious diseases consultation recommended long-term treatment with voriconazole with serial chest CT evaluations after discharge. Owing to the known drug–drug interactions between voriconazole and efavirenz, voriconazole maintenance dose was increased to 400 mg twice daily with a reduced efavirenz dose of 300 mg daily [4]. Standard daily dosing of emtricitabine and tenofovir was continued. One month after discharge, the patient was evaluated by his infectious diseases specialist, reported a 4.5-kg weight gain, but still endorsed hemoptysis. An HIV genotype ordered prior to hospital discharge revealed the mutations: K65R, K103N, V108I, V118I, M184V, K219R, P225H, M36I and A71V. On the basis of the patient's genotypic results and historic antiretrovirals, a ritonavir-boosted protease inhibitor-based regimen was considered the most potent option [14]. However, low-dose ritonavir (100–400 mg daily) significantly decreases voriconazole concentrations [4,5,15]. Unboosted atazanavir is metabolized by and inhibits CYP3A4 with additional inhibition of CYP2C8 and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) [16]. Atazanavir does not affect CYP2C19; thus, in patients without 2C19 polymorphisms, no expected voriconazole pharmacokinetic alterations are expected [5,16]. Voriconazole inhibits CYP3A4 and may increase atazanavir similarly to low-dose ritonavir [16]. The addition of raltegravir was considered favorable in this patient due to its lack of cross-class ART resistance and UGT1A1 elimination, which does not interact with voriconazole [17,18]. Raltegravir use with atazanavir has the added benefit of increased raltegravir concentrations via atazanavir's UGT1A1 inhibition without any apparent increase in toxicity [18,19]. In light of the complexity of the drug–drug interactions between voriconazole and ART, the patient's ART regimen was changed to daily unboosted atazanavir 300 mg, with raltegravir 400 mg twice daily and continuation of daily emtricitabine 200 mg/tenofovir 300 mg. Voriconazole was reduced to 200 mg twice daily following efavirenz discontinuation. Two weeks later, the patient's HIV viral load decreased to 649 copies/ml (CD4 cell count not drawn). One month after new ART initiation, the patient's CD4 cell count and HIV PCR were 126 cells/μl (9%) and 124 copies/ml, respectively. The patient had gained weight, but reported nonadherence to his voriconazole. Repeat chest CT at this time demonstrated an enlarged mycetoma in the right upper lobe. Voriconazole was reinitiated with continuation of current ART. Three months later, the patient reported continued weight gain without any subjective complaints and was receiving his ART regimen with standard dose voriconazole. CD4 cell count and HIV PCR were 153 cells/μl (9%) and less than 48 copies/ml. One month later (8 months after ART/voriconazole initiation), the patient remained symptom free with an undetectable viral load and continued immune reconstitution [CD4 cell count = 168 cells/μl (12%)]. After this visit, the patient was lost to follow-up and no further data are available. Despite the lack of plasma drug concentrations, our case report demonstrates a positive immunologic and virologic response for a patient with multidrug-resistant HIV using atazanavir concurrently with voriconazole. Acknowledgements Conflicts of interest There are no conflicts of interest.
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Open Access
Jul 6, 2017
Stephen J Aston 
