Drug interactions between voriconazole,darunavir/ritonavir and tenofovir/emtricitabine in an HIV-infected patient treated for Aspergillus candidus lung abscess

Abstract

We report an unusual case of pulmonary aspergillosis in a patient with AIDS and we demonstrated the drug-drug interactions between voriconazole, darunavir/ritonavir and tenofovir/emtricitabine. The combination darunavir-ritonavir-voriconazole should be avoided.

Keywords

Aspergillus candidus HIV AIDS opportunistic infection aspergillosis treatment antiretroviral therapy drug-drug interactions voriconazole

The occurrence of pulmonary aspergillosis is unusual during the course of AIDS. Patients at risk have a CD4 count under 50 cells/mm³, combined with other risk factors in 50% of cases. Aspergillus fumigatus is found in >90% of infections, followed by A. niger and A. flavus. Aspergillus candidus is rare.^1–5 We report the first case of A. candidus pulmonary abscess in an HIV-infected patient treated with voriconazole (200 mg twice daily), ritonavir-boosted darunavir (DRV/RTV, 800/100 mg daily) and tenofovir/emtricitabine (300/200 mg daily), and we illustrate a new case of drug–drug interactions between DRV/RTV and voriconazole.

A 29-year-old Brazilian man was admitted to the emergency ward (December, 2012) for thoracic pain, unproductive cough, loss of weight (−8 kg, body weight: 50 kg), diarrhoea and moderate fever (38°C) of 3-week duration. Physical examination was otherwise unremarkable, except for hypoaesthesia on the external right of the right thigh. Biological tests were as follows: WBC: 2000/mm³; neutrophils: 850/mm³; lymphocytes: 790/mm³; platelets: 189,000/mm³; haemoglobin: 14.7 g/l; C-reactive protein; 1 mg/l. Renal and hepatic functions were normal. He was positive for HIV and negative for hepatitis C and B and toxoplasmosis. The CD4 lymphocyte count was 6 cells/mm³ (1.3%). HIV viral load was 750,000 copies/ml. Pulmonary CT scan showed a lung abscess in the medio-basal segment with a pleural reaction. Bronchiolo-alveolar lavage was negative for Mycobacterium sp., Cryptococcus sp., Pneumocystis and tumoral cells. Biopsy was positive for A. candidus. Pathology found pseudo-inflammatory lesions, but no tumoral cells. He was treated with DRV/RTV 800/100 mg daily, tenofovir/emtricitabine 300/200 mg daily and voriconazole 800 mg at day 1 followed by 400 mg daily. Trimethoprim/sulfamethoxazole was initially started, but rapidly stopped because of allergy and replaced with monthly aerosolised pentamidine. Other medication included alprazolam 25 mg bid and tramadol 200 mg/d, which were stopped 2 weeks before his discharge from hospital. Plasma samples of DRV, RTV, tenofovir, emtricitabine and voriconazole were isolated by centrifugation and stored at −20°C until analysis. The plasma concentrations were measured by multiplex liquid chromatography coupled with mass spectrometry at months 1, 2, 3 and 4 after fungal and antiretroviral treatment initiation (Figure 1). Specimens were collected just before or within 15 minutes before the next dose after one week of treatment. There was no missing dose.

Figure 1.

Plasma concentrations of darunavir, ritonavir, tenofovir/emtricitabine and voriconazole (C trough by multiplex liquid chromatography coupled with mass spectrometry, 15 minutes before drug was taken). * the dosages at month-2 were performed after 14 h of drug intake).

There was no polymorphism of cytochrome P450 2C19, 2C9, 3A4, 3A5, respectively. Four months after antiretroviral treatment initiation, the patient had an increased CD4 cell count (79 cells/mm³; 5.4%) and the HIV viral load was undetectable (Table 1).

This case report highlights the complex drug-drug interaction between DRV/RTV and voriconazole with low plasma concentration of voriconazole.

RTV is a substrate for P-glycoprotein and cytochrome CYP 3A. It can inhibit and induce both P-glycoprotein and CYP 3A, depending on dose and duration of treatment. DRV, a non-peptidic HIV protease inhibitor is metabolised by CYP 3A. Most of the azoles such as ketoconazole, itraconazole, fluconazole and possibly voriconazole are also inhibitors of CYP, including CYP3A4, 2C19 and 2C9. Low plasma concentrations of DRV or voriconazole are known to be associated with poor outcome.⁶ Boosted with low dose of RTV, DRV is rapidly absorbed, reaching peak plasma concentration within 2–4 h. It is due to inhibition of CYP and P-glycoprotein MDR-1, thereby enhancing the transport and reducing clearance of DRV.

However, RTV at high dose with longer dose may induce both CYP and P-glycoprotein MDR-1. In contrast with voriconazole, there are no data with DRV and high dose of RTV.^7,8 A high dose (400 mg BID) of RTV substantially reduced the AUC of voriconazole by 82%, while 100 mg of BID RTV decreased it by 39%. Although the net effect of ritonavir on CYP3A was inhibitory, it appears that CYP3A inhibition was offset by CYP2C19 and CYP2C9 induction, since CYP3A is not a major pathway for voriconazole metabolism. There are no data concerning the drug-drug interaction between DRV and voriconazole. The mechanism is not very clear, using possibly the way of CYP and P-glycoprotein. Recently, Toy et al.⁹ reported a low-trough DRV plasma concentration (0.54 mg/l) and an undetectable RTV concentration in an HIV-infected patient treated with DRV/RTV (900/100 mg daily), etravirine (ETV, 200 mg twice a day) and voriconazole 400 mg twice daily for Aspergillus pneumonia. After stopping voriconazole, trough DRV and RTV increased to 2.3 and 0.04 mg/l, respectively. In contrast, Aouri et al.¹⁰ published another observation of drugs interactions in an HIV-infected multiresistant patient, with initiation of antiretroviral treatment including DRV/RTV 800/100 mg daily, etravirine 150 mg daily and tenofovir/emtricitabine 300/200 mg daily, associated with voriconazole 600 mg daily for oesophageal candidiasis. Under 600 mg daily, voriconazole trough plasma concentrations were within the therapeutic range. However, they observed a 50% decrease in DRV clearance by voriconazole co-administration.

In our patient, RTV plasma concentrations remained above 0.03 mg/L during voriconazole treatment, but sufficiently high to guarantee the efficient boosting of DRV. Tenofovir and emtricitabine were not greatly affected by voriconazole or RTV. Four months after treatment initiation, while the patient was compliant, the increasing of DRV/RTV and voriconazole was not effective, suggesting an interaction between these two drugs (Figure 2). Note that alprazolam and tramadol are also substrates as well as inhibitors of CYP but the patient took these drugs only during the two first weeks of his discharge from hospital.

Figure 2.

Mechanism of drug-drug interaction between darunavir/ritonavir/voriconazole.

For our patient, alternative treatments were antiretroviral therapy without a boosted protease inhibitor (for example tenofovir/emtricitabine and raltegravir) and voriconazole or antiretroviral therapy with a boosted protease inhibitor and caspofungin.

Table 1.

Plasma concentrations of darunavir, ritonavir, tenofovir, emtricitabine and voriconazole (C trough and C max) (* concentration 14 h after drug intake).

	C trough plasma concentrations (mg/l)				C max plasma concentrations (mg/l)
Month after treatment initiation	1	2	3	4	1	2	3	4
Voriconazole (400 mg/d)	0.14	0.15			0.18	0.59
Voriconazole (600 mg/d)				0.24				0.65
Darunavir (800 mg/d)	2.23	0.81*			3.51	5.77
Ritonavir (100 mg/d)	0.04	0.03			0.04	0.33
Darunavir (600 mg bid)				2.66
Ritonavir (100 mg bid)				0.11
Tenofovir /emtricitabine (200 mg/d)	0.049/0.046	0.056/0.035		0.085/0.108	0.096/0.378	0.176/0.386
CD4 count (cells/mm³, %)	41 (3.5)	39 (2.6)	46 (3.2)	79 (5.4)
HIV viral load (copies/ml)	540	130		<25

In conclusion, drug interactions have become an increasingly complex challenge for clinicians treating patients with HIV infection, especially when metabolised by cytochrome P450 isoenzymes. Because of low plasma concentration of voriconazole when combined with darunavir boosted by low dose of ritonavir, this combination should be avoided.

Consent

The patient gave his consent for the publication.

Footnotes

Acknowledgements

Thanks to Jerri Bram for English assistance.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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