Many anti-HIV drugs, particularly protease inhibitors and non-nukes (NNRTIs), are processed by enzymes in the liver. Some of these drugs speed up the activity of liver enzymes, resulting in a particular drug being broken down faster than usual. Other drugs can reduce the activity of liver enzymes, resulting in a drug being broken down slowly. Speeding up or slowing down the rate at which liver enzymes process a drug can affect the concentration of a drug in the blood. When a person is taking two or more drugs, these drugs can affect the activity of liver enzymes and, consequently, each other’s concentration in the blood. This is called a drug interaction. Predicting the outcome of drug interactions grows more difficult with each drug a person adds to a regimen.
Voriconazole (Vfend) is a powerful antifungal drug that is used in people with weakened immune systems who have developed life-threatening infections caused by the mould or fungus Aspergillus fumigatus.
Researchers at the Ottawa Hospital (Ontario) recently reported complex drug interactions in an HIV-positive person who had been diagnosed with aspergillosis. He was taking voriconazole together with the anti-HIV drugs darunavir (Prezista), ritonavir (Norvir), etravirine (Intelence) and Truvada (tenofovir + FTC).
About aspergillosis
The fungus Aspergillus fumigatus infects the lungs when people inhale fungal spores. As Aspergillus spores are widespread in the environment, inhalation probably occurs daily. In people whose immune systems are working normally, infection with this fungus is quickly brought under control. However, in a person whose immune system has been weakened from HIV infection, transplant medications, cancer or other conditions, Aspergillus can begin to slowly grow and cause disease (aspergillosis). Initially this may not cause any symptoms but—particularly in people with asthma—an allergic reaction is triggered with coughing, wheezing and problems breathing.
As the mould grows within the lungs, symptoms such as these can develop:
- chest pain
- wheezing
- shortness of breath
- unintentional weight loss
- fever
In severe cases of aspergillosis, the mould spreads beyond the lungs, affecting major organs including the brain, heart and kidneys. The antifungal drug voriconazole can be used to treat aspergillosis. However, sometimes the disease does not respond well to this drug and then another antifungal agent, such as caspofungin (Cancidas), may be needed instead.
Case details
Researchers in Ottawa reported details on a 54-year-old man who had been HIV positive for 23 years. Three months prior to his hospitalization for pneumonia, he had been taking the following medicines:
- darunavir 900 mg once daily
- ritonavir 100 mg once daily
- etravirine 200 mg twice daily
- Truvada (tenofovir 300 mg + FTC 200 mg) once daily
He sought care at the Ottawa Hospital because he had pneumonia that had grown worse over the course of a week. At admission to the hospital, his CD4+ count was 230 cells and viral load was about 3,000 copies/ml.
Doctors admitted him to the hospital’s intensive care unit (ICU) and hooked him up to machines to help him breathe. Fluid samples from his lungs tested positive for Aspergillus so doctors gave him the following schedule of medicines:
- voriconazole 400 mg intravenously twice daily on days 1 through 7
- caspofungin 50 mg intravenously once daily on days 8 through 25
- voriconazole 400 mg orally twice daily on days 12 to 45
Doctors also continued the man’s anti-HIV medicines, except for Truvada because his kidneys stopped working—likely due to complications from aspergillosis. So nurses performed an additional intervention and cleaned the man’s blood using dialysis.
After 46 days in the hospital he recovered from aspergillosis and was sent home taking darunavir-ritonavir and etravirine and Kivexa (abacavir + 3TC) instead of Truvada. At this time his CD4+ count was 249 cells and viral load was less than 50 copies/ml.
Drug levels
Samples of the man’s blood were collected before and after his exposure to voriconazole. As this drug is known to interact with HIV medicines such as efavirenz (Sustiva and in Atripla) and ritonavir, the Ottawa team focused on voriconazole rather than caspofungin for possible drug interactions. Analyses found the following in the man’s blood samples:
- The concentration of voriconazole was at the upper end of the normal range.
- The concentration of etravirine was about 134% of normal when he was taking voriconazole.
- Shortly before it was time for his next dose, the concentrations of darunavir and ritonavir were much lower than expected. Once he stopped taking voriconazole his levels of darunavir and ritonavir returned to their normal ranges.
In the future
Based on their findings, the Ottawa team suggests that voriconazole be used with “caution” in people who are also taking darunavir, ritonavir and etravirine. If voriconazole must be prescribed then the team suggests that physicians consider dosing darunavir and ritonavir twice daily (as is etravirine). Also, they add that a formal study needs to be undertaken in a large group of volunteers to better understand the complex interactions between all four of these drugs.
Acknowledgement
We thank pharmacologist Charles la Porte, PhD, for helpful discussion, research assistance and expert review.
—Sean R. Hosein
REFERENCES:
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- Snelders E, van der Lee HA, Kuijpers J, et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Medicine. 2008 Nov 11;5(11):e219.
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- Toy J, Giguère P, Kravcik S, la Porte CJ. Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia. AIDS. 2011 Feb 20;25(4):541-2.