Fluconazole doubles nevirapine levels, greatly increasing risk of liver toxicity

Researchers from South Africa have discovered that the anti-fungal drug fluconazole doubles nevirapine levels, leading to a significantly higher incidence of drug-related adverse events, including nevirapine-related liver toxicity. The findings were presented in an oral session at the Fifteenth International AIDS Conference in Bangkok.

Pitt and colleagues from the Desmond Tutu HIV Centre at the University of Cape Town undertook a single-centre, open-label, single-arm trial examining the pharmacokinetic parameters of fluconazole alone and in combination with nevirapine in 24 men and women on a stable regimen of three nucleoside analogue antiretrovirals. The majority of individuals were black (76%) and female (68% in the PK study, 71% in the safety study).

Nevirapine was given in the usual way: 200mg once daily for the first two weeks, in order to avoid the rash associated with nevirapine, and then 200mg twice daily. They found that the effect of nevirapine on fluconazole pharmacokinetic parameters was minimal.

However, the clearance of nevirapine was halved when added to fluconazole, resulting in an approximate doubling of nevirapine C_min, C_max and AUC compared with historical data from Boehringer Ingelheim’s (BI) own studies. The high peak nevirapine levels (C_max = 12.9ng/ml; range 3.0-17.9) seen led to a surprisingly high incidence of nevirapine-related liver toxicity, compared with historical data (2.5%). It was only after full dosing with nevirapine (day 39 of the study) that 95% of the nevirapine-related adverse events occurred. During this phase 25% (CI 7-43%) of patients developed serious hepatotoxicity including two cases of clinical hepatitis (8.3%) and six cases of transient grade 4 transaminase elevation (25%). Three cases of rash were seen, two (8.3%) macular-papular, and one (4.2%) vesicular.

There are some limitations to this study. This was a small study done in a population the majority of which were African women, who may be particularly susceptible to the liver toxicity associated with nevirapine. Levels of nevirapine may also be higher than historical controls due to the lower body weight seen in both women and in Africans compared with the majority of Caucasian men including in BI's studies. Additionally, genetic disposition to nevirapine hypersensitivity reactions cannot be ruled out.

In the question and answer session that followed, there was some concern regarding the conclusions of the study that “the combination of nevirapine and fluconazole should be used with caution, but that no dose adjustments are currently recommended.” Session co-chair, noted pharmacologist Professor David Back of Liverpool University, said that this was “potentially very important data that goes against the perceived wisdom about fluconazole... But the suggestion that no dose adjustments are recommended means this study needs to be followed up.”

The importance of examining drug-drug interactions between nevirapine – which is used in two of the four WHO-recommended generic combinations for their 3x5 programme – and other drugs used widely in people with HIV/AIDS in resource-limited settings, is crucial. Where available, and affordable, antifungals are used for both prophylaxis and treatment. Since it is already known that nevirapine reduces levels of another antifungal, ketoconazole, by 63%, fluconazole is likely to be widely used alongside nevirapine. A recent Thai study found that primary prophylaxis with fluconazole reduced the risk of death fourfold in people with advanced HIV disease. In Uganda, cryptococcal meningitis – the main opportunistic infection that fluconazole prevents and treats – accounts for 38% of AIDS-defining illnesses amongst hospital admissions and 17% of deaths.

Nevirapine was originally manufactured by Boehringer Ingelheim under the trade name Viramune. A generic version, called Nevimune, is manufactured by the Indian company Cipla. Aurobindo Pharma also produce a generic version of nevirapine known as Nevirex.

Nevirapine is also included in a number of fixed-dose combinations:

• d4T/3TC/nevirapine: Triomune (made by Cipla); Nevilast (Genixpharma); Stavex LN (Aurobindo), Triviro LNS (Ranbaxy); GPOVir (GPO, Thailand).
• AZT/3TC/nevirapine: Duovir-N (made by Cipla), Zidovex-LN (Ranbaxy).