Anne Kiuru¹, Jens D. Lundgren², Ralph Edwards¹

¹ WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre, Sweden

² Copenhagen HIV Programme, Hvidovre University Hospital, Denmark

Nevirapine belongs to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI's) and is one of the recommended drugs in the WHO first-line antiretroviral (ARV) regimens for the treatment of adult and adolescent HIV patients (1). Nevirapine has been associated with severe liver toxicity in some cases. The product label has been revised several times over the last couple of years to include more information on liver toxicity associated with long-term nevirapine use; health-care providers and patients have been warned about the appropriate use of ARV triple combination therapy containing nevirapine (2).

The package insert for Boehringer Ingelheim's proprietary version of nevirapine (Viramune®) includes the warning that unless clinical benefit outweighs risk, nevirapine therapy is not recommended for women with CD4+ cell counts >250 cells/mm3 or in men with CD4+ cell counts >400 cells/mm3 (3). It is, however, likely that many clinicians are unaware of this issue and continue prescribing without discrimination, thereby jeopardizing the safety of HIV patients. An additional concern might be that other companies marketing nevirapine may not yet have included a similar warning.

Liver toxicity (2)

Both clinically symptomatic and asymptomatic liver toxicity are observed with the use of nevirapine, either as a single dose treatment to reduce mother-to-child transmission or in combination with other HIV drugs. The symptoms of nevirapine liver toxicity may be misleading: a rash, a fever or flu-like symptoms. Any of these symptoms may be associated with elevated liver enzymes. On the other hand, patients may be asymptomatic before the onset of rapidly progressive liver failure and death. Nevirapine liver toxicity typically occurs after only a few weeks of dosing and may progress to liver failure despite monitoring of laboratory tests, which is not characteristic of other antiretrovirals. Conversely, if a patient has not experienced liver toxicity within the first 3-4 months of treatment with a nevirapine-containing regimen, the risk of subsequent liver toxicity is low.

Females and patients with higher CD4+ cell counts are at increased risk of liver toxicity. Females have a three fold higher risk of symptomatic nevirapine liver toxicity than males, and females with CD4+ cell counts > 250 cells/mm3 have a 12 fold higher risk of symptomatic liver toxicity than females with CD4+ cell counts < 250 (11% vs. 0.9%). Males with CD4+ cell counts > 400 cells/mm3 have a five fold higher risk of symptomatic liver toxicity than males with CD4+ cell counts < 400 (6.3% vs. 1.2%). The product information from Boehringer Ingelheim (as mentioned above) is thus consistent with these observations.

Nevirapine-related deaths due to symptomatic liver toxicity, including some in HIV-infected pregnant women, have been reported to the Food and Drug Administration Medwatch programme in the United States (2). Serious and fatal liver toxicity have also been reported to the World Health Organization (WHO) Adverse Drug Reaction database, Vigibase. (see Table 1).

Table 1. Number of reports in Vigibase for nevirapine and WHO-ART* preferred terms belonging to the System Organ Class ‘Liver and biliary disorders’.

* WHO Adverse Reaction Terminology

In addition, Vigibase contains reports of increased hepatic enzymes, hepatocellular damage and hepatitis with a combination product containing stavudine, nevirapine and lamivudine.

Globally, NNRTI-based regimens are the most widely prescribed combinations for initial therapy. In spite of the potential for serious and life-threatening liver toxicity and skin rashes with nevirapine, it remains an important part of the HIV treatment regimen for many HIV-infected individuals worldwide. It is a potent NNRTI with demonstrated clinical efficacy when administered in appropriate combination regimens. The hepatotoxicity however, makes it less suitable for treating patients who use other hepatotoxic drugs such as rifampicin. On the other hand, nevirapine may be the best choice in women of childbearing potential or who are pregnant.

Fixed dose combinations (FDCs)

Nevirapine is also available as a Fixed Dose Combination (FDC) with two other drugs, lamivudine and stavudine. FDCs simplify treatment and drug management issues, improve adherence of health-care workers to treatment standards, decrease errors in drug administration, simplify drug forecasting, procurement, distribution and stocking because fewer items and lower volumes are necessary, and reduce the risk of misuse of single drugs. Due to these advantages the use of FDCs is likely to increase, particularly in countries with limited health-system infrastructures. However, since CD4 testing facilities are not always available in these settings, there is a real danger of indiscriminate use of FDCs containing nevirapine also in those individuals who may be at real risk for hepatotoxicity.

Conclusion

Health professionals responsible for the management of HIV-infected persons are advised that significant liver toxicity may develop if a nevirapine-containing regimen is initiated in patients with relatively high CD4+ cell counts. This adverse effect is linked to the chemical composition of the drug and hence, will likely develop regardless of whether the drug is formulated separately or as part of a FDC. It remains important to improve laboratory testing facilities in locations where antiretroviral therapy is distributed to identify and manage this and other possible adverse effects.

References

1. Scaling up antiretroviral therapy in resource-limited settings: Treatment guidelines for a public health approach. Geneva, World Health Organization, 2003.

2. FDA Public Health Advisory for nevirapine (Viramune). United States Food and Drug Administration, 19 January 2005 (http://www.fda.gov/cder/drug/advisory/nevirapine.htm).

3. http://www.boehringer-ingelheim.com/hiv/prod/downloads/Viramune_Product_Mono_April2005.pdf