Report on the Immunotoxicity of Nevirapine in Female B6C3F1/N Mice (CAS No. 129618-40-2)
Report Date: August 2012
The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.
Nevirapine, which is marketed under the brand name Viramune, belongs to a class of drugs known as non-nucleoside reverse transcriptase inhibitors and is used for the treatment of acquired immune deficiency syndrome and human immunodeficiency virus. Because HIV can infect immune cells, i.e., CD4+ T cells, it is important to establish if drugs designed to treat the infection can impact the various functions of immune system. Drug hypersensitivity has been demonstrated in mice following NVP treatment using the lymph node proliferation assay (Weaver et al., 2005) and has been reported in HIV-positive humans having CD4+ cell counts greater than 250 cells per microliter (Wit et al., 2008). Furthermore, cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, which are two rare immune-mediated cutaneous adverse reactions, have been linked to NVP treatment (Barvaliya et al., 2011).
The NTP requested that a study be conducted to establish the potential effects of NVP on the immune system. These studies were conducted in female B6C3F1/N mice. Animals were exposed to NVP twice daily for 28 days. NVP was prepared weekly as a solution in the vehicle 0.2% methylcellulose with 0.1% Tween 80.
Treatment with NVP twice daily for 28 days did not affect body weights, body weight gain, or hematological parameters. Absolute and relative liver weights were significantly increased in a dose-dependent manner, while the absolute and relative weights of the spleen, thymus, lung, and kidneys with adrenals were unaffected with the exception of a decrease in absolute spleen weights, in one study.
NVP treatment did not affect total spleen cell numbers or the percent values of B cells, T cells, T cell subsets, natural killer cells, or macrophages. However, the absolute number of B cells was decreased at doses ≥ 176 mg/kg/day, and the absolute number of macrophages was decreased at all doses ≥ 88 mg/kg/day. Absolute numbers of T cells, T cell subsets, and NK cells were unaffected. The humoral immune response was suppressed by NVP treatment, as indicated by decreases in the Immunoglobulin M antibody-forming cell response to sheep erythrocytes and in serum anti-keyhole limpet hemocyanin IgM antibody levels. No effects were observed on serum anti-sRBC IgM antibody levels, however a decreasing trend was observed. Cell-mediated immunity was unaffected, as no effects were observed on the mixed leukocyte response, while effects observed on anti-CD3 stimulated T cell proliferation were sporadic and not dose-related. NK cell activity, a measure of innate immune function, was enhanced at all effector:target ratios.
Weaver J.L., Chapdelaine J.M., Descotes J., Germolec D., Holsapple M., House R., Lebrec H., Meade J., Pieters R., Hastings K.L., & Dean J.H. (2005). Evaluation of a lymph node proliferation assay for its ability to detect pharmaceuticals with potential to cause immune-mediated drug reactions. J Immunotoxicol 2:11-20.
Wit F.W., Kesselring A.M., Gras L., Richter C., van der Ende M.E., Brinkman K., Lange J.M., de Wolf F., & Reiss P. (2008). Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naïve patients: the ATHENA cohort study. Clin Infect Dis 46(6):933-40.
Barvaliya M., Sanmukhani J., Patel T., Paliwal N., Shah H., & Tripathi C. (2011). Drug-induced Stevens-Johnson syndrome, toxic epidermal necrolysis, and SJS-TEN overlap: A multicentric retrospective study. J Postgrad Med 57(2):115-9.