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Nevirapine liver toxicity associated with CD4 percentage over 25% and genetic factors, rash alone with genetic factors only
Edwin J. Bernard, Friday, July 16, 2004
Australian researchers presented late breaking research on the final working day of the Fifteenth International AIDS Conference in Bangkok that suggests a combination of genetic factors and a CD4 percentage over 25% leads to the liver toxicity associated with the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine. They also found that rash alone is associated only with slightly different genetic factors.

Two years ago, the same researchers from the Centre for Clinical Immunology and Biomedical Statistics in Perth, Australia, discovered the genetic factors that were associated with the abacavir hypersensitivity reaction, and this time Martin and colleagues reported on their findings around particular gene arrangements that are associated with an increased risk of nevirapine hypersensitivity. These arrangements are called haplotypes (HLAs), and refer to the markers on the surface of cells.

In this retrospective study of 241 individuals, they examined whether genetic or immunological factors were associated with the development of adverse reactions to nevirapine during the first six weeks of treatment with the drug. This is when the rash, liver toxicity (hepatitis) and fever associated with nevirapine is most likely to occur. A genetic predisposition to adverse reactions to nevirapine was determined by HLA typing, which was carried out using routine serological or DNA sequence assays.

After reviewing individuals’ medical records, they identified a total of 26 cases of various types of allergic reaction to nevirapine. During this review the investigators were blinded to the HLA typing results. In total there were 21 instances of rash, eleven instances of fever, and nine instances of hepatitis. Some individuals experienced single side-effects (twelve cases of rash and one of hepatitis were experienced alone), whereas others experienced a combination of side-effects (five cases of rash and hepatitis, four cases of hepatitis and fever, and two cases of rash and hepatitis were seen). Two individuals experienced a combination of rash, fever and hepatitis.

In terms of demographics, there were no significant differences seen regarding the age, gender, ethnicity, CD4 count or CD4 percentage of this cohort. However, the investigators noted that since the majority (85%) were Caucasians, these results could only be interpreted within a Caucasian population. This is because haplotypes are passed from one generation to another with little alteration.

When all hypersensitivity reactions were considered together, there was a significant association between adverse reactions to nevirapine and the presence of HLA-DRB1*0101 (p = 0.014). In further analysis, a highly significant interaction was found between HLA-DRB1*0101, CD4 cell percentage and the development of nevirapine rash (p < 0.001). However, when the investigators employed logistic regression analysis, no significant individual association between HLA-DRB1*0101 and immunological status (CD4 count or CD4 percentage) was found (p = 0.1).

The investigators then considered individual side-effects, or combinations of side-effects, associated with nevirapine. Interestingly, they found that rash alone was associated with a slightly different sequence in HLA (HLA-DRB7*0101, p = 0.04), and there was no significant relationship with either HLA-DRB1*0101 (p = 0.24), or CD4 cell percentage (p > 0.1).

However, when the investigators looked at rash and hepatitis together, or hepatitis or fever individually they found a significant interaction between HLA-DRB1*0101 and CD4 cell percentage greater than 25% (p < 0.01). In other words, there is an interaction between genetic disposition and a better functioning immune system that predisposes to liver toxicity with rash and/or fever. They calculated that screening for this genetic disposition would prevent one-in-14 potentially fatal hypersensitivity reactions in Caucasians with a CD4 percentage over 25%.

Although more research is needed in this area, particularly in non-Caucasian populations – where nevirapine is being used on a large scale as part of two of the four WHO-preferred 3x5 regimens – the investigators conclude that HLA-DRB1*0101 may determine susceptibility to the liver toxicity and/or fever with or without rash that is associated with nevirapine hypersensitivity reactions, and that this effect may be significantly reduced with a CD4 percentage below 25%.

This suggests that in the absence of genetic typing, individuals with CD4 percentages above 25% – including pregnant women using nevirapine to prevent mother-to-child-transmission – should use nevirapine with extra caution. These data also support the recent warning from Boehringer Ingelheim regarding the use of nevirapine in pregnant women with CD4 counts above 250 cells/mm3.

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).


Reference
Martin A et al. Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*01 and higher CD4+ T cell counts XV International AIDS Conference, Bangkok, abstract LbOrB13, 2004.


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