More genetic clues about how to predict who might suffer liver problems with NNRTIs have come from two US studies published in the September 15th edition of Clinical Infectious Diseases.
A particular genetic form of an enzyme called P-glycoprotein - which is involved in drug metabolism - has been implicated, termed MDR1 3435C-T.
One of the most frequently prescribed and most effective initial HAART regimens is an NNRTI, either nevirapine or efavirenz-plus two nucleoside analogues.
But severe, life-threatening, and in some cases fatal hepatotoxicity (liver damage), particularly in the first 18 weeks, occurs in approximately 1 - 5% of people treated with nevirapine.
It tends to be more common in women with CD4 counts above 250 cells/mm3 and men with CD4 cell counts above 400 cells/mm3 but can occur in either gender at any CD4 count. Patients with chronic hepatitis B or C infection also appear to be at higher risk. But a much higher proportion of people – up to 25% in some studies – experience serious liver enzyme elevations without experiencing hepatitis.
Some patients have similar asymptomatic liver enzyme elevations with efavirenz although the toxicity is less frequent, occurring in up to 8% of people who receive the drug.
The problem seems to be due to genetic differences between individuals, particularly in the way the drugs are metabolised in the liver by an enzyme called cytochrome p450 and throughout the body by another enzyme called P-glycoprotein (Pgp). P-glycoprotein, dubbed the ‘cellular vacuum cleaner’, flushes drugs out of cells and back into the gut. Intracellular concentrations of nevirapine are known to be high where Pgp expression is low, and vice versa, although it remains unclear whether Pgp is a transporter of nevirapine across the cell membrane.
The two studies looked at differences in the DNA which codes for Pgp with the eventual aim of finding out which DNA forms cause the toxicity. Patients could then be pre-screened and those more likely to have the side-effect given other HAART regimens.
The first study (Ritchie 2006) looked at 423 patients who started taking nevirapine or efavirenz, 20 of whom (4.7%) suffered severe hepatotoxicity, 14 who had started nevirapine and six who had taken efavirenz. Severe hepatotoxicity was defined as one or more ALT or AST measurement more than five times the upper limit of normal in individuals with a baseline value no more than three times the upper limit of normal.
When they analysed the genes coding for the enzymes responsible for drug metabolism in these patients they found that a variant form, or polymorphism, of the gene which encodes Pgp called MDR1 was associated with a lower risk of NNRTI liver toxicity.
It is a very small difference at position 3435 in the DNA chain - where a cytosine nucleoside (DNA building block) is switched with thymidine - which gives the gene mutation its name MDR1 3435C-T.
People who had the form with cytosine (MDR1 3435C) had a much higher risk of hepatoxicity. The association was strongest of all in patients co-infected with hepatitis B. In these cases hepatoxicity occurred 82% of the time.
Individuals with the CT polymorphism had a significantly lower risk of hepatotoxicity (OR 0.25, p=0.021).
The researchers admit their study is small but point out that another study in the same issue of Clinical Infectious Diseases (Haas 2006) backs up the importance of the MDR1 gene.
This study looked at the same gene in 53 patients who had suffered hepatoxicity while taking nevirapine and in 108 people who had not. Hepatotoxicity was classified as any grade 3 or 4 ALT or AST elevation
They found the same association- MDR1 3435C-T was associated with a significantly lower risk of nevirapine hepatotoxicity (risk ratio 0.30, p=0.016).
They also looked at variations in the cytochrome P450 liver enzyme which previous research had suggested might be a problem and found no association after controlling for the presence of MDR1 3435C-T.
The researchers say that MDR1 3435C-T needs to be studied in larger groups of patients treated with NNRTIs along with other potential predictors of NNRTI toxicity.
For instance there is increasing evidence that nevirapine toxicity is associated with a changes in a group of genes called the human leukocyte antigen (HLA) system.
The eventual hope is that all these predictive markers can be brought together to screen HIV-infected people before treatment, so avoiding NNRTIs in those at highest risk of developing liver toxicity.
Ritchie MD et al. Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse transcriptase inhibitor hepatotoxicity. Clinical Infectious Diseases 2006;43:779-782.
Haas DW. Pharmacogenetics of nevirapine-associated hepatotoxity: an adult AIDS clinical trials group collaboration. Clinical Infectious Diseases 2006;34:783-786.