Scientists have identified a variety of genes that seem to influence levels of anti-HIV drugs, and thus the success of highly active antiretroviral therapy (HAART), in a study of 123 Swiss patients.
The findings open up the possibility that a genetic test prior to treatment could be used to identify those individuals most in need of therapeutic drug monitoring and design of a drug regimen to overcome a person’s built-in disadvantage.
However, the study also revealed a paradoxical relationship between drug levels and treatment success that cannot be fully explained.
Multidrug resistance gene is key
Dr Amalio Telenti of the Swiss HIV Cohort Study found that median drug concentrations in patients receiving nelfinavir or efavirenz were strongly associated with particular gene patterns in the multidrug-resistance transporter gene. This gene governs the production of p-glycoprotein, which in turn controls how much of a foreign substance is allowed to cross barriers in the body such as the wall of the intestine and the barrier between the blood and the brain. High levels of p-glycoprotein are associated with low levels of protease inhibitors.
The research group found that individuals with the MDR-1 TT genotype had significantly lower median drug concentrations than individuals with the CT or CC genotypes. Paradoxically, those with the TT genotype (and the lowest average plasma drug concentrations) had the largest CD4 cell increases 6 months after starting treatment (257 cells vs 165 cells in the CT group and 121 cells in the CC group).
The association between MDR-1 genotype and immunological response to treatment was also analysed in a separate study of 80 patients with high baseline CD4 cell counts (>500 cells/mm3) who received amprenavir, saquinavir or nelfinavir in clinical trials together with abacavir. MDR-1 3435 TT genotype was associated with a significantly greater CD4 cell increase after six months of treatment than the other genotypes (196 cells vs 161 and 142 cells for the CT and CC genotypes respectively).
When the research group looked at expression of the MDR1 gene, which controls p-glycoprotein, expression was found to be significantly lower in individuals with the TT genotype, when compared with the CT or CC genotypes, and this relationship was echoed in an analysis of p-glycoprotein levels in PBMCs (the class of blood cells that includes lyhphocytes.
“The findings were suprising, particularly relating to drug levels, because we expected to see lower plasma levels of the drug in the presence of higher p-glycoprotein levels – which suggests pgp in the gut is not that important, and that p-glycoprotein levels may be more important elsewhere – for example in the lymphocytes, pumping drug out” said Professor David Back of Liverpool University’s Department of Pharamacology, which contributed to the study.
In Caucasians, the MDR-1 genotypes are distributed in the following proportions: CC (25%), CT (50%), TT (25%). In non-Caucasians distribution differs, with the TT genotype seen in lower proportions among Black Africans and people of African descent.
Cytochrome p450: slow metaboliser gene linked to higher drug levels
Drug concentrations were also analysed according to genotype for particular cytochrome p450 isoenzymes (CYP3A4, CYP3A5, CYP2D6 and CYP2C19). These isonzymes are involved in the metabolism of protease inhibitors, so differences between individuals in the capacity of the enzyme to break down the drug might have an effect on response to treatment.
No relationship between cytochrome p450 genotypes and drug concentrations was found except in CYP2D6, where a genetic pattern consistent with slow metabolism of drugs was associated with higher nelfinavir and efavirenz levels. Nor was cytochrome p450 genotype associated with response to treatment.
The researchers suggest that high plasma drug concentrations may not be the only explanation for the better immune reconstitution seen in those with the MDR 3435 TT genotype. Lower levels of p-glycoprotein activity may also allow the penetration of antiretroviral drugs into more cells and more cell types, but Professor David Back told aidsmap that this explanation remains to be proved.
“We know that there is differential expression of MDR-1 in peripheral blood mononuclear cells, but we don’t know whether that extends to other cell types. They did not look at the viral load decay rate in this study, so we cannot be certain that there is a direct relationship.
“It’s far too early to say that one gene can predict the success of treatment – we’re clearly going down the genotyping route with respect to targeting the use of therapeutic drug monitoring, but we’ve got to link particular transporter molecules and genes to the cytochrome p450 enzymes, drug levels and treatment response. But it’s not just genetics – it’s environment interacting with genes too – simple things like smoking, diet, drinking, other drugs – all these can affect the activity of cytochrome p450 and levels of antiretrovirals”.
Fellay J et al. Response to antiretroviral treatment in HIV-1 infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. The Lancet 359: 30-36, 2002.