Is There a Genetic Predisposition To Responding Better To Therapy? Maybe
     Reported by Jules Levin

The findings in this study suggest that a genetic predisposition in the genes that process drugs in the human body may affect drug levels in blood which may in turn affect some individual's response to therapy. This is very early research and of course may not turn out to be meaningful. But it reflects the possibility that with further research we may be able to understand why some individuals who are fully adherent & on good regimens are able to retain full viral suppression and others are not able to remain undetectable. If these findings are one day confirmed, this data suggests that if individuals are found to have a certain genetic predisposition drug dosing might be able to be adjusted to improve initial response to therapy and durability of response.

These researchers analyzed individual genetic differences in the enzymes of the p450 metabolism system that metabolizes drugs such as PIs & NNRTIs. They did the same for PGP which is a system that may be responsible for the influx & efflux of PIs into and out of cells. This may regulate how much PI concentration stays in a cell & for how long and how quickly the drug is kicked out of the cell. Let's bear in mind we've yet to establish this eflux, & influx is relevant to success or failure with therapy, i.e. is it relevant to keeping viral suppressed?

The authors concluded there were individual differences in genetics between individuals who had higher or lower blood levels of drugs. In this study, 44% of individuals with a certain PGP genetic makeup had higher blood levels for drugs compared to 8% who had lower blood levels. This suggests that if you have this genetic makeup, you might get higher drug blood levels & respond to therapy better with more durable suppression. The authors also found that a particular but different genetic makeup was present in individuals with low drug blood levels (44% vs 12%).

Predictive Power of P- Glycoprotein and CYP2D6 Polymorphisms for Plasma Levels of Antiretroviral Agents
J. Fellay*, C. Marzolini, G. Greub, T. Buclin, C. B. Eap, and A. Telenti., CHUV. Lausanne, Switzerland.

Background:
Important inter-individual variability is observed in drug plasma levels among HIV-infected patients receiving antiretroviral treatment (ART), which may explain differences in toxicity and efficacy. Numerous allelic variations have been described within genes coding for P-glycoprotein (PGP) and enzymes of cytochrome P450 (CYP), which are important in the metabolism of ART. We analyzed the association between various alleles and drug plasma levels.

Methods:
We studied 63 Caucasian patients with plasma viremia <400 copies/ml while receiving a PI- or Efavirenz-containing regimen. They were distributed in tertiles according to their drug plasma levels. PGP (promoter and exon 26), CYP3A4 (promoter and exon 7), CYP2C19 (exon 4 and 5) and CYP2D6 (selected alleles and gene duplication) were analyzed.

Results:
Homozygosity CC at PGP codon 1145 (exon 26) was present in 12 (44%) of 27 patients with high drug levels as compared to 3 (8.3%) of 36 subjects with lower levels (p = 0.002). Homozygosity TT at the same codon was present in 7 (44%) of 16 patients with low drug levels as compared to 6 (12.8%) of 47 subjects with higher levels (p = 0.014). For CYP2D6, 10 (37%) of 27 patients with high levels were homo- or heterozygous for at least one allele defining the poor metabolizer (PM) phenotype, as compared to 3 (8.3%) of 36 subjects with lower levels (p = 0.01). The only patient with a multicopy CYP2D6 gene (ultrarapid metabolizer = UM) had low levels. No other polymorphism in analyzed genes was correlated to drug plasma levels.

Overall, in the low drug level group, 50% of patients had either a TT allele (PGP) or UM genotype (CYP2D6); in the high level group, 63% had a CC and/or PM genotype. In multivariate logistic regression adjusted for age and sex, the odds ratio of having a CC allele (PGP) and/or PM genotype (CYP2D6) was 2.2 (CI95: 1.5-3.4) for the high drug level group. For the low level group, the odds ratio of having a TT allele (PGP) and/or UM genotype (CYP2D6) was 8.4 (2- 35.4).

Conclusions:
The marked inter-patient variability in drug plasma levels could be explained to a significant extent by the allelic pattern of two genes involved in the metabolism or transport of antiretrovirals. This information could be of potential use to better predict drug levels, treatment failure and toxicity.