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  ICAAC 41st Interscience Conference on Antimicrobial Agents and Chemotherapy
Chicago, Illinois, December 16-19
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Pharmacogenetics of Antiretrovirals
Written for NATAP by Michael Norton, PA, Boriken Family Health Clinic, NYC
  Pharmacogentics is a field of science that concentrates on the different drug metabolism rates between people and the underlying genetic reasons for those differences. Amalio Telenti's presentation on this topic was certainly one of the highlights of this ICAAC.
Telenti began by noting that there is a 1-log variance in Cmaxes across a population of patients (Cmax is the peak level in blood that a drug achieves). Put another way, the amount of drug that gets into one persons blood stream after taking a dose of a medication can be a lot more or less then someone else taking the same amount of medication (dose).
Currently it appears that perhaps the causes of these drug metabolism differences can be explained by genetic differences in both the P450 enzyme system that resides in the liver and the P-glycoprotein (PGP) system that is strategically placed throughout the body.
MDR1 (multidrug resistant-1) is the genetic marker (code) for making P-glycoprotein (PGP). In other words MDR1 produces the genetic makeup of PGP, which is a protein. The MDR gene can differ between people. It has a form that encodes for lots of PGP, a form that encodes for a relatively small amount of PGP, and a form in between that encodes a moderate amount of PGP. MDR or multi-drug resistance in this setting has nothing to do with resist ance to HIV drugs. MDR is a historical name given to this gene because it was found to be associated with the development of resistance to chemotherapy in cancer patients. PGP, the protein that is the product of the gene MDR1, can be found in the brain (blood brain barrier), gut lumen, testes, bone marrow, placenta, and on na´ve lymphocytes. PGP acts as a defense mechanism pumping things out of these areas that should not gain entry. Unfortunately drugs we may want to penetrate these regions of the body in order to stop HIV replication or to stop cancer cells from dividing can be pumped out by PGP.
Editorial note: a popular notion among researchers is that HIV drugs are unable to penetrate or to be distributed as well in certain tissues or "sanctuaries" (as in blood) and this may play a role in the inability to eradicate HIV, in viral rebound, or the development of resistance to drugs in certain "compartments".
Telenti stated to the audience that Felley et. al. will be publishing a paper in the January 5, 2002 issue of The Lancet on this subject.
Some findings from this study:
- in caucasions, 2 genes predicted poor metabolism of Nelfinavir (Viracept) and Efavirenz (Sustiva).
- MDR1 has been shown to be a genetic marker that can predict cd4 recovery after HAART.
Already it has been shown that inhibiting the P450 enzyme system with Ritonavir (Norvir) translates into enhanced pK parameters for the other protease inhibitors as well as improved efficacy when compared to non- boosted PI's. Thus the question at hand is: Should we also inhibit PGP? There are currently under study a number of compounds that effectively inhibit PGP at least at the gut level. However are their risks in inhibiting PGP? Will toxins that should be kept out of certain sites ( i.e Brain or Testes) be able to penetrate causing harm if PGP is inhibited? Will there be gains in efficacy if PGP is inhibited? How will we observe those gains? To date the patients that have been studied showing differences in PGP and drug levels have been done among patients who achieved viral loads of <50 copies/ml suggesting that, at least regarding initial viral response and using our current technology, differences in efficacy might not be detected. Another potential benefit of this genetic testing possibly combined with drug level monitoring is that we may be able to avert or readily identify individuals whose drugs levels are higher then therapeutically needed and thus at the highest risk of medication induced side effects. In other words we may someday perform a genetic test prior to deciding upon an antiviral dose for a particular patient.
Telenti concluded his presentation with a call for pharmacogenetic studies to be added to HIV clinical trials.
Editorial note: a core of HIV researchers have been following this subject matter for a few years. It also appears that drug companies are interested in the research in this area. In his report to NATAP from ICAAC, Mike Youle reported on Telenti's talk: "Őfinally some disturbing data was shown suggesting that since there is a major variability in MDR genotype by ethnicity that this could translate into an important determinant factor for the pharmacokinetics of HIV therapy".