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
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
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".