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HIV Treatment – HAART (Efficacy of Therapy) [T88.7]

OMIM numbers: 609423, 601373 (CCR5), 601267 (CCR2), 171050 (ABCB1), 124030 (CYP2D6), 124010 (CYP3A4)

Dipl.-Biol. Birgit Busse, Dipl.-Biol. Christine Schack

Scientific Background

During highly active antiretroviral treatment (HAART), a combination of several drugs are administered at the same time to increase the chance of successful treatment. Efficacy and compatibility of an HIV treatment depends on the genetic disposition of a patient. Polymorphisms in the genes of proteins that interact with the active agents play an important role.

CYP2D6 is involved in the metabolism of the active agent ritonavir, which is used in combination drugs (such as lopinavir/ritonavir) for inhibition of the CYP3A4 enzyme, thereby preventing too rapid degradation of the drug. In the presence of a CYP2D6 gene amplification (CYP2D6*XN allele), the expression of the enzyme is increased and therefore the metabolism of CYP2D6 substrates such as ritonavir as well. As a consequence the efficacy of the combination therapy lopinavir/ritonavir (e.g. Kaletra) may be decreased. Approximately 2-5% of all Caucasians are ultra-rapid metabolizers.

CYP3A4 is involved in the metabolism of protease inhibitors such as lopinavir, ritonavir or saquinavir. The activity of the enzyme exhibits a very high interindividual variability and is furthermore inhibited or induced by many substances. There are many known genetic variants in the CYP3A4 gene that have been associated with altered enzyme activity. The alleles CYP3A4*8, *11, *13, *16, *17 and *20 have been associated with a reduced enzyme activity. The frequency of most variant CYP3A4 alleles is low within the Caucasian population (approx. 2%).

The ABCB1 gene (MDR1) codes for the P-glycoprotein (PGP), which is an integral part of the cell membrane. As an efflux transporter, PGP is responsible for the energy-dependent transport of substrates from the cell. Protease inhibitors (e.g. lopinavir, ritonavar, saquinavir, atanazavir) or NNRTIs (e.g. efavirenz, nevirapin) are PGP substrates. Several studies show a correlation of the sequence variant c.3534C>T in the ABCB1 gene with the plasma level of various active agents. The data is controversially discussed in the literature, which is why the clinical relevance of polymorphisms in the ABCB1 gene is still unclear. Induction and inhibition of the ABCB1 gene by drugs, phytopharmaceuticals and diet can play an important role in PGP expression, thereby affecting the transport capacity for substrates. HIV drugs are inductors and inhibitors of the P-glycoprotein.

For the course of treatment, the polymorphisms in the genes of the co-receptors CCR5, CCR2, CX3CR1, and CXCR4 as well as their ligands (e.g. SDF-1) play a role as well. The frequency of the CCR5-Δ-32 bp allele is remarkably lower in patients infected with HIV 1 than in healthy controls. However, if the deletion allele is present in an HIV patient it is associated with a better response to the HAART regime (own data, Brien and Dien, 1998).

Maraviroc is an entry inhibitor for CCR5-tropic HIV strains, which prevents the virus from entering by blocking the receptor. A functional CCR5 receptor is necessary for a response to treatment. The 32bp deletion in the CCR5 gene is an indicator for response to treatment.