At this workshop more so than in previous years, there was an increasing emphasis on the impact of pharmaco-genetics, the intersection between host genetic influences and drug metabolism.
Simon Mallal from Perth who first characterised B*5701, the ancestral haplotype correlated with abacavir hyper-sensitivity reaction (ABC HSR), presented an intriguing description of genetic variations that may influence AZT phosphorylation. Their study was based upon the different rates of AZT-related toxicities observed in racial groups, including anaemia and neutropenia.
The major metabolite of AZT is its intracellular monophosphate, implicating deoxythmidylate kinase (dTMPK) as the rate-limiting step for AZT activation. The purpose of the study was to identify the significance of nucleotide polymorphisms and characterise dTMPK haploptypes using pooled and familial DNA to determine the impact on various haematological parameters.
The patient profile consisted of 116 patients using AZT as first-line therapy, 48 d4T-experienced AZT recipients (41 with first-line d4T) and 82 AZT-experienced d4T recipients. They found three previously reported and nine novel SNPs (single nucleotide polymorphisms) and five common haplotypes analysed from Caucasian family DNA that interestingly appear to have evolved as recombinants of distinct 3' and 5' haplotypes. As may be expected, AZT use was associated with lower haemoglobin and neutrophil counts compared to d4T treatment. But of note, higher haemoglobin levels in response to AZT were found in patients homozygous for either the 33,309 C allele or the 36,187 A allele. However, this result seems to be explained by higher baseline haemoglobin levels and possible higher viral loads at baseline in the homozygous patients since the changes observed whilst on treatment remained similar between the two groups.
Dr Mallal noted that these findings may be useful in understanding treatment effects in different groups based on genetic influences, but more importantly they may help to identify individuals prone to anaemia and other AZT-related toxicities. Charles Boucher from Utrecht University asked if this effect had been reported in patients without HIV infection. Dr Mallal confirmed that whilst this had not yet been studied, it was important to distinguish between drug and disease effect.
C Pace et al. Investigation of deoxythymidylate kinase genetic variation and its influence on haematological response to zidovudine treatment. HIV Pharmacology Workshop, Lisbon, abstract 32, 2006.