For the past several years "genotyping" and "resistance testing" have almost been synonymous. However, it is has become increasingly apparent that genotypic resistance testing - in which the protease and RT genes are sequenced - provides an incomplete picture of a patient's probable response to a new treatment regimen. This should not be surprising considering the variability of the natural history of HIV disease progression. Some individuals become sick within 2 to 3 years following infection. Other individuals remain healthy for 15 to 20 years even without treatment. The factors responsible for this variability are likely to be as important for individuals receiving treatment as they are in untreated individuals.

Increasing amounts of data suggest that host genotypic factors - not just viral genotypic factors - are responsible for the variability in disease progression. Increasing amounts of data also suggest that host genetic factors influence how drugs are metabolized, which in turn influences their activity and associated toxicity. At the 9th Conference on Retroviruses and Opportunistic Infections, there were 12 presentations on the influence of host genomic factors on the natural history of HIV infection, the metabolism of antiretroviral drugs, and the risk of drug toxicity.

Abacavir hypersensitivity reactions
Two groups presented data linking variation in the human MHC region with risk for abacavir hypersensitivity. Each of these has since been published in the March 30th issue of The Lancet [1,2].

Mallal and colleagues from the Royal Perth Hospital in Western Australia reported that HLA typing was done on a cohort of 200 Western Australian patients treated with abacavir. Among 18 patients with abacavir hypersensitivity, 14 (78%) had the HLA-B57 allele compared with 4 of 167 (2%) of abacavir-tolerant patients [1]. Fifteen patients experienced some symptoms but did not meet the criteria for abacavir hypersensitivity. Two of the patients with hypersensitivity reactions that did not have the HLA-B57 allele started abacavir and nevirapine concurrently. The presence of two additional alleles (HLA-DR7 and HLA-DQ3) increased the positive predictive value to 100% and lowered the negative predictive value to 97% in this population. Approximately 90% of the patients were Caucasian and approximately 85% were male.

Hetherington and colleagues from GlaxoSmithKline found in a case-control study that 39 of 84 (46%) North American patients, compared with 4 of 113 (4%) controls had the HLA-B57 allele [2]. In this study, the association between HLA-B57 and abacavir hypersensitivity was particularly strong in Caucasians. None of the nine African American patients and only one of the ten Hispanic patients had the HLA-B57 allele, and the genotypic abacavir hypersensitivity association could not be demonstrated in these demographic groups. Because this was a case-control study, the positive and negative predictive value of the HLA-B57 allele could not be calculated.

The weaker correlation in the second study compared with that demonstrated by the Australian study is probably a result of the greater genetic diversity in the North American population compared with the Western Australian population. In Western Australia, HLA typing would be strongly predictive of abacavir hypersensitivity. In contrast, HLA typing would only be of limited use in identifying North American Caucasian individuals at higher risk for hypersensitivity.

The strong linkage with the HLA-B57 allele does not pin down the molecular basis for abacavir hypersensitivity. Further work is needed to identify the specific genetic changes associated with hypersensitivity and to determine whether these changes are the same in different human populations. Most diseases that are associated with a specific HLA allele are never fully dependent or fully explained by the presence of that allele. A hypersensitivity reaction may be different, however.

Drug metabolism
Genetic polymorphisms of cytochrome P450 (CYP) isoenzymes and of at least two transporter proteins (P-glycoprotein receptor, the gene product of MDR1, and multidrug resistance protein 1, which is coded for by the MRP1 gene) influence the metabolism of protease inhibitors (PI) and possibly nonnucleoside RT inhibitors (NNRTI). These genes are highly polymorphic and explain the considerable inter-individual variability in plasma concentrations of PI. Another recent study in The Lancet has shown that an MDR1 polymorphism associated with decreased P-glycoprotein receptor expression is associated with greater immune recovery after starting HAART [3]. At the 9th CROI, investigators from Liverpool reported that lymphocyte expression of P-glycoprotein and MRP1 were inversely correlated with intracellular levels of ritonavir and saquinavir, supporting the concept that these transporters play a role in the efflux of these PI from lymphocytes [4].

Natural history of disease progression
Multiple host genetic factors influence the rate of immunologic HIV disease progression. These factors include variations in the genes that encode chemokine receptors (e.g., CCR5-?32, CCR2-64I) and their ligands (SDF, RANTES, EOTAXIN), HLA molecules, and several cytokines. Each of these has been validated in multiple cohorts and ethnic groups as well as in combined cohort analyses, and combined, these genes account for much of the variability in rates of disease progression. While not the focus of this article, the 9th CROI's Poster Session 51 - Impact of Host Genetics on Viral Transmission and Disease Progression - contained a considerable number of new findings on host genetics and disease progression. New data concerning host genetic determinants of HIV disease progression, and their possible implications in the treatment of HIV-infected patients, will be reviewed in a subsequent article.

References

Mallal, S., D. Nolan, C. Witt, G. Masel, A. M. Martin, C. Moore, D. Sayer, A. Castley, C. Mamotte, D. Maxwell, I. James, and F. T. Christiansen. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359:727-32.
Hetherington, S., A. R. Hughes, M. Mosteller, D. Shortino, K. L. Baker, W. Spreen, E. Lai, K. Davies, A. Handley, D. J. Dow, M. E. Fling, M. Stocum, C. Bowman, L. M. Thurmond, and A. D. Roses. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002;359:1121-2.
Fellay, J., C. Marzolini, E. R. Meaden, D. J. Back, T. Buclin, J. P. Chave, L. A. Decosterd, H. Furrer, M. Opravil, G. Pantaleo, D. Retelska, L. Ruiz, A. H. Schinkel, P. Vernazza, C. B. Eap, and A. Telenti. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet. 2002;359:30-6.
E. Meaden, P. Hoggard, P. Newton, J. F. Tjia, D. Aldam, D. Cornforth, J. Lloyd, A. Smith, I. Williams, N. Beeching, E. Stockwell, E. Wilkins, P. Carey, D. Back, S. Khoo. Reduced Accumulation of Ritonavir and Saquinavir in PBMCs in Vivo is Associated with Increased P-gp and MRP1 Expression in HIV-Infected Individuals. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 127.