Two studies published in the 23rd July edition of AIDS provide further evidence for the role of genetics in predicting the response to antiretroviral treatment and in disease progression in HIV-positive patients. They suggest that genetic testing may eventually allow clinicians to predict how a patient's disease will develop and how well they will respond to antiretroviral therapy.
In one study, the investigators report that the durability of response to HAART before treatment failure is affected by genes for inflammatory cytokines, particularly interleukin-1α (IL-1α). The accompanying case-control study shows that mutations in either of two genes can increase the susceptibility to pancreas disorders in HIV-positive patients.
While these findings add to the growing list of genes known to influence the progression of HIV disease, particularly the human leukocyte antigen (HLA) genes, it remains unclear how these findings will translate into clinical practice in the near future, despite the authors' optimism. Nevertheless, these discoveries, in conjunction with future findings, may eventually allow clinical decisions to be guided by a patient’s genetic make-up.
The IL-1α gene predicts response to HAART
In an attempt to understand the genetic basis of virological failure after initiation of HAART, the first study’s investigators from Perth, Australia followed a cohort of 81 HIV-positive patients for over five years. All of the patients began HAART with CD4 counts below 100 cells/mm3.
The authors examined which variants of the gene for IL-1α the patients possessed, using a technique called restriction fragment length polymorphism analysis. They concentrated on one position in the gene, IL1A-889, which can exist in one of two forms or ‘alleles’. They found that patients with allele 2 were more likely to experience virological failure – characterised as an HIV viral load above 400 copies/ml – in the five years of follow-up (p = 0.002).
Since everyone possesses two copies of this gene – one passed down from the mother and the other from the father – the investigators went on to examine whether having one or two copies of this gene made a difference.
More than 70% of the ten patients with two copies of allele 2 (‘homozygotes’) had failed their HAART regimen after three years, although this decreased to 60% after five years. In contrast, only around 30% of the patients with two copies of allele 1 had viral loads above 400 copies/ml for the first three years of treatment, declining to 20% by five years (p = 0.007). Patients with one copy of each allele ('heterozygotes') had an intermediate response, with around 50% of patients experiencing failure, after an initial good response during the first year of therapy.
This effect was independent of baseline viral load or CD4 count, duration of dual nucleoside analogue therapy and age. Surprisingly, however, the patients’ genetic make-up did not affect their CD4 cell count increases, despite their alterations in virological response.
“Alleles of IL1A-889 are associated with the attainment and maintenance of undetectable levels of HIV RNA in the plasma of HIV-1 patients receiving HAART,” conclude the authors. “We suggest that IL1A genotyping may identify patients at greatest risk of virological failure, so that drug regimens with maximal efficacy and durability can be selected.”
Subsequent analysis revealed that a number of related cytokine genes, including IL6, TNFA, IL1B and IL12B also had minor effects on the control of viral loads in these patients.
Genetic susceptibility to pancreatitis
In the second study, the investigators identified 51 HIV-positive patients who had high levels of amylase in the blood – a marker of pancreatitis - from the 1152 participants of the Swiss HIV Cohort Study. After matching each patient with an HIV-positive control without pancreatitis, according to sex, age, CD4 count, viral load and medication use, they examined the prevalence of variants of the CFTR and SPINK-1 genes that are associated with pancreatic disorders in HIV-negative people.
Overall, amylase levels were similar in the patients with and without the disease-associated variants. However, when they examined only the patients with elevated amylase levels, the investigators found that the six patients with pancreatitis-associated alleles had higher mean levels of amylase than those without the mutations (648 vs. 232 U/l, p = 0.025), suggesting that “these mutations may increase the susceptibility to pancreatitis when exposed to environmental risk factors.”
Furthermore, four of the ten patients with acute pancreatitis (40%) - characterised by abdominal pain and elevated amylase levels - had disease-associated variants of either CFTR or SPINK-1 genes, in contrast to only seven (14%) of the 50 control patients (p = 0.011). Although the origin of acute pancreatitis was unclear in six of the ten patients, it was ascribed to alcohol abuse in the remaining four.
“Pancreatic disorders including the asymptomatic elevation on pancreatic enzymes and clinical acute pancreatitis remain frequent in HIV-positive patients receiving antiretroviral therapy,” state the authors. “Our genetic results may suggest a role for CFTR mutations and SPINK-1 polymorphisms in the occurrence of pancreatitis in HIV-positive patients, particularly in the presence of alcohol abuse.”
Price P et al. Alleles of the gene encoding IL-1α may predict control of plasma viraemia in HIV-1 patients on highly active antiretroviral therapy. AIDS 18: 1495-1501, 2004.
Felley C et al. The role of CFTR and SPINK-1 mutations in pancreatic disorders in HIV-positive patients: a case-control study. AIDS 18: 1521-1527, 2004.