Bespoke treatments could be closer than you think.

by Rob Dawson

The advent of genetic screening is seeing established drugs tailored to the individual. Data presented at the fourth International AIDS Society Conference showed just how it could be used to eliminate side-effects and improve outcomes.

Abacavir – also found in the co-formulations Kivexa and Trizivir – can cause a hypersensitivity reaction (HSR) in a minority of people. This serious side-effect can cause fever, rash and shortness of breath. In some cases, particularly when the drug is stopped and restarted, it can even be fatal. Various studies have shown that people with an inherited genetic variant (called the HLA-B*5701 allele) are more likely to experience HSR than those who don't have the gene.¹

While many clinics already test for HLA-B*5701, studies have been ongoing to try and get genetic screening routinely used. The main hurdle has been trying to determine how accurate the test is at predicting HSR.

HLA-B*5701 is predominantly a Caucasian allele and in Black Africans it is far less common. The SHAPE study was conducted to examine the link between abacavir hypersensitivity and the prevalence of the HLA-B*5701 allele in white and black populations.

So far it has been difficult to get an exact measure of the correlation because there are many things that could confuse the diagnosis, such as similar side-effects caused by other drugs. However, where the SHAPE study triumphed was in its use of patch testing. This involves putting abacavir onto the skin and seeing if a reaction develops. This skin reaction tells researchers that there is a genuine (immune-mediated) HSR to abacavir. The SHAPE study found a perfect correlation between true abacavir hypersensitivity (as shown by positive patch tests) and the presence of the HLA-B*5701 allele in both ethnicities.²

The author of the study concluded that genetic screening in patients of all ethnicities will therefore reduce the incidence of misdiagnosed HSR and minimise situations where abacavir is inappropriately withdrawn. She also noted that while patch testing is a very useful research tool, it isn’t a routine clinical test because it can underperform for technical or biologic reasons. It is designed to look at reported HSR and determine if it is true (immune-mediated) HSR.

The PREDICT-1 study gave more robust data. Patients were randomised to either begin abacavir treatment without testing, or to be tested for HLA-B*5701 and given abacavir accordingly – those with the gene did not start abacavir, whereas those who without the gene started treatment with the drug.

If symptoms of HSR occurred among those on abacavir treatment, they were 'clinically' diagnosed. This was followed up using a patch test to confirm true HSR to abacavir.

The results of the study were that ‘clinical’ diagnosis of HSR fell from 7.8% (in untested patients) to 3.4% (in those tested). When patch testing was used to confirm true cases of HSR, only 2.7% of individuals in the non-screened arm tested positive and all of those patients that had the HLA-B*5701 allele were true HSR negative.³ So the 100% sensitivity of HLA-B*5701 to patch test positive HSR held up in both the PREDICT-1 study and the SHAPE study.

The studies seem to show that genetic screening could make it highly unlikely that a true HSR to abacavir will occur.

"What we have found with this study is that we can tailor therapy based on the genetic makeup of the patient," said Simon Mallal, Director of Immunology and Infectious Diseases in Murdoch University, Australia, who presented the study.

Although this study did not see any, it was noted that the chance of rare immunological reactions to abacavir that are not related to HLA-B*5701 cannot be ruled out and that clinical vigilance should remain a priority.

References

1. Rauch A et al. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in Western Australian HIV Cohort Study. Clin Infect Dis 43: 99 – 102, 2006.
2. Mallal S et al. PREDICT-1: a novel randomised prospective study to determine the clinical utility of HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects (study CNA106030). Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney. Abstract WESS101, 2007.
3. Phillips E at al. High sensitivity of HLA-B*5701 in Whites and Blacks in immunologically-confirmed cases of abacavir hypersensitivity (ABC HSR). Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney. Abstract WEAB305. 2007.