HIV therapy leads way in personalised medicine

The pharma heavyweight has successfully completed a clinical trial which shows a specific genetic mutation causes the only serious side-effect seen with its HIV drug Ziagen (abacavir). GSK hopes that by testing potential patients, this potentially fatal adverse event can now be eradicated from antiretroviral therapy. Speaking at the International Aids Society (IAS) conference, held last week in Sydney, Austraila, Dr David Haas of the Vanderbilt Infectious Diseases Clinic, Germany, explained to delegates that there are effectively two types of genetic variations that could be exploited in personalised medicine. The first are genetic mutations that cause disease or poor disease prognosis, and the others are mutations that change the effectiveness of a certain drug. In this case, the presence of the HLA-B* 5701 genetic variation on genes controlling the human leukocyte antigen (HLA) has now been proved to cause hypersensitive reactions in patients taking Ziagen. The side-effect is seen in around 5 to 8 per cent of patients on the drug - although that figure may be inflated by incorrect diagnoses. It initially causes symptoms such as rash and fever and if treatment is kept up or restarted, it can potentially be life-threatening. "In the past, we always had to expose a patient to a drug to see if there is a reaction. This, to the best of my knowledge, is the first example where we can predict an allergic response without having to expose the patient,"​ said Dr Haas. "That is a pretty remarkable achievement." ​ The results of the PREDICT-1 trial were outlined by chief investigator Professor Simon Mallal, director of the Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital. He explained that HLA plays a major role in the immune system by identifying foreign invaders and "tagging" them for destruction. It is thought that the side-effect is caused when the genetic variation trips an strong immune reaction against the drug. Specifically, a drug metabolite travels to the surface of the cell, where immune system T cells recognise it and attack it. Afterward his presentation, Prof. Mallal explained to DrugResearcher.com the significance of the trial results. "Every day we hear about new genetic associations. Yet there is a gulf between those published and those actually being used in the clinic,"​ he said. The regulator-approved, double-blinded study used to validate the effect of the HLA-B* 5701 allele on Ziagen may now enable others to conduct their own trials and push genetic associations into the clinic - something that has proved difficult in the past. "It has been a long, hard road, but we have now laid the path for others to follow and we may see other tests coming through now every year or two. We are delivering on the promise of personalised medicine for the masses." ​ Prof. Mallal explained that the biggest benefit to this particular test, is that it takes away any anxiety and uncertainty in prescribing Ziagen. GSK will be hoping that this persuades more doctors to prescribe its drug, with a resulting upturn in sales. A further advantage is that now, if an adverse reaction is seen whilst a tested patient is taking Ziagen, it will no longer be falsely put down to a hypersensitivity reaction, leaving the doctor more able to make a correct diagnosis. Out of 100 patients, six would be expected to have the HLA-B* 5701 mutation, according to Prof. Mallal. However, only four of those would definitely suffer the hypersensitivity reaction. Therefore, two patients who have taken the new test will now be wrongly excluded from treatment with Ziagen. However, this will be balanced out by those wrongly diagnosed with hypersensitivity to the drug if no testing is done. New drug target as well? ​ Intriguingly, as well as indicating a strong immune response to Ziagen, this same genetic mutation has been recently shown to indicate a strong response against HIV itself. The results from the first genome-wide association study of an infectious disease were published in the 19 July online edition of the journal Science.​ Although Prof. Mallal is listed as one of a series of authors, the study was directed by David Goldstein at Duke University's Center for HIV/AIDS Vaccine Immunology (CHAVI),. The research has yielded new information on why some people can naturally suppress virus levels following HIV infection. "The clearer picture of host responses to the virus achieved through this examination of genomes could lead to improved HIV therapies and provides new targets for vaccine developers,"​ said Dr Elias Zerhouni, director of the US National Institutes of Health (NIH). The study identified three gene variants that help patients fight off the virus. One of the polymorphisms found is associated with the HLA-B* 5701 allelle. The genetic variation allows the body to have a strong immune response against the virus. HLA-A and HLA-B are normally switched off by HIV, thus preventing the immune system from recognising the virus as foreign. However, a second polymorphism, which was found near the HLA-C gene, could provide a better target for new therapies. The study suggests that for some individuals at least HLA-C is involved in controlling HIV-1. Importantly, this gene is not thought to be turned off by HIV-1 and so it might provide a powerful target for an AIDS vaccine which the virus will be unable to thwart. More analysis also implicated a third locus encoding a RNA polymerase subunit, according to the research paper.