A simple and cheap screening test could offer an alternative to HLA typing as a way of predicting who will develop hypersensitivity to the nucleoside analogue abacavir (Ziagen), say Canadian researchers. One of the biggest potential benefits is that the technique - called the RT codon 245 test - could be done as part of routine HIV drug resistance testing at no additional cost.
Abacavir hypersensitivity reaction is a potentially life-threatening adverse reaction that affects up to eight per cent of people who start taking it. People who have a particular gene type called the human leukocyte antigen (HLA) B*5701 are around 100 times more likely to developed the hypersensitivity reaction than those who do not have this HLA gene type.
Screening everyone who is about to start abacavir for this gene type would largely prevent the problem, but fully gene typing HLA genes is very expensive and time consuming although it has started being used in some centres. For example, last year the London HIV Consortium agreed to pay for the test for anyone in the city starting or thinking of switching to a regime including abacavir. However researchers have been searching for easier and cheaper ways of testing.
Canadian researchers have published a study looking at a mutation in one of the enzymes produced by HIV, called reverse transcriptase, which is thought to strongly correlate with the presence of B*5701. They studied this link between B*5701 and the mutation - termed the RT codon 245 variation - in 392 HIV-infected adults naive to antiretroviral therapy who were about to start therapy. A very strong correlation was found - with only one patient who had the B*5701 HLA gene type having the usual - or “wild type” - form of the HIV reverse transcriptase at codon 245 (Chui 2007).
However they add that the positive predictive value of the test is relatively low, i.e. some people who have the codon 245 variation will not have the B*5701 gene and will therefore not be at risk of the hypersensitivity reaction. But the negative predictive value is very high- over 99% - meaning that very few people who do not have the codon 245 variation will have the B*5701 gene.
In other words the test might wrongly classify some people as being at high risk of developing abacavir hypersensitivity when in fact they are not. But it would hardly ever classify a patient as not being at risk when they are. They add that the RT codon 245 test might in fact involve no additional cost, as it could be done as part of routine HIV drug resistance testing. But they advise the next step in validating the test would be for all commercially available antiretroviral resistance tests to start reporting the variations in HIV reverse transcriptase at codon 245 to build up a more complete database of variations.
French researchers have described another potential alternative to full HLA gene typing as a way of predicting abacavir hypersensitivity. The two-stage technique amplifies a small section of the B*5701 gene using a technique called polymerase chain reaction (PCR). They carried out the test in a racially mixed group of 49 HIV infected people previously treated with abacavir and 137 patients about to start therapy with the NRTI. The PCR test saw the incidence of hypersensitivity drop from 12% before screening to zero after, with the rate of abacavir therapy interruptions dropped from 12% to 0.73% (Zucman 2007).
Chui CKS et al. A simple screening approach to reduce B*5701-associated abacavir hypersensitivity on the basis of sequence variation in HIV reverse transcriptase. Clinical Infectious Diseases 44:1 503-1508, 2007.
Zucman D et al. Prospective screening for human leukocyte antigen B*5701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV population. Journal of Acquired Immune Deficiency Syndrome 45: 1-3, 2007.