Use HLA-B*58:01 genotyping to guide allopurinol treatment?

Last Updated: 2015-10-02

By Megan Brooks

NEW YORK (Reuters Health) - HLA-B*58:01 genotyping can help prevent severe cutaneous allergic reactions induced by allopurinol, according to a study from Taiwan.

Allopurinol is a first-line drug for gout and hyperuricemia, but it's also one of "the most common causes of severe cutaneous adverse reactions (SCARs) in many countries," the investigators note in the BMJ online September 23. "There is a strong association between the HLA-B*58:01 allele and allopurinol induced SCARs in people of Han Chinese, Thai, Japanese, Korean, European, and Portuguese descent."

Dr. Chen-Tang Shen and the Taiwan Allopurinol-SCAR Consortium set out to see if prospective screening for HLA-B*58:01 before starting allopurinol in patients with an indication for the drug could cut the incidence of allopurinol induced SCARs.

They did HLA-B*58:01 genotyping in more than 2,900 patients eligible for allopurinol but with no previous exposure to the drug. The 571 patients (19.6%) who tested positive for the HLA-B*58:01 allele were prescribed something other than allopurinol or advised to stick with their prestudy treatment. Those who tested negative (80.4%) were given allopurinol.

During follow-up, a total of 97 patients (3%) developed mild, transient rash without blisters. "SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01," the investigators report. By contrast, based on historical incidence of allopurinol induced SCARs, they expected to see seven cases of SCARs.

In this study, prospective screening for the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, "significantly decreased" the incidence of allopurinol induced SCARs in Taiwanese medical centers, the investigators conclude.

So is routine genetic testing for patients needing allopurinol ready for prime time? "Not yet," writes Dr. Alain Li-Wan-Po, director of the Centre for Evidence-Based Pharmacotherapy, Nottingham, U.K., in a linked editorial.

He notes that all of the participants were Han Chinese from Taiwan, a population with a high prevalence of the HLA-B*58:01 allele (about 10%).

"While the association has been reported in other populations, there are several reasons for caution. The risk allele frequency is low in white populations (<1%). More importantly, even in other Asian populations, the strength of association between allele and reaction is weaker. Almost all carriers of HLA-B*58:01 (about 98%) do not develop SCARs, and in some ethnic groups (including white populations), many patients with the adverse effect do not carry the risk allele," he explains.

"Even when genetic prediction of risk is robust, there are important trade-offs when considering routine testing before treatment," Dr. Li-Wan-Po adds.

In this study, the main alternative to allopurinol was benzbromarone, "a drug with a well defined efficacy and safety profile. Although no major adverse effects were observed, benzbromarone has been withdrawn from the market in many countries because of its potential for hepatotoxicity. The other alternative, febuxostat, is a new and expensive drug with a poorly defined, long term safety profile that includes reports of potentially lethal liver failure and cardiovascular events. If genotyping is not available, prescribers could be tempted to substitute allopurinol for less safe or effective alternatives, to the detriment of most patients," Dr. Li-Wan-Po warns.

In email to Reuters Health, Dr. Shen said, "It is time to do this type of screening routinely in specific patient populations."

"In countries where the HLA-B*58:01 is relatively prevalent (for example, the carrier prevalence among Taiwanese population with HLA-B*58:01 is 20%) and where a tight association has been found, screening for this allele could be beneficial for preventing allopurinol induced SCARs," Dr. Shen wrote.

"However, the implementation of HLA- B*58:01 screening certainly requires caution in some populations, such as Japanese and European groups, because not all patients with allopurinol induced SCARs carry the allele in those populations. Furthermore, in countries where the allele frequency is low (about 1%), restricting the screening for this allele to a more high risk group of patients (for example, chronic renal failure) could also be a strategy for preventing SCARs," Dr. Shen added.

The study had no commercial funding and the authors have no relevant disclosures.

SOURCE: http://bit.ly/1KXj6Lc and http://bit.ly/1N5jWfH

BMJ 2015.