By Liz Highleyman

Many doctors are hesitant to prescribe the NRTI abacavir (Ziagen) due to the risk of hypersensitivity reactions. The drug is also a component of the fixed-dose combination pills Trizivir (AZT/3TC/abacavir) and Epzicom (3TC/abacavir).

The hypersensitivity reaction -- which has been seen in about 3%-8% of cases - is typically characterized by skin rash, fever, and gastrointestinal and respiratory symptoms. Individuals who experience such a reaction should never take abacavir again, since doing so can be life-threatening. Because of this danger, physicians recommend that patients stop taking the abacavir when there is any reason to suspect a reaction. However, this may lead to some individuals avoiding the drug unnecessarily, since their symptoms may not truly be due to hypersensitivity.

In recent years, researchers have confirmed that a specific human genetic variation, known as HLA-B*5071, is associated with susceptibility to abacavir hypersensitivity.

At the 4th International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention this week in Sydney, Australia, researchers presented data showing that a genetic test for HLA-B*5071 accurately predicts which patients are at risk for hypersensitivity.

In the PREDICT-1 study (funded by abacavir manufacturer GlaxoSmithKline), 1956 abacavir-naive subjects from 314 centers in Europe and Australia started abacavir-containing antiretroviral regimens. Participants received pharmacogenetic screening for the HLA-B*5071 gene variation. About half used the test results to determine whether they should use abacavir, while the remainder had their test results stored for later analysis.

If a person experienced a suspected abacavir hypersensitivity reaction, the drug was stopped immediately and the individual received a skin patch test to provide immunological confirmation that the reaction was related to abacavir hypersensitivity.

A total of 1650 patients who started abacavir and had available follow-up data were included in the final analysis; of these, 84% were white and 12% were of African descent.

Results

• Patients in the intervention arm (genetic test used to guide treatment) were about half as likely to as those without test guidance to develop hypersensitivity reactions (3.4% vs 7.8%, respectively).

• 2.7% of patients in the arm without test guidance had immunologically confirmed hypersensitivity reactions, compared with none in the intervention arm.

• The test had a negative predictive value of 100%.

• The positive predictive value was 48% (i.e., some people who tested positive for HLA-B*5701 did not have hypersensitivity reactions).

• Fewer than half the patients with suspected hypersensitivity reactions in the arm without test guidance had immunologically confirmed hypersensitivity.

• Patients with immunologically confirmed reactions had more symptoms than those with misdiagnosed hypersensitivity.

• Subjects who started abacavir and an NNRTI at the same time were more likely to have suspected hypersensitivity reactions.

"The results from this landmark study demonstrate that prospective HLA-B*5701 screening results in a dramatic, clinically relevant and statistically significant reduction in abacavir hypersensitivity reactions," the researchers concluded.

They added that, "The PREDICT-1 study provides the high level of evidence required to support the implementation of HLA-B*5701 screening into routine clinical practice and is the first randomised, blinded and powered study to validate pharmacogenetic screening as a clinical tool to personalise therapy."

Another study presented at the conference also found that HLA-B*5071 screening reduced the risk of abacavir hypersensitivity reactions in a "real world" clinical setting.

Among 231 patients at a Montreal clinic who started abacavir after pre-treatment genetic screening was implemented in April 2006, none experienced a hypersensitivity reaction. Prior to implementation of pre-treatment screening, 71% of patients with clinically suspected hypersensitivity reactions were found to be HLA-B*5701 negative when tested retrospectively, suggesting that physicians tended to "over diagnose" abacavir hypersensitivity.

HLA-B*5071 screening in black patients

The HLA-B*5071 variation occurs with different frequencies in people of different racial/ethnic groups. It is more common in whites and more rare in people of African descent (though less so in African-Americans compared with Africans due to more racial mixing).

In a related study also presented in Sydney, researchers sought to estimate the sensitivity of the HLA-B*5701 gene in whites and blacks using skin patch testing to supplement clinical diagnosis of abacavir hypersensitivity reactions. In the patch test, a small amount of abacavir is applied to the skin, and a hard, raised, red area develops if a person is hypersensitive.

The SHAPE study included 130 white patients with clinically suspected hypersensitivity reactions, 202 white control subjects who tolerated abacavir with no hypersensitivity, 69 African-American patients with suspected hypersensitivity, and 206 black control subjects.

Results

• All patients with a positive skin patch test result also tested positive for HLA-B*5701.

• However, not all patients who tested HLA-B*5701 positive had a positive skin patch test.

• 44% of whites with suspected reactions were later confirmed to be HLA-B*5701 positive, compared with 14% of blacks.

• The sensitivity of HLA-B*5701 as a marker for hypersensitivity reactions when skin patch testing was done was 100% for both white and black patients.

• In this study, too, most confirmed reactions involved multiple symptoms, which almost always included fever (96% of cases).

"These data suggest that prospective HLA-B*5701 screening may reduce abacavir hypersensitivity reaction rates in whites and blacks," the researchers concluded.

Nevertheless, they cautioned - echoing the PREDICT-1 researchers - that "HLA-B*5701 screening may augment clinical management of hypersensitivity reaction, but must never substitute for clinical vigilance."

07/27/07

References

S Mallal, E Phillips, G Carosi, and others. 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). 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract WESS101.

B Trottier, R Thomas, VK Nguyen, and others. How effectively HLA screening can reduce the early discontinuation of abacavir in real life? 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract MOAB103.

M Saag, R Balu, P Brachman, and others. High sensitivity of HLA-B*5701 in Whites and Blacks in immunologically-confirmed cases of abacavir hypersensitivity (ABC HSR). 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract WEAB305.

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