HLA-B*5701 Screening for Abacavir Hypersensitivity

By Liz Highleyman

An estimated 2% to 8% of people who take the nucleoside reverse transcriptase inhibitor abacavir (Ziagen, also in the Epzicom and Trizivir fixed-dose coformulations) develop a potentially severe allergic hypersensitivity reaction. The rate varies across racial/ethnic groups, being highest in people of European origin and lower among people of African descent.

Abacavir Hypersensitivity

This hypersensitivity reaction is characterized by some combination of skin rash, fever, gastrointestinal, and respiratory symptoms, usually within the first 6 weeks after starting the drug. Individuals who experience such symptoms should not take abacavir again, since doing so can be life-threatening. Because of this risk, clinicians usually recommended that patients stop taking abacavir if they have a suspected reaction, although this may lead some people to discontinue the drug unnecessarily.

Researchers discovered a few years ago that a human genetic variation known as HLA-B*5071 is strongly associated with susceptibility to abacavir hypersensitivity. A genetic screening test is now available and should be used before starting the drug, according to the latest U.S. and European HIV treatment guidelines.

As previously reported, the PREDICT-1 study -- which included 1956 HIV positive participants in Australia and Europe -- showed that the HLA-B*5071 test can accurately predict which patients are at risk for abacavir hypersensitivity, enabling them to avoid the drug.

HLA-B*5701 Screening in North America

Results from the first large, multicenter prospective study of HLA-B*5701 screening in a racially diverse population in North America was described in a research letter in the August 20, 200 issue of AIDS.

Investigators initially screened 725 individuals (84% of them men) for HLA-B*5701 status. They identified 41 patients (5.7%) as HLA-B*5701-positive, including 7.2% whites, 2.8% blacks, and 5.6% of other race/ethnicity.

They then sought to determine the rate of abacavir hypersensitivity reactions among 517 participants in the ARIES trial who tested HLA-B*5701 negative. In this trial, treatment-naive patients who initially received abacavir, lamivudine (3TC, Epivir), atazanavir (Reyataz), and ritonavir (Norvir) either continued on this regimen or discontinued ritonavir.

Results

• Prospective HLA-B*5701 screening in this North American population resulted in less than 1% of individuals being diagnosed with a suspected abacavir hypersensitivity reaction.

• Among individuals who tested HLA-B*5701 negative, none had positive skin patch tests for hypersensitivity through 30 weeks.

• During the first 30 weeks on abacavir-containing therapy, 4 of 517 individuals (0.8%) were diagnosed with clinically suspected abacavir hypersensitivity reactions: 2 Caucasian males, 1 Hispanic female, and 1 Native Hawaiian female.

• The time to onset of hypersensitivity symptoms was less than 2 weeks from therapy initiation for all individuals.

• Not all individuals met the case definition of hypersensitivity reaction that requires the presence of at least 2 symptoms from 5 symptom categories.

• However, all 4 individuals reported rash as part of their reaction.

• In all cases, the entire regimen was stopped, symptoms resolved, and the patients resumed therapy with atazanavir, ritonavir, lamivudine, and zidovudine (AZT; Retrovir):

• 1 patient's rash reappeared shortly after resuming the substitute regimen, and a rash due to atazanavir was later suspected;

• 1 patient reported a recurrent rash 8 days after switching from abacavir to zidovudine.

• Abacavir skin patch testing, performed at least 6 weeks after symptom resolution, was negative for all 4 patients.

"In this study, abacavir hypersensitivity reaction rates were dramatically lower after implementation of HLA-B*5701 screening compared with historical studies without prospective screening in this diverse patient population," the study authors concluded. "Among HLA-B*5701-negative individuals, less than 1% of individuals were diagnosed with a suspected abacavir hypersensitivity reaction through 30 weeks and no individual had a positive skin patch test."

"Use of prospective HLA-B*5701 screening will help North American healthcare providers individualize treatment and identify appropriate candidates for abacavir therapy by excluding patients at high risk of developing hypersensitivity reaction," they continued.

"Although it is impossible to definitively rule out hypersensitivity reaction" in the 4 cases described, they added, "the absence of both HLA-B*5701 and a positive skin patch test suggests that the reported symptoms may have been caused by an alternative agent and/or disease process."

Cost-effectiveness

In a related study, researchers used mathematical modeling to determine whether abacavir hypersensitivity testing is cost-effective; results were published in the October 1, 2008 issue of AIDS.

Abacavir is less expensive than its main competitor, tenofovir (Viread, also in the Truvada and Atripla fixed-dose combination pills), but the need for hypersensitivity testing before starting therapy could outweigh this advantage.

The model incorporated data on HLA-B*5701 prevalence and the probabilities of confirmed and unconfirmed severe systemic hypersensitivity reaction from the PREDICT-1 study. They adjusted the 5.7% hypersensitivity rate in that study down to 4.1% to account for the racial/ethnic breakdown in the U.S. (given that the HLA-B*5701 variation is less common among blacks than whites). The monthly costs of abacavir-based and tenofovir-based regimens were $1135 and $1139, respectively.

The researchers compared 3 first-line treatment strategies:

• Abacavir (Ziagen, also in the Epzicom and Trizivir combination pills), lamivudine (3TC; Epivir, also included in Epzicom and Trizivir), and efavirenz (Sustiva) without pre-treatment HLA-B*5701 testing;

• The same regimen preceded by HLA-B*5701 screening;

• Tenofovir, emtricitabine (Emtriva, also in the Truvada and Atripla pills), and efavirenz.

The investigators initially assumed that abacavir and tenofovir had similar virological efficacy, and then varied this assumption in sensitivity analysis. The main outcome measures were quality-adjusted life years (QALYs) and lifetime medical costs discounted at 3% per annum, used to determine cost-effectiveness ratios ($/QALY).

Results

• Abacavir-based treatment without HLA-B*5701 testing resulted in a projected 30.93 years life expectancy, 16.23 discounted quality-adjusted life years, and $472,200 discounted lifetime cost per person.

• HLA-B*5701 testing added 0.04 quality-adjusted months at an incremental cost of $110, resulting in a cost-effectiveness ratio of $36,700/QALY compared with no testing.

• Starting treatment with a tenofovir-based regimen increased costs without improving quality-adjusted life expectancy.

• However, HLA-B*5701 testing remained the preferred strategy only if abacavir-based treatment had equal efficacy and cost less per month than tenofovir-based treatment.

• Results were also sensitive to the cost of HLA-B*5701 testing and the prevalence of the HLA-B*5701 genetic variation within a population.

Based on these findings, the study authors concluded, "Pharmacogenetic testing for HLA-B*5701 is cost-effective only if abacavir-based treatment is as effective and costs less than tenofovir-based treatment."

"We found that HLA-B*5701 testing to guide selection of a first-line ART regimen is cost-effective, with a cost-effectiveness ratio below the commonly accepted thresholds in the United States of $50 000-$100 000/QALY," they continued in their discussion. "The results were critically dependent on the comparable efficacy and lower cost of abacavir-based treatment compared with tenofovir-based treatment."

As reported at the recent XVII International AIDS Conference in Mexico City, recent studies of the comparative efficacy of the 2 drugs have produced conflicting data, in particular among individuals with a high baseline viral load. The model found that restricting abacavir use to patients with baseline HIV RNA below 100,000 copies/mL would be more cost-effective.

The model assumed that some percentage of patients would develop kidney problems related to tenofovir and would subsequently switch to a different NRTI; studies looking at rates of tenofovir kidney toxicity have also yielded mixed results. The model did not incorporate recent findings -- also subject to debate -- concerning an elevated risk of cardiovascular disease linked to abacavir.

HCP5 Single-Nucleotide Polymorphism

Finally, researchers with the Swiss HIV Cohort Study assessed the usefulness of genotyping a HCP5 single-nucleotide polymorphism (SNP), known as rs2395029, in relation to abacavir hypersensitivity reactions. SNPs refer to amino acid substitutions at specific positions on the genome.

Looking at 1103 individuals, they found that in populations with European ancestry, rs2395029 is in "linkage disequilibrium" with HLA-B*5701. The HCP5 SNP was present in all 98 HLA-B*5701 positive individuals, but absent in 999 of 1005 HLA-B*5701 negative persons.

Furthermore, rs2395029 was overrepresented in 80% of 25 patients with clinically likely abacavir hypersensitivity reactions, compared with just 2% of 175 abacavir-tolerant individuals without such reactions.

Therefore, the investigators concluded, "HCP5 genotyping could serve as a simple screening tool for abacavir hypersensitivity reaction, particularly in settings where sequence-based HLA typing is not available."

10/10/08

References

B Young, K Squires, P Patel, and others. First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America. AIDS 22(13): 1673-1675. August 20, 2008. (Abstract).

BR Schackman, CA Scott, RP Walensky, and others. The cost-effectiveness of HLA-B*5701 genetic screening to guide initial antiretroviral therapy for HIV. AIDS 22(15): 2025-2033. October 1, 2008. (Abstract).

S Colombo, A Rauch, M Rotger, and others. the HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir. Journal of Infectious Diseases 198(6): 864-867. September 15, 2008. (Abstract).