Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

16th Annual Canadian Conference on HIV/AIDS Research (CAHR)

Toronto, Ontario / April 26-29, 2007

Screening patients for the presence of the HLA-B*5701 allele prior to exposing them to abacavir (ABC) virtually eliminates any risk of developing a hypersensitivity reaction to therapy, according to speakers here, and markedly reduces the likelihood of early discontinuation from therapy. This in turn allows individuals to benefit from the real advantages of ABC, including an excellent efficacy and safety profile, with no fat, renal or bone pathology.

Western Australia: Setting the Stage

As discussed here by Dr. Elizabeth Phillips, Professor of Pharmacology, Murdoch University, Perth, Australia, prospective data from the Western Australian HLA-B*5701 screening experience demonstrated that the hypersensitivity reaction seen in approximately 5% of patients exposed to ABC in clinical trials can be successfully detected and avoided when ABC-naive patients undergo prior pharmacogenetic screening. As speakers here emphasized, the hypersensitivity reaction to ABC is exquisitely restricted to patients harbouring the HLA-B*5701 allele, although it is now believed that the presence of other alleles may trigger the reaction as well.

Since the genetic screening program was initiated in Western Australia in 2002, 160 patients have been exposed to ABC for greater than six weeks, of whom 157 tested negative for the allele. “All 157 patients proved 100% tolerant to ABC,” Dr. Phillips reported. The three patients who tested positive for the allele all developed a hypersensitivity reaction within two weeks. (In two patients, the test was not checked prior to initiating treatment with ABC which was why they were exposed to the compound.)

“These findings indicate that genetic screening significantly decreased not only the incidence of true ABC hypersensitivity over the course of the three-year screening program but also the incidence of misdiagnosis,” Dr. Phillips stated, adding that genetic screening may favourably influence all-cause early discontinuation of treatment.

Global Screening Findings

The Western Australian prospective genetic screening experience has been duplicated elsewhere, Dr. Phillips told listeners. In Brighton, UK, for example, the incidence of ABC hypersensitivity reactions fell from 6.5% prior to the introduction of pharmacogenetic testing to 0% thereafter. Over the past several years, France has also tested patients prospectively for the HLA-B*5701 allele and they, too, have seen a decrease in the incidence of ABC hypersensitivity from a reported high of 12.2% prior to routine genetic screening to essentially 0% thereafter. Thus, as Dr. Phillips emphasized, screening ABC-naive patients for the presence of the allele could represent an important new management strategy, as physicians can avoid exposing HLA-B*5701-positive patients to ABC.

Some of the potential value of pharmacogenetic screening was demonstrated by findings from the British Columbia Drug Treatment Program. Out of 1448 patients who were enrolled in the program, 171 (12%) ever exposed to ABC discontinued treatment early (defined as within six weeks of initiating therapy). In those who discontinued treatment, early discontinuation was associated with a significantly longer time to viral load suppression to fewer than 500 copies/mL at 131 days vs. 81 days for those who tolerated ABC. “Patients stopping treatment early were also more likely to seek care from emergency room physicians or specialists with higher costs for services within the first 60 days of starting ABC,” Dr. Phillips added.

PREDICT-1, SHAPE

Importantly, the pharmacogenetic experience of individual centres is about to be expanded in the form of PREDICT-1, the first randomized, prospective study of its kind designed to evaluate whether pharmacogenetic testing prior to the introduction of an ABC-containing regimen reduces or eliminates hypersensitivity reactions.

As investigators stated in a poster presentation of the PREDICT-1 study, the primary objective is to determine if screening adults for the HLA-B*5701 allele prior to treatment with ABC results in a significantly lower incidence of both clinically-suspected and immunologically-confirmed hypersensitivity reactions compared with current standard of care, which does not include either genetic screening or skin patch testing. ABC-naive participants will be randomized to either no prospective genetic screening and an ABC-containing regimen, then monitored for a hypersensitivity reaction, or to prospective genetic screening first and subsequently to an ABC-containing regimen, provided they test negative for the allele. Those who test positive for the allele will be excluded from the trial.

Another pharmacogenetic study, SHAPE, is a retrospective, case-controlled analysis designed to evaluate the performance characteristics of HLA-B*5701 in both Caucasians and African Americans. African Americans have a very low prevalence of HLA-B*5701 positivity, but should they harbour the allele, it is believed that they are just as likely to develop a hypersensitivity reaction to ABC as allele-positive Caucasians.

“Screening for HLA-B*5701 to prevent hypersensitivity reactions to ABC is both feasible and cost-effective with current technology, and we hope that findings from PREDICT-1 and SHAPE will support widespread genetic screening,” Dr. Phillips concluded.

Canadian Efforts at the Forefront

Canada is leading the way for the implementation of routine pharmacogenetic screening prior to exposing patients to ABC. As noted by Dr. Simon Mallal, Professor and Executive Director, Centre for Clinical Immunology and Biomedical Statistics, Perth, Australia, Canadian health authorities have rapidly scaled up genetic testing for the HLA-B*5701 allele and now have standardized results using a robust assay that can be analyzed with existing PCR technology. Laboratory results to date suggest that the frequency of the allele among Canadian patients is between 4% and 5%, “so the labs are all performing extremely well,” observed Dr. Mallal.

At the Ottawa Hospital Immunodeficiency Clinic, for example, scientists have run over 500 tests to date, with a turnaround time of two to three weeks and where the rate of HLA-B*5701-positive tests is approximately 7%. Since the introduction of pre-screening in the Ottawa setting, the number of patients who have had to stop ABC has been dramatically reduced to 2% to 3% from about 12% to 15% prior to the introduction of pharmacogenetic screening.

Montreal researchers also reported that 68% of patients who stopped ABC because of probable hypersensitivity reactions were actually negative for HLA-B*5701 when subjected to pharmacogenetic screening, and that early discontinuation of ABC dropped significantly to 2.9% when preceded by testing from 15.5% when patients were not pre-tested.

Long-term Benefits

Short-term gains for the great majority of patients who tolerate ABC are important to consider, as Dr. Mallal pointed out, but long-term benefits are equally compelling. As physicians are well aware, thymidine analogues, especially stavudine (d4T), but to some extent zidovudine as well, cause a marked degree of mitochondrial DNA depletion in fat cells. “Ultimately, this translates into a loss of function in the fat cell,” Dr. Mallal explained. Although this loss of function may not be visible clinically, the percentage of fat continues to decline with continued therapy.

“Once the pathology has been induced in peripheral fat, it is exceedingly difficult to reverse—even when the analogue is discontinued,” Dr. Mallal noted. This is because once the insult has occurred, a pro-inflammatory state is established and adiponectin production, an important metabolizer of fat, falls. With decreased levels of adiponectin, there is ongoing insulin resistance, a key contributor to the metabolic syndrome, Dr. Mallal explained.

When given in combination with 3TC as part of a nucleoside-reverse transcriptase inhibitor backbone, ABC is not associated with the same lipodystrophy phenomenon, Dr. Mallal observed. Indeed, in the ABCDE study, in which the incidence of lipoatrophy was compared between ABC-treated patients and those receiving d4T, investigators reported a low incidence of lipoatrophy (under 5%) for the former therapy vs. over 38% for the latter.

Nevertheless, speakers did emphasize that until results from PREDICT-1 and SHAPE are available, pharmacovigilance remains vital to successful ABC treatment.