Reports

As discussed by Dr. Simon Mallal, clinical immunologist, Royal Perth Hospital, and Head, Centre for Clinical Immunology and Biomedical Statistics, Murdoch University, Perth, Australia, polymorphisms in both the host infected with HIV and the virus itself dictate the course of the disease as well as response to treatment. “Every patient has a different variant of HIV,” he noted, “and polymorphisms of the host and the pathogen interact at multiple levels over time.”

However, even within a particular organism, certain proteins are more polymorphic than others, he added. The CD4+ cell, for example, does not vary between hosts but human leukocyte antigen (HLA) molecules are highly diverse. Understanding the role of polymorphisms on drug disposition is important as it influences how to use certain compounds.

Understanding Hypersensitivity

The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is predominantly metabolized by the CYP2B6 enzyme system. A CYP2B6 polymorphism—G516T—is more common in African Americans than in Caucasians but it has now been associated with a tendency for patients to develop higher efavirenz levels and an increase in central nervous system toxicity than normally occur. This is because efavirenz levels take longer than normal to decline in patients with the G516T polymorphism and patients are thus at greater risk to develop resistance to efavirenz than those without the G516T. “The same problem has been raised with nevirapine,” Dr. Mallal noted. This NNRTI also tends to cause a hypersensitivity reaction (HSR) in patients who still have a high CD4+ cell count. In looking for an association between nevirapine hypersensitivity and HLA molecules, Dr. Mallal and colleagues observed that the HLA-DR allele tends to direct CD4+ cells and that patients with the HLA-DR0101 allele in particular are predisposed to develop a hypersensitivity reaction to nevirapine.

Similarly, work by Dr. Mallal and Dr. Elizabeth Phillips, BC Centre for Excellence in HIV/AIDS, and Associate Professor of Medicine, University of British Columbia, Vancouver, honed in on a specific allele, HLA-B*5701, as a key determinant in the development of a hypersensitivity reaction to the nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC). As physicians are aware, the ABC hypersensitivity syndrome occurs in up to 8% of Caucasians and usually presents within the first few weeks after initiation of treatment.

“The important clinical clue is that symptoms and intensity of symptoms evolve over time with each dose given, and you must stop the drug if symptoms continue to intensify,” Dr. Mallal told delegates.

The process leading to this hypersensitivity reaction (HSR) takes place in the HLA-B*5701 allele where, following metabolism of ABC to an aldehyde metabolite, the metabolite chemically alters a peptide that sits in the HLA molecule, and to which the immune system then mounts a vigorous response. “This is a very severe reaction which, if the patient doesn’t recognize what is causing the problem and keeps on taking ABC, can be life-threatening,” Dr. Mallal cautioned.

According to ABC clinical trial findings, 2 to 3% of patients in the non-ABC-containing arms have been diagnosed with HSR. Dr. Mallal observed that HSR can be over-diagnosed and treatment prematurely and unnecessarily interrupted.

As developed by Dr. Phillips, physicians have been able to patch test patients following ABC exposure. If patients have been previously exposed to ABC and have become sensitized to it, their propensity to develop HSR shows up as a local reaction on patch testing. This patch test is both sensitive and specific for ABC HSR but as Dr. Mallal emphasized, “Patch testing only becomes positive after the patient has been sensitized to the drug and therefore it can only be used to improve the clinical diagnosis of HSR.”

Results from Genetic Screening

In contrast, prospective genetic screening can be used to prevent HSR by identifying those patients who should or should not receive ABC. Such a test has now been developed and validated by Dr. Mallal and colleagues. In a Western Australian HIV Cohort Study, major histocompatibility complex (MHC) region typing was carried out in the first 200 participants exposed to ABC. A definite HSR was identified in 18 patients, and the HLA-B*5701 was found to be present in 14 out of the 18, yielding a positive predictive value of approximately 80%. In contrast, if patients test negative for the HLA-B*5701 allele, only about 2% still might develop HSR to ABC, Dr. Mallal noted.

Since the introduction of prospective genetic screening in Australia, discontinuation of ABC due to HSR has dropped, as has all-cause discontinuation of the same agent. Consequently, “Over-diagnosis of HSR in the pre-genetic screening era has dropped off dramatically as well,” Dr. Mallal reported. Importantly as well, patients in Australia who are being screened for HLA-B*5701 are no longer being exposed needlessly to ABC.

In Brighton, UK, where they have implemented use of the same screening test, the pre-screening rate of HSR was 6.5% vs. 0% in the post-screening era. A new trial, PREDICT-1 (Pharmacogenetic Validation Study), is currently taking place in Europe and Australia, where the primary goal will be to reduce the incidence of clinically diagnosed and immunologically confirmed HSR through prospective genetic screening with the HLA-B*5701 test.

“Genetic screening can prevent immunologically-mediated ABC HSR and lower the rate of false positive diagnoses of HSR,” Dr. Mallal concluded. “It can also be cost-effective in lowering the morbidity associated with true HSR and inappropriate early discontinuation of treatment. What it cannot do is be used as a substitute for clinical judgement or pharmacovigilance, and it cannot be used as a rationale for rechallenge.”

Canadian Physicians Adopting Genetic Screening Test

In Canada, physicians in Toronto, Calgary and Montreal appear to be ready to adopt the HLA-B*5701 genetic screening test. To date, approximately 120 tests have been carried out in various centers outside of Montreal and seven were positive for HLA-B*5701. So far, no instance of HSR has occurred among tested patients. In a pilot project spearheaded by Dr. Richard Lalonde, Medical Director, Immunodeficiency Service, McGill AIDS Centre, and Associate Professor of Medicine, Division of Infectious Diseases, McGill University, Montreal, Quebec, investigators are hoping to better identify determinants of ABC HSR according to race, gender and immune system status.

Polymerase chain reaction (PCR) amplification from patient DNA will be used to detect the presence or absence of HLA-B*5701, and participating sites must receive training in the diagnosis of HSR, the performance of the HLA-B*5701 test and continued vigilance for HSR in response to ABC. “If we are to use this test, it would be reserved for ABC-naïve patients-not just treatment-naïve patients going on ABC-and then conserved on the patient chart for possible future use,” Dr. Lalonde told delegates. Requests to gain access to the test have currently overwhelmed the Quebec-based laboratory where the HLA-B*5701 test will be carried out.

But of 86 tests performed to date in Quebec, only one patient has been identified as positive for the HLA-B*5701 allele and no instance of HSR has been seen in any patients tested so far-although as Dr. Lalonde noted, it’s very early days and only a handful of individuals who have been screened have also received ABC.

“We need to embrace this technology to help us in our clinical management of HIV patients and avoid using drugs for which a toxicity is identified a priori,” symposium chair Dr. Anita Rachlis, University of Toronto,Ontario, concurred.