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4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention

Sydney, Australia / July 22-25, 2007

Results from the PREDICT-1 (Prospective Randomised Evaluation of DNA Screening in a Clinical Trial) have provided the highest level of evidence necessary to support the introduction of HLA-B*5701 screening into routine clinical practice. The findings show prospective screening results in a clinically relevant and statistically significant reduction in abacavir (ABC) hypersensitivity reaction in HIV patients. It is the first randomized, blinded and powered study to validate pharmacogenetic screening as a clinical tool to personalize therapy.

PREDICT-1 Study Design

ABC-naive adults from 265 centres in Europe and Australia were randomized to either no prospective genetic screening and an ABC-containing regimen, and then hypersensitivity monitoring, or to prospective pharmacogenetic screening and, if they tested negative for the HLA-B*5701 allele, to an ABC-containing regimen. Patients who tested positive were excluded from the trial. Co-primary end points were incidence of clinically suspected ABC hypersensitivity and clinically suspected ABC hypersensitivity with immunological confirmation. Lead author Dr. Simon Mallal, Professor and Executive Director, Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Australia, said if there was any clinically suspected ABC hypersensitivity, the drug was stopped. “If one takes this sort of approach, one expects to see 2% to 7% over-diagnosis of ABC hypersensitivity,” he added.

Study Results

Immunologically confirmed ABC hypersensitivity was determined about six weeks after initial clinical diagnosis using epicutaneous patch testing. Data from 1650 patients, mostly male and Caucasian, were analyzed.

The incidence of both clinically diagnosed and immunologically (skin patch) confirmed hypersensitivity was significantly lower in the prospective screening arm compared with the control arm. In the prospective screening arm, no patient had immunologically confirmed hypersensitivity. “Really, one could not expect a more perfect result than this,” Dr. Mallal commented. Of patients who were prospectively screened, 3.4% had clinically suspected hypersensitivity, which was in keeping with the expected rate of overdiagnosis of hypersensitivity demonstrated in previous blinded, randomized clinical trials.

The study proved that the HLA-B*5701 screening test had a 100% negative predictive value for immunologically confirmed hypersensitivity. Dr. Mallal stated he would recommend HLA-B*5701 testing where possible for all patients before they were prescribed ABC to assure them and their physicians of its short-term predictability. “We have full confidence in its long-term safety profile and lack of toxicity. If you have short-term predictability and long-term confidence, you really have the ideal situation.” He remarked that it was gratifying to see personalized medicine finally make its way into clinics, with routine screening now performed in Canada, Australia and the UK. Screening is widely available, lasts the lifetime of the patient and is not expensive, he noted. The cost is more than offset by that incurred by the side effects that can occur with hypersensitivity reaction.

Another advantage of HLA-B*5701 screening is that by ruling out hypersensitivity, physicians will check for other causes if the patient has symptoms suggestive of hypersensitivity, such as fever, flu-like symptoms, diarrhea, gastrointestinal symptoms, respiratory problems or rash, Dr. Mallal noted. “If symptoms do arise in the first few weeks after the patient goes on the drug, the patient and physician are correctly directed to the real cause.”

Canada has led the way in terms of implementation of laboratory testing for the gene and has played an important role in quality assurance for laboratories. “Having good quality assurance of the assays is essential,” Dr. Mallal confirmed. “You need to have absolute confidence that if the laboratory says HLA-B*5701 is negative, it really is negative.”

While pharmacogenetic screening provides an additional layer of safety, clinical vigilance remains the cornerstone of successful ABC risk management.

SHAPE Study

Dr. Mallal noted that if a genetic test such as HLA-B*5701 was shown to work well in Caucasians, it was necessary also to demonstrate its efficacy in other races. The SHAPE (Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation) arose because although HLA-B*5701 is highly associated with ABC hypersensitivity in Caucasians, variable sensitivities have been reported across studies and races where clinical data alone defined ABC hypersensitivity.

The retrospective, case-controlled analysis estimated the sensitivity of HLA-B*5701 in Caucasians and African Americans using skin patch testing (SPT) to supplement hypersensitivity diagnosis. Study co-author Dr. Elizabeth Phillips, Director, Centre for Clinical Pharmacology and Infectious Diseases, Murdoch University, Perth, explained that the case-control study design was necessary because of the low prevalence rates of ABC hypersensitivity in African Americans, about 2%.

Patients with clinically-suspected ABC hypersensitivity were retrospectively identified, tested for HLA-B*5701 and then underwent ABC SPT. Cases were defined as all ABC hypersensitivity regardless of SPT results and ABC hypersensitivity with a positive SPT result. There were 130 Caucasian cases and 69 African American cases of ABC hypersensitivity but only 42 and five, respectively, were identified as SPT-positive. Controls were subjects who tolerated ABC for ³12 weeks without hypersensitivity reaction. Results showed that the sensitivity of HLA-B*5701 screening for SPT-positive hypersensitivity was 100% in both races. Sensitivity was reduced when hypersensitivity was defined by clinical diagnosis alone (44% for Caucasians and 14% for African Americans).

Dr. Phillips characterized the results as very compelling and suggested HLA-B*5701 screening could reduce ABC hypersensitivity in both races. “When you screen patients, it is not only the true hypersensitivity that disappears but also discontinuation for other causes,” she observed. “It has come to the point where there are cheap, reliable, quick diagnostic tests with a quick turnaround time, a yes/no answer and easy- to-read reports. The tests are easy for physicians to order and interpret.” Screening is likely to be very cost-effective.

“We have to look at the true carriage rate of HLA-B*5701 in the population but also take into account that for every 100 patients who start ABC without screening, 3% to 7% would stop because of false positive clinical diagnosis,” Dr. Phillips noted. In addition, all HIV patients in the developed world and many in developing countries undergo CD4+ and CD8+ cell count testing as part of their routine care and the HLA-B*5701 test could be incorporated into it. The uptake of testing has been very large in Canada and Canadian colleagues who used the HLA-B*5701 test are enthusiastic about it, Dr Phillips noted. “They don’t see ABC hypersensitivity any more after they start screening,” she added.

In the opinion of Dr. David Haas, Director, AIDS Clinical Trials Center, and Associate Professor of Medicine, Division of Infectious Disease (joint affiliation with the Department of Microbiology and Immunology), Vanderbilt University, Nashville, Tennessee, HLA testing for ABC hypersensitivity reaction was a remarkable development. “It is the first example of being able to predict an allergy to a drug without having to expose the patient to the drug; a paradigm shift.”

Beyond Hypersensitivity Reaction

According to Dr. Jürgen Rockstroh, Professor of Medicine, University of Bonn, Germany, ABC is well suited to long-term use. This is important because HIV is a chronic, treatable disease that requires long-term treatment, he explained. Yet only one-third of patients remain on their original HAART regimen, switching to another regimen primarily because of toxicity.

A wealth of data from more than one million patient-years of exposure to ABC can reassure users about its long-term safety profile. There is no evidence of bone or fat toxicity and no potential for lipoatrophy with ABC treatment. As patients age, renal toxicity appears to play a bigger role and an increasing proportion of HIV patients aged >50 years have renal disease, Dr. Rockstroh noted. However, there has been no evidence of renal toxicity with ABC. Again, as patients age, they tend to have more comorbidities that require medications but there are very few drug-drug interactions with ABC/3TC, Dr. Rockstroh added. ABC has been shown to be a potent agent whose potency is maintained over time. He confirmed, “ABC is well tolerated and effective.”

Summary

Screening HIV patients for the HLA-B*5701 allele to reduce ABC hypersensitivity represents a paradigm shift and is seen as personalized medicine at its best—selecting a medication on the basis of the genetic makeup of the individual. Pharmacogenetic screening adds a new layer of safety to ABC-containing regimens, resulting in short-term predictability and long-term confidence.