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11th European AIDS Conference

Madrid, Spain / October 24-27, 2007

Currently, the goal of HIV therapy is to achieve sustained viral suppression and the extent to which this is achieved depends on both viral and host factors. Viral factors include viral sensitivity, viral load and viral subtype. In the case of the host, “Adherence to the regimen is clearly the most important factor,” stated Prof. Jean-Michel Molina, Head, Division of Infectious and Tropical Diseases, Hôpital Saint-Louis, University of Paris 7, France. Other host factors include drug interactions, underlying disease and pharmacogenetic factors. It has been suggested that pharmacogenetics may help predict toxicity such as atazanavir-associated hyperbilirubinemia, nevirapine hypersensitivity and efavirenz-associated neurotoxicity, but the most promising potential application at present—and the one supported by the most solid body of evidence—is predicting abacavir (ABC) hypersensitivity reactions.

Screening for HLA-B*5701

ABC hypersensitivity reactions generally involve fever and rash. Median time to onset is 11 days and 93% of reactions will have become evident within six weeks (Hetherington et al. Clin Ther 2001;23(10):1603-14). Prof. Molina pointed out, “Hypersensitivity reactions are often overdiagnosed according to evidence from clinical trials.” Thus, in blinded studies, hypersensitivity reactions have been reported in 6.5% of the ABC-treated patients compared to 4.5% of those in control groups.

An immunological component was suspected on the grounds of delayed onset, rapid resolution on drug discontinuation and relapse on re-exposure. In a retrospective Australian study, Mallal et al. (Lancet 2002;359(9308):727-32) identified HLA-B*5701 as the main HLA marker of possible hypersensitivity reactions. The potential benefit of screening was reflected in a number of studies such as one in France, in which the number of patients discontinuing treatment dropped to below 1% on implementation of prospective screening. Prof. Molina told the audience that, “For a screening test to change a treating physician’s clinical practice, it must have a high positive predictive value, high sensitivity and a high negative predictive value.” In retrospective studies, when an epicutaneous patch test (EPT) was used to confirm immune-mediated hypersensitivity reactions, the sensitivity was as high as 94%, but according to Prof. Molina, “We still need powered, randomized, controlled clinical trials to demonstrate clinical utility of genetic screening.” To that end, the PREDICT-1 trial was engineered.

Benefit of HLA-B*5701 Screening: The PREDICT-1 and SHAPE Studies

The PREDICT-1 study randomized 1956 ABC-naïve patients mainly from Europe to prospective HLA-B*5701 screening or a control arm (with retrospective HLA-B*5701 assessment). The mean age of the patients was 42 years and baseline demographics were well balanced. In the prospective screening arm, 5.6% of the patients were positive for HLA-B*5701 and did not receive ABC. Importantly, neither the patient nor the investigator knew whether prospective screening had occurred. “Such a design is likely to yield a conservative result vs. an open-label design,” commented Prof. Molina. The co-primary end points were clinically diagnosed hypersensitivity reactions and positive EPT.

In the control arm, 66/847 patients (7.8%) had clinically suspected hypersensitivity reactions compared to 27/803 (3.4%) in the prospective screening arm. Hypersensitivity reactions confirmed by EPT were reported in 23/842 patients (2.7%) in the control arm—all HLA-B*5701-positive; no cases were reported in the prospective screening arm. Prof. Molina concluded, “Prospective HLA-B*5701 screening allows physicians to avoid exposing patients who are HLA-B*5701-positive to a high risk of ABC hypersensitivity reactions whereas HLA-B*5701-negative patients are at a very low risk and physicians could use ABC with confidence.” He did emphasize, however, that clinical vigilance would still be mandatory.

Health resource utilization was measured as a secondary end point. In this analysis, 21% of patients in the control arm reported unscheduled usage of any healthcare facility compared to 16% in the prospective screening arm (P=0.008). Another secondary objective was to assess the concordance of three different technologies used for HLA typing. The fact that this was 100% should facilitate widespread availability of HLA-B*5701 testing.

The PREDICT-1 study enrolled mainly Caucasian patients (who have the highest prevalence of the HLA-B*5701 allele) so the question remains whether the benefit of HLA-B*5701 screening applies to other races. The SHAPE study retrospectively compared patients who had an ABC hypersensitivity event confirmed by EPT and who had undergone HLA-B*5701 screening with event-free control patients. Among blacks, no EPT-confirmed hypersensitivity event was identified in HLA-B*5701-negative blacks and the sensitivity was 1.0 for both whites (95% confidence interval [CI], 0.92-1.0) and blacks (95% CI, 0.48-1.0). Prof. Molina characterized these results as evidence that “HLA screening to reduce hypersensitivity reactions can be generalized to both races.”

Hypersensitivity Reactions in the BICOMBO Study

The BICOMBO study was the first comparison of tenofovir plus emtricitabine and ABC plus lamivudine. In total, 335 patients with a viral load of £200 copies/mL were randomized to switch from a lamivudine-containing HAART to one of these two regimens. The primary end point was the proportion of patients with treatment failure in the intent-to-treat population. Discontinuations were counted as treatment failures. A sub-analysis presented in a poster at this year’s meeting of patients never exposed to tenofovir or ABC (n=265) revealed that the group who switched to ABC plus lamivudine did not meet the non-inferiority end point compared to the tenofovir plus emtricitabine group—in line with the main analysis. The authors pointed out, however, that the difference was mainly driven by discontinuations in the ABC plus lamivudine group due to suspected ABC hypersensitivity. When asked whether HLA-B*5701 screening might have influenced these findings, Dr. Jose Gatell, Hospital Clinic, Barcelona, and President, European AIDS Clinical Society, affirmed, “The HLA-B*5701 screening test was not a standard of care when these patients were recruited and so it was not done. Would such a test have avoided the differences seen in this study? The answer is probably yes.” Indeed, in retrospective testing, six of the nine patients who discontinued for this reason were positive for HLA-B*5701.

Long-term Management

In general terms, antiretroviral toxicity can be either short-term early-onset toxicity, which is usually relatively easy to predict and manage, or long-term toxicity such as lipodystrophy, neuropathy, cardiovascular (CV) disease, renal toxicity and decreased bone mineral density. Since it was first approved for HIV treatment in 1999, the patient-year exposure to ABC-containing products is thought to exceed 1 million. Studies have shown that its long-term use is not associated with insulin resistance, diabetes or osteopenia. As patients get older, renal disease will become increasingly important. Dr. Estéban Martínez, Hospital Clinic, Barcelona, pointed out, “ABC is the only nucleoside reverse transcriptase inhibitor that can be used without any change in dose or any fear of toxicity.” CV risk is perhaps one of the most important potential concerns with long-term AIDS therapy. According to the ABCDE study, 4% of ABC-treated patients took lipid-lowering drugs compared to 17% of stavudine-treated patients (Podzamczer et al. J Acquir Immune Defic Syndr 2007;44(2):139-47).

Summary

Numerous studies suggest that potential long-term side effects such as lipodystrophy, neuropathy and CV disease are manageable. The findings of PREDICT-1 have confirmed the value of HLA-B*5701 screening for substantially reducing the risk of ABC hypersensitivity reactions. This pharmacogenetic test represents a step towards more individualized therapies, thereby addressing the need to balance the short-term adverse event of hypersensitivity against potential long-term toxicities.