patient who has once experienced HSR starts taking abacavir again, the HSR returns very quickly—in a matter of hours to a day or so—and this time it is lethal.

The HSR phenotype is complex. About 78 percent of HSR patients have fever, about 65 percent have rash, and about 96 percent exhibit fever or rash or both. There is a long list of other symptoms that appear in at least 10 percent of HSR cases: nausea/vomiting, malaise/fatigue, muscle or joint pain, headache, diarrhea, itching, abdominal pain, dyspnea, and cough. Most patients have three or more of these symptoms in varying combinations.

The time of onset is also variable. A number of patients experience HSR within the first week of taking abacavir, sometimes within 24 hours, but for others it takes longer, and the median time to onset is about 11 days. About 93 percent of reported cases occur within 6 weeks of starting abacavir, so one of the exclusion criteria in the GSK studies is that a patient must experience HSR within the first 6 weeks.

In 1999, at the time of abacavir’s approval, a two-part postmarket risk management program was established. The first part was aimed at educating health care providers; this included updating labeling information on a regular basis and monitoring the occurrence of HSR among abacavir users. Monitoring data have revealed that although the number of people taking abacavir has increased steadily over the past 8 years—to more than 1 million in 2006—the number of deaths caused by the drugs has remained relatively stable since 2002 (see Figure 6-1). Thus one can infer that physicians now know that once any kind of HSR-related symptoms appear in a patient taking abacavir, the patient must be taken off the drug and never given it again. Despite physician awareness, however, the rate of spontaneous HSR has not decreased, as it is not possible to predict whether a patient will exhibit HSR until abacavir is taken. The second part of the postmarket risk management program included a pharmacogenetics study designed to look for genetic factors associated with abacavir-related HSR.

The goal of GSK’s pharmacogenetics program was to identify genetic markers that could predict patients at risk of developing HSR from abacavir and prevent them from taking the drug, thereby improving its benefit-risk balance. The study would involve gathering patients who had developed HSR; matching them with patients who had not; and then performing association studies, first with candidate genes and then later—as it became possible—with whole-genome analysis.