Abacavir (Ziagen)

Although abacavir (Ziagen) is usually well tolerated, clinical trials and post-marketing data suggest that abacavir hypersensitivity reactions may occur in about 3 to 5% of patients within the first six weeks of treatment.

Hypersensitivity is a multi-organ syndrome that would include two or more of the following symptoms: fever; skin rash; fatigue; gastrointestinal symptoms such as nausea, vomiting, diarrhoea, or abdominal pain; myalgia; and respiratory symptoms such as pharyngitis, fatigue, or cough. About 20 to 30% of patients with hypersensitivity develop cough, sore throat, and shortness of breath.¹

Subsequent dosing usually exacerbates symptoms. If hypersensitivity is suspected, the drug should be discontinued immediately. Patients should be advised to seek emergency care in the event of rapidly worsening symptoms. Adverse reactions will usually occur in the first two weeks of treatment and 90% within the first six weeks of treatment (median time 11 days).² 

Sometimes the cause of the reaction may actually be a concomitant illness or another drug, but if hypersensitivity is even suspected, once treatment is stopped, it should never be restarted. Re-challenge can lead to severe hypotension, Stevens-Johnson syndrome, or other adverse events. By early 2006, some 30 deaths due to abacavir hypersensitivity had been reported.

Abacavir is the only nucleoside reverse transcriptase inhibitor (NRTI) associated with hypersensitivity. Fortunately, there is a way to screen for abacavir hypersensitivity reaction (AHR), through use of an immunogenetic marker. The PREDICT-1 study confirmed that a specific human genetic variation, the HLA-B*5701 allele, is strongly associated with susceptibility to AHR.³ 

In this study, just six percent of the cohort tested positive for the presence of the HLA-B*5701 allele. None of the people who were screened and tested negative for the presence of HLA-B*5701 experienced AHR. In the control arm, which received drug without a screening test, 2.7% experienced AHR. Further studies have found that 61% of those who carry the HLA-B*5701 allele were likely to have AHR.

No one with a positive HLA-B*5701 should ever be given abacavir. A negative patch test would not justify re-challenge with abacavir. Patients beginning an abacavir-containing regimen without prior screening should be counselled concerning any symptoms that may develop. British, US, and European guidelines all recommend screening for HLA-B*5701 before prescribing abacavir.

Recognising that cost might put DNA-PCR screening out of reach for many antiretroviral programmes, one approach being investigated is the use of flow cytometry technology. In one study, a flow cytometry test for HLA-B17 was used to screen for HLA-B*5701. All samples found to be negative by flow cytometry were confirmed negative by PCR. The investigators suggest that the flow cytometry test might be used for initial screening, and only those samples that were positive or indeterminate undergo further screening by molecular testing.⁴