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Frequently Asked Questions

How can the potential for abacavir hypersensitivity reactions be minimized?

Background
Clinicians involved in the care of patients with Human Immunodeficiency Virus (HIV) are constantly faced with the challenge of choosing the appropriate drug regimens to effectively reduce viral loads and improve CD4 counts, monitoring and managing numerous adverse drug reactions, avoiding drug interactions and toxicities, and educating patients. Abacavir, a nucleoside reverse transcriptase inhibitor (NRTI), is indicated for the treatment of HIV infection in combination with other antiretroviral agents.1,2 Its major limiting toxicity is a hypersensitivity reaction (HSR) that typically occurs within the first 6 weeks of therapy. The symptoms of the reaction are nonspecific and overlap with other types of reactions making the diagnosis of abacavir HSR difficult. The symptoms can include skin rash and/or 1 or more symptoms from at least 2 of the following groups:

  • Group 1: fever
  • Group 2: nausea, vomiting, diarrhea, abdominal pain
  • Group 3: fatigue, myalgia, arthralgia, generally ill feeling
  • Group 4: shortness of breath, cough, sore throat

Hypotension can also occur due to severe fluid losses.1,2 Laboratory changes include leukopenia, thrombocytopenia, lymphopenia, and increased liver enzymes, serum creatinine, and creatine kinase. Symptoms tend to worsen with each subsequent dose. Patch testing, the application of dilute concentrations of abacavir to the skin, has been used in clinical trials to aid in confirming abacavir HSR. Unfortunately, it is still experimental; therefore, abacavir HSR is established through clinical diagnosis only. Case reports have demonstrated that patients with abacavir HSR can develop more severe reactions if rechallenged. For this reason, rechallenge with the drug is contraindicated in patients with previous abacavir HSR.

Immediate discontinuation of abacavir is required if HSR is diagnosed. Symptoms typically resolve within 1 to 3 days.1,2 Symptomatic management with intravenous fluids may be required if hypotension and/or severe dehydration occurs. Analgesics, antiemetics and antipyretics can be administered if necessary.

Caucasians and treatment-naïve patients have been identified as potential high risk groups for developing abacavir HSR.2 The risk of developing abacavir HSR has also been shown to have a strong genetic link to the presence of the HLA-B*5701 allele. Two recently published studies, PREDICT-1 and SHAPE, evaluated the clinical utility of screening patients for the presence of this allele.

Literature review: PREDICT-1 and SHAPE
The objective of the PREDICT-1 study was to evaluate the effectiveness of genetic screening in reducing the rate of abacavir HSR.3 Over 1900 patients were randomized to receive either abacavir treatment only after screening negative for the HLA-B*5701 allele or to receive abacavir treatment without genetic screening. Patients were monitored for abacavir HSR for 6 weeks with diagnosis confirmed using the patch test.

Over 80% of the patients were white and approximately 18% of patients were naïve to antiretroviral treatment.3 The incidence of clinically diagnosed and immunologically confirmed abacavir HSR was significantly lower in the prospective screening group compared to the control group (p<0.001 for all comparisons). Of the 803 evaluable patients in the prospective screening group, 27 patients (3.4%) were clinically diagnosed with abacavir HSR, but all of these cases had negative patch tests and therefore, could not be considered immunologically confirmed abacavir HSR. Of the 847 evaluable patients in the control group, 66 patients (7.8%) were clinically diagnosed with abacavir HSR, of these 23 cases (2.7%) were immunologically confirmed using the patch test. The incidence of clinically diagnosed HSR and immunologically confirmed HSR was reduced by 56% and 100%, respectively through HLA-B*5701 screening compared to no screening. The reduction in clinically diagnosed HSR is more relevant to clinical practice as the patch test used for immunological confirmation is currently experimental.

The positive predictive value of a test describes the probability of the patient developing the condition if the test is positive and the negative predictive value is the probability that the condition will not occur if the test is negative. Based on the results of the study, the positive predictive value of the genetic screen for developing clinically diagnosed abacavir HSR is 61.2%.3 In other words, 61% of patients who test positive for the allele are likely to receive a clinical diagnosis for abacavir HSR. The negative predictive value of 95.5% for the genetic screen suggests only 4.5% of patients who test negative are likely to receive a clinical diagnosis for abacavir HSR. The authors concluded that a genetic screen for the HLA-B*5701 allele is a valid test to help reduce the occurrence of abacavir HSR.

The objective of the SHAPE study was similar to that of PREDICT-1.4 However, this retrospective case control study further aimed to evaluate the utility of the genetic screen in both white and black patients. Through chart review, black and white case patients were classified as having clinically suspected abacavir HSR and controls were racially matched patients who tolerated abacavir therapy for 12 weeks or more. Case patients and controls underwent patch testing (to immunologically confirm HSR) as well as genetic testing for presence of the HLA-B*5701 allele. Of the 130 white patients with clinically suspected HSR, 42 (32.3%) had immunologically confirmed HSR, and all 42 patients tested positive for the HLA-B*5701 allele. Of the 69 black patients with clinically suspected HSR, 5 (7.2%) had immunologically confirmed HSR and all 5 patients tested positive for the HLA-B*5701 allele. Eight (4%) of 202 of white subjects and 2 (<1%) of 206 black subjects in the control group tested positive for the allele.

The association between the presence of the allele and abacavir HSR was determined by calculation of an odds ratio.4 The odds ratio of 1945 [95% confidence interval (CI), 110 to 34352] for white patients and 900 [95% CI, 38 to 21045] for black patients suggests a strong association between the presence of the HLA-B*5701 allele and abacavir HSR regardless of race.

Summary
Based on the data from these studies, the Food and Drug Administration (FDA) has recently alerted health care professionals regarding its recommendation to screen all patients for the HLA-B*5701 allele prior to initiation or re-initiation of abacavir therapy.5 According to the FDA, genetic tests for the HLA-B*5701 allele are available and will help to minimize the potential for abacavir HSR. Use of the drug is not recommended in patients who test positive for this allele. Surveillance of abacavir HSR, however, should continue in patients who test negative for the allele and who are initiated on abacavir therapy since the reaction may develop in a small number of patients without the allele.

References

  1. Ziagen [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2002.
  2. Hughes CA, Foisy MM, Dewhurst N, et al. Abacavir hypersensitivity reaction: an update. Ann Pharmacother. 2008;42(3):387-396.
  3. Mallal S, Philips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-579.
  4. Saag M, Balu R, Philips E, et al. High sensitivity of human leukocyte antigen-B*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. 2008:46(7):1111-1118.
  5. Anon. Information for healthcare professionals: abacavir (marketed as Ziagen) and abacavir containing medications. FDA Alert. Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/abacavirHCP.htm Accessed July 28, 2008.