Hypersensitivity reaction

Abacavir, also found in the co-formulations Kivexa and Trizivir, causes a hypersensitivity reaction in approximately 5% of people starting these drugs. A strong association between the hypersensitivity reaction and the B*5701 allele (genetic variant) has been established. A hypersensitivity reaction may be life threatening. Although the symptoms vary, most cases involve a fever. Other symptoms include rash, nausea, vomiting, diarrhoea and abdominal pain.¹

Less common symptoms include lethargy, muscle or joint pain, headache, numbness on the skin, puffiness of the throat, face and neck, swollen glands, conjunctivitis, mouth ulcers, and low blood pressure. Rash and gastrointestinal symptoms are more common in children experiencing a hypersensitivity reaction. The key difference between hypersensitivity and influenza is the presence of gastrointestinal symptoms in abacavir hypersensitivity, as well as the presence of more than two symptoms.^{1 2}

Typically, a pattern of symptoms builds up over a period of days, often worsening as successive doses are taken. A hypersensitivity reaction is most commonly seen in the first two to six weeks of taking the drug, although cases after only one dose have been reported.³ However, as hypersensitivity can occur at any time during abacavir treatment, everyone taking abacavir should familiarise themselves with the symptoms of the reaction and notify their doctor immediately if they develop. 

Testing for the genetic variant that can cause a hypersensitivity reaction to abacavir reduced the incidence of ‘immunologically-confirmed’ hypersensitivity reactions to zero in a randomised controlled trial of nearly 2000 people.⁴

The study was funded by the drug’s manufacturer, GlaxoSmithKline (GSK) to establish whether the presence of B*5701 was a necessary condition for the reaction and whether withholding abacavir from people with B*5701 would eliminate ‘true’ hypersensitivity reactions. The PREDICT study appears to show that this is the case.

All participants with immunologically confirmed hypersensitivity reactions had multiple symptoms: about two-thirds had the presence of at least three symptoms (fever, rash, plus another systemic symptom) and a third consisted of fever plus rash alone. In contrast, a high proportion of suspected hypersensitivity reactions that were not immunologically confirmed tended to consist of one or more constitutional symptoms such as diarrhoea or respiratory symptoms and lack one or both of the defining symptoms of fever or rash.

Apart from ethnicity, the only other factors strongly associated with a clinically suspected hypersensitivity reaction were either existing protease inhibitor therapy or starting therapy with an NNRTI at the same time as abacavir. In both cases, and especially with new NNRTIs, it would be easy to mistake a reaction to one of the other drugs in the regimen for an abacavir hypersensitivity reaction.

Persons of African descent report hypersensitivity to abacavir-containing regimens less frequently. A separate study done by the SHAPE (Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation) study team, determined that gene screening is 100% sensitive for HLA-B*5701 in both white and black people. In that study, only 14% of African-Americans with suspected hypersensitivity reactions had the B*5701 variant as compared to 44% of white people. The study confirmed that suspected hypersensitivity reactions are more likely to prove to be ‘false positives’ in African-American people than in those of white ethnicity and more often lack the defining symptoms of fever and/or rash.^{5 6}

Results of that trial suggest that genetic testing should be routine for people of all ethnicities and for all people starting abacavir to reduce instances of misdiagnosis of hypersensitivity reaction and situations in which abacavir is inappropriately withdrawn from patients who could have benefited from it. If screening for B*5701 is not possible, clinical vigilance needs to be relied upon. Patch testing should only be used as a confirmatory research tool and not for screening purposes.

Although over half of patients positive for B*5701 do not develop a hypersensitivity reaction, it is thought that they are at very high risk of developing one, and GSK recommends that no patient positive for B*5701 be given abacavir. If patients develop an apparent hypersensitivity reaction and abacavir is stopped, GSK currently recommends that the drug is not restarted, even if the patient subsequently tests negative for B*5701.

The consequences of re-challenge are serious enough that the small chance of a false-negative test cannot be neglected. Although this study did not see any, the chance of rare immunological reactions to abacavir that are not related to B*5701 cannot be ruled out. 

It is recommended that people starting abacavir be monitored very closely for the first two months of therapy, with consultation every two weeks. If a person who has recently started abacavir develops at least two symptoms associated with hypersensitivity, abacavir should be discontinued as soon as a doctor has made a formal diagnosis. Abacavir should not be stopped in the absence of medical advice.

In August 2000, a warning was issued about the potential for rapid onset of hypersensitivity reactions in people who restart abacavir after a period off the drug. In some cases, early symptoms of the hypersensitivity reaction may not have been diagnosed before treatment was stopped or treatment may have stopped very soon after abacavir was started.

Cases of hypersensitivity reaction after treatment interruptions have been reported in patients showing no signs of allergy despite taking abacavir for over a year before stopping the drug.⁷ In cases where symptoms of the hypersensitivity reaction may have occurred before interrupting abacavir, patients in whom restarting abacavir is necessary must do so in hospital to allow for immediate identification of a reaction.

Risk factors for a hypersensitivity reaction include:

• Female sex.
• Not being of African origin.
• No prior AIDS diagnosis.⁸
• A history of adverse drug reactions.
• A history of allergic reactions, such as asthma, hay fever or eczema.
• Viral load above 100,000 copies/ml.⁹

A recent meta-analysis found that once-daily abacavir might have an elevated risk of hypersensitivity reactions and diarrhoea than twice-daily regimens.¹⁰ Abacavir hypersensitivity may also be more frequent in people who start taking the drug during primary HIV infection, particularly patients with lower CD8 cell counts and lower HIV viral loads.¹¹ A case report has also suggested that taking abacavir and the lipid-lowering drug ciprofibrate (Modalim) may have been responsible for the severe breakdown of muscle cells in a patient experiencing a hypersensitivity reaction.¹²

Hypersensitivity may also be heralded by a sudden CD4 cell decline, but it is unclear how clinically useful this information is, unless a CD4 cell count can be repeated rapidly to check the trend.¹³

Administration of the corticosteroid prednisolone, which suppresses immune activation, does not alleviate the risk associated with the hypersensitivity reaction.¹⁴