The potentially life-threatening hypersensitivity reaction to abacavir (Ziagen) is often presaged by transient falls in CD4 and CD8 cell counts, according to research presented today at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington DC. In a separate study, also presented to the conference, investigators found that 18% of individuals with primary HIV infection who took abacavir developed the hypersensitivity reaction.
It is thought that approximately 5% of individuals with chronic HIV infection who take abacavir will develop a hypersensitivity reaction to the drug within the first few months of treatment.
Symptoms of hypersensitivity to abacavir include fever, rash, nausea, vomiting and abdominal pain. 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.
CD4 count declines and abacavir hypersensitivity
Four cases of abacavir hypersensitivity were detected during an AIDS Clinical Trials Group (ACTG) study in which patients received Trizivir (AZT/3TC/abacavir), adding efavirenz after seven days, with a randomisation to receive ciclosporin (Neoral / Sandimmun) 4mg/kg twice daily or placebo during the first two weeks of the study. The study was intended to investigate whether initial treatment with ciclosporin improved CD4 T-cell recovery after beginning HAART. Because of the study design, frequent CD4 and CD8 cell count measurements were carried out during the early weeks of treatment.
All the patients who developed a hypersensitivity reaction were white, four were male, and the mean age was a little over 36 years.
Symptoms of the hypersensitivity reaction developed a mean of 21 days after starting therapy with the drug, and symptoms of the allergic reaction were present for a mean of 6.8 days before hypersensitivity was diagnosed.
Investigators noted that there was a sudden and dramatic fall in CD4 cell count in four patients prior to the onset of the hypersensitivity reaction. Median CD4 cell count fell by 200 cells/mm3 despite ongoing HAART and falls in HIV viral load.
In addition, median CD8 cell count dropped by a median of 436 cells/mm3 in four patients prior to the onset of symptoms of allergy to abacavir.
The deterioration in immune function led to the development of oral thrush in one patient. No other opportunistic infections were reported.
Both CD4 and CD8 cell counts returned to baseline values in all four patients once therapy with abacavir was discontinued.
The investigators also note that nine patients started abacavir at the same time as the five patients with hypersensitivity to the drug, but did not experience an allergic reaction. None of these nine patients experienced sudden falls in their CD4 or CD8 cell counts.
A disregulated cytokine milieu during the hypersensitivity reaction could, the investigators suggest, explain the sudden drop in CD4 and CD8 cell count. Although they conclude that a sudden drop in CD4 and CD8 cell count after starting abacavir could warn of an impending hypersensitivity reaction, they recommend that doctors’ clinical judgment should remain the main diagnostic tool, and admit that CD4 T-cell monitoring may not provide a useful warning of possible abacavir hypersensitivity unless it is taking place frequently during the early months of treatment.
Hypersensitivity in primary infection
In a separate study, investigators examined the incidence of, and risk factors for, abacavir hypersensitivity reaction when the drug is used during primary HIV infection.
A total of 50 patients with early HIV infection were treated with a HAART regimen containing abacavir at the Seattle Primary Infection Clinic. A total of nine patients (18%) developed hypersensitivity to the drug. These patients had a median age of 30.6 years. Investigators noted that two patients had the HLA-B*5701 polymorphism compared to none of the patients who did not develop an allergic reaction to abacavir (p = 0.032). However, 7 of 9 reactions occurred in patients without the polymorphism, raising doubts about the usefulness of screening for HLA-B*5701, say the investigators.
The investigators noted that at baseline, individuals developing the hypersensitivity reaction had lower CD8 cell count (p = 0.012), and lower HIV viral load (p = 0.037) than individuals taking abacavir who did not experience the reaction. In addition, when taking the drug, there was a trend for patients who were hypersensitive to have greater falls in viral load than patients who took the drug without a reaction (p = 0.088).
What’s more, the investigators noted a trend for individuals who developed a reaction to the drug to have been infected for HIV for longer (median of 103 days versus 48 days for patients with allergy to abacavir, p = 0.86).
Several conclusions are drawn by the investigators:
- There is a high rate of hypersensitivity reaction to abacavir when the drug is used to treat primary HIV infection, and its use should be avoided at this time.
- HLA-B*5701 is associated with a risk of abacavir hypersensitivity reaction.
- Levels of CD8 cell count and viral load may be independent risk factors for hypersensitivity, although this may be correlated with the HLA-B*5701 polymorphism.
- Hypersensitivity may be related to later primary infection.
Rodriguez B et al. Abacavir hypersensitivity reactions are heralded by transient declines in circulating CD4 cell counts. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-171, 2004.
Stekler J et al. Abacavir hypersensitivity reaction in primary HIV infection. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-168, 2004.