The main side-effects of abacavir (Ziagen) are nausea, vomiting, lethargy and fatigue. Other commonly reported side-effects are fever, headache, diarrhoea and loss of appetite. In general, these appear in the first few weeks of treatment. They tend to resolve themselves and to be of mild or moderate severity.

Hypersensitivity reaction

The most serious side-effect of abacavir is a hypersensitivity reaction, a severe allergic reaction that occurs in around 8% of people who begin abacavir treatment^[1]. 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^[2]. 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.

Although respiratory symptoms (shortness of breath, difficulty breathing, cough and sore throat) have been named as signs of abacavir hypersensitivity, a recent study found that they are not reliable indicators of hypersensitivity^[3]. 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^[4][5].

Typically, a pattern of symptoms builds up over a period of days, often worsening as successive doses are taken. The 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^[6]. However, as hypersensitivity can occur at any time during abacavir treatment, all abacavir users should familiarise themselves with the symptoms of the reaction and notify their doctor immediately if they develop.

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.

Once abacavir has been stopped because of hypersensitivity, the drug must never be taken again as re-starting in these circumstances can cause the allergic reaction to reappear within hours in a much more severe form. This can result in low blood pressure and death. Re-starting abacavir at a low dose following a hypersensitivity reaction (a technique used to ‘sensitise’ people to the anti-Pneumocystis pneumonia [PCP] drug co-trimoxazole [Septrin]) is not considered safe and is not recommended.

In August 2000, a warning was issued about the potential for rapid onset of hypersensitivity reactions in people who re-start 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 re-starting abacavir is necessary must do so in hospital to allow for immediate identification of a reaction.

Unfortunately, it can be difficult to distinguish a hypersensitivity reaction from the fever, chills and aches that often accompany an infection. For this reason, any patient experiencing symptoms of hypersensitivity should seek medical advice if they are taking abacavir, even though there is a chance that the symptoms could have another cause. Testing a patch of skin for a reaction to abacavir can be used to assess whether a patient is experiencing a hypersensitivity reaction or not, but this technique has not yet entered routine clinical practice^[8]. As skin patch testing remains positive for over 25 months, it is probable that this test may also be used to determine whether a patient can safely re-start abacavir after stopping due to a suspected hypersensitivity reaction^[9].

Risk factors for a hypersensitivity reaction include:

• Female sex.
• Not being of African origin.
• No prior AIDS diagnosis^[10].
• 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^[11].

A recent meta-analysis found that once-daily abacavir might have an elevated risk of hypersensitivity reactions and diarrhoea than twice-daily regimens^[12]. 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^[13]. 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^[14].

A genetic test can be used to predict whether a patient is likely to experience a hypersensitivity reaction after starting abacavir. Patients who do not have the HLA-B*5701 gene have a very low probability of experiencing this side-effect^[15][16]. See Abacavir hypersensitivity reaction for further information.

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^[17].

Administration of the corticosteroid prednisolone, which suppresses immune activation, does not alleviate the risk associated with the hypersensitivity reaction^[18].

Other side-effects

Abacavir seems to damage mitochondria to a lesser extent than other nucleoside reverse transcriptase inhibitors (NRTIs)^[19]. It is therefore less likely to cause side-effects related to mitochondrial damage, such as fat loss from under the skin, than NRTIs such as d4T (stavudine, Zerit) and AZT (zidovudine, Retrovir)^[20]. A number of studies have examined the effects of switching from these drugs to abacavir, with most showing modest improvements in fat levels^{[21][22][23][24]}. For more information, see Treating body fat and metabolic changes - switching drugs.

Lactic acidosis is a rare but serious side-effect of all NRTIs including abacavir. Symptoms include an enlarged and tender liver, nausea and malaise. Lactic acidosis usually develops within a few months of starting treatment with NRTIs, and is more common in women, and people with obesity or liver disease.

Three case reports of changes in mental state in patients starting abacavir have been reported. Although rare, symptoms include depression, suicidal thoughts, auditory hallucinations, psychosis, headaches and nightmares^[25][26][27].