+VE DRUGWATCH
 
HYPE OR SENSITIVE REACTION

Abacavir is a commonly used anti-HIV medication, but there have been a few deaths as a direct result of hypersensitivity reactions, as Tracy Barnes explains.

HOW ABACAVIR WORKS:
Abacavir belongs to the group of drugs referred to as nucleoside reverse transcriptase inhibitors (NRTIs) or nucleoside analogues. This class of drugs combat viral replication of HIV by disrupting the essential transcription process of HIV genetic material (RNA) into DNA. Abacavir is usually taken in combination with at least two other anti-retroviral drugs.

HISTORY:
In 1997 abacavir was approved in Europe for use in combination anti-retroviral therapy for HIV-positive adults; license for use in the USA was granted in December 1998. Prior to its registration abacavir was known by its code 1592U89. Abacavir is also combined with two other nucleoside analogues, AZT and 3TC, in a drug called Trizivir. Trizivir was granted a licence for use in Europe in July 2000.

COMBINATION THERAPY:
Abacavir is established as an effective component of combination anti-retroviral therapy when used with at least two other anti-retrovirals. Its effectiveness as a nucleoside analogue component of combination therapy has been proven, although several studies have indicated that Trizivir is less potent than triple combinations that contain more than one drug class.  Abacavir, as well as AZT and d4T, is able to cross the blood-brain barrier and is therefore effective in combating HIV in the brain and the central nervous system.

DOSING:
Abacavir is produced in an oval shaped, beige, 300mg tablet that is taken twice daily, 12 hours apart, with or without food. It is also available as an oral suspension with each millilitre containing 20mg of abacavir. Trizivir is also taken twice daily with no food restrictions or requirements.

DOSING RESTRICTIONS:
There are no dietary restrictions for abacavir. Dosing modification may be necessary in the presence of liver function impairment. Abacavir should not be administered if a hypersensitivity reaction is confirmed (see side effects).
 

SIDE EFFECTS:
The most serious side effect of abacavir is a hypersensitivity reaction.   Although hypersensitivity reactions only occur in approximately 4% of those treated, it can be life-threatening. In most cases, symptoms occur within the first six weeks of treatment and include fever. Additional symptoms include:

• Rash;
• Nausea;
• Vomiting;
• Diarrhoea;
• Abdominal pain.
   

Some may also experience joint and muscle pain, headache, numbness of the skin, swelling in the throat, face, neck and/or glands, and a cough or shortness of breath. Symptoms of hypersensitivity emerge over a period of days, growing in intensity. The presence of at least two symptoms is usually an indicator to stop treatment.

If a hypersensitivity reaction is confirmed, treatment with abacavir should be discontinued immediately and not resumed at a later date.

Resuming treatment with abacavir may result in a more aggressive allergic response to the drug than was initially experienced and this may be fatal.

As with most anti-retrovirals common side effects are more likely to occur during the first few weeks after commencing treatment. The most frequently reported side effects of abacavir are nausea, vomiting, lethargy and fatigue. In addition, fever, headache, diarrhoea and loss of appetite are relatively common.

RARE SIDE EFFECTS:
Lactic acidosis is a potentially life-threatening condition, characterised by unexplained and often severe tiredness, sickness and nausea, abdominal and/or liver pain, unexplained weight loss, breathlessness, poor circulation and sudden onset of peripheral neuropathy.  Lactic acidosis is a rare side effect of all nucleoside reverse transcriptase inhibitors, including abacavir. Women and those who are overweight appear to be at greater risk of lactic acidosis.

PRE-EXISTING CONDITIONS:
As abacavir is metabolised through the liver, people with cirrhosis or moderate liver impairment are generally not recommended to include abacavir in their antiretroviral combination therapy. The same may also be true of people co-infected with hepatitis B and/or C, although in any of these cases a reduced dose may be prescribed for those with mild liver impairment. You should awlays check this first with your
consultant(s). If you have an existing liver or kidney condition, you should make this known to your physician, who may indicate that abacavir should not be included in your treatment regime, or that a dose restriction is necessary.

If a hypersisitivity reaction to abacavir has been confirmed and treatment discontinued, it should not be readministered.

PAEDIATRIC USE:
Abacavir has just received its European license to treat HIV-positive children aged 3 months to 12 years. The oral solution is a slightly cloudy liquid with strawberry and banana flavouring. The recommended daily dose is weight-based as follows: 8mg per kilogram body weight with a maximum daily dose of 600mg.

Each dose should be administered twice daily - 12 hours apart (Oral solution contains 20mg/ml of abacavir as abacavir sulphate).

There is insufficient safety data to recommend the use of abacavir in infants less than three months old.

USE DURING PREGNANCY:
Safety of abacavir for use during pregnancy remains unknown. Until sufficient data becomes available, abacavir is not recommended for use in the treatment of HIV-positive pregnant women.

ABACAVIR RESISTANT HIV:
Within the whole nucleoside analogue class of drugs there is considerable cross resistance. Abacavir may be effective against HIV that has only low levels of resistance to other nuceloside analogues.

Studies have shown that those patients who have acquired high level resistance to AZT are unlikely to benefit from abacavir. Resistance to 3TC does not necessarily indicate that abacavir will be ineffective, provided it is not accompanied with AZT resistance as well. This is an important fact when considering treatment sequencing and future treatment options.