Abacavir is an anti-HIV drug that reduces the amount of virus in the body. Anti-HIV drugs such as abacavir slow down or prevent damage to the immune system and reduce the risk of developing AIDS-related illnesses.
Abacavir belongs to a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). When HIV infects a cell, the enzyme reverse transcriptase copies the viral single-stranded RNA genome into double-stranded viral DNA. This viral DNA is then integrated into the CD4 chromosomal DNA and can go on to reproduce in the body. Four natural nucleosides complete the DNA synthesis: adenosine, cytidine, guanosine, and thymidine. An NRTI drug substitutes a defective version of one of the nucleosides, causing premature termination of the proviral DNA chain.
In July 1999, abacavir was approved by the European Union licensing body for use in combination with other anti-HIV drugs. The drug was licensed in the United States in December 1998. Once-daily abacavir was also approved in the European Union in November 2004.
Abacavir was previously known by the codename 1592U89 and has been registered under the trade name Ziagen. It is made by ViiV Healthcare, the company that also produces zidovudine (AZT, Retrovir), lamivudine, (3TC, Epivir) and dolutegravir (Tivicay).
Abacavir is also available as part of the following combinations:
Kivexa (600mg abacavir combined with 300mg lamivudine). See Kivexa for further details. Also marketed as Epzicom in the United States. Generic versions of this product are available.
Triumeq (600mg abacavir combined with 300mg lamivudine and 50mg dolutegravir). See Triumeq for further details.
Trizivir, a pill that combines 300mg abacavir, 150mg lamivudine and 300mg zidovudine is also available from ViiV Healthcare. It was approved in the United States in November 2000 and in the European Union in March 2001. Trizivir is no longer recommended for use as first-line treatment.
Clinical studies have shown that abacavir (Ziagen) can reduce HIV viral load and improve immune function in the majority of people when taken in combination with at least two other anti-HIV drugs. It is regarded as a highly potent nucleoside reverse transcriptase inhibitor (NRTI) in people who have not taken previous antiretroviral therapy, although it often retains an anti-HIV effect in individuals who have previously taken treatment. Abacavir is active against HIV-1 and HIV-2.
Abacavir was licensed after the results of the CNA 3003 study showed that adding the drug to a combination of zidovudine (AZT, Retrovir) and lamivudine (3TC, Epivir) led to more patients having suppressed viral loads when patients were taking antiretroviral therapy for the first time. (Fischl) The CNAB 3005 study extended this by comparing abacavir to the protease inhibitor indinavir (Crixivan), in combination with zidovudine and lamivudine, with both groups having similar viral load reductions. (Staszewski)
Since its approval, studies have shown that abacavir is effective when used as a part of a dual NRTI ‘backbone’. The CNA 30024 study showed that abacavir is just as effective in reducing viral load as zidovudine when combined with lamivudine and efavirenz (Sustiva). However, people who received abacavir had a significantly better CD4 cell count increase after 48 weeks. (de Jesus)
The ZODIAC study showed that once-daily dosing of abacavir was just as safe and effective as the twice-daily separate doses in people starting antiretroviral therapy for the first time. The two dosing schedules produced similar rates of side-effects. (Moyle, 2005)
The ACTG-5202 study found that abacavir/lamivudine was inferior to tenofovir/emtricitabine in people with baseline viral load above 100,000 copies/ml. (Sax)
Abacavir/lamivudine is recommended as an alternative to tenofovir/emtricitabine in United Kingdom guidelines as a backbone for first-line antiretroviral therapy, for people with viral load below 100,000 copies/ml. United States guidelines recommend the use of abacavir in first-line treatment in combination with lamivudine and dolutegravir (Triumeq), or as part of an alternative to the preferred regimens, if combined with lamivudine and either darunavir/ritonavir, raltegravir or efavirenz. In all cases, abacavir should be used only in people who test HLA-B*5701 negative (see Hypersensitivity reaction below).
Like zidovudine and stavudine (d4T, Zerit), abacavir is able to cross the blood-brain barrier and combat HIV in the central nervous system. One study of treatment-experienced people with dementia found that abacavir reduces the viral load in the cerebrospinal fluid that surrounds the brain and spinal cord. (Lanier, 2001)
The standard dose of abacavir (Ziagen) is one 300mg tablet twice a day, twelve hours apart, or once a day at a dose of 600mg. It can be taken with or without food. Abacavir is dosed once daily when combined with lamivudine in the tablet coformulation (Kivexa/Epzicom).
A strawberry- and banana-flavoured abacavir solution at a concentration of 20mg/ml is also available for use in children and adults who cannot take tablets. The oral solution of abacavir contains 340mg/l sorbitol. This means that the product is unsuitable for people with hereditary fructose intolerance. Sorbitol can also cause stomach upset and diarrhoea.
Abacavir is generally not recommended for people with cirrhosis or mild liver impairment because they are not able to process the drug properly and high drug levels occur. One study has recommended an abacavir dose of 150mg twice daily for people with liver damage, although there are no definitive recommendations on appropriate dose adjustments. (Raffi)
Abacavir should not be taken by people with end-stage kidney disease.
As with all anti-HIV drugs, it is important to take the drug as prescribed in order to maintain the right level of the drug in the blood. If blood levels of the drug fall too low, this will help the development of resistance to abacavir and may affect future treatment options.
The most common 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, symptoms appear in the first few weeks of treatment, are mild to moderate in severity, and tend to resolve on their own.
Abacavir seems to be less damaging to mitochondria than some of the other nucleoside reverse transcriptase inhibitors (NRTIs), such as stavudine (d4T, Zerit) and zidovudine (AZT, Retrovir). (Hoy) It is therefore less likely than some of the other NRTIs to cause side-effects related to mitochondrial damage, such as fat loss from under the skin. (Podzamczer) A number of studies have examined the effects of switching from these drugs to abacavir, with most showing modest improvements in fat levels. (Martin) (Katlama, 2003) (Moyle, 2003)
There is conflicting evidence as to whether abacavir increases the risk of myocardial infarction. Recent data on this issue are described below.
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. This side-effect seems to occur more commonly in women and in individuals with existing liver disease or who are obese.
Liver toxicity was reported in two women 10 to 12 weeks after switching to an abacavir-containing regimen. Neither had underlying risk factors for liver disease and both tested HLA-B*5701 negative before starting the drug. Laboratory values were normal at six weeks, but alanine aminotransferase (ALT) were well over five times the upper limit of normal a short time later. The one biopsy done found severe inflammation in one women. Hypersensitivity reaction and hepatitis were both ruled out as causative agents. Lab values returned to normal and Inflammation resolved after treatment with abacavir was stopped. The authors point out that even minor symptoms after starting therapy should be reported and investigated. (Soni)
Three case reports of changes in mental state in people starting abacavir have been reported. Although rare, symptoms include depression, suicidal thoughts, auditory hallucinations, psychosis, headaches and nightmares. (Colebunders) (Foster, 2003) (Foster, 2004)
Risk of cardiovascular disease
There is conflicting evidence regarding the impact of abacavir use on the risk of cardiovascular disease.
In 2009, D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) investigators presented information collected from over 33,000 participants from 11 prospective cohorts. They found that recent abacavir use (in the past six months) increased the risk of myocardial infarction by 68%; that risk rose with correspondingly longer time on abacavir. (Lundgren)
Results from SMART (Strategies for Management of Anti-Retroviral Therapy) study also found an excess risk of cardiovascular disease with abacavir use as compared to other NRTIs. Events included myocardial infarction; stroke, coronary artery disease, congestive heart failure, peripheral vascular disease, and death. Researchers believe that abacavir may cause vascular inflammation, increasing the risk of cardiovascular events, particularly in those already highly vulnerable.
A subsequent systematic review of studies looking at the relationship between antiretroviral drugs and cardiovascular disease found that the evidence of an association between recent exposure and cumulative exposure to abacavir and heart attack was mixed. (Bavinger) The lack of consistency in findings is due to differing inclusion criteria, varying ages of cohorts and lack of statistical power to measure significant differences in events. As a consequence of the uncertainty, the British HIV Association has concluded that abacavir should be avoided wherever possible by people with a high risk of cardiovascular disease.
As with all other anti-HIV drugs, strains of HIV that are resistant to abacavir (Ziagen) may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug.
There is considerable cross-resistance amongst the nucleoside reverse transcriptase inhibitors (NRTIs). This means that once a patient has HIV that is resistant to one NRTI, other NRTIs will have less effect on HIV viral load. Abacavir may have an effect against HIV that has low-level resistance to some other NRTIs, but HIV that has multiple resistance mutations to NRTIs such as zidovudine (AZT, Retrovir), lamivudine (3TC, Epivir) and didanosine (ddI, Videx /VidexEC) is unlikely to be controlled by abacavir. (Mellors) Although people who have developed lamivudine resistance can still benefit from abacavir, if lamivudine resistance is combined with high-level zidovudine resistance, abacavir is unlikely to be effective. (Katlama, 2000) (Falloon)
Resistance to abacavir tends to emerge slowly, since a number of mutations must develop for the drug’s efficacy to decrease. Low-level (two- to sixfold) reductions in effectiveness can occur following development of mutation M184V, which is usually associated with lamivudine resistance. (Fenner) Subsequent mutations K65R, L74V and Y115F confer high-level (tenfold or greater) resistance to abacavir. (Harrigan) Similarly, the Q151M brings about low-level resistance to abacavir, but resistance is increased following additional mutations at positions 62, 75, 77 and 116.
Resistance seems to develop at similar rates in people taking abacavir once and twice a day. (Craig)
GlaxoSmithKline and ViroLogic investigated the degree of resistance that makes abacavir ineffective. The study reported that less than 4.5-fold resistance to abacavir does not substantially reduce the drug’s effects but that sevenfold or greater resistance renders abacavir largely ineffective. (Lanier, CROI 2001)
Cross-resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors is very rare.
There is test tube evidence that abacavir (Ziagen) enhances the effects of the protease inhibitor amprenavir (Agenerase), although this may not translate into a more effective combination in people. (Drusano)
A drug called mycophenolic acid (Myfortic) enhances the antiviral effectiveness of abacavir in test tube studies. (Margolis) Although clinical trials are ongoing to determine whether mycophenolic acid can improve the anti-HIV effects of abacavir without inducing high-level toxicity, a small safety study found no significant benefit of the combination. (Toukas) At this stage, combining abacavir with mycophenolic acid is experimental and not recommended as standard treatment.
Clearance of methadone hydrochloride (Methadose) is increased by 22% when combined with abacavir, but no dose modification of methadone hydrochloride is required. However, people taking both drugs should be monitored for methadone hydrochloride withdrawal symptoms.
Alcohol is known to increase blood levels of abacavir, but this has been found not to be clinically significant. Dose adjustments are not required. (McDowell)
The lack of an interaction between abacavir and the tuberculosis drug rifampicin (Rifadin/Rimactane) has led to suggestions that triple nucleoside reverse transcriptase inhibitor (NRTI) combinations including abacavir might be useful during anti-tuberculosis therapy. The drawback in this strategy is that abacavir hypersensitivity cannot be distinguished from immune restoration inflammatory syndrome that can occur when people with tuberculosis begin antiretroviral therapy. This condition is caused when the immune system begins to recover and mounts a new or stronger response to the organisms that cause tuberculosis. The outcome is a temporary worsening of symptoms, which often includes fever, and may be mistaken for a hypersensitivity reaction.
The recommended dose of abacavir (Ziagen) for infants and children between three months and twelve years of age is 8mg/kg twice a day, up to a maximum dose of 600mg a day. (Kline) There are limited data to suggest that a dose of 2mg/kg twice daily may be suitable for infants 30 days or younger.
Children weighing between 14kg and 20kg may receive one 300mg tablet once daily or half of one 300mg tablet twice daily. Children weighing 20kg-25kg may receive one and a half 300mg tablets once daily, or a full tablet and a half tablet split between morning and evening doses.
Abacavir does not need to be dosed with food. Patients who are HLA-B*5701 positive should not use abacavir; testing should be considered prior to therapy initiation (see Hypersensitivity reaction below).
The 48-week PENTA 5 study demonstrated that lamivudine with abacavir offered better virological suppression and growth than did regimens with a NNRTI backbone of either zidovudine/lamivudine or zidovudine and abacavir. It should be preferred as a first-line NRTI backbone. (PENTA)
After five years of follow-up, 31% of children who started treatment with abacavir and lamivudine had changed regimens versus 39% of the children initially randomised to zidovudine/lamivudine, and 46% of children taking zidovudine and abacavir. Patients taking abacavir/lamivudine were significantly less likely to change therapy with an undetectable viral load than were patients in either of the other two treatment arms, indicating the tolerability of the abacavir/lamivudine regimen.
Abacavir can be used during pregnancy. There is no evidence that abacavir causes harm to the foetus.
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. (Keiser)
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. (Keiser) (Phillips, 2006)
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. (de la Rosa) 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.
Genetic testing for hypersensitivity
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. (Mallal)
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. (Phillips, 2007) (Saag)
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.
Monitoring for hypersensitivity
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. (Sahly) 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. (Brothers)
- 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. (Leoty-Bernard)
A recent meta-analysis found that once-daily abacavir might have an elevated risk of hypersensitivity reactions and diarrhoea than twice-daily regimens. (Goedken) 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. (Stekler) 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. (Fontaine)
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. (Rodriguez)
Administration of the corticosteroid prednisolone, which suppresses immune activation, does not alleviate the risk associated with the hypersensitivity reaction. (Wit)
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