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Controversial findings on abacavir and heart attacks
Abacavir (Ziagen) is a commonly used anti-HIV drug that belongs to a family of medicines called nucleoside analogues, or nukes. Abacavir is found in the following combinations:
- Kivexa (abacavir + 3TC [lamivudine])
- Trizivir (abacavir + 3TC + AZT [Retrovir, zidovudine])
A drawback of some nukes is that they can cause lipoatrophy—a process in which the fatty layer just under the skin (subcutaneous fat) wastes away. Abacavir alone or in combination with 3TC (Kivexa) is not associated with fat wasting. Indeed, abacavir users may even develop increased fat in their limbs.
In several clinical trials, abacavir has been found to be an effective part of combination therapy, lowering viral loads and raising CD4+ counts.
The use of abacavir is associated with the possibility of a hypersensitivity reaction in up to 8% of people who took the drug. However, in many high-income countries today, a simple blood test is available that can predict the likelihood of such a reaction. Potential abacavir users can have this test performed before they start using the drug. Armed with this screening tool, doctors can now prescribe abacavir to patients who have a negative test result, knowing that the chance of a hypersensitivity reaction occurring during abacavir therapy is very, very low.
Digging deeper
DAD is the name of a large database project centred in Copenhagen, Denmark, that collects information from 212 HIV clinics, mostly in Europe but also from some clinics in Australia and the United States. Health-related information from more than 33,000 participants is stored in DAD’s database. From time to time, DAD’s scientists query the database in an effort to answer research questions.
Drugs such as d4T (Zerit, stavudine) and AZT are called thymidine analogues (the T in both drugs stands for thymidine). Unfortunately, the use of d4T is associated with nerve damage, lipoatrophy and increased levels of cholesterol and triglycerides in the blood. AZT to a lesser extent can sometimes cause fat wasting. So the DAD team decided to investigate if there was any link between the use of thymidine analogues (AZT and d4T) and cardiovascular disease. When they did not find a link, they decided to look at other nukes, namely abacavir, ddI (Videx EC, didanosine) and 3TC. It is important to note that DAD did not have enough patients on tenofovir (Viread) to analyze the possibility of a link between this drug and heart disease.
Unexpected results
In February 2008 at the 15th Conference on Retroviruses and Opportunistic Infections (CROI), researchers from Copenhagen presented findings from an analysis of DAD. They unexpectedly found that the recent use of abacavir (in the past six months), and to a lesser extent ddI, was linked to an increased risk of heart attacks.
Because of abacavir’s good safety record, many researchers were puzzled by these findings. Initially, so was the DAD study team, so they reviewed their findings just to be sure.
Focus on heart attacks
Out of 33,347 HIV positive people, heart attacks occurred in 517 as of February 2008. The distribution of heart attacks among people using certain medications was as follows:
- 124 people were either using ddI or had recently stopped using ddI (within the past six months) when a heart attack occurred.
- 192 people were either using abacavir or had recently stopped using abacavir when a heart attack occurred.
- 237 people had been using HAART, but not abacavir or ddI, and also had a heart attack.
Bear in mind that the overall proportion of people with heart attack was relatively low—1.6%.
At risk for heart attacks
HIV positive people who had recently used abacavir were likely to fit the following profile:
- males 45 years and older
- females 55 years and older
- diabetic
- higher-than-normal blood pressure
- higher-than-normal levels of lipids—cholesterol and triglycerides—in the blood
This profile is striking and worthy of further attention because the DAD team declared that “patients with a high underlying cardiovascular risk” seemed to be more likely to have a heart attack. Other key points from the study are as follows:
- Exposure to abacavir was not linked to the development of other forms of cardiovascular disease, such as stroke.
- The risk of a heart attack in recent abacavir users was double what would normally be expected.
- Discontinuing abacavir or ddI reduced the risk of developing a heart attack.
- There was no link between CD4+ counts, viral load and heart attacks.
The findings from the DAD study are startling and now require additional investigation to confirm, understand and explain the results. Researchers are puzzled by the findings because abacavir has been in use in high-income countries for over a decade yet it has never been associated with heart attacks.
What’s next?
The DAD study is an observational study. These types of studies are useful for finding associations but cannot prove cause and effect. Observational studies, because they are not randomized, cannot entirely rule out the possibility of bias when interpreting their findings. For example, abacavir was approved later than all of the other nukes to which it was compared, suggesting that abacavir users may have differed in ways that were not captured by the DAD study.
Moreover, the DAD study was unable to take into account every bit of data that might have been useful in making a link between abacavir, ddI and heart attacks. Also, as previously noted, tenofovir was not included in the analysis, so we do not know if it is associated with an increased risk of heart disease in the DAD cohort. For these and perhaps other reasons, the results from DAD are controversial.
Now that the DAD analysis has been released, it should incite the following courses of action:
- Regulatory agencies need to review their databases, checking for reports of abacavir- and ddI-related side effects, particularly looking at heart attacks and related issues.
- Other databases held by hospitals and research agencies, such as the large Veterans Administration (VA) database in the United States, need to be queried about heart attacks among HIV positive people and whether there was any link with abacavir or ddI. The VA database is one of the largest in the world, containing health information on more than 40,000 HIV positive people.
Querying databases such as the VA and others takes on additional importance in light of the DAD findings. This is because conducting a randomized controlled trial to try to investigate the issue of abacavir, ddI and heart attacks would require about 20,000 HIV positive volunteers at high risk for cardiovascular disease and take at least three years to complete. Such a trial would be expensive and complex and may therefore be difficult to conduct.
- GlaxoSmithKline (GSK), the manufacturer of abacavir, has begun checking its own databases of abacavir-related adverse effects. Preliminary results from a review of 15,000 patient records in the GSK database have not found any link between abacavir and heart attacks (Tjark Reblin GSK, personal communication).
- Research-cardiologists need to be made part of the investigating team to try to resolve the issue of abacavir, ddI and heart attacks.
- HIV infection appears to increase inflammation, both directly and indirectly. Proteins produced by HIV-infected cells appear to damage heart muscles and HIV itself can infect blood vessels. Also, inflammation associated with many other diseases unrelated to HIV increases the risk of heart attacks. These all complicate the mystery of abacavir’s potential role in heart attacks as reported by DAD.
Unanswered questions
Clinics that have sent data to DAD need to review cases of heart attacks among abacavir and ddI users to try to better understand how these or other drugs might have played a role in the DAD results. In reviewing medical records, some issues that are worth noting or pursuing include the following:
- Were any abacavir or ddI users who had heart attacks also taking statins (drugs to lower cholesterol)? These drugs also have anti-inflammatory activity and their use can reduce the risk of a heart attack.
- What proportion of the people using abacavir who experienced heart attacks had undergone abacavir hypersensitivity screening? This question is important because, as we mentioned earlier, abacavir can cause hypersensitivity reactions in a small proportion of people.
Hypersensitivity reactions can occur with many drugs. In the case of some anti-cancer drugs, the severe inflammation associated with a hypersensitivity reaction can lead to a heart attack. Speculation: It is plausible that inflammation triggered by exposure to abacavir in an HIV positive person at high risk for cardiovascular disease might have led to a heart attack. So it may be worth investigating clinic records to find out if abacavir hypersensitivity screening was done for patients who experienced a heart attack in the DAD study.
- The short-term use of abacavir was linked to an increased risk of heart attack in the DAD study. Clinics need to review their data to find out why some patients were given abacavir. Were these patients at high risk for heart attacks before they received abacavir?
- Abacavir is widely prescribed by doctors in high-income countries, and, in general, heart attacks remain rare among people with HIV/AIDS.
Options
For the average healthy HIV positive person taking abacavir who has minimal risk factors for cardiovascular disease, there is probably little risk in continuing to take abacavir. However, HIV positive people who take abacavir should speak to their doctor if they have one or more of the following characteristics:
- smoke tobacco
- are male and 45 years or older
- are female and 55 years or older
- have higher-than-normal blood pressure
- have higher-than-normal levels of lipids in their blood
- have cardiovascular disease
- have a close family member who has a history of heart attacks or cardiovascular disease
- have diabetes
Depending on the outcome of this discussion and their doctor’s approval, it might be useful for some HIV positive people taking abacavir to lower their risk for cardiovascular disease. This can begin in a number of ways, including the following:
- seeking help, support and instructions for quitting smoking (this point is noteworthy because smoking is perhaps the greatest risk factor for a heart attack)
- getting therapy to lower high lipid levels and blood pressure
- receiving treatment for diabetes
- obtaining dietary advice
- beginning an exercise program
For people at high risk for cardiovascular disease, in addition to the steps mentioned above, and after discussion and agreement with their physician, discontinuing abacavir and replacing it with another medication is also an option. But bear in mind that if abacavir is discontinued the other nuke or nucleotide analogue that might be used as a substitute can also have side effects. Here are just a few:
- d4T – This nuke can cause lipoatrophy, nerve damage and increased lipid levels. So the use of d4T does not seem to be appropriate for HIV positive people at high risk for cardiovascular disease.
- tenofovir (Viread, and in Truvada and in Atripla) – This nucleotide analogue is generally effective and safe in patients beginning anti-HIV therapy. However, in people at high risk for cardiovascular disease, some of whom have high blood pressure, the kidneys will not likely be functioning normally. Since tenofovir is processed by the kidneys and can cause kidney dysfunction, it may not be the most appropriate choice for some patients at high risk for cardiovascular disease. For all we know, it may be as bad as or worse than abacavir, as we have no information on tenofovir from DAD.
The DAD findings on abacavir and ddI suggest that better guidelines are needed to ensure that HIV is appropriately treated and that cardiovascular risk is identified and reduced where possible. Later this year, a team of Canadian researchers will unveil such guidelines.
Acknowledgements
We would like to thank the following researchers for their helpful discussion and, in some cases, review:
- Julian Falutz, MD – McGill University, Montreal
- Marianne Harris, MD – St. Paul’s Hospital, Vancouver
- Richard Lalonde, MD – Montreal Chest Institute, Montreal
- Julio Montaner, MD – St. Paul’s Hospital, Vancouver
- Marek Smeija, MD, PhD – McMaster University Hospital, Hamilton
—Sean R. Hosein
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