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TreatmentUpdate 172

Volume 21 Issue 3

2009 March/April

II COMPLICATIONS AND SIDE EFFECTS - B. France: a large hospital database looks at heart attacks

In 1989, doctors in France established the French Hospital Database (FHDB), which has collected health-related information on more than 77,000 HIV positive people. Researchers working in HIV sought to assess rates of heart attacks among HIV positive patients in France and looked at cases between the years 2000 and 2008. During this time they found 289 cases of heart attack, all of which were confirmed by a research cardiologist. These 289 cases of heart attack occurred among more than 77,000 people, about 80% of whom were using HAART (personal communication, Dominique Castagliola, PhD). To perform their analysis, researchers matched each case with at least one control patient. Each control was also HIV positive, had no history of cardiovascular disease, was of similar age and gender and went to the same clinic. The average profile of people with heart attacks (cases) was as follows:

• 10% female, 90% male
• age – 47 years
• CD4+ count – 427 cells
• viral load – 43% had a viral load below the 50-copy mark

Often, people who had experienced a heart attack (cases) had at least one risk factor for cardiovascular disease, as follows:

• smoking – 73%
• higher-than-normal levels of cholesterol – 52%
• higher-than-normal blood pressure – 21% of cases
• family history of CVD – 19%

Results—different anti-HIV agents

The research team assessed any relationship between the use of specific anti-HIV agents and the development of a heart attack. Here’s what they found:

• Abacavir (Ziagen and in Kivexa and Trizivir) posed a heart attack risk only in some people who had used it for less than one year. The risk is very low, about 1%. There was no long-term heart attack risk with the use of abacavir. Also, there was no link between the use of abacavir, having a risk factor for CVD and the development of a heart attack. This last finding was deeply puzzling and suggests the possibility that abacavir use might trigger the development of a heart attack in an unexpected way. Note that 90% of people who were using abacavir had previously received d4T or tenofovir.
• Other nukes: There was a trend for an increased risk of heart attacks in people who had used AZT (zidovudine, Retrovir and in Combivir) and d4T (stavudine, Zerit). However, this trend did not become statistically significant and further investigation is needed to clarify it.
• Overall, the use of a protease inhibitor (PI) boosted with ritonavir was linked to a 16% increase in risk of heart attack for each year these drugs were used.
• Fosamprenavir (Telzir, Lexiva) was linked to a 52% increased risk of heart attack. Over a period of 10 years of continuous use, this risk would climb.
• Lopinavir-ritonavir (Kaletra) appeared to increase the risk of heart attack by 37% for each year used.

Bear in mind

1. The findings from France are interesting but not definitive. Because this was an observational study, the FHDB can find associations but cannot conclusively prove that exposure to a particular drug does indeed cause heart attacks.

That abacavir is somehow associated with the rare risk of a heart attack is unexpected, as until recently this drug had an excellent safety record. According to the FHDB, traditional risk factors for heart attacks were not linked to abacavir-associated heart attacks, which simply adds to the mystery.

2. An important point is that abacavir can cause inflammation—as seen in the hypersensitivity reaction that can occur in up to 8% of abacavir users who are not tested for their risk for this problem. In people who are tested for hypersensitivity before using abacavir, the risk of this problem (hypersensitivity) is rare.

In the FHDB, abacavir hypersensitivity testing results were not taken into account when looking at abacavir-related heart attacks. This is probably because hypersensitivity testing has been available in Western Europe only for the past several years. This is an important point and here’s why:

• In abacavir-related hypersensitivity reactions, inflammation occurs. In theory, such inflammation could play a role in cardiovascular-related events, such as the unnecessary formation of blot clots or even a heart attack.
• Abacavir hypersensitivity testing has only been introduced in Western Europe over the past several years. Armed with the results of this testing, physicians only prescribe abacavir to people who are unlikely to develop a hypersensitivity reaction. Yet the French database used data on people who used abacavir since 2000—a time when hypersensitivity testing was not available. It is possible that some of the people who used abacavir and who also developed a heart attack had this problem because they were susceptible to an abacavir hypersensitivity reaction—with its attendant inflammation—and, subsequently, a heart attack.
• Now that abacavir hypersensitivity testing is increasingly part of various blood tests that doctors request, only people at very low risk for abacavir hypersensitivity are prescribed abacavir. It is possible that, in theory, people screened for this hypersensitivity reaction could be at very low risk for an abacavir-related heart attack. Therefore, collecting information on people who were screened for this reaction and who also developed a heart attack is important in trying to understand how abacavir might play a role in heart attacks.

3. The FHDB has found that, in general, the use of a PI with ritonavir results in about a 16% increased risk of heart attack with each year this combination is taken.

Some combinations have a higher-than-average risk of heart attack: lopinavir-ritonavir (Kaletra) is associated with a 37% increased risk and fosamprenavir-ritonavir (Telzir) is associated with a 52% increased risk of this event. Perhaps what is most shocking about the FHDB’s findings is that the heart attack risk associated with a PI-ritonavir combination does not go away when this combination is stopped. Moreover, removing ritonavir from their calculations did not reduce the risk. Researchers are not sure why this is the case but this finding is disturbing.

4. Not enough data was available on people who used other PIs, such as darunavir (Prezista) or atazanavir (Reytataz), for the French researchers to make clear conclusions about their use and potential heart attack risk.

Clearly more research is needed in the area of heart attacks and HIV medicines.

Created on: 2009 May 1

Author: Hosein SR

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