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Does Ziagen raise heart disease risk?

Two large studies of HIV patients found a link between treatment with the nucleoside Ziagen (abacavir) and a higher risk of heart attacks (myocardial infarction, MI) and other heart disease. (1),(2) But analysis of people who took Ziagen in recent trials found no such link. (3) Understanding these results is important because Ziagen is widely used in antiretroviral combinations, often as part of a double-nucleoside pill (Kivexa or Epzicom, which also includes Epivir [lamivudine] or a triple-nucleoside pill Trizivir, which also includes Epivir and Retrovir [zidovudine]).

None of these studies proves or disproves that Ziagen causes heart disease. The first two studies--an analysis of the large DAD group of people with HIV (1) and a look at heart disease rates in the completed SMART trial (2)--show a higher relative rate or excess risk of MI or other heart disease with Ziagen than with other nucleosides. A higher relative rate means study participants who took Ziagen had more new heart disease diagnosed than people who took other nucleosides.

The absolute rate of heart disease with Ziagen was not high for people with an otherwise low risk of heart disease. In other words, although the risk of heart disease was higher in people who took Ziagen than in those taking other nucleosides, their overall risk of heart disease was still small. However, that higher absolute rate with Ziagen may be worrisome for people who have other heart risk factors, like being overweight or smoking.

Researchers from GlaxoSmithKline, Ziagen's maker, conducted the third study, which compared rates of heart disease in people who did or did not take Ziagen in 54 randomized trials. (3) They found no heart disease difference between people who took Ziagen and people who did not.

* How the three studies worked.

DAD is an ongoing study of more than 30,000 people with HIV infection.(1) This research compared Ml rates in people who took the nucleosides Ziagen, Videx (didano-sine), Epivir, Zerit (stavudine), or Retrovir. DAD researchers did not report MI rates with Viread (tenofovir) or Emtriva (emtricitabine) because patients had not taken these two medications long enough to allow statistical comparisons. The investigators estimated MI risk for both total use and current use of these nucleosides. To estimate risk, the investigators used statistical methods that also considered other MI risk factors.

SMART is the international trial that randomly assigned HIV-infected people to continuous antiretroviral therapy or to intermittent therapy guided by CD4 counts. (4) The study showed that interrupting treatment with this strategy raises the risk of new AIDS diseases as well as non-AIDS diseases, including heart disease. (5) Because of the DAD report,(1) SMART investigators measured rates of MI, major cardiovascular disease, and an even broader group of cardiovascular diseases in three groups from the trial's continuous-therapy group: (1) people who took Ziagen without Videx, (2) people who took Videx, and (3) people who took other nucleosides. (2) This analysis included all 2752 people who took continuous antiretroviral therapy in the SMART trial. As people entered the trial, the SMART team also measured levels of health markers that may boost the risk of heart disease. This marker analysis included some people from SMART'S treatment interruption group.

GlaxoSmithKline investigators compared rates of Ml and coronary artery disease in 9639 people who took Ziagen in 54 clinical trials that assessed Ziagen and in 5044 people who did not take Ziagen in these studies. (3) Length of treatment averaged 24 to 48 weeks.

* What the studies found.

DAD researchers found that current use of Ziagen raised the relative MI rate 90% compared with people not currently using Ziagen. (1) This higher rate was highly statistically significant (P < 0.0001, meaning there is less than a 1 in 10,000 possibility that the finding occurred by chance). Current use of Videx raised the relative MI rate 49% compared with no Videx use. People who took Ziagen or Videx but stopped these nucleosides more than 6 months ago no longer had higher relative MI rates than people who never took Ziagen or Videx.

These higher relative Ml rates remained the same after the investigators factored in other findings that contribute to heart disease. In other words, these other MI risk factors did not appear to explain why people taking Ziagen or Videx had a higher MI risk than people not taking these agents. The absolute MI rate in DAD patients was 6.1 Mis per 1000 person-years with current Ziagen (versus 2.6 without current Ziagen) (Figure 8) and 4.5 per 1000 person-years with current Videx (versus 3.0 without current Videx). In the SMART analysis, current Ziagen use doubled the risk of major cardiovascular disease or broadly defined major cardiovascular disease when compared with other medications, including Viread. (2) Other heart disease risk factors did not appear to affect this higher risk with abacavir. Levels of two possible heart disease markers were significantly higher in people taking Ziagen than in those taking other nucleosides when SMART began. Neither Videx nor any other nucleoside had any impact on cardiovascular disease risk or on these heart disease markers.
 Glaxo DAD

M1 with Ziagen 2.04 6.1

M1 without Ziagen 2.36 2.6

CAD with Ziagen 3.4

CAD without Ziagen 5.82

Per 1000 person-years of follow-up
Figure 8. Analysis of 54 clinical trials found no difference in heart
attack risk or coronary artery disease risk with or without Ziagen
(blue bars). But a study of more than 30,000 patients in the DAD group
found a higher heart attack rate with Ziagen than without Ziagen (red
NOTE: Table Made from the bar graph

The 54-trial GlaxoSmithKline analysis did not find higher rates of MI or coronary artery disease in people taking Ziagen-containing regimens than in those taking non-Ziagen regimens. (3) MI rates in Ziagen takers were lower in this analysis than in the DAD study (2.04 versus 6. Mis per 1000 person-years), perhaps because the GlaxoSmithKline study group was younger than the DAD patients (median 36 years versus 48 years) and the GlaxoSmithKline trial participants included a lower proportion of men (86% among antiretroviral-experienced participants versus 92% of DAD members). Older people have a higher heart disease risk than younger people, and men have a higher risk than women.

* What the findings mean for you. All of these investigators caution that cohort studies and analyses of completed trials cannot give a final answer on heart disease risk with Ziagen or any other antiretroviral. In the GlaxoSmithKline trials, random assignment of study participants to Ziagen or no-Ziagen regimens helps ensure that heart disease risks were similar in the two groups when the studies began. However, in their studies DAD and SMART investigators did make statistical adjustments for as many heart risk factors as they could.

At the same time, people taking non-Ziagen regimens in the GlaxoSmithKline trials may have been taking other antiretrovirals--such as certain protease inhibitors--that are also known to increase heart disease risk. In such cases it is impossible to separate the potential heart-disease effect of Ziagen from the potential effect of the protease inhibitor.

GlaxoSmrthKhne studies

* 14,174 people analyzed

* 7845 person-years of follow-up in Ziagen group

* 4663 person-years of follow-up in non-Ziagen group

DAD study

* 33.347 people analyzed

* 157,912 person-years of follow-up

Ml: myocardial infarction (heart attacks)

CAD: coronary artery disease

The DAD analysis was much bigger than the 54-trial GlaxoSmithKline analysis--33,347 people studied through 157,912 person-years of follow-up in DAD, versus 14,683 people (14,174 adults) in the GlaxoSmithKline trials studied through 7845 person-years in the Ziagen group and through 4653 person-years in the non-Ziagen group. A larger study may detect small differences between groups that a smaller study will miss.

DAD researchers advised HIV physicians who consider stopping Ziagen because of their findings to assess possible risks and benefits of such a change. (1) That assessment, they wrote, should consider a person's "underlying risk of myocardial infarction, the availability of other treatment options after taking into account their history of past treatment and HIV resistance testing, and the safety profile of alternative HIV medication." All antiretrovirals that might replace Ziagen may cause harmful side effects.

Higher rates of two heart disease markers in Ziagen takers in SMART hint that Ziagen may boost the risk of heart disease by causing inflammation in arteries. This inflammation may lead already existing plaques to break and cause Ml. GlaxoSmithKline is also measuring markers of inflammation in people who took part in Ziagen trials. In one trial, HEAT, these markers improved in people taking either Kivexa or Truvada with Kaletra (lopinavir/ ritonavir). (3) It is important to remember that all studies of heart disease in people taking antiretrovirals show the importance of other risk factors, including heart disease in the family, high cholesterol, high blood pressure, diabetes, and smoking.

After the DAD results appeared, the FDA announced it will study all findings on heart disease risk in people taking Ziagen and other nucleosides. (6) In November 2008 the US government-sponsored antiretroviral treatment panel moved Ziagen plus Epivir off the "preferred" list of nucleoside combinations to the "alternative" list. The change, the panel said, reflects "concerns regarding an increased risk of myocardial infarction [heart attacks] in patients with high cardiac risk factors, as suggested by-large observational cohort studies, and concerns regarding virologic potency in patients with [pretreatmentj viral loads above 100,000 copies.' (7) (For studies on the virologic potency of Ziagen, see the report starting on page 26.)


(1.) DAD Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study. Lancet. 2008;371:1417-1426.

(2.) The SMART/INSIGHT and the D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008; 22:F17-F24.

(3.) Cutrell A. Hernandez J, Veo J, el al. Is abacavii -containing combination antiretroviral therapy associated with myocardial infarction? No assoc iation identified in pooled summary of 54 clinical trials. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract VVLAB0106.

(4.) The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296.

(5.) Phillips AN. Carr A, Neuhaus J, et al. Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-I infection: explanatory analysis from the SMART trial. Antivir Thei: 2008;13:177-187.

(6.) Klein R, Struble K. Early communication about an ongoing safety review of Ziagen (abacavir) and Videx (didanosine). Food and Drug Administration. March 27. 2007.

(7.) DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. November 3. 2008 (
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Title Annotation:Study 12
Publication:HIV Treatment: ALERTS!
Date:Dec 1, 2008
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