Controversies over cardiac risk

Not all clinicians agree that the cholesterol elevations seen in HAART patients are predictive of heart disease.

There is clear evidence that different drugs tend to produce different patterns of cholesterol elevation. For example, in the Atlantic study, after two year on treatment with nevirapine participants experienced a 40% increase in HDL cholesterol levels, but a non-significant change in LDL cholesterol levels. In the indinavir arm of the same study, LDL cholesterol rose significantly (by 14%) but HDL cholesterol levels did not. The total cholesterol levels rose by 22% in both the indinavir and the nevirapine arms in this study, but only one of these changes could be defined as atherogenic.1 Efavirenz treatment has also been shown to elevate HDL cholesterol.

Despite these attempts to downplay the risk of heart disease among people taking protease inhibitors (PIs), other clinicians are more cautious. They point to the fact that heart attacks and other cardiovascular events in people under the age of 45 have been associated with as few as one or two of the risk factors associated with heart disease. A study of HIV-negative individuals from the Framingham database found that very high lipid levels are not necessary for individuals to experience an increased risk of heart disease. Quite marginal increases in the presence of other risk factors such as raised blood pressure and smoking resulted in an elevated risk.2

Although it appears that high triglyceride levels also contribute to cardiac risk in people with HIV, it is not clear how strongly they predict risk, or how much benefit triglyceride-lowering interventions might have. Although some analyses have not shown triglycerides to be an independent risk factor in the development of heart disease, the Framingham analysis suggests that the LDL:HDL cholesterol ratio and triglycerides may be relevant markers of cardiovascular risk in HIV disease. An analysis from the large D:A:D study also found that higher triglyceride levels were independently associated with a higher risk of myocardial infarction, or heart attack. The D:A:D researchers suggested, however, that triglycerides had limited prognostic value after taking cholesterol levels into account, and that triglyceride-lowering therapies would be unlikely to have a substantial impact.3

Studies by FRAM (Fat Redistribution and Metabolic Change in HIV Infection) and D:A:D investigators have found that intima-media thickness (IMT) was not associated with PI use or HIV status, but rather with 'traditional' risk factors such as age and body mass index. (An exception found in one study was an unexpected protective effect from tenofovir.) 4 5 6 These recent studies are in agreement with older findings that HAART did not impact on the arteries 7 8 or that individuals on PIs had very mild arterial thickening.9

Several recent studies have reached the opposite conclusion – that HIV infection and/or HAART do in fact contribute to hardening of the arteries. The reason for the disparity is not completely explained, but may be due to differences in the techniques used to assess the degree of atherosclerosis. Studies using a common diagnostic measure, carotid IMT, have generally found no difference due to HIV infection or HAART. 

One such 'dissenting' study found that outcomes depended on the precise site of the IMT measurement. In the common carotid artery, where IMT is usually measured, differences between HIV-positive patients and matched HIV-negative controls were small and not statistically significant. In contrast, measurements in the carotid bulb showed that HIV increased the extent of atherosclerosis by about the same amount as the strongest traditional risk factors such as smoking, diabetes and male sex.10

Another study, which found that atherosclerotic risk increased with HIV infection and increased still more with HAART use, used another different measure (pulse wave velocity) to gauge arterial stiffness.11

Other researchers also suggest that traditional risk factors do not entirely account for, and therefore underestimate, cardiac risk in people with HIV. One Italian study used electron-beam tomography (CAT) scanning to identify patients with high-risk levels of calcification and hardening of the arteries. CAT scans identified a need for medical intervention in roughly 7% of high-risk patients who were not diagnosed as needing intervention by the Framingham Risk Score or the European Society for Hypertension guidelines.12

Others have found that biomarkers not yet in routine use, such as D-dimer, are also independent predictors of cardiovascular disease and may therefore play an important role alongside traditional factors in identifying patients at risk.13

References

  1. van der Valk M et al. Lipodystrophy in HIV-1-positive patients is associated with insulin resistance in multiple metabolic pathways. AIDS 15: 2093-2100, 2001b
  2. Lloyd-Jones DM et al. The risk of congestive heart failure: sobering lessons from the Framingham Heart Study. Current Cardiology Reports 3(3): 184-190, 2001
  3. Worm S et al. Triglycerides and the risk of myocardial infarction in the D:A:D study. Seventeenth Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 127, 2010
  4. Currier JS et al. Carotid artery intima-media thickness and HIV infection: traditional risk factors overshadow impact of protease inhibitor exposure. AIDS 19: 927-933, 2005
  5. Delaney JAC et al. Associations of antiretroviral drug use and HIV-specific risk factors with carotid intima-media thickness. AIDS 24: online edition, DOI: 10.1097/QAD. Obo13e32833d2132, 2010
  6. The D:A:D Writing Committee Cardio- and cerebrovascular events in HIV-infected persons. AIDS 18: 1811-1817, 2004
  7. Depairon M et al. Noninvasive morphological analysis of carotid and femoral arteries in protease-inhibitor-treated HIV-infected individuals. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 29, 2000
  8. Currier JS et al. A pilot study of carotid intima media thickness (IMT) in HIV-infected women treated with protease inhibitors. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 32, 2000
  9. Cheminot N et al. Diagnosis and determination of subclinical arterial disease in HIV 1-infected patients on HAART. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 31, 2000
  10. Grunfeld C et al. HIV infection is an independent risk factor for atherosclerosis similar in magnitude to traditional cardiovascular disease risk factors. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 146, 2009
  11. Lekakis J et al. Association of highly active antiretroviral therapy with increased arterial stiffness in patients infected with human immunodeficiency virus. American Journal of Hypertension (online edition), 2009
  12. Guaraldi G et al. Moving from risk factor assessment to atherosclerosis imaging to select the most appropriate patient for primary prevention. 12th European AIDS Conference, Cologne. Abstract BPD 2/2, 2009
  13. Ford ES et al. Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection. AIDS, online edition: DOI: 10.1097/QAD.0b013e32833ad914, 2010
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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