Long-term HIV infection and poor inflammation control, not treatment, predicts risk of atherosclerosis

Keith Alcorn
Published: 07 March 2011

Long-term HIV infection is the only significant factor associated with thickening of the carotid intima media, a marker for atherosclerosis, a French case-control study has reported.

A strong anti-inflammatory response also appears to reduce the risk of carotid intima media thickening, independent of the duration of HIV infection. (The thickening of the wall of the carotid artery due to the accumulation of cholesterol, calcium and plaques is considered a reliable indicator of the progression of cardiovascular disease).

A number of studies have shown that people with HIV infection have a higher risk of cardiovascular disease than their HIV-negative counterparts. Various risk factors have been identified, including treatment with several protease inhibitors, with the NRTIs abacavir and with ddI, as well as the widely known risk factors for heart disease of age, smoking and high lipid levels.

However some studies suggest that HIV infection itself, and the inflammatory state that uncontrolled HIV infection creates, are important risk factors for cardiovascular disease.

The difficulty in assessing which of the major risk factors is most important lies in untangling the many confounding factors. For example, the majority of people with HIV in many cohort studies either smoke or have an extensive smoking history. Also, not all studies control for duration of infection, for immunodeficiency, for viral load or for duration of treatment.

The new findings, presented last week at the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, come from a study carefully designed to exclude biases, by some of the leading international experts in the metabolic complications of HIV infection, led by Dr Moise Desvarieux.

The study compared men with long-term HIV infection who had been infected for a median of more than 7.9 years with men who had been infected for less than 7.9 years, and to untreated men and to HIV-negative age-matched men.

The study recruited 100 men who had been infected for between 3.8 years (median period of infection in the untreated group <7.9 years duration of infection) to 14 years in the treated group with a median duration of infection greater than 7.9 years.

There were no significant differences in any cardiovascular indicators (total cholesterol, LDL and HDL cholesterol or triglycerides) between the groups. Nor was there any significant difference in age between the groups recruited (the median age of the groups ranged from 38.9 to 43 years).

The study only recruited men who had never smoked in order to rule out any bias introduced by smoking, which is common in men with HIV infection and an independent risk factor for atherosclerosis (hardening of the arteries). The analysis controlled for CD4 count, viral load and duration of treatment.

Carotid intima media thickness (cIMT) was significantly associated with duration of infection, after adjusting for nadir (lowest ever) CD4 count, regardless of antiretroviral treatment. Greater cIMT was also associated with low levels of anti-inflammatory cytokines. Declining levels of adiponectin, a substance which regulates a number of metabolic pathways and which has been associated with a reduced risk of cardiovascular disease, was strongly correlated with cIMT thickness.

However, higher levels of pro-inflammatory cytokines, suspected by some as a cause of cardiovascular disease in people with HIV, were much less strongly associated with greater cIMT.

Another study, which looked at 235,000 patients receiving care through the Kaiser Permanente network of clinics in California (20,775 HIV-positive), found that individuals with HIV infection had a 40% higher risk of myocardial infarction and 20% higher risk of any cardiovascular disease than their HIV-negative counterparts after controlling for age (both values p < 0.001).

In HIV-positive patients on treatment, immunodeficiency had a significant impact on cardiovascular risk: individuals with a current CD4 count below 500 cells/mm3 had a significantly higher risk of cardiovascular disease (risk ratio 1.4 for CD4 200 to 499, risk ratio 1.7 for CD4 < 200, p < 0.001). Those with nadir CD4 counts below 200 and now on treatment also had an elevated risk (RR 1.4, p < 0.001).

A similar pattern for myocardial infarction was observed in treated patients, although the elevation in risk was marginally greater.

In untreated patients the only elevation in risk was observed in the stratum of patients with lowest CD4 counts between 200 and 499. This result may be explained by duration of infection, since individuals would need to pass through this stratum in order to reach one of the treated strata described above.

Unsurprisingly the study also found that among HIV-positive patients, age had the strongest impact on a person's risk of cardiovascular disease, with individuals aged 65 and over at 12-fold greater risk of a diagnosis of coronary heart disease than individuals aged 18 to 39, even after controlling for years since HIV diagnosis. Individuals aged 50 to 64 had a sixfold greater risk, and 40 to 49 years a 2.5-fold greater risk when compared to 18 to 39 year olds. Time since HIV diagnosis had no significant impact on risk, and even smoking had a modest impact on risk in comparison to age (RR 1.9, p < 0.001).

Although the authors caution that the results may be less generalisable to women and ethnic minorities, and note that they could not control for family history of heart disease, they note that their findings support earlier initiation of antiretroviral treatment.

A role for CCR5 inhibitors in reducing cardiovascular risk?

An intriguing study from Priscilla Hsue and Steven Deeks' group at the University of California, San Francisco, showed that endothelial dysfunction, an early marker of cardiovascular disease, is significantly associated with a higher frequency of CCR5+ CD4 T-cells in HIV-positive men with viral load suppressed below 75 copies/ml.

The study looked at 58 individuals, largely men, with a median CD4 count of 502 and very low flow-mediated dilatation (a marker of endothelial dysfunction).

The researchers were looking for the immunologic correlates of endothelial dysfunction – specifically, whether any markers of immune activation or ongoing low-level viremia were associated with loss of endothelial function in people with controlled HIV infection.

They also looked at whether CMV-specific immune responses might be associated with endothelial dysfunction in this population; CMV has been linked to cardiovascular disease in other studies in the general population.

They found no association between CMV-specific activated cells, but did observe a significant association between the level of CCR5+ CD4 and CD8 cells in the peripheral blood (r = –0.26, p = 0.045).

They now plan to look at the effect of treatment intensification with the antiretroviral drug maraviroc, a CCR5 inhibitor, on endothelial dysfunction, and to test whether treatment intensification with raltegravir, an integrase inhibitor, has an effect on immune activation related to low-level viremia, and in turn, on endothelial dysfunction.

References

Desvarieux M et al. Carotid atherosclerosis is related to HIV duration and anti-inflammatory profile and not to ARV exposure: the CHIC controlled study. Eighteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 803, 2011.

Klein D et al. Contribution of immunodeficiency to CHD: cohort study of HIV+ and HIV Kaiser Permanente members. Eighteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 810, 2011.

Hunt P et al. Impaired endothelial function is associated with increased frequencies of CCR5+ and HIV-specific T Cells during treated HIV infection. Eighteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 814, 2011.

Abstracts and webcasts

You can view the abstracts from this research on the official conference website:

Abstract 803: www.retroconference.org/2011/Abstracts/41184.htm

Abstract 810 and PDF of poster: www.retroconference.org/2011/Abstracts/40434.htm

Abstract 814 and PDF of poster: www.retroconference.org/2011/Abstracts/42214.htm

You can also watch webcasts of presentations made at the conference.

The webcast from the conference session Atherosclerosis and HIV: Risk Factors and Pathogenesis includes the presenter Daniel Klein.

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