Both HIV replication and some types of antiretroviral therapy contribute to cardiovascular risk

US research published in the online edition of Clinical Infectious Diseases suggests that both uncontrolled HIV replication and therapy with some types of antiretroviral drug contribute to hardening of the arteries, an important early warning sign of cardiovascular disease.

Investigators from the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (the SUN study), found that suppressing viral load to undetectable levels lessened the progression of atherosclerosis. Patients whose HIV therapy included a non-nucleoside reverse transcriptase inhibitor (NNRTI) were less likely than those who received a protease inhibitor to experience hardening of the arteries.

“Our findings suggest that maintaining a clinically suppressed VL [viral load] protects against atherosclerotic progression,” comment the authors. “After adjusting for the protective effects of viral suppression, use of NNRTI-based cART [combination antiretroviral therapy] was associated with less [hardening of the arteries] than was PI-based cART.”

Cardiovascular disease is now an important cause of illness and death in patients with HIV. The exact reasons are unclear but appear to include a number of factors. These include the ageing of the HIV population and the high prevalence of traditional risk factors, for example smoking.

However, some research has suggested that uncontrolled HIV replication may be an important risk factor. This is probably related to the inflammatory effects of the virus.

Overall, patients taking antiretroviral therapy have a lower risk of cardiovascular disease than individuals not taking anti-HIV drugs. But, studies have suggested that protease inhibitors increase the risk of cardiovascular disease. There is also controversy about the risk of heart attack associated with abacavir (Ziagen, also in the combination pill Kivexa).

Researchers from the SUN study wanted to clarify the causes of cardiovascular disease in patients with HIV.

An important early-warning sign of cardiovascular disease is hardening of the carotid artery. Therefore the investigators monitored the carotid artery intima-media thickness (CIMT) of 389 HIV-positive patients over a two-year period. The patients were recruited between 2004 and 2006.

At baseline the patients had a median age of 42 years, and 77% were men. A third of patients were smokers and 36% had a diagnosis of hypertension when they entered the study.

The median baseline CD4 cell count was 485 cells/mm³ and 78% of patients were taking HIV therapy. At the start of the study, 88% of the treated patients had an undetectable viral load and 61% maintained a viral load below the limit of detection for the two years of the research.

Similar proportions of patients were taking NNRTI-based and PI-based HIV therapy. Approximately a quarter of patients were taking abacavir and 36% were prescribed tenofovir (Viread, also in the combination pills Truvada and Atripla).

Median CIMT at baseline was 0.707 mm and this increased to 0.721 mm after two years. The median two-year change of 0.016 mm was significant (p < 0.001).

Less CIMT progression was seen in patients who were prescribed HIV therapy at baseline than in those who were not (0.014 mm vs. 0.019 mm) and in patients with a suppressed baseline viral load (0.013mm vs. 0.021 mm). These differences approached significance.

However, the investigators found that patients who maintained an undetectable viral load throughout the two years of the study had less CIMT progression than patients with detectable virus (0.015 mm vs. 0.019 mm, p < 0.001).

CIMT progression was also less in those prescribed an NNRTI than in those taking a protease inhibitor (0.011mm vs. 0.019 mm, p = 0.012).

The investigators’ first analysis showed that a higher body mass index was associated with hardening of the arteries (p < 0.01), as was poorer kidney function (p = 0.029), a persistently detectable viral load (p = 0.023) and treatment with a protease inhibitor (p = 0.004).

 Further analysis controlled for potentially confounding factors. This showed that a detectable viral load at baseline (p = 0.015) and during follow-up (p < 0.001) both remained associated with CIMT progression, as did a higher body mass index (p < 0.001).

“Clinically detectable HIV replication is associated with greater CIMT,” comment the authors.

Analysis was then restricted to the patients taking HIV therapy.

After adjusting for traditional risk factors and HIV suppression during follow-up, the investigators found that therapy with a protease inhibitor was associated with more extensive hardening of the arteries than treatment based on an NNRTI (p = 0.011).

This relationship persisted when the analysis only included individuals who did not switch between NNRTIs and protease inhibitors during the course of the study (p = 0.02).

There was no evidence that abacavir increased the risk of CIMT progression.

“Our findings implicating PI exposure are consistent with data from the D:A:D study,” write the investigators, “but we observed no differences in CIMT progression between abacavir and tenofovir.”

They conclude: “Persistent suppression of HIV replication below clinical thresholds was associated with less atherosclerotic progression. Future controlled studies are needed to replicate these findings and better characterise the proatherogenic mechanisms of HIV replication as well as evaluate the net benefit of specific antiretrovirals on long-term CVD risk.”