Anti-inflammatory drug could reduce heart disease risk in patients with HIV

Treatment with the anti-inflammatory drug salsalate improves the function of key cells in the blood vessels of HIV-positive individuals who aren’t taking antiretroviral therapy, according to a study published in the March 12^th edition of AIDS. But treatment with salsalate was associated with abnormal liver function in a large proportion of patients. The investigators call for further studies using lower doses of salsalate or other anti-inflammatory drugs.

There is concern that HIV-positive patients may have an increased risk of heart disease. Some (but by no means all) studies have suggested that antiretroviral therapy can increase the risk of heart disease for some patients.

Furthermore, the SMART treatment interruption study was stopped early when it was shown that patients who interrupted treatment were, amongst other things, more likely to develop heart disease than patients who took treatment all the time. It has also been suggested that inflammation caused by HIV can increase the risk of heart disease, although the reasons for this are not yet fully understood.

One possible reason is that HIV can cause long-term inflammation. This inflammation can mean that the cells lining the blood vessels, endothelial cells, don’t work properly, a condition called endothelial dysfunction. This can make it harder for blood to flow through the veins, and endothelial dysfunction often develops before hardening of the arteries, or atherosclerosis.

US investigators speculated that treatment with the anti-inflammatory drug salsalate would, by reducing inflammation throughout the body, improve endothelial function.

There is no information on the safety of salsalate in HIV-positive patients, so the researchers designed a small pilot study to see if the drug is safe. They hoped that this information would be of use in any later, larger studies.

A total of eleven patients were recruited to the study. All were 18 years or older. None of the patients were taking antiretroviral therapy and all had a CD4 cell count above 350 cells/mm³, the current threshold for starting anti-HIV therapy.

Treatment with an oral salsalate dose of 1500mg twice-daily was provided for eight weeks.

Tests to assess the flow of blood through the veins were performed on entry to the study and then after four and eights weeks of treatment. Other tests looking at levels of inflammation were also performed, as were screens to determine the safety of treatment.

Flow-mediated dilation, the diameter of blood vessels when blood flows through them, was low in all the patients at 2.7%, showing the presence of endothelial dysfunction.

Four weeks of treatment with salsalate lead to a slight improvement in flow mediated dilation in nine patients. This improvement was significant at the end of the eight week study in the eight patients who completed the trial (median increase, 4.2%, p = 0.02).

Other tests showed that were was no change in HIV viral load or in any other markers of inflammation.

But the investigators were concerned to see that one patient experienced a severe deterioration in liver function after two weeks of treatment, as did a second patient after three weeks. Both patients stopped salsalate treatment and withdrew from the study, with liver function returning to normal. Two other patients had mild elevations in their liver enzymes and reduced their dose of salsalate to 750mg twice-daily.

“Our data provide support for the concept that HIV, via systemic inflammation, may promote atherosclerosis independent of combination antiretroviral therapy”, write the investigators.

The rate of liver toxicity seen in the study was higher than expected, and the investigators think that this is may be because of the inflammation that HIV can cause.

“This pilot study demonstrates that anti-inflammatory therapy has the potential to improve endothelial dysfunction in HIV-infected subjects not receiving combination antiretroviral therapy”, conclude the investigators, adding, “further studies should evaluate either lower doses of salsalate or other anti-inflammatory agents with the goal of reducing cardiovascular events in this population.”