Statin therapy reduces immune activation in HIV-positive patients

Michael Carter
Published: 21 February 2011

High-dose statin therapy suppresses immune activation in antiretroviral-naïve HIV-positive patients, according to the results of a small clinical trial published in March 15th edition of The Journal of Infectious Diseases.

However, there was no evidence that treatment with statins lowered viral load.

Nevertheless, the investigators were encouraged by their finding that statin therapy “may influence the chronic immune activation observed in HIV-infected patients” and call for longer, larger studies “to investigate any clinical benefit of this drug for HIV-infected patients.”

But the author of an accompanying editorial cast doubt on the clinical significance of the study’s findings, and notes that the significance of changes in markers of immune activation in response to treatment is unknown.

Statins are best known as lipid-lowering drugs. However, laboratory studies suggest that they may also have an anti-HIV effect and may lower levels of immune activation.

Studies looking at the effect of statin therapy on viral load have had conflicting results.

To gain a better understanding of the anti-HIV effects of statins, US investigators designed a randomised, double-blind, placebo controlled, cross-over study. It involved a total of 22 HIV-positive patients. None were currently taking antiretroviral therapy and all had a CD4 cell count above 350 cells/mm3.

They were randomised into arms. The first was treated with a once-daily 80 mg dose of atorvastatin, the other with a placebo. After eight weeks, treatment was stopped and was followed by a “washout” phase, after which the patients switched their treatment assignments and the study entered a second eight-week phase.

The investigators monitored the impact of statin therapy on viral load. Tests were also performed to assess the impact of the drug on markers of cellular immune activation: expression of CD38 and HLA-DR on CD4 and CD8 cells. Liver and kidney function were regularly monitored to assess the safety of treatment.

During the statin phase of therapy, viral load fell by a median of 0.03 log10 copies/ml, compared to a fall of 0.08 log10 copies/ml during the placebo phase. These differences were not significant, and the investigators comment: “we did not observe an overall effect on HIV-1 RNA levels.”

However, statin therapy did have an effect on markers of cellular immune activation.

Expression of HLA-DR on CD4 cells and CD8 cells was significantly lower during treatment with atorvastatin than during the placebo phase (p = 0.02 and p = 0.0060 respectively. In addition, statin therapy lead to a reduction in expression of both CD38 and HLA-DR on CD8 cells (p = 0.03).

The investigators noted that the patients who had the greatest reductions in immune activation when taking statins also had the biggest falls in their viral load.

Total cholesterol and LDL cholesterol were also significantly reduced during the statin phase of the study (both p < 0.001). However, there was no relationship between levels of cholesterol and markers of immune activation.

Treatment was safe, and none of the patients had moderate or severe changes in their liver function. Three patients had altered kidney function, but this was possibly connected to their patterns of exercise.

“Although atorvastatin had no overall effect on HIV-1 RNA levels in our study, its used resulted in significant reductions in the proportion of activated CD8+ T lymphocytes,” write the investigators.

They stress that their study was not “designed to demonstrate clinical benefits” and they call for larger studies with longer follow-up periods to investigate any benefits from therapy with this drug.

Nevertheless they conclude: “The availability of generic formulations and the results of recent studies revealing a benefit to statin use in the primary prevention of cardiovascular disease, a common complication in HIV-infected patients, make the continued study of statins as disease-modifying agents in HIV-infected individuals particularly attractive.”

Andrew Carr, the author of the accompanying editorial, believes that the results of this study mean that statins should be evaluated over a longer period in a trial involving patients who are taking successful HIV therapy, but who continue to have immune activation.

However, he cautions that “a very large study would probably be required to determine whether the potentially positive effects of statin therapy on inflammatory biomarkers will translate into less HIV disease progression and fewer cases of inflammatory non-AIDS-related illnesses, such as cardiovascular disease and end-stage liver disease.”

Reference

Ganesan A et al. High dose atorvastatin decreases cellular markers of immune activation without affecting HIV-1 RNA levels: results of a double-blind randomized placebo controlled clinical trial. J Infect Dis 203: 756-64, 2011 (click here for the free abstract).

 Carr A. Statins as anti-inflammatory therapy in HIV disease? J Infect Dis 203: 1-2, 2011 (click here for an extract of the text).