A trip through Saturn with low-dose rosuvastatin among HIV-positive people
HIV infection is associated with an increased risk for cardiovascular disease, including heart attack and stroke. This risk is likely driven by several factors, including HIV infection, changes to the immune system, and inflammation. Taking potent combination anti-HIV therapy (commonly called ART or HAART) can greatly reduce HIV-related inflammation and improve overall health, but additional steps are needed to reduce the risk for cardiovascular disease. For more information about how to reduce this risk, see the CATIE fact sheet HIV and cardiovascular disease.
Past studies with thousands of participants have found that elevated levels of certain proteins in the blood are associated with an increased risk of serious complications and death among HIV-positive people. Examples of these proteins include the following:
- high-sensitivity C-reactive protein (hsCRP)
- interleukin-6 (IL-6)
Many research teams are studying ways to help reduce excess inflammation in ART users.
Among HIV-negative people, the use of certain cholesterol-lowering medicines called statins, such as atorvastatin (Lipitor) and rosuvastatin (Crestor), has been found to reduce the level of proteins associated with inflammation and immune activation in the blood.
Researchers in Cleveland in the U.S. are conducting a study called Saturn designed to assess the impact of low-dose rosuvastatin (10 mg/day) vs. placebo among HIV-positive people with normal levels of cholesterol but elevated levels of inflammation or immune activation.
Interim results from Saturn have not found any signals of harm from exposure to low-dose rosuvastatin. This should not be surprising, as low-dose rosuvastatin is generally well tolerated. Furthermore, participants who took rosuvastatin had significantly decreased levels of bad cholesterol (LDL-C). However, most proteins or markers associated with immune activation and inflammation did not change appreciably. Saturn is an ongoing study so further results are expected in the years ahead.
Researchers enrolled adult HIV-positive participants who had normal LDL-C but elevated levels of inflammation or T-cell activation as assessed by blood tests. All participants were using ART and were randomly assigned to receive one of the following:
- 72 people – rosuvastatin 10 mg (one pill daily)
- 75 people – fake rosuvastatin (placebo, one pill daily)
The average profile of participants at the start of the study was as follows:
- age – 47 years
- 78% men, 22% women
- CD4+ cell count – 613 cells/mm3
- HIV viral load less than 50 copies/ml – 76%
- duration of HIV infection – 12 years
By the 24th week of the study, levels of LDL-C decreased by 28% among rosuvastatin users compared to an increase of 4% in people on placebo.
No significant differences between participants who used rosuvastatin or placebo were found when researchers reviewed levels of commonly assessed fatty substances in the blood such as good cholesterol (HDL-C) and triglycerides.
Researchers found that rosuvastatin helped to greatly slow the decline of the kidneys’ ability to filter the blood when compared to placebo. This finding of preservation of kidney function is important. Over a decade ago, when rosuvastatin first became available, it was taken at much higher doses and it adversely affected kidney health. However, the present and other recent studies reinforce the overall safety of low-dose rosuvastatin.
Researchers conducted extensive analyses of blood proteins or markers associated with inflammation and immune activation. Surprisingly, there were no significant differences in changes of such markers between users of rosuvastatin or placebo. Past smaller studies in HIV-positive people had found minor changes in such markers.
An unusual marker
Failing to find changes in the usual assessments of inflammation and immune activation, the researchers focused on an uncommonly used protein called lipoprotein-associated phospholipase A2 (Lp-PLA2). Levels of this protein fell by 10% among rosuvastatin users compared to a 2% decrease among placebo-users; this difference was statistically significant. However, other researchers have questioned whether this difference made any difference to the health of users. In other words, did this change have any clinical significance? Lp-PLA2 levels are not routinely assessed as part of the care and treatment of HIV-positive people, nor are levels of this protein routinely assessed in HIV clinical trials.
Furthermore, it is noteworthy that the experimental drug darapladib was being tested in a placebo-controlled trial called Stability with HIV-negative people. The drug lowers Lp-PLA2 levels and was hoped to have an impact on cardiovascular events such as heart attack, stroke and so on. Unfortunately, this drug did not have a significant effect on these events in the Stability study. Thus caution is needed when assessing changes in Lp-PLA2 levels and trying to make projections about the future health of patients based on those changes.
Looking at the future
As mentioned earlier, the Saturn study is ongoing and researchers plan additional analyses, such as ultrasound scans of the arteries in the neck. Such assessments that measure the narrowing of arteries due to cardiovascular disease are a well-validated method for predicting the risk of future events such as a stroke.
Even if Saturn and other studies ultimately show that statins fail to significantly suppress HIV-related inflammation, they will have yielded valuable information. Such information may cause scientists to question the source of the excess inflammation in HIV-positive people and attempt further experiments to address the following issues:
- Is the excess inflammation linked to T-cells or other cells of the immune system such as monocytes and/or macrophages?
- Is the excess inflammation caused directly by HIV or its proteins and their impact on the immune system?
- Do other germs, particularly herpes viruses, play a role in excess inflammation seen in HIV-positive people?
—Sean R. Hosein
- Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012 Aug 11;380(9841):565-71.
- Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2014; in press.
- Frayling TM. Statins and type 2 diabetes: genetic studies on target. Lancet. 2014; in press.
- Watts GF, Ooi EM. Balancing the cardiometabolic benefits and risks of statins. Lancet. 2012 Aug 11;380(9841):541-3.
- Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Annals of Internal Medicine. 2013 Apr 2;158(7):526-34.
- Longenecker CT, Hileman CO, Funderburg NT, et al. Rosuvastatin preserves renal function and lowers cystatin C in HIV-infected subjects on antiretroviral therapy: the SATURN-HIV trial. Clinical Infectious Diseases. 2014 Oct 15;59(8):1148-56.
- Dubé MP. Will statins be an effective anti-inflammatory intervention for prevention of cardiovascular disease in patients with HIV? Journal of Infectious Diseases. 2014 Apr 15;209(8):1149-50.
- Eckard AR, Jiang Y, Debanne SM, et al. Effect of 24 weeks of statin therapy on systemic and vascular inflammation in HIV-infected subjects receiving antiretroviral therapy. Journal of Infectious Diseases. 2014 Apr 15;209(8):1156-64.
- Masiá M, Robledano C, Ortiz de la Tabla V, et al. Coinfection with human herpesvirus 8 is associated with persistent inflammation and immune activation in virologically suppressed HIV-infected patients. PLoS One. 2014 Aug 18;9(8):e105442.