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Pilot Study Explores ACE Inhibitor and Statin as Anti-inflammatory Therapy for HIV
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19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini
Lisinopril, an ACE inhibitor, lowered blood pressure and eased inflammatory markers in a pilot study that enrolled antiretroviral-treated people with an low viral load [1]. Pravastatin had little effect on cholesterol or inflammatory markers in this small study, which aimed to assess adherence, tolerability, and feasibility.
Because inflammation persists in people with well-controlled HIV infection, the search is on for a tolerable, easy-to-take pill that will douse inflammatory fires and so perhaps avert inflammation-driven conditions, including cardiovascular disease. Jason Baker (University of Minnesota) and colleagues planned this pilot trial to test two potential anti-inflammatories for people with HIV, the ACE inhibitor lisinopril and the statin pravastatin. Lisinopril is licensed to treat hypertension and heart failure, while pravastatin is a cholesterol-lowering drug. Both, the investigators noted, are relatively inexpensive and safe agents.
Baker and coworkers recruited antiretroviral-treated people with a viral load below 200 copies, no contraindications for ACE inhibitors or statins, and a Framingham Risk Score at or above 3% for coronary heart disease over 10 years. The study excluded people with (1) known cardiovascular disease, diabetes, or a Framingham score over 20%, (2) blood pressure at or above 140/90 mm Hg, (3) low-density lipoprotein (LDL) cholesterol at or above 160 mg/dL with a Framingham score below 10%, or LDL cholesterol at or above 130 mg/dL and a Framingham score of 10% to 20%, (4) cirrhosis or liver enzymes more than 5 times the upper limit of normal, and (5) chronic kidney disease.
The researchers randomized 37 participants to (1) 10 mg of lisinopril daily plus 20 mg of pravastatin daily, (2) pravastatin plus lisinopril placebo, (3) lisinopril plus pravastatin placebo, or (4) placebo plus placebo. Study participants had a median age of 48 years (interquartile range [IQR] 44 to 55), 36 were men, and 17 (46%) were black, 16 (43%) white, and 3 (8%) Hispanic. Twenty-five people (68%) smoked, 12 (32%) had hepatitis B or C, 24 (65%) were taking a protease inhibitor, and no one ever injected drugs.
Median CD4 count stood at 495 (IQR 318 to 595). Median blood pressure was 123/76 mm Hg, total cholesterol 185 mg/dL (IQR 162 to 198), LDL cholesterol 98 mg/dL (IQR 86 to 117), and 10-year Framingham score 7.7% (IQR 4.9 to 10.6).
By self-report through 4 months of follow-up, side effects troubled 18% taking lisinopril versus 6% taking lisinopril placebo, a nonsignificant difference (P = 0.60). One person in each group reported "lisinopril cough." Self-reported side effects arose in 11% taking pravastatin and 12% taking pravastatin placebo.
Adherence through 4 months proved significantly worse with lisinopril than with lisinopril placebo, whether measured as percentage with no missed doses (13% versus 65%, P = 0.004) or percentage with better than 90% adherence by pill count (58% versus 100%, P = 0.01). While 39% and 40% taking pravastatin or pravastatin placebo reported missing no doses, 80% in each group had better than 90% adherence by pill count.
People taking pravastatin did not differ significantly from those taking pravastatin placebo in 1-month or 4-month change in total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, or total-to-HDL cholesterol ratio. Pravastatin had no impact on inflammatory markers at month 1 or 4, and there was no evidence of a pravastatin-lisinopril treatment interaction.
Through 4 months lisinopril lowered diastolic (but not systolic) blood pressure significantly more than placebo (P = 0.05). High-sensitivity C-reactive protein (hsCRP) rose over 4 months with placebo while falling slightly with lisinopril (P = 0.02). TNF-alpha rose with placebo and fell with lisinopril (P = 0.04). IL-6 changes did not differ significantly between lisinopril and placebo, but an overall inflammatory rank score improved with lisinopril while staying flat with placebo (P = 0.05).
Baker and colleagues stressed that the small sample size results in low power to detect treatment interactions. But they believe their findings "support the hypothesis that ACE inhibitor therapy may have anti-inflammatory benefits, beyond traditional risk factor modification, for antiretroviral-treated people with HIV infection."
Reference
1.Baker J, Huppler Hullsiek K, Prosser R, et al. ACEi or HMG-CoA reductase inhibitor (statin) treatment as adjunct therapy for persons with HIV infection: a pilot study. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 825. http://www.retroconference.org/2012b/PDFs/825.pdf.
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