An important study called REPRIEVE, aims to answer some important questions regarding heart disease risk for people living with HIV. The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), or A5332, is a multi-centered, mainly US based, study is investigating the use of prophylactic statin therapy as a preventative method against cardiovascular disease (CVD) in HIV-positive people. REPRIEVE is one of the largest prospective interventional studies to be conducted among HIV patients, and the first major study to widely test a prevention strategy for cardiovascular disease in the HIV population. If successful, the prophylactic use of statins could provide an important means of significantly reducing the occurrence of heart disease in the HIV-positive population.
HIV positive individuals experience cardiovascular disease at a 1.5 to 2-fold higher rate than their negative counterparts making CVD a leading cause of illness and death in HIV- positive people. Researchers believe that there are several reasons for this. Some general risk factors for CVD, such as smoking, IV drug use, diabetes and sedentary life style, occur more frequently among people with HIV/AIDS. HIV patients also quite often have a higher rate of elevated lipids (dyslipemia) that can lead to CVD. It is believed that HIV itself can contribute to CVD due to, among other factors, increased rates of subclinical atherosclerosis, immune activation and inflammation. Various antiretroviral medications, particularly some protease inhibitors, may increase CVD risk as well through effects on lipids, glucose and body composition. However, recent data suggests that viral suppression related to ART may be useful to reduce inflammation and immune activation.
According to Dr. Steven Grinspoon MD, Professor of Medicine at Harvard Medical School and the Mass General Hospital, and principal investigator of the REPRIEVE study, “Cardiovascular disease is increased among HIV-infected patients, and often presents in relatively young asymptomatic patients. There is a critical need to develop prevention strategies for heart disease in the HIV population, and REPRIEVE will be the first large scale study to investigate such a strategy. If successful, REPRIEVE will change practice and demonstrate a new strategy to prevent excess cardiovascular disease in the large population of HIV patients without significant traditional risk and not easily identified by current risk stratification algorithms”.
REPRIEVE is a landmark randomized double-blind, nationwide study that is evaluating the prophylactic effect of Pitavastatin on cardiovascular disease in HIV-positive participants. The National Heart, Lung and Blood Institute (NHLBI) along with the National Institute of Allergy and Infectious Diseases (NIAID) will sponsor the trial through the AIDS Clinical Trials Group as well as other NIAID network sites. The 100 site study will enroll 6,500 HIV positive individuals ages 40-75 on ART that have no indication of cardiovascular disease. Participants will receive either a 4 mg. dose of Pitavastatin or placebo over the course of study, for up to 72 months. The main goal of the study is to assess for the occurrence of cardiac events in people on statin therapy, but it will also look at immune activation, LDL cholesterol levels and non CVD events including cancers, end-stage liver and kidney disease and AIDS-defining events.
In addition, in order to identify how statins work in the primary prevention of CVD, 800 study participants from the group of 6,500 will receive thorough assessments of the impact of Pitavastatin on the characteristics of arterial plaques and biomarkers of inflammation. Arterial plaque can lead to myocardial infarction (also known as heart attack) and inflammation is thought to be a leading contributor to CVD.
Pitavastatin, the drug used in the study, is a statin (HMG-coenzyme A reductase inhibitors). Statins are considered the most effective drug at lowering increased LDL cholesterol. Several observational studies also suggest that statins can lower inflammation and may increase survival. Damaging inflammation occurs in HIV positive people despite antiretroviral therapy that lowers but does not eliminate inflammation. Despite these beneficial effects, statins may cause muscle irritation in some patients. Some statins are metabolized in the liver using P450 CYP3A4, the same pathway that protease inhibitors use to metabolize. Because of this, some protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) can cause a significant increase of statin levels in the blood that in turn can contribute to muscle aches and pains, making specific statins difficult to tolerate with certain antiretroviral therapy regimens. However, a study2 presented at CROI in 2014 by Kowa Pharmaceuticals, the makers of Pitavastatin, showed that Pitavastatin was safe and effective in lowering LDL levels, with or without Ritonavir, in people living with HIV. Pitavastatin is not metabolized by the P450 system and thus has no significant interactions with antiretroviral therapy
Lipids are fats that along with carbohydrates and proteins are the main parts of a cell. Lipids include various types of cholesterol, phospholipids, and triglycerides (TG). LDL is cholesterol often referred to as “bad cholesterol”. Elevated LDL places a person at risk of CVD including myocardial infarction, stroke and blood clots. HIV as well as some antiretroviral medications can cause high lipid levels, though these effects are largely on TG levels. Nonetheless, recent data suggest from non HIV patients, suggest that that even patients with modestly increased LDL levels may benefit from further LDL lowering, and this hypothesis will be tested in REPRIEVE.
Cardiovascular disease is a leading cause of illness and death in people living with HIV in the post-ART era. Measures to decrease the high rate of CVD are desperately needed. The six-year REPRIEVE study is the largest study to date on reducing CVD risk in the HIV-positive population and could change the protocol for CVD prevention in the HIV population. For more information on this study please see: https://clinicaltrials.gov/ct2/show/NCT02344290
by Anil Singh
REFERENCES 1. Association between Use of HMG CoA Reductase Inhibitors and Mortality in HIV-Infected Patients. RD Moore, JG Bartlett, and JE Gallant. PLoS ONE 6(7):e21843 (July12, 2011). 2. Risk of Coronary Disease in HIV Patients Markella V. Zanni, Judith Schouten, Steven K. Grinspoon and Peter Reiss Nat. Rev Cardiol 11, 728-741(2014): published online Oct 21, 2014: doi10.1038/nrcardio2014.167 2. Pitavastatin 4 mg is Superior to Pravastatin 40 mg on LDL-C Reduction after 12 and 52 Weeks of Treatment in Patients with HIV Infection and Dyslipidemia with and without Ritonavir-based Therapy Craig A. Sponseller, Roger E. Morgan, Vladimir A. Kryzhanovsk, Judith A. Aberg XX International AIDS Conference Melbourne, Australia Abstract THPE036