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INTREPID results support Livalo as optimal treatment for HIV patients with dyslipidemia
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Because patients with HIV are living longer due to recent advances in treatment, other health issues such as cardiovascular disease are becoming more evident in this population.
According to Judith A. Aberg, MD, FIDA, FACP, director of infectious disease at Icahn School of Medicine at Mount Sinai, and colleagues, the risk for myocardial infarction is 1.5 to 2 times higher in people living with HIV compared with uninfected individuals. In addition, dyslipidemia has been reported in up to 80% of patients with HIV. Although statin therapy is typically recommended for the condition, it has been a challenge to implement in this population because of adverse drug interactions with ART, which can sometimes lead to intolerance or reduced efficacy.
New data from the INTREPID trial, however, demonstrated that Livalo (pitavastatin, Kowa), a relatively new statin, resulted in greater reductions in LDL cholesterol, inflammation and other potential contributors to cardiovascular disease (CVD), compared with Pravachol (pravastatin, Bristol-Myers Squibb) in HIV–infected patients with dyslipidemia.
“The INTREPID trial is, to our knowledge, the first randomized, double-blind, active-controlled, head-to-head trial assessing the efficacy and safety of statin therapy in adults with HIV and dyslipidemia taking ART, Aberg and colleagues wrote. “Moreover, we believe that this trial is the first to evaluate the efficacy and safety of pitavastatin in this difficult-to-treat population.”
Pitavastatin shows promise in INTREPID analyses
The effects of pitavastatin were examined in three separate analyses of the INTREPID trial — a phase 4 trial involving 252 patients with HIV and dyslipidemia (mean age, 50 years; 86% men) at 45 sites in the U.S. and Puerto Rico. For the trial, researchers randomly assigned participants to either 4 mg of pitavastatin (n = 126) or 40 mg of pravastatin, an “active comparator” with potency similar to pravastatin, according to Aberg and colleagues.
In the primary analysis, published recently in the Lancet HIV, the researchers examined changes in LDL cholesterol with 12 weeks of treatment, followed by a 40-week safety extension. A total of 224 patients completed 12 weeks of the study and 190 completed the full 52 weeks.
Aberg and colleagues reported that, at week 12, there was a 31.1% reduction in LDL cholesterol among patients who received pitavastatin vs. a 20.9% reduction among those who received pravastatin (P < .0001). These outcomes were sustained at week 52, with a 29.7% reduction in the pitavastatin arm vs. a 20.5% reduction in the pravastatin arm (P = .0007). Pitavastatin also resulted in greater reductions in non-HDL cholesterol (-26.1% vs. -19.0%; P = .0120), apolipoprotein B (–25.4% vs. –19.6%; P = .0178), total cholesterol (–19.1% vs. –13.7%; P = .009), apolipoprotein B to apolipoprotein A1 ratio (–27.7% vs. –21.0%; P = .018) and total cholesterol to HDL cholesterol ratio (–24.1% vs. –18.1%; P = .039), compared with pravastatin.
Patients in both the pitavastatin and pravastatin arms had similar rates of virological failure (3% vs. 5%), treatment-emergent adverse events (68% vs. 70%) that led to discontinuations (5% vs. 4%) and treatment-emergent serious adverse events (6% vs. 2%).
“Equally important, neither of the drugs raised glucose,” Steven K. Grinspoon, MD, professor of medicine at Harvard Medical School, told Infectious Disease News. “So, neither drug exacerbated diabetes, and that’s important among HIV patients who may be more prone to insulin resistance.”
Results from another analysis conducted by Grinspoon and colleagues showed that 52 weeks of pitavastatin treatment led to greater reductions in certain markers of immune activation and arterial inflammation compared with pravastatin.
“HIV patients, even those who are on ART with good immunological control, still have significant immune activation,” Grinspoon said. “The body may be fighting residual virus at very low levels or bacterial products leaking through the gut. This persistent immune activation relates to plaque and plaque inflammation, and really is thought to be a major contributor of CVD in HIV patients.”
According to Grinspoon, pitavastatin had a significantly greater effect than pravastatin on soluble CD14 (–10.0% vs. 0.6%; P = .02), an important immune activation marker, as well as oxidized LDL (–26.9% vs. –17.5%; P = .02), which plays a role in plaque formation, and lipoprotein-associated phospholipase 2 (–26.6% vs. –15.5%; P = .005), a marker for arterial inflammation.
“Therefore, not only does pitavastatin lower LDL, but it also has these impressive effects on immune markers,” Grinspoon said.
For the third analysis, Parag H. Joshi, MD, of the division of cardiology at the University of Texas Southwestern Medical Center and the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, and colleagues evaluated 213 study participants with lipoprotein subfraction data. They found that at 12 weeks, pitavastatin lowered another emerging risk factor for CVD known as remnant lipoprotein cholesterol (–11.6 mg/dL vs. –8.5 mg/dL; P = .01) more so than pravastatin.
Researchers to further assess pitavastatin in REPRIEVE trial
Although the results from the INTREPID trial indicate that pitavastatin is a promising drug in HIV patients with high cholesterol, more research is needed to determine the full extent of its benefit, according to Grinspoon.
“These trials provide some excellent data to suggest that pitavastatin is a good drug, and they help give clinicians guidelines for which statin to use in HIV patients with high cholesterol,” he said. “What the study is not addressing is whether pitavastatin or any other statin will prevent heart disease. That is now ongoing in the REPRIEVE trial.”
Grinspoon, who is a coinvestigator on the REPRIEVE trial, said the study will examine whether and how pitavastatin can prevent a major cardiovascular event in patients with HIV who have a low-to-moderate risk for CVD. The researchers will randomly assign approximately 6,500 participants to 4 mg of pitavastatin or placebo and follow them for 4 to 5 years.
“It is the largest NIH-funded trial involving HIV and CVD,” Grinspoon said. “I’m happy to say that we recently hit our 50% enrollment mark.”
He added that the trial entails a lot of multidisciplinary work across several specialties.
“ID practitioners are learning about cholesterol management and cholesterol management providers are learning about which statins to use in ID, and we are drawing on knowledge from cardiovascular specialists who use statins all of the time,” he said. “These communities are benefiting from collaborative knowledge that will be used to develop our best approaches to address this issue.” – by Stephanie Viguers
References:
Aberg JA, et al. Lancet HIV. 2017;doi:10.1016/S2352-3018(17)30075-9.
Joshi PH, et al. AIDS. 2017;doi:10.1097/QAD.0000000000001423.
Toribio M, et al. AIDS. 2017;doi:10.1097/QAD.0000000000001427.
Disclosures: Aberg reports receiving grants from Bristol-Myers Squibb, Gilead Sciences and Kowa, and has received scientific advisory board personal fees from Jansseen, Merck and ViiV Healthcare. Grinspoon has received research funding on behalf of his institution from Kowa for REPRIEVE. Please see the studies for a full list of all other authors’ relevant financial disclosures.