Pitavastatin an Option for High LDL-C With Antiretrovirals for HIV

Liam Davenport

April 24, 2017

LONDON, UK — Treating HIV-positive patients with a statin that has a low potential for adversely interacting with antiretroviral therapy can significantly improve lipoproteins and other dyslipidemia markers without affecting rates of virologic failure or glucose metabolism, suggests a small randomized trial[1].

The double-placebo trial, HIV-Infected Patients and Treatment With Pitavastatin vs Pravastatin for Dyslipidemia (INTREPID), compared two such statin agents, pitavastatin ‎(Livalo, Livazo, Kowa Pharmaceuticals) and pravastatin, and saw that both agents significantly reduced levels of LDL cholesterol.

But in this study supported by Kowa, the reductions were more profound for patients on pitavastatin than on pravastatin, without more adverse effects.

An Alternative for Some Patients With HIV?

Persons infected with HIV are at increased CV risk compared with the generation population, with dyslipidemia reported in up to 80% of such patients, according to the study's published report, which was published April 13, 2017 in Lancet HIV.

But according to the authors, led by Dr Judith A Aberg (Icahn School of Medicine at Mount Sinai, New York, NY), statin therapy can be a challenge in HIV-positive patients because most statins and some commonly used antiretroviral agents are both metabolized via the cytochrome P450 enzyme pathway.

Neither pitavastatin nor pravastatin, however, rely on the cytochrome P450 pathway for their primary metabolism.

It's important to treat dyslipidemia "whether it's in individuals with HIV or any other condition," Aberg told heartwire from Medscape. "We still should follow whatever the national and international guidelines are to prevent cardiovascular disease and, certainly, people who have coronary heart disease should be offered a statin."

The current study's patients "really do have a true clinical indication to be on a statin, and what we saw was that pitavastatin was highly effective in reducing LDL cholesterol, as well as other lipid parameters, and that it was safe and well tolerated," she said.

"So it really should be considered an option for those who have HIV [as] an effective way to reduce their lipids."

In an accompanying commentary[2], infectious-disease specialists Dr Philip E Tarr (University of Basel, Switzerland) and Dr Helen Kovari (University Hospital Zurich, Switzerland) write that the results "establish pitavastatin as an additional appropriate option to treat dyslipidemia also in HIV."

However, the increasing use of integrase inhibitors, which tend to interact less with other drugs, has made the clinical need for statins such as pitavastatin "less urgent," according to Tarr and Kovari. Indeed, changing HIV treatment from protease inhibitors to drugs that cause fewer metabolic disturbances "could have made a statin unnecessary."

Nonetheless, they add, "pitavastatin might be a valuable alternative statin choice in patients with dyslipidemia treated with integrase inhibitors who are unable to tolerate other statins."

In another critical point, Tarr and Kovari emphasize that "we do not yet know whether statin treatment translates into meaningful clinical benefits in people with HIV." Statin therapy, they observe, "reduces atherosclerotic plaque in people with HIV, but conclusive data that statins reduce the cardiovascular-event rate in this population are not yet available."

INTREPID Patients and Clinicians

The group recruited 252 adults (mean age 50) with HIV infection that was well controlled on antiretroviral therapy for at least 6 months who also had dyslipidemia, with fasting LDL-cholesterol levels of 3.4 to 5.7 mmol/L (130–220 mg/dL) and triglycerides ≤4.5 mmol/L (≤400 mg/dL).

At baseline, they had been infected with HIV for a mean 12.6 years; 10% were also infected with the hepatitis B or C virus.

The patients were randomly assigned pitavastatin at 4 mg/day or pravastatin at 40 mg/day with matching placebos, once daily orally for 12 weeks; safety end points were followed for 40 more weeks.

LDL cholesterol fell by 31.1% after 12 weeks in patients given pitavastatin, a significantly greater drop than the 20.9% reduction seen in the pravastatin group (least squares mean difference 9.8%; P<0.0001).

That significant difference between the two groups was sustained at week 52 (least squares mean difference 8.4%; P=0.0007) and remained so after adjustment for treatment site, hepatitis B or C coinfection, and the use of efavirenz or ritonavir (which might have had interaction potential with pitavastatin, according to the authors).

The team also found that, compared with pravastatin, use of pitavastatin was associated with significant reductions in levels of non-HDL cholesterol both at week 12 (P<0.0001) and week 52 (P=0.012), as well as significant reductions in apolipoprotein B at week 12 (P<0.0001) and week 52 (P=0.018).

The statin groups showed no significant differences in changes in levels of apolipoprotein A1, triglycerides, HDL cholesterol, or high-sensitivity C-reactive protein at either week 12 or week 52, the group reports. Markers of glycemia also were not significantly different.

Nor were there significant differences in the proportion of patients who experienced virologic failure at week 52; it was 3% in the pitavastatin group and 5% for those taking pravastatin.

Adverse events during statin therapy were seen in 68% of pitavastatin recipients and 70% of those on pravastatin. They were considered to be treatment-related in 13% and 10% overall, respectively, and serious in 6% and 2% overall, respectively. They were associated with treatment discontinuation in only 5% of those on pitavastatin and 4% on pravastatin. Nobody died.

"No serious adverse event occurred in more than one patient, and no serious adverse event was treatment-related according to investigator assessment," the group writes.

Next Steps

As for the critical point of whether statin therapy can improve outcomes in HIV-infected persons who don't have a conventional statin indication, both the authors and the editorialists point to the ongoing REPRIEVE primary-prevention study, jointly sponsored by Kowa and the US National Institute of Allergy and Infectious Diseases (NIAID).

Aberg said that REPRIEVE, which is randomizing a projected 6500 persons with HIV but no known CV disease to pitavastatin at 4 mg/day or placebo on top of standard management, should help demonstrate whether "there is an increased risk of cardiovascular disease from underlying inflammation and immune dysfunction secondary to the HIV itself."

But a large outcomes trial in such patients who do have a standard statin indication probably isn't necessary, according to Aberg.

"We know that statins are effective in reducing lipids, and we have large studies in the general population, so I don't think there's any reason to believe that we should be treating HIV-infected person any differently from the general population," she said.

"We typically look at the people at risk," she said, "and we don't even know in the big cardiovascular statin studies whether or not individuals did or did not have HIV."

According to the editorialists, "that lipid-lowering treatment with statins is as relevant to people with HIV at increased cardiovascular risk as it is in the general population remains a reasonable but unproved assumption."

This study was funded by Kowa Pharmaceuticals America and Eli Lilly. Aberg discloses receiving grants from Kowa, Bristol-Myers Squibb, and Gilead Sciences and scientific advisory board fees from Janssen, Merck, and ViiV Healthcare. Disclosures for the coauthors are listed in the paper. Kovari discloses receiving grants and travel grants paid to her institution from Gilead Sciences and financial support paid to the institution for advisory boards by MSD and Gilead Sciences. Tarr discloses that his institution has received grants and advisory board fees from Gilead, lecture fees from Schwabe Pharma, and grants from ViiV.

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