Pitavastatin had greater low-density lipoprotein (LDL)-lowering effects than pravastatin without unfavourable effects on glucose metabolism or rates of virological failure in patients with HIV and dyslipidemia. This was according to the results of the INTREPID (HIV-Infected Patients and Treatment With Pitavastatin vs Pravastatin for Dyslipidemia) study.
“Nowadays, the treatment of HIV is very effective, and patients who take antiviral medications often do well and lead a normal life. What’s happened with HIV is that the other factors that affect a person’s health have become more important,” Dr Douglas J Ward, from Dupont Circle Physicians Group and clinical associate professor of medicine at George Washington University Medical School in Washington DC, is quoted in an Infectious Disease Advisor report. “There is a high incidence of elevated cholesterol in the HIV population. In addition, the HIV population is at greater risk for heart disease due to a higher incidence of smoking and HIV itself, so it’s really important to control cholesterol in this population.”
According to Ward, pravastatin is commonly the statin of choice for patients with HIV with hyperlipidemia. Pravastatin, unlike most other statins, does not rely on the cytochrome P450 (CYP) enzyme system for metabolism, and is therefore less likely to interact with HIV medications, such as protease inhibitors, that depend on CYP metabolism. Pravastatin, however, is “one of the weakest of the statins, and may still have some potential interactions with the protease inhibitors or other HIV medications.”
Pitavastatin is minimally metabolised by the CYP system and does not have clinically meaningful interactions with protease inhibitor therapy. A previous phase 3 study showed that compared with pravastatin, pitavastatin significantly decreased LDL in elderly patients with dyslipidemia.
The report says in the phase 4 INTREPID study, researchers led by Ward and Dr Judith A Aberg, from the Icahn School of Medicine at Mount Sinai in New York, compared the safety and efficacy of pitavastatin with that of pravastatin in adult patients (aged 18-70 years) with HIV and dyslipidemia.
A total of 252 patients with controlled HIV (defined as CD4 counts >200 cells/μL and HIV-1 RNA200 copies/mL) were randomly assigned in a 1:1 ratio to receive pravastatin or pitavastatin.
The percentage change in fasting LDL at 12 weeks, the primary endpoint, was higher in the pitavastatin group than in the pravastatin group (31.1% vs 20.9% LDL reduction, respectively; P <.0001). Pitavastatin also reduced non-HDL cholesterol and apolipoprotein B to a greater extent than pravastatin.1
Rates of virological failure at 1 year were similar in both groups (3% for pitavastatin vs 5% for pravastatin).
Patients with HIV have an increased risk for impaired glucose metabolism, and statins may promote insulin resistance. However, both treatments had no significant effect on fasting blood glucose, fasting plasma insulin, or HbA1c.1
Rates of treatment-emergent adverse events were similar in the pravastatin and pitavastatin groups (70% vs 68%). Diarrhea and upper respiratory tract infection were the most common adverse events in the pitavastatin and pravastatin groups, respectively. Serious adverse events occurred in 6% of pitavastatin patients compared with 2% of pravastatin patients.
“The INTREPID trial showed that pitavastatin is well-tolerated and more effective at lowering cholesterol, particularly LDL cholesterol, compared to the traditional go-to statin, pravastatin,” Ward concluded.
“However, this trial does not answer the question of whether statins reduce the risk of heart disease in this population,” he noted. “The ongoing REPRIEVE trial, which is looking at using pitavastatin to reduce heart disease in HIV patients, hopefully will give us some information on that question.”
Background: People living with HIV-1 infection are at greater risk for cardiovascular disease than seronegative adults. Treatment of dyslipidaemia with statins has been challenging in people with HIV because of an increased potential for drug interactions due to competing cytochrome P450 metabolism between statins and commonly used antiretroviral agents. Neither pitavastatin nor pravastatin depend on cytochrome P450 for primary metabolism. We aimed to assess the safety and efficacy of pitavastatin versus pravastatin in adults with HIV and dyslipidaemia.
Methods: In the INTREPID (HIV-infected patieNts and TREatment with PItavastatin vs pravastatin for Dyslipidemia) randomised, double-blind, active-controlled, phase 4 trial (INTREPID, we recruited adults aged 18–70 years with controlled HIV (with CD4 counts >200 cells per μL and HIV-1 RNA <200 copies per mL) on antiretroviral therapy for at least 6 months and dyslipidaemia (LDL cholesterol 3·4–5·7 mmol/L and triglycerides ≤4·5 mmol/L) from 45 sites in the USA and Puerto Rico. Patients being treated with darunavir, or who had homozygous familial hypercholesterolaemia or any condition causing secondary dyslipidaemia, or a history of statin intolerance, diabetes, or coronary artery disease were not eligible. We randomly assigned patients (1:1) to pitavastatin 4 mg or pravastatin 40 mg with matching placebos once daily orally for 12 weeks, followed by a 40 week safety extension. Randomisation was stratified by viral hepatitis B or C coinfection and computer-generated. Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was percentage change in fasting serum LDL cholesterol from baseline to week 12 and the primary efficacy analysis was done in the modified intention-to-treat population. The safety analysis included all patients who took at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT01301066.
Findings: Between Feb 23, 2011, and March 29, 2013, we randomly assigned 252 patients to the pitavastatin (n=126) or pravastatin group (n=126). LDL cholesterol reduction was 31·1% with pitavastatin and 20·9% with pravastatin (least squares mean difference −9·8%, 95% CI −13·8 to −5·9; p<0·0001) at 12 weeks. At week 52, four patients (3%) in the pitavastatin group and six (5%) in the pravastatin group had virological failure, with no significant difference between treatments. Both treatments had neutral effects on glucose metabolism parameters. 85 patients treated with pitavastatin (68%) and 88 patients treated with pravastatin (70%) reported treatment-emergent adverse events, and these caused study discontinuation in six patients (5%) versus five patients (4%). No serious adverse event occurred in more than one participant and none were treatment-related according to investigator assessment. The most common treatment-emergent adverse events were diarrhoea in the pitavastatin group (n=12, 10%) and upper respiratory tract infection in the pravastatin group (n=14, 11%). 11 treatment-emergent serious adverse events were noted in seven patients (6%) in the pitavastatin group (atrial septal defect, chronic obstructive pulmonary disease, chest pain, diverticulitis, enterovesical fistula, gastroenteritis, viral gastroenteritis, herpes dermatitis, multiple fractures, respiratory failure, and transient ischaemic attack) and four events in three patients (2%) in the pravastatin group (cerebrovascular accident, arteriosclerosis coronary artery, myocardial infraction, and muscle haemorrhage). In the pravastatin treatment group, one additional patient discontinued due to an adverse event (prostate cancer that was diagnosed during the screening period, 42 days before first dose of study treatment, and therefore was not a treatment-emergent adverse event).
Interpretation: The INTREPID results support guideline recommendations for pitavastatin as a preferred drug in the treatment of dyslipidaemia in people with HIV
Judith A Aberg, Craig A Sponseller, Douglas J Ward, Vladimir A Kryzhanovski, Stuart E Campbell, Melanie A Thompson