Bococizumab HIV Evaluation (B-HIVE) Study

B-HIVE is a Phase 3, double blind, placebo-controlled, randomized, parallel group study, designed to compare the efficacy and safety of bococizumab 150 mg subcutaneously every 2 weeks to bococizumab placebo subcutaneously every 2 weeks for LDL-C lowering in HIV-infected subjects.

Cardiovascular disease (CVD) due to atherosclerosis continues to be the leading single cause of death in industrialized countries. High serum lipid levels, and especially high low-density lipoprotein cholesterol (LDL-C) levels, have been demonstrated to strongly and directly correlate with CVD risks by numerous epidemiological studies. Moreover, large prospective clinical outcome trials have demonstrated that lowering LDL-C decreases cardiovascular morbidity and mortality (1). A meta-analysis of 26 randomized clinical trials comprising 170,000 participants showed that more intensive statin therapy compared to less intensive regimens will reduce coronary deaths or myocardial infarction by an additional 13% (2). HIV-infected individuals represent a unique and increasing subset of atherosclerosis. With the advent of antiretroviral therapy, HIV-infected individuals now have much improved survival and are faced with health issues related to aging, including cardiovascular disease. Individuals with HIV have higher rates of coronary events compared to controls even in the setting of treated and suppressed disease and a growing body of literature suggests that they are at increased risk for myocardial infarction, atherosclerosis, and sudden cardiac death (3-5). Many facets of atherosclerosis differ in HIV-infected individuals compared to uninfected individuals with atherosclerosis. HIV-infected patients with acute coronary syndromes are younger and more likely to be males and smokers, with low high density lipoprotein-cholesterol (HDL-C), compared to other acute coronary syndrome patients (6). With respect to pathophysiology, viral replication, antiretroviral drugs and inflammation all contribute to atherosclerosis (7,8). HIV-associated inflammation induces pro-atherogenic lipid abnormalities and anti-retroviral therapy leads to the development of metabolic abnormalities such as dyslipidemia, lipodystrophy and insulin resistance (9,10) In a large cross-sectional study, 27% of subjects receiving combination therapy including a protease inhibitor had a total cholesterol level exceeding 240 mg/dl, compared to 8% of untreated HIV subjects, and 40% had triglyceride levels above 200 mg/dl, compared to 15% in untreated subjects (11). The prevalence and severity of dyslipidemia varies among different antiretroviral drugs; (9) however, hypertriglyceridemia and low HDL-cholesterol were associated with HIV infection even before the advent of antiretroviral therapy (12). Total, HDL-C, and LDL-C decrease at the time of HIV infection, and with antiretroviral treatment total and LDL-C levels increase to pre-infection levels while HDL-C remains low (13). Abnormalities in body composition have been reported in 40-50% of HIV-infected patients, with higher rates in those receiving combination antiretroviral therapy (9). Subcutaneous lipoatrophy commonly affects the face, limbs, and buttocks, and is accompanied by central fat accumulation. Hyperinsulinemia is often also present. In a representative study, (14) diabetes was present in 7% of HIV-infected adults with fat accumulation or lipoatrophy, as compared to 0.5% of control subjects matched for age and BMI. The corresponding rates of glucose intolerance were 35% and 5% respectively (14). Compared to healthy control subjects, HIV-infected men treated with combination antiretroviral therapy were 4 times as likely to develop diabetes over a 3-year observation period (15). The increased cardiovascular risk and dyslipidemia in HIV-infected individuals is difficult to treat for several reasons. Statins reduce LDL-C levels less in HIV-infected individuals compared to uninfected controls (16). Fibrates reduce triglyceride levels less in HIV-infected individuals compared to uninfected controls as well (16). Drug-drug interactions between statins and protease inhibitors increase the risk of adverse events (17,18). Due to these interactions, simvastatin and lovastatin are contraindicated among individuals receiving protease inhibitors and the dose of atorvastatin should not exceed 40 mg (17). Even interactions with rosuvastatin, which is not metabolized by the cytochrome P450 system, have been described (19,20). As a consequence, physicians may avoid treating HIV-infected individuals who would benefit from statins, or use lower doses or less potent statins, reducing the potential for cardiovascular event reduction. High triglyceride levels in HIV-infected subjects are common, and the combination of a fibrate plus antiretroviral therapy increases the risk of drug-drug adverse events, even before consideration of a statin. Statin treatment reduces lipid levels modestly in HIV subjects. Among 72 HIV-infected subjects in the SATURN-HIV trial randomized to rosuvastatin 10 mg/day, LDL-C was reduced by 25.3% by week 24 (21). In another study, of 83 HIV-infected subjects, rosuvastatin 10 mg and pravastatin 40 mg/day reduced LDL-C by 37% and 19% respectively at 45 days (22). Among 151 HIV-infected subjects randomized to rosuvastatin 10 mg, atorvastatin 10 mg, or pravastatin 40 mg/day, LDL-C reductions were greater with rosuvastatin at this dose, but all 3 statins significantly and similarly reduced serum levels of hs-CRP and TNF (23). That statins might favorably influence the evolution of atherosclerosis in HIV-infected subjects is suggested by a recent trial where 40 HIV subjects with mild coronary atherosclerosis by CT angiography and aortic inflammation by FDG-PET imaging were randomized to atorvastatin 20-40 mg/day or placebo and were followed for 12 months (24). Atorvastatin significantly reduced non-calcified coronary plaque volume relative to placebo, as well as the number of high-risk plaques. Approximately 1/3 of individuals with HIV-infection are co-infected with hepatitis C (25). Elevated hepatic enzymes due to hepatitis C represent a relative contraindication to statin therapy, and some evidence suggests that a statin might increase hepatitis C activity (26). Finally, HIV-infected patients often need many medications and have a large daily pill burden. Compliance suffers, but has been shown to improve when single tablet regimens reduce daily pill load.27 Long-acting injectable antiretroviral drugs are under development as a strategy to reduce pill burden and improve compliance (28). PCSK9 inhibitor injections would dovetail well with this approach. For these reasons, PCSK9 inhibitor therapy offers advantages over statin therapy in this unique population. Bococizumab (RN316/PF-04950615) is a novel humanized PCSK9 monoclonal antibody. In a 24-week, multicenter, randomized, double-blind, placebo-controlled phase II trial, the LDL-C lowering effects of bococizumab, administered every 2 or 4 weeks in statin-treated adults with LDL-C ≥80 mg/dL was assessed (29). Subjects were randomized to placebo, bococizumab 50 mg, 100 mg, or 150 mg every 2 weeks, or placebo, bococizumab 200 mg or 300 mg monthly. The dose was reduced if LDL-C was ≤25 mg/dL. The primary analysis was the placebo-adjusted treatment difference for the change from baseline in LDL-C at week 12. Overall, 354 patients were randomized, 351 received study treatment, and 299 completed the study. Bococizumab significantly reduced LDL-C across all doses. The placebo-adjusted LDL-C reduction at 12 weeks for the 2-weekly dosing regimen was 34.3% with 50 mg, 45.1% for 100 mg and 53.4% for 150 mg, and for the monthly dosing regimen was 27.6% for 200 mg and 44.9% for 300 mg. The incidence and profile of adverse events were similar across placebo and bococizumab groups. Based on these findings, 150 mg every 2 weeks was selected as the dose for phase III trials, including this trial. Because multiple doses of bococizumab as high as 150 mg every 2 weeks and 300 mg every 4 weeks up to 12 weeks were safe and well tolerated, the primary rationale for dose selection was the pharmacokinetic/pharmacodynamic model that predicted LDL-C change from baseline. Based on population PK/PD modeling, a dose of 150 mg every 2 weeks in patients on a background of statins is estimated to be equivalent to approximately 80% of the maximal response for LDL-C lowering (-67%). Assuming an average LDL C at baseline of 100 mg/dL for HIV-infected individuals, the mean absolute LDL-C reduction is predicted to be approximately 60 mg/dL.