14_0036_Dube.qxp 23/11/06 16:54 Page 1081 Antiviral Therapy 11:1081–1089 Safety and efficacy of extended-release niacin for the treatment of dyslipidaemia in patients with HIV infection: AIDS Clinical Trials Group Study A5148 Michael P Dubé1,2*, Julia W Wu3, Judith A Aberg4, Mark A Deeg1,5, Beverly L Alston-Smith6, Mark E McGovern7, Daniel Lee8, Sharon L Shriver 9, Ana I Martinez 6, Martha Greenwald1,2 and James H Stein10 for the AIDS Clinical Trials Group A5148 Study Team 1Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA 2Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, IN, USA 3Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA, USA 4Department of Medicine and Division of Infectious Diseases, New York University, New York, NY, USA 5Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA 6Division of AIDS, NIAID, NIH, Bethesda, MD, USA 7Kos Pharmaceuticals, Weston, FL, USA 8Department of Medicine, University of California, San Diego, CA, USA 9Social & Scientific Systems, Inc., Silver Spring, MD, USA 10Department of Medicine and Division of Cardiology, University of Wisconsin Medical School, Madison, WI, USA *Corresponding author: Tel: +1 317 630 6119; Fax: +1 317 630 7522; E-mail: [email protected] Background: Dyslipidaemia is very common in patients with resistance measures from the 2-h oral glucose tolerance HIV infection, but current therapies are often suboptimal. test only transiently worsened. No subject developed Since niacin may cause insulin resistance and hepatotoxi- persistent fasting hyperglycaemia; one had persistently city, it has generally been avoided in this setting. elevated 2-h glucose >11.1 mmol/l. There were no Methods: Non-diabetic male subjects (n=33) who had significant changes in serum transaminases or uric acid. well-controlled HIV infection on antiretroviral therapy, At week 48, the median change in fasting lipid levels in fasting triglycerides ≥2.26 mmol/l and non-high density mmol/l (interquartile range) were: total cholesterol lipoprotein cholesterol (non-HDL-C) ≥4.66 mmol/l –0.21 (–1.35, –0.05), HDL-C +0.013 (–0.03, +0.28), received escalating doses of extended-release niacin non-HDL-C –0.49 (–1.37, +0.08) and triglycerides (ERN) up to 2,000 mg nightly for up to 44 weeks. –1.73 (–3.68, –0.72). Favourable changes in large HDL Results: Fourteen subjects (42%) had pre-diabetes at and large very low density lipoprotein particle concen- entry. Twenty-three subjects (70%) received the tration were observed by nuclear magnetic resonance maximum dose, eight (24%) received 1,500 mg. Niacin spectroscopy. was well-tolerated. Only four subjects (12%) discon- Conclusions: ERN in doses up to 2,000 mg daily was safe, tinued study treatment. There were small increases in well-tolerated and efficacious in HIV-infected subjects fasting glycaemia and insulin resistance estimated by with atherogenic dyslipidaemia. Increases in glycaemia the homeostasis model assessment, but insulin and insulin resistance tended to be transient. Introduction Dyslipidaemia is very common in patients with HIV [10], worsening of diabetic control [11] and hepato- infection [1–3] and is accentuated by treatment with toxicity [12,13]. Thus, niacin has generally been antiretroviral drugs [4,5]. The lipid changes induced by avoided in HIV-infected patients [8], where insulin antiretrovirals appear to be responsible at least in part resistance and diabetes mellitus are increasingly for the increase in myocardial infarction reported common, especially among those receiving ART among HIV-infected patients receiving combination [14,15] and when lipodystrophy is present [16]. antiretroviral therapy (ART) [6,7]. Although guidelines In a recent cross-sectional evaluation of 100 stable, suggest using statins and fibrates in patients on ART long-term recipients of indinavir-based antiretroviral [8], the effectiveness of these agents is limited, even in regimens, 46% of subjects had fasting triglyceride levels combination [9]. Niacin may cause insulin resistance of >2.26 mmol/l, 75% had high density lipoprotein © 2006 International Medical Press 1359-6535 1081 14_0036_Dube.qxp 23/11/06 16:54 Page 1082 MP Dubé et al. cholesterol (HDL-C) levels of <1.0 mmol/l and 23% oestrogens were allowed. A total of 37 subjects entered had both triglycerides >2.26 mmol/l and non-HDL-C the trial; results are presented for those 33 subjects who levels of >4.66 mmol/l [17]. Elevations in very low were eligible to initiate study drug at week 4. All density lipoprotein (VLDL) cholesterol and low HDL- subjects provided written informed consent per the C are much more common than isolated elevations in guidelines of each of the seven participating AIDS low density lipoprotein (LDL) in patients on ART Clinical Trials Group sites’ Institutional Review [4,18]. Thus, lipid abnormalities that are potentially Boards. treatable with niacin [19,20] are particularly prevalent among HIV-infected subjects receiving ART and Drug treatment emphasize the need to identify additional agents for ERN (Niaspan®, Kos Pharmaceuticals, Weston, FL, treatment such as niacin. USA) was supplied as 500 mg and 1,000 mg tablets. At Recent studies suggest that the effect of niacin on week 4, all subjects initiated ERN at 500 mg before glycaemic control in diabetic subjects is small or tran- bedtime with a low-fat snack. At week 8 (week 4 of sient [21,22]. A 14-week study in 14 HIV-infected niacin administration), all subjects increased ERN to subjects showed that extended-release niacin (ERN) 1,000 mg before bedtime. Subsequent dose increases improved total cholesterol, non-HDL-C and triglyc- were dependent upon drug tolerability and achieving a erides but suggested that the drug caused insulin resis- composite lipid goal of non-HDL-C <4.14 mmol/l, LDL tance [23]. The purpose of this 48-week study was to cholesterol (LDL-C) <3.37 mmol/l and triglycerides determine if ERN is safe and effective in dyslipidaemic <5.65 mmol/l. If the triglycerides were >4.52 mmol/l patients with HIV infection on ART. In particular, we and the LDL-C could not be calculated, then the deci- examined effects on glucose metabolism over an sion to dose escalate was dependent on a composite extended period of time goal of non-HDL-C <4.14 mmol/l and triglycerides <5.65 mmol/l. At week 14 (week 10 of niacin adminis- Materials and methods tration), subjects who had not achieved the composite lipid goal at their week 12 evaluation increased to Subjects 1,500 mg before bedtime. At week 20 (week 16 of HIV-infected individuals aged 18 years or older were niacin adminstration), subjects who had not achieved eligible for entry if they had fasting non-HDL-C the composite lipid goal at their week 18 evaluation ≥4.66 mmol/l and serum triglycerides ≥2.26 mmol/l increased to 2,000 mg before bedtime. Subjects then within 30 days of study entry; were on stable ART for remained on the dose reached by week 20 throughout 3 months prior to study entry and planning to stay on the remainder of the study. Those who were unable to current therapy; were not pregnant and, if capable of tolerate a dosage increase continued at the previously becoming pregnant, using adequate contraception. tolerated dose for the duration of the study. All doses Laboratory criteria included fasting glucose level of niacin were given with 325 mg of enteric-coated <7.0 mmol/l, platelets ≥50,000/mm3, absolute aspirin 30 min prior to niacin dosing to help counteract neutrophil count >750/mm3, haemoglobin >91 g/l for the cutaneous flushing side effect. Aspirin-intolerant men and >89 g/l women, serum creatinine <2 times the subjects had the option to use ibuprofen 200 mg or upper limit of normal (ULN), total bilirubin <2.5 times naproxen 225 mg instead of aspirin. ULN and alanine aminotransferase and aspartate aminotransferase <2 times ULN. Subjects were Evaluations excluded if they had known coronary heart disease or Fasting serum glucose (defined as at least 8 h with no a coronary heart disease risk equivalent [19], class III food or beverage other than water), uric acid, creatinine or IV congestive heart failure, uncontrolled hyperten- and aminotransferase levels were performed locally at sion, acute gout, active peptic ulcer disease, current each site, and standard lipid profiles (performed diagnosis of diabetes mellitus, untreated hypothy- centrally) were obtained at entry and weeks 4, 8, 12, 18, roidism, active or symptomatic gallbladder disease 24, 32, 40 and 48. An oral glucose tolerance test within 1 year, receipt of any prescription lipid-lowering (OGTT), with sampling at –10, –5, 30, 60, 90 and 120 agents or any niacin-containing products that contain min relative to ingestion of 75 g dextrose, was carried >100 mg daily within 30 days, systemic glucocorticoids out at weeks 4, 12, 24 and 48. Plasma for advanced above replacement levels, antidiabetic medication, lipoprotein testing, lipoprotein (a), and C-reactive serious drug dependence, active opportunistic infec- protein were collected at 4, 24 and 48 weeks. tion, or any other acute illness. At week 4 of study, subjects were required to have serum glucose <11.1 Assays mmol/l 2 h after glucose challenge, before the study Centrally performed assays used specimens stored at drug was started. Replacement doses of androgens and –70°C and shipped on dry ice. Advanced lipoprotein 1082 © 2006 International Medical Press 14_0036_Dube.qxp 23/11/06 16:54 Page 1083 Niacin for HIV dyslipidaemia testing was done by nuclear magnetic resonance conducted on lipid endpoints with censoring at the time spectroscopy [24] (NMR Lipoprofile®; LipoScience, of the regimen change. The study was powered based Inc., Raleigh, NC, USA) high sensitivity C-reactive on both the primary safety objective and one of the protein was done using an immunometric assay (DPC secondary objectives.