In Excess of 200% over Baseline Values in 65% of Patients Receiving Ritonavir. These Effects on Serum Lipids Appear to Be Dose-related

Two weeks later, he was seen in our lipid clinic. He was thin the dose. It is not yet known if use of ritonavir is safe for patients with abnormal lipid values at baseline; however, further investiga(weight, 63 kg) and muscle wasting was noted, but otherwise the examination findings were unremarkable. The CD4/ lymtion is warranted. phocyte count was 517/mm, and the viral load, as determined by HIV-RNA PCR, was 8,815 copies/mL. Blood glucose, hemoR. Clark Perry, Herbert E. Cushing, Mark A. Deeg, and globin Alc, thyroid-stimulating hormone, and serum aminoMelvin J. Prince* transferase levels were normal. The triglyceride level, however, Divisions of Endocrinology and Metabolism and of Infectious Diseases, had again risen to 25.24 mmol/L (2,234 mg/dL). The total choDepartment of Medicine, Indiana University School of Medicine; and Endocrinology Section, Richard Roudebush Veterans Affairs Medical lesterol value was 7.26 mmol/L (281 mg/dL), and that of HDL Center, Indianapolis, Indiana cholesterol was 0.41 mmol/L (16 mg/dL). Gemfibrozil therapy was initiated. Antiretroviral therapy was reinstituted with zidovudine, didanosine, delaviridine, nelfinavir, and saquinavir, and References no complications were noted. Currently his cholesterol level is 1. Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral therapy for 4.91 mmol/L (190 mg/dL), and the triglyceride level is 4.79 HIV infection in 1997: updated recommendations of the International mmol/L (424 mg/dL). AIDS Society–USA Panel. JAMA 1997;277:1962–9. Markowitz et al. [3] demonstrated triglyceride level elevations 2. Danner SA, Carr A, Leonard JM, et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protein excess of 200% over baseline values in 65% of patients receiving ase. N Engl J Med 1995;333:1528–33. ritonavir. These effects on serum lipids appear to be dose-related 3. Markowitz M, Saag M, Powderly WG, et al. A preliminary study of ritoand can be seen as early as 1 week after initiation of therapy with navir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl ritonavir [2]. J Med 1995;333:1534–9. The mechanisms leading to hyperlipidemia with ritonavir 4. Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome are not known. Although ritonavir inhibits the CYP3A4 isoP450 isoforms by the protease inhibitors ritonavir, saquinavir, and indiform of cytochrome P450 [4], there is no definitive evidence navir. Br J Clin Pharmacol 1997;44:190–4. that inhibition of this enzyme leads to hyperlipidemia [5]. Re5. Gylling H, Vanhanen H, Miettinen TA. Hypolipidemic effect and mechacently, it has been suggested that protease inhibitors may alter nism of ketoconazole without and with cholestyramine in familial hyperthe structure or function of the peroxisome proliferator– acticholesterolemia. Metabolism 1991;40:35–41. 6. Carr A, Samaras K, Chisholm DJ, Copper DA. Pathogenesis of HIV-1 vated receptor type gamma (PPAR-gamma), but this has yet protease inhibitor–associated peripheral lipodystrophy, hyperlipidaemia, to be studied fully [6]. and insulin resistance. Lancet 1998;351:1881–3. HIV infection alone is associated with hypertriglyceridemia, 7. Constans J, Pellegrin JL, Peuchant E, et al. Plasma lipids in HIV-infected patients: and the triglyceride level correlates inversely with the CD4/ a prospective study in 95 patients. Eur J Clin Invest 1994;24:416–20. lymphocyte count [7]. The degree of hypertriglyceridemia attrib8. Feingold KR, Krauss RM, Pang M, Doerrler W, Jensen P, Grunfeld C. The uted to HIV infection, however, is generally less than that dehypertriglyceridemia of acquired immunodeficiency syndrome is associscribed in this case [8]. Furthermore, triglyceride levels tend to ated with an increased prevalence of low density lipoprotein subclass be normal in HIV-infected individuals who have no manifestapattern B. J Clin Endocrinol Metab 1993;76:1423–7. tions of AIDS [9]. 9. Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Clinicians need to be familiar with the association between ritoLipids, lipoproteins, triglyceride clearance, and cytokines in human imnavir and hyperlipidemia, and serum lipids should be monitored munodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992;74:1045–52. during the early stages of ritonavir treatment or with escalation of