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Infectious Diseases in Clinical Practice:
doi: 10.1097/IPC.0b013e3181461755
Case Reports

Protease Inhibitor-Induced Hyperlipidemia Treated With Pioglitazone

Bonilla, Hector MD; Espiritu, Rachel MD

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Summa Health System, Akron, OH.

Address correspondence and reprint requests to Hector Bonilla, MD, 75 Arch St, Suite 105, Akron, OH 44304. E-mail: bonillah@summa-health.org.

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Patients infected with human immunodeficiency virus (HIV) have been found to be prone to lipid abnormalities because of specific antiretroviral therapy (ART) and HIV infection itself and thus may be more susceptible to coronary artery disease. Antiretroviral drugs associated with the development of dyslipidemia in these patients include protease inhibitors and nucleotide reverse transcriptase inhibitors. Management of ART-associated hyperlipidemia may pose some challenges because of the increased risk of complications with the use of medications, particularly 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors and fibric acid derivatives that may interact with various ART drugs. Because of the proven antihyperlipidemic effects of pioglitazone, a thiazolidinedione, in patients with type 2 diabetes mellitus and the lack of adverse effects, it may be used effectively in the treatment of ART-induced hyperlipidemia. We present a case of a 49-year-old man infected with HIV whose protease inhibitor-induced hyperlipidemia improved with the administration of high-dose pioglitazone.

Hyperlipidemia with increased total and low-density lipoprotein (LDL) cholesterol has been associated with coronary heart disease in the general population.1 In human immunodeficiency virus (HIV)-infected individuals who are undergoing antiretroviral therapy (ART), lipid elevations have been reported at higher frequencies compared with the general population.2,3 It has been reported that in the first 4 to 6 years of highly active antiretroviral therapy (HAART), there is a 25% increase likelihood of coronary artery disease.4 Although it remains uncertain whether such metabolic changes can actually accelerate cardiovascular disease and how this might occur, physicians treating HIV-infected patients are nevertheless interested at lowering any potential cardiovascular risks in this patient population.5

It is becoming increasingly evident that certain antiretroviral therapies can be associated with specific lipid alterations, most commonly, hypertriglyceridemia. Several studies have shown that the rate of hyperlipidemia can be high especially in patients treated with protease inhibitor (PI)-based regimens.3 Nucleoside reverse transcriptase inhibitors have also been proposed as a potential risk factor in the development of lipid abnormalities in HIV patients.6 However, current evidence suggests that it is overly simplistic to attribute "cause" exclusively to any single ART class and to assume that all changes are harmful.7,8 Some lipid changes are considered to be a reversal of infection-related effect as a result of immune reconstitution by treatment.9

There have been a few prospective studies evaluating lipid-lowering therapy in HIV-infected patients that suggest that treatment may improve lipid levels. A study by Calza et al showed that fibrate and statin therapy significantly lower triglycerides (by 35%-40%, P < 0.001) and total cholesterol (by 21%-25%, P < 0.001) over 12 months with a maximal benefit noted after 6 months of therapy.10 However, interactions with the combination of statins and PIs have shown increase in levels of statins, in particular, simvastatin.5 Therefore, the potential toxicity associated with this combination of drugs, such as myopathy and rhabdomyolysis, leads us to consider alternatives for the management of hyperlipidemia in this population. Here we present the case of a patient with ART-associated hypertriglyceridemia whose lipid disorder was satisfactorily managed with pioglitazone 60 mg daily.

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This patient, a 49-year-old white man, tested positive for HIV-1 antibodies in April 1990. He was also coinfected with hepatitis B virus. He has no other comorbid conditions. There is no family history of coronary artery disease or dyslipidemia. He does not drink alcohol. The patient has been on several HAART regimens for HIV since his diagnosis. He participated in ACTG 303 (zidovudine, didanosine, lamivudine) for several years and then switched to stavudine/lamivudine; subsequently, indinavir was added to his regimen. He came to our clinic (Care Center, Akron, Ohio) in June 1997. Since attending our clinic, his treatment regimen has been switched numerous times because of multiple side effects. Additional past ARTs included abacavir sulfate/lamivudine/zidovudine, tenofovir, lopinavir/ritonavir, and atazanavir.

On March 1, 2005, he was started on a salvage ART regimen of tipranavir, ritonavir, emtricitabine, and enfuvirtide. Total cholesterol and triglycerides were measured before initiating this regimen (January 25, 2005) and were 145 and 228 mg/dL, respectively. Shortly after initiating treatment (March 12, 2005), the patient developed hyperlipidemia (total cholesterol, 255 mg/dL; triglycerides, 1506 mg/dL). There was no evidence of insulin resistance (fasting insulin of 8.9 μU/mL and fasting glucose of 90 mg/dL) or lipodystrophy. One month later, his lipid levels increased further (total cholesterol, 382 mg/dL; triglycerides, 2232 mg/dL), and the patient was started on pioglitazone 30 mg/d. At the following visit (May 10, 2005), lipid levels were still elevated (total cholesterol, 449 mg/dL; triglycerides, 2279 mg/dL), and the pioglitazone dose was increased to 60 mg/d. His lipid levels decreased dramatically after this dose increase (Fig. 1). There has been no significant change in his dietary habits or exercise patterns during this period. He has not taken any new medication or fish oil supplements. His weight has been relatively stable. The patient's hyperlipidemia continued to improve except on 1 occasion. In July 2005, the patient was unable to take pioglitazone for a month because of a pharmacy error, and his lipid levels increased during this period (total cholesterol, 393 mg/dL; triglycerides, 1535 mg/dL). Since restarting pioglitazone (60 mg/d), the patient's lipid levels have steadily decreased (total cholesterol, 239 mg/dL, and triglycerides, 375 mg/dL, as of January 2007). All his lipid profiles were collected during a fasting state.

Figure 1
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We presented an HIV-infected patient who developed hyperlipidemia 1 month after initiating a PI-boosted regimen (tipranavir/ritonavir) with significant improvement in total cholesterol and triglyceride levels using pioglitazone 60 mg daily.

Pioglitazone is a thiazolidinedione derivative antidiabetic agent that acts primarily by decreasing hepatic and peripheral insulin resistance, therefore improving hyperglycemia and hyperlipidemia in type 2 diabetes mellitus.11,12 This beneficial effect on hyperlipidemia has been well established in patients with diabetes.

One study showed that non-HIV patients treated with pioglitazone had mean decreases in triglycerides, mean increases in high-density lipoprotein (HDL) cholesterol, and no consistent mean changes in LDL and total cholesterol.12 In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels decreased in the 15, 30, and 45 mg pioglitazone dose groups compared with a mean increase in the placebo group.12 Mean HDL levels increased to a greater extent in patients treated with pioglitazone than in the placebo-treated patients.12 A randomized controlled study by Goldberg et al13 showed that patients with type 2 diabetes mellitus with dyslipidemia treated with pioglitazone 30 mg/d for 12 weeks had significant improvements in triglyceride and HDL levels. The Framingham study has demonstrated a significant inverse relationship between HDL cholesterol and cardiovascular disease risk and that it will be an advantage for the treatment of hyperlipidemia in HIV-infected individuals.14

However, studies elucidating the effect of pioglitazone in HIV/HAART-associated hyperlipidemia are limited and inconsistent. In an open-label trial of 11 patients with HIV treated with HAART, the use of pioglitazone (30 mg for 3 months then 45 mg for 3 months) was not associated with any improvement in total cholesterol, triglyceride, or LDL levels compared with baseline.11,15 A randomized controlled trial, on the other hand, showed a statistically significant improvement in triglyceride levels in HAART-induced metabolic syndrome after treatment with pioglitazone up to 45 mg/d for 12 months.15 One case report also supports the beneficial effect of pioglitazone in the management of dyslipidemia in HIV-associated lipodystrophy.16

This is the first case study to demonstrate the effectiveness of pioglitazone 60 mg daily which is above the recommended maximum dose of 45 mg/d. It is unsure whether higher doses of pioglitazone may be required in some cases to achieve a beneficial effect on hyperlipidemia induced by ART. Small studies have not shown serious side effects associated with pioglitazone in HIV-infected individuals on HAART.11 Doses up to 60 mg daily has been shown in open-label studies to have similar safety profiles to lower doses when used as monotherapy in patients with diabetes mellitus.17

This effect on lipids can be explained by pioglitazone's high affinity for intracellular ligands for peroxisome proliferator-activated receptors (PPARs).18 The PPAR is a family of ligand-activated transcription factors. Three subtypes have been identified: PPAR-α (predominantly in the liver), which regulates the expression of genes involved in the fatty acid catabolism that reflects in lower cholesterol and triglycerides; PPAR-γ, which is involved in adipocyte differentiation and lipid storage); and PPAR-δ (unclear role). By using transactivation assays, pioglitazone has been shown greater activity for PPAR-α may explain effect in lipids.18 The activation of these systems is dose-dependent. This can explain why the changes in our patient's cholesterol and triglyceride levels did not occur at lower doses of pioglitazone.18 Thiazolidinediones also increase the expression and plasma concentration of adiponectin, a protein secreted by the adipocytes, which play a role in the development of insulin resistance and dyslipidemia in HIV patients.6

This patient has clearly responded well to this course of treatment, indicating that pioglitazone, possibly up to 60 mg daily, may be used as an alternative treatment option in the management of hyperlipidemia induced by certain PI regimens. However, larger randomized trials are needed to further evaluate this possible benefit and safety profile of high-dose pioglitazone in hyperlipidemia induced by ART.

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1. Singh B, Mehta J. Management of dyslipidemia in the primary prevention of coronary heart disease. Curr Opin Cardiol. 2002;17:503-511.

2. Cotter B. Epidemiology of HIV cardiac disease. Prog Cardiovasc Dis. 2003;45:319-326.

3. Fellay J, Boubaker K, Ledergerber B, et al. Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV cohort study. Lancet. 2001;258:1322-1327.

4. Davidson MH. Management of dyslipidemia in patients with complicated metabolic syndrome. Am J Cardiol. 2005;96(suppl):22E-25E.

5. Green M. Evaluation and management of dyslipidemia in patients with HIV infection. J Gen Intern Med. 2003;17:797-810.

6. Leow MKS, Addy CL, Mantrozos CS. Human immunodeficiency virus/highly active antiretroviral therapy-associated metabolic syndrome: clinical presentation, pathophysiology, and therapeutic strategies. J Clin Endocrinol Metab. 2003;88:1961-1976.

7. Youle M, Gerstoft J, Fox Z, et al. The final week 48 analysis of a phase IV, randomized, multi-centre trial to evaluate safety and efficacy of lopinavir/ritonavir (400/100 mg bid) versus saquinavir/ritonavir (1000/100 mg bid): the MaxCmin2 trial. Presented at the Ninth European AIDS Conference (EACS); October 25-29, 2003; Warsaw, Poland. European AIDS Clinical Society. 2003:F11/3.

8. Dragsted U, Gerstoft J, Pederson C, et al. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial. J Infect Dis. 2003;188:635-642.

9. Riddler SA, Smit E, Cole SR, et al. Impact of HIV infection and HAART on serum lipids in men. JAMA. 2003;289:2978-2983.

10. Calza L, Manfredi R, Chiodo F. Statins and fibrates for the treatment of hyperlipidemia in HIV-infected patients receiving HAART. AIDS. 2003;17:851-859.

11. Calmy A, Hirschel B, Hans D, et al. Glitazone in lipodystrophy syndrome induced by highly active antiretroviral therapy. AIDS. 2003;17:770-772.

12. Gillies P, Dunn C. Pioglitazone. Drugs. 2000;60:333-343.

13. Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005;28:1547-1554.

14. Castelli WP, Garrinson RJ, Wilson PWF, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham study. JAMA. 1986;256:2835-2838.

15. Gavrila A, Hsu W, Tsiodras S, et al. Improvement in highly active antiretroviral therapy-induced metabolic syndrome by treatment with pioglitazone but not with fenofibrate: a 2 × 2 factorial, randomized, double-blinded, placebo-controlled trial. Clin Infect Dis. 2005;40:745-749.

16. Prasithsirikul W, Bunnag P. Improvement of fat redistribution, insulin resistance and hepatic fatty infiltration in HIV-associated lipodystrophy syndrome by pioglitazone: a case report. J Med Assoc Thai. 2004;87:166-172.

17. Belcher G, Matthews DR. Safety and tolerability of pioglitazone. Exp Clin Endocrinol Diabetes. 2000;108(suppl 2):267-273.

18. Sakamoto J, Kimura H, Moriyama S, et al. Activation of human peroxisome proliferators-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun. 2000;278:704-711.

© 2008 Lippincott Williams & Wilkins, Inc.