Correspondence

HIV-Protease Inhibitors

N Engl J Med 1998; 339:773-774September 10, 1998

Article

To the Editor:

In his review of inhibitors of human immunodeficiency virus (HIV)–encoded protease (April 30 issue),1 Dr. Flexner states that ritonavir causes hypertriglyceridemia in no more than 5 percent of patients and has not caused pancreatitis. However, we found that of 52 patients treated with ritonavir for six months, 41 (79 percent) had hypertriglyceridemia (serum triglyceride concentration, >160 mg per deciliter [1.8 mmol per liter]), with values higher than 500 mg per deciliter (5.6 mmol per liter) in 22 patients (42 percent) and higher than 1000 mg per deciliter (11.3 mmol per liter) in 8 (15 percent). The risk varied as a function of the base-line serum triglyceride concentration. Among the 24 patients who had normal base-line concentrations, 5 (21 percent) had concentrations higher than 500 mg per deciliter (in at least one determination at month 1, 3, or 6), whereas 17 of the 28 patients (61 percent) with high concentrations before treatment had further increases during treatment. The risk of a serum triglyceride concentration higher than 1000 mg per deciliter during treatment was 4 percent in the group with normal base-line values and 25 percent in the group with elevated base-line values. Acute pancreatitis developed in two patients in the latter group (serum triglyceride concentrations, 1980 and 1880 mg per deciliter [22.4 and 21.2 mmol per liter]); it resolved with conventional medical management and the withdrawal of ritonavir. In both patients, the serum triglyceride concentration was less than 500 mg per deciliter within 10 days after the withdrawal of ritonavir.

We believe that serum triglyceride concentrations should be monitored in patients receiving ritonavir, especially those who have elevated concentrations at base line, and that the drug should be discontinued if the value exceeds 1000 mg per deciliter.

Giovanni Di Perri, M.D., D.T.M.&H., Ph.D.
Paola Del Bravo, M.D.
Ercole Concia, M.D.
University of Verona, 37126 Verona, Italy

1 References

1. 1

   Flexner C. HIV-protease inhibitors. N Engl J Med 1998;338:1281-1292
   Full Text | Web of Science | Medline

To the Editor:

Flexner's review of HIV-protease inhibitors clearly explains how these drugs work and describes the properties of the various protease inhibitors. However, the references to the protease inhibitor saquinavir do not explicitly differentiate between the two available formulations of saquinavir: Fortovase and Invirase. Fortovase, a new, soft-gel formulation of saquinavir, is more potent than Invirase. Physicians treating their patients with saquinavir should prescribe Fortovase.

In addition, two statements in the article concerning saquinavir need to be clarified. In Table 1, the dose of saquinavir is given as 600 mg three times a day. That dose is for Invirase. The dose of Fortovase is 1200 mg three times a day. (Fortovase, like other protease inhibitors, is recommended for use in combination with two nucleoside analogues.) The same table lists saquinavir's bioavailability as less than 4 percent, a figure that also applies only to Invirase. The bioavailability of Fortovase is substantially higher than that of Invirase. For physicians who want more information about Fortovase, Hoffmann–LaRoche has a toll-free information number (800-526-6367) staffed by health care experts knowledgeable about all aspects of the drug's use.

Sandra Palleja, M.D.
Hoffmann–LaRoche, Nutley, NJ 07110-1199

Author/Editor Response

Dr. Flexner replies:

To the Editor: I appreciate the report by Di Perri and colleagues about the prevalence of hypertriglyceridemia in patients treated with ritonavir. It would be helpful to know whether the two patients in whom pancreatitis developed had other risk factors for it. Although the authors recommend that ritonavir be discontinued in all patients with serum triglyceride concentrations exceeding 1000 mg per deciliter (11.3 mmol per liter), in some patients, hypertriglyceridemia may be tolerated and the benefit of continued ritonavir therapy may outweigh the risk of pancreatitis.

I acknowledge Dr. Palleja's comments on the difference between the two commercially available formulations of saquinavir. The Fortovase formulation became available while the article was in press and therefore was not included in the table of pharmacokinetic properties.

Charles W. Flexner, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21287-5554

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   S Collot-Teixeira, F De Lorenzo, L Waters, C Fletcher, D Back, S Mandalia, A Pozniak, S Yilmaz, JL McGregor, B Gazzard, M Boffito. (2009) Impact of Different Low-Dose Ritonavir Regimens on Lipids, CD36, and Adipophilin Expression. Clinical Pharmacology & Therapeutics 85:4, 375-378
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   Leonardo Calza, Roberto Manfredi, Vincenzo Colangeli, Livia Tampellini, Teresa Sebastiani, Daria Pocaterra, Francesco Chiodo. (2005) Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia. AIDS 19:10, 1051-1058
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   Leonardo Calza, Roberto Manfredi, Francesco Chiodo. (2003) Hyperlipidaemia in patients with HIV-1 infection receiving highly active antiretroviral therapy: epidemiology, pathogenesis, clinical course and management. International Journal of Antimicrobial Agents 22:2, 89-99
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   Leonardo Calza, Roberto Manfredi, Francesco Chiodo. (2003) Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART. AIDS 17:6, 851-859
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   Scott R Penzak, Susan K Chuck. (2002) Risk-benefit of HMG-CoA reductase inhibitors in the treatment of HIV protease inhibitor-related hyperlipidaemia. Expert Opinion on Drug Safety 1:1, 5-17
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   Pauline S. Hervey, Caroline M. Perry. (2000) Abacavir. Drugs 60:2, 447-479
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   James C. Thomas, Maria F. Lopes-Virella, Victor E. Del Bene, Joli D. Cerveny, Kelly B. Taylor, Laura S. McWhorter, Nanette C. Bultemeier. (2000) Use of Fenofibrate in the Management of Protease Inhibitor-Associated Lipid Abnormalities. Pharmacotherapy 20:6, 727-734
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    (2000) British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Medicine 1:2, 76-101
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    Georg M.N. Behrens, Matthias Stoll, Reinhold E. Schmidt. (2000) Lipodystrophy Syndrome in HIV Infection. Drug Safety 23:1, 57-76
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12. 12

    &NA;. (1998) Hypertriglyceridaemia common with ritonavir. Reactions Weekly &NA;:719, 2
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