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Originally published online as doi:10.2353/ajpath.2007.070667 on September 14, 2007

Published online before print September 14, 2007
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(American Journal of Pathology. 2007;171:1724-1725.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070667

Correspondence

Modeling Metabolic Effects of the HIV Protease Inhibitor Ritonavir In Vitro

Jeffrey Laurence and Rozbeh Modarresi

Weill Medical College of Cornell University New York, New York

To the Editor-in-Chief:

Wang et al,1 in an article entitled "Human Immunodeficiency Virus Protease Inhibitor Ritonavir Inhibits Cholesterol Efflux from Human Macrophage-Derived Foam Cells," attempts to relate the dyslipidemia, lipodystrophy, and metabolic syndromes associated with ritonavir to the ability of this drug to interfere with cholesterol efflux in vitro. However, the concentrations of ritonavir used are suprapharmacologic and thus of uncertain clinical significance.

The authors state in their abstract that "a clinically relevant concentration of ritonavir (15 µmol/L)" was used. They modify this statement in the Discussion by correctly noting that the recommended dose of ritonavir, as a sole protease inhibitor, is "600 mg every 12 hours resulting in a maximum plasma concentration of 8 to 15 µmol/L," equivalent to 5.6 to 10.5 µg/ml. Yet ritonavir is now rarely used at this dose, being most effective and most widely incorporated into combination antiretroviral regimens as part of a protease inhibitor-boosted strategy in which the maximum concentration is 0.677 µg/ml for men and 0.918 µg/ml for women, with an area under the concentration-time curve of 4 to 5 µg ml–1 h–1.2 The clinical syndromes complicating ritonavir administration have been seen with both high and low (protease inhibitor-boosted) dosage regimens, demanding that pathophysiologic explanations derive from studies with the lower concentrations. Levels of ritonavir used by the authors have been reported as cytotoxic to cells of the monocyte/macrophage lineage.3

The use of similar suprapharmacologic levels of ritonavir has also led to other potentially spurious reports in the literature. For example, osteoclast formation is suppressed in vitro by levels of ritonavir exceeding 10 µg/ml,4 but doses in the appropriate pharmacological range of 0.7 to 3.6 µg/ml (1 to 5 µmol/L) enhance osteoclast formation in vitro,5 and clinically, ritonavir seems to accelerate bone mineral density loss, not suppress it.6 Returning to lipid metabolism, Liang et al7 showed that ritonavir inhibits apolipoprotein B degradation at what they stated were "therapeutically relevant concentrations (5 to 100 µmol/L)." However, others have commented on the probable irrelevance in vivo of the very high concentrations required to inhibit this proteasome-based reaction, 25 to 40 µmol/L.8 To reveal clinically pertinent insights into the myriad metabolic disturbances that have been attributed to antiretroviral therapies over the years, care must be taken to use drug concentrations in vitro equivalent to pharmacologically appropriate levels, with attention paid to more than just the maximum concentration of the highest level of drug possibly achievable.

References

  1. Wang X, Mu H, Chai H, Liao D, Yao Q, Chen C: Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells. Am J Pathol 2007, 171:304-314[Abstract/Free Full Text]
  2. Umeh O, Currier J, Park JG, Cramer Y, Owens S, Hermes A, Fletcher C: Sex differences in lopinavir/ritonavir soft gel capsule pharmacokinetics among HIV-infected females and males. 14th Conference on Retroviruses and Opportunistic Infections, 2007 February 25–28, Los Angeles, CA, Abstract 786
  3. Zhou H, Pandak WM, Jr, Lydall V, Natarajan R, Hylemon PB: HIV protease inhibitors activate the unfolded protein response in macrophages: implication for atherosclerosis and cardiovascular disease. Mol Pharmacol 2005, 68:690-700[Abstract/Free Full Text]
  4. Wang MW-H, Wei S, Faccio R, Takeshita S, Tebas P, Powderly WG, Teitelbaum SL, Ross FP: The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL induced signaling. J Clin Invest 2004, 114:206-213[CrossRef][Medline]
  5. Fakruddin JM, Laurence J: HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor {kappa}B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-{gamma}/RANKL cross-talk. J Biol Chem 2003, 278:48251-48258[Abstract/Free Full Text]
  6. Fakruddin JM, Yin M, Laurence J: Pathophysiologic correlates of RANKL deregulation in HIV infection and its therapy. 12th Conference on Retroviruses and Opportunistic Infections, 2005 February 22–25, Boston, MA, Abstract 822
  7. Liang J-S, Distler O, Cooper DA, Jamil H, Deckelbaum RJ, Ginsberg HN, Sturley SL: HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med 2001, 7:1327-1331[CrossRef][Medline]
  8. Kelleher AD, Sewell AK, Price DA: Dyslipidemia due to retroviral protease inhibitors. Nat Med 2002, 8:308[Medline]
 

Xinwen Wang, Qizhi Yao and Changyi Chen

Baylor College of Medicine Houston, Texas

Authors’ Reply:

This is a response to the Correspondence written by Drs. Laurence and Modarresi regarding our recent publication1 in The American Journal of Pathology. The authors have concerns that the concentrations of ritonavir used in our study are suprapharmacologic and thus of uncertain clinical significance. We believe the concentration of ritonavir around 15 µmol/L used in our study is clinically relevant. The recommended clinical dose of ritonavir is 400 to 600 mg every 12 hours, which may result in maximum serum concentration (Cmax) values of 7.1 to 11.2 µg/ml,2,3 equivalent to 10 to 16 µmol/L. Even though it is now rarely used as monotherapy, ritonavir at this dose range has been used in combination antiretroviral regimens in both adults and children.3–17

Our current study may be of clinical significance. Ritonavir was exposed to human macrophages for 24 hours and showed significant inhibition in cholesterol efflux. This finding may be used to explain, at least in part, the clinical association of cardiovascular disease with ritonavir treatment in some HIV-infected patients. In addition, ritonavir induced oxidative stress in macrophages. These data may imply that clinical usage of antioxidant therapy may be effective in minimizing the adverse effects of ritonavir. For now, it is not possible to overinterpret our findings based solely on in vitro experiments. Different protease inhibitors may have different effects on cholesterol efflux or produce different degrees of oxidative stress. Because many different types of antioxidants with a variety of actions are available, it is likely that certain antioxidants may be more effective than others to minimize the adverse effects of ritonavir. Therefore, it is strongly warranted to investigate further these issues of cholesterol efflux and antioxidant therapy in animal models and clinical trials. It is also possible that future HIV drugs might be able to minimize effects on cholesterol efflux.

As part of highly active antiretroviral therapy, ritonavir or other anti-HIV drugs are usually used continually in patients for months or years. Even low-dose ritonavir used in humans may still have significant adverse effects on the cardiovascular systems due to long-term therapy. Because HIV infection became a chronic but controllable disease, we must pay great attention to the adverse effects of these anti-HIV drugs.

References

  1. Wang X, Mu H, Chai H, Liao D, Yao Q, Chen C: Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells. Am J Pathol 2007, 171:304-314[Abstract/Free Full Text]
  2. Flexner C: HIV-protease inhibitors. N Engl J Med 1998, 338:1281-1292[Free Full Text]
  3. Danner SA, Carr A, Leonard JM, Lehman LM, Gudiol F, Gonzales J, Raventos A, Rubio R, Bouza E, Pintado V, Aguado AG, de Lomas JG, Delgado R, Borleffs JCC, Hsu A, Valdes JM, Boucher CAB, Cooper DA: A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. N Engl J Med 1995, 333:1528-1534[Abstract/Free Full Text]
  4. Jayaweera DT, Scerpella E, Robinson M, Rode R, Campo R, Rodriguez A, Asthana D, Tanner T, Kolber MA: The safety and efficacy of indinavir and ritonavir (400/400 mg BID) in HIV-1-infected individuals from an inner-city minority population: a pilot study. Int J STD AIDS 2003, 14:732-736[Abstract/Free Full Text]
  5. Rolla VC, da Silva Vieira MA, Pereira Pinto D, Lourenço MC, de Jesus Cda S, Gonçalves Morgado M, Ferreira Filho M, Werneck-Barroso E: Safety, efficacy and pharmacokinetics of ritonavir 400mg/saquinavir 400mg twice daily plus rifampicin combined therapy in HIV patients with tuberculosis. Clin Drug Investig 2006, 26:469-479[CrossRef][Medline]
  6. Nachman SA, Stanley K, Yogev R, Pelton S, Wiznia A, Lee S, Mofenson L, Fiscus S, Rathore M, Jimenez E, Borkowsky W, Pitt J, Smith ME, Wells B, McIntosh K: Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial. JAMA 2000, 283:492-498[Abstract/Free Full Text]
  7. Cameron DW, Japour AJ, Xu Y, Hsu A, Mellors J, Farthing C, Cohen C, Poretz D, Markowitz M, Follansbee S, Angel JB, McMahon D, Ho D, Devanarayan V, Rode R, Salgo M, Kempf DJ, Granneman R, Leonard JM, Sun E: Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS 1999, 13:213-224[CrossRef][Medline]
  8. Buss N, Snell P, Bock J, Hsu A, Jorga K: Saquinavir and ritonavir pharmacokinetics following combined ritonavir and saquinavir (soft gelatin capsules) administration. Br J Clin Pharmacol 2001, 52:255-264[CrossRef][Medline]
  9. Dumon C, Solas C, Thuret I, Chambost H, Lacarelle B, Michel G, Durand A: Relationship between efficacy, tolerance, and plasma drug concentration of ritonavir in children with advanced HIV infection. Ther Drug Monit 2000, 22:402-408[CrossRef][Medline]
  10. Rublein JC, Eron JJ, Jr, Butts JD, Raasch RH: Discontinuation rates for protease inhibitor regimens containing ritonavir 600 mg versus ritonavir 400 mg plus saquinavir 400 mg. Ann Pharmacother 1999, 33:899-905[Abstract]
  11. Michelet C, Bellissant E, Ruffault A, Arvieux C, Delfraissy JF, Raffi F, Bazin C, Renard I, Sebille V, Chauvin JP, Dohin E, Cartier F: Safety and efficacy of ritonavir and saquinavir in combination with zidovudine and lamivudine. Clin Pharmacol Ther 1999, 65:661-671[CrossRef][Medline]
  12. Deeks SG, Grant RM, Beatty GW, Horton C, Detmer J, Eastman S: Activity of a ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure. AIDS 1998, 12:F97-F102[CrossRef][Medline]
  13. Hoffmann F, Notheis G, Wintergerst U, Eberle J, Gurtler L, Belohradsky BH: Comparison of ritonavir plus saquinavir- and nelfinavir plus saquinavir-containing regimens as salvage therapy in children with human immunodeficiency type 1 infection. Pediatr Infect Dis J 2000, 19:47-51[CrossRef][Medline]
  14. Hall CS, Raines CP, Barnett SH, Moore RD, Gallant JE: Efficacy of salvage therapy containing ritonavir and saquinavir after failure of single protease inhibitor-containing regimens. AIDS 1999, 13:1207-1212[CrossRef][Medline]
  15. Tebas P, Patick AK, Kane EM, Klebert MK, Simpson JH, Erice A, Powderly WG, Henry K: Virologic responses to a ritonavir-saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999, 13:F23-F28[CrossRef][Medline]
  16. Rhone SA, Hogg RS, Yip B, Sherlock C, Conway B, Schechter MT, O’Shaughnessy MV, Montaner JS: The antiviral effect of ritonavir and saquinavir in combination amongst HIV-infected adults: results from a community-based study. AIDS 1998, 12:619-624[Medline]
  17. Lafeuillade A, Poggi C, Chadapaud S, Hittinger G, Chouraqui M, Delbeke E: HIV-1 induction-maintenance at the lymph node level: the "Apollo-97" Study. J Acquir Immune Defic Syndr 2001, 28:154-157[CrossRef][Medline]




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