Safety of lopinavir/ritonavir for the treatment of HIV-infection

Expert Opinion on Drug Safety

Volumn 4, Issue 3, 2005, Pages 403-420

  Vogel, Martin ^a   Rockstroh, Jürgen K ^a  

^a UNIVERSITY OF BONN   (Germany)

Author keywords

Antiretroviral therapy (ART); HIV infection; Lopinavir; Ritonavir

Indexed keywords

ANTIARRHYTHMIC AGENT; ANTICONVULSIVE AGENT; ANTIHISTAMINIC AGENT; ANTILIPEMIC AGENT; CALCIUM CHANNEL BLOCKING AGENT; CLARITHROMYCIN; DEXAMETHASONE; DISULFIRAM; EFAVIRENZ; EMTRICITABINE; ERGOT DERIVATIVE; GASTROINTESTINAL AGENT; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; HYPERICUM PERFORATUM EXTRACT; IMMUNOSUPPRESSIVE AGENT; LAMIVUDINE; LOPINAVIR PLUS RITONAVIR; METHADONE; MEVINOLIN; NELFINAVIR; NEUROLEPTIC AGENT; NEVIRAPINE; PROTON PUMP INHIBITOR; RIFABUTIN; RIFAMPICIN; SILDENAFIL; STAVUDINE; TENOFOVIR; WARFARIN; ZIDOVUDINE;

ABDOMINAL DISTENSION; ABDOMINAL PAIN; ABNORMAL SUBSTRATE CONCENTRATION IN BLOOD; ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; ARTHRALGIA; ASTHENIA; BREAST HYPERTROPHY; BURKITT LYMPHOMA; CARCINOGENICITY; CARDIOVASCULAR DISEASE; CENTRAL NERVOUS SYSTEM DISEASE; CLINICAL TRIAL; CONSTIPATION; CUSHINGOID SYNDROME; DIABETES MELLITUS; DIARRHEA; DOSE CALCULATION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG COMPETITION; DRUG CONTRAINDICATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG ERUPTION; DRUG EXPOSURE; DRUG FATALITY; DRUG FEVER; DRUG METABOLISM; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG WITHDRAWAL; DRY SKIN; DYSLIPIDEMIA; FATTY LIVER; FERTILITY; FLATULENCE; FOOD DRUG INTERACTION; GASTROINTESTINAL DISEASE; HEADACHE; HEART ARRHYTHMIA; HEPATITIS B; HEPATITIS C; HEPATOMEGALY; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYPERAMYLASEMIA; HYPERCHOLESTEROLEMIA; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPERTRIGLYCERIDEMIA; IMPAIRED GLUCOSE TOLERANCE; INFECTION CONTROL; LACTIC ACIDOSIS; LIPODYSTROPHY; LIPOMA; LIVER PAIN; LIVER TOXICITY; LONG TERM CARE; METABOLIC DISORDER; MYOPATHY; NAUSEA; NEUTROPENIA; NONHUMAN; PANCREATITIS; PHARMACODYNAMICS; REVIEW; RHABDOMYOLYSIS; RISK BENEFIT ANALYSIS; TASTE DISORDER; TERATOGENICITY; VIRUS INFECTION; VOMITING;

ANTI-HIV AGENTS; ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; DRUG APPROVAL; DRUG INTERACTIONS; HIV INFECTIONS; HUMANS; PYRIMIDINONES; SAFETY;

EID: 19444371370     PISSN: 14740338     EISSN: None     Source Type: Journal    
DOI: 10.1517/14740338.4.3.403     Document Type: Review

References (79)

1. LEE LM, KARON JM, SELIK R, NEAL JJ, FLEMING PL: Survival after AIDS diagnosis in adolescents and adults during the treatment era, United States, 1984-1997. JAMA (2001) 285:1308-1315.
2. MOCROFT A, LEDERGERBER B, KATLAMA C et al.: Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet (2003) 362:22-29.
3. SMITH KY: Selected metabolic and morphologic complications associated with highly active antiretroviral therapy. J. Infect. Dis. (2002) 185:S123-S127.
4. MONTESSORI V, PRESS N, HARRIS M, AKAGI L, MONTANER JS: Adverse effects of antiretroviral therapy for HIV infection. CMAJ (2004) 170:229-238.
5. AMMASSARI A, MURRI R, PEZZOTTI P et al.: Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J. Acquir. Immune Defic. Syndr. (2001) 28:445-449.
6. MORGELLO S, MAHBOOB R, YAKOUSHINA T, KHAN S, HAGUE K: Autopsy findings in a human immunodeficiency virus-infected population over 2 decades: influences of gender, ethnicity, risk factors, and time. Arch. Pathol. Lab. Med. (2002) 126:182-190.
7. FRIIS-MOLLER N, SABIN CA, WEBER R et al.: Combination antiretroviral therapy and the risk of myocardial infarction. N. Engl. J. Med. (2003) 349:1993-2003.
8. ROSENTHAL E, POIREE M, PRADIER C et al.: Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Morravic 2001 study). AIDS (2003) 17:1803-1809.
9. SHAM HL, KEMPF DJ, MOLLA A et al.: ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob. Agents Chemother. (1998) 42:3218-3224.
10. ROBERTS NA, MARTIN JA, KINCHINGTON D et al.: Rational design of peptide-based HIV proteinase inhibitors. Science (1990) 248:358-361.
11. LAL R, HSU A, GRANNEMAN G et al.: Mulitple Dose Safety, Tolerability and Pharmacokinetics of ABT-378 in Combination with Ritonavir. 5th Conference of Retroviruses and opportunistic Infections. Chicago, IL, USA (1998).
12. ABBOTT Laboratories: Kaletra Package Insert. (2004):03-5341-R10-Rev. February, 2004.
13. ERON JJ, FEINBERG J, KESSLER HA et al.: Once-daily versus twice-daily lopinavir/ritonavir in antiretroviral-naive HIV-positive patients: a 48-week randomized clinical trial. J. Infect. Dis. (2004) 189:265-272.
14. GUILLEMI S, ALEXANDER C, BONNER S et al.: Lopinavir trough concentration remains consistent for adult patients regardless of age. 7th International Congress on Drug Therapy in HIV-Infection. Glasgow (2004).
15. STEK A, MIROCHNICK M, CAPPARELLI E et al.: Reduced lopinavir exposure during pregnancy: preliminary pharmacokinetic results from PACTG 1026. XV International AIDS Conference. Bangkok, Thailand (2004).
16. SAEZ-LLORENS X, VIOLARI A, DEETZ CO et al.: Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children. Pediatr. Infect. Dis. J. (2003) 22:216-224.
17. GUSTAVSON L, LAM W, BERTZ R et al.: Assessment of the Bioequivence and Food Effects for Liquid and Soft Elastic Capsule Co-Formulations of ABT-378/ritonavir (ABT-378/r) iin Healthy Subjects. 40th Interscience Conference on Antimicriobial Agents and Chemotherapy. Toronto, Ontario, Canada (2000).
18. BERTZ R, CHIU Y, NAYLOR C, LUFF K, BRUN S: Lack of effect of gastric acid reducing agents on lopinavir/ritonavir plasma concentrations in HW-infected patients. 7th International Conference on Drug Therapy in HIV-Infection. Glasgow, United Kingdom (2004).
19. BOFFITO M, LUCCHINI A, MAIELLO A et al.: Lopinavir/ritonavir absorption in a gastrectomized patient. AIDS (2003) 17:136-137.
20. KUMAR GN, RODRIGUES AD, BUKO AM, DENISSEN JF: Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J. Pharmacol. Exp. Ther. (1996) 277:423-431.
21. KEMPF DJ, MARSH KC, KUMAR G et al.: Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with: ritonavir. Antimicrob. Agents Chemother. (1997) 41:654-660.
22. IZZEDINE H, LAUNAY-VACHER V, LEGRAND M, LIEBERHERR D, CAUMES E, DERAY G: ABT 378/r: a novel inhibitor of HIV-1 protease in haemodialysis. AIDS (2001) 15:662-664.
23. ARRIBAS J, PULIDO F, PENG J et al.: Evaluation of Multiple-Dose Pharmacokinetics of Lopinavir/Ritonavir (LPV/r) in HIV and HCV Co-Infected Subjects with Mild or Moderate Hepatic Insufficiency. 9th European AIDS Conference. Warsaw (2003).
24. ABBOTT Laboratories: Kaletra - European Summary of Product Characteristics. (2002) 20 March 2001.
25. WALMSLEY S, BERNSTEIN B, KING M et al.: Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N. Engl. J. Med. (2002) 346:2039-2046.
26. RUANE P, MENDONCA J, TIMERMAN A et al.: Kaletra versus Nelfinavir in Antiretroviral Naive Subjects: Week 60 Comparison in a Phase III, Blinded, Randomized Clinical Trial. 1st International AIDS Society Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina (2001).
27. DA SILVA B, KING M, CERNOHOUS P, KELLY C, TRESSLER R, BRUN S: Risk Factors for Body Fat Composition Changes in Antiretroviral Naive Patients Treated with Lopinavir/ritonavir (LPV/r) or Nelfinavir (NFV). 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. Paris, France (2003).
28. GULICK R, DA SILVA B, MCMILLAN F et al.: Lopinavir/ritonavir (LPV/r)-Based Therapy in Antiretroviral (ARV)-Naive, HIV-Infected Patients: 6-year Follow-Up of Study 720. 7th International Congress on Drug Therapy in HIV Infection. Glasgow, UK (2004).
29. MURPHY RL, BRUN S, HICKS C et al.: ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results. AIDS (2001) 15:F1-F9.
30. POLLARD R, THOMPSON M, HICKS C et al.: Phase III Comparison of Lopinavir/ritonavir versus Investigator-Selected Protease Inhibitors in Single PI-Experienced, NNRTI-Naive Patients: 48-Week Results of Study M98-888.7th International Congress on Drug Therapy in HIV-Infection. Glasgow, United Kingdom (2004).
31. BENSON CA, DEEKS SG, BRUN SC et al.: Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus Type 1-infected protease inhibitor-experienced patients. J. Inject. Dis. (2002) 185:599-607.
32. HICKS C, BRUN S, KING M et al.: Kaletra (Lopinavir/ritonavir) Therapy in Single Protease Inhibitor Experienced Patients: 144 week Follow Up. 8th European Conference on Clinical Aspects and Treatment of HIV Infection. Athens, Greece (2001).
33. DANNER S, BRUN S, RICHARDS B et al.: Kaletra (Lopinavir/ritonavir) and Efavirenz: 72-Week Safety and Efficacy Evaluation in Multiple PI-Experienced Patients. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy Chicago, Illinois, USA (2001).
34. HSU A, ISAACSON J, BRUN S et al.: Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. (2003) 47:350-359.
35. KEMPF DJ, ISAACSON JD, KING MS et al.: Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy. Antivir. Ther. (2002) 7:165-174.
36. BERNSTEIN B, MOSELEY J, KING M et al.: Safety of Kaletra: Results from Phase II and III Clinical Trials. 1st International AIDS Society Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina (2001).
37. BERTZ R, FOIT C, BURT D et al.: Assessment of the effect of nevirapine on the pharmacokinetics of lopinavir/ritonavir (Kaletra) after multiple dosing in HIV-infected adults. XIV International AIDS Conference. Barcelona, Spain (2002).
38. CERNOHOUS P, BERNSTEIN B, MOSELEY J, KING M, BAUER E, SUN E: Safety and Efficacy of Lopinavir/ritonavir in Women in a Phase III Study of Antiretroviral-Naive Subjects. XIV International AIDS Conference. Barcelona, Spain (2002).
39. SAEZ-LLORENS X, RENZ C, DEETZ C et al.: Kaletra (ABT-378/ritonavir) in HIV-infected Children at 60 Weeks. 8th Conference on Retroviruses and Opportunistic Infections. Chicago, Illinois, USA (2001).
40. MAUSS S, STECHEL J, WILLERS R, SCHMUTZ G, BERGER F, RICHTER WO: Differentiating hyperlipidaemia associated with antiretroviral therapy. AIDS (2003) 17:189-194.
41. LEE GA, SENEVIRATNE T, NOOR MA et al.: The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS (2004) 18:641-649.
42. RICHTER W, BERGER F, MAUSS S: Lopinavir/ritonavir Does Not Alter Very-Low-Density Lipoprotein (VLDL) Composition in HIV-infected Patients. 7th International Congress on Drug Therapy in HIV Infection. Glasgow, United Kingdom (2004).
43. NEGREDO E, MOLTO J, BURGER D et al.: Lopinavir/Ritonavir Plus Nevirapine as a Nucleoside-Sparing Approach in Antiretroviral-Experienced Patients (NEKA Study). J. Acquir. Immune Defic. Syndr. (2005) 38:47-52.
44. GATHE J, PODZAMCZER D, JOHNSON M et al.: Once-Daily versus Twice-Daily Lopinavir/ritonavir in Antiretroviral-Naive Patients: 48-Week Results. 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA, USA (2004).
45. MARTINEZ E, DOMINGO P, GALINDO MJ et al.: Risk of metabolic abnormalities in patients infected with HIV receiving antiretroviral therapy that contains lopinavir-ritonavir. Clin. Infect. Dis. (2004) 38:1017-1023.
46. NOOR MA, PARKER RA, O'MARA E et al.: The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults. AIDS (2004) 18:2137-2144.
47. CARR A, COOPER DA: Adverse effects of antiretroviral therapy. Lancet (2000) 356:1423-1430.
48. FELLAY J, BOUBAKER K, LEDERGERBER B et al.: Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study. Lancet (2001) 358:1322-1327.
49. SENSION M, SHEN Y, BUSH L et al.: Gastrointestinal Tolerability After PI/NNRTI Substitution of Lopinavir/ritonavir. 43rd Interscience Conference on Antimicrobial Agents Chemotherapy. Chicago, IL, USA (2003).
50. DA SILVA B, KING M, CERNOHOUS P, BRUN S: Lopinavir/ritonavir (LPV/r) Safety, Tolerability and Efficacy in Hepatitis C and/or Hepatitis B-infected Patients: Review of Clinical Trials. XV International AIDS Conference. Bangkok, Thailand (2004).
51. SULKOWSKI MS, THOMAS DL, CHAISSON RE, MOORE RD: Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA (2000) 283:74-80.
52. GONZALEZ DE REQUENA D, BLANCO F, GARCIA-BENAYAS T, JIMENEZ-NACHER I, GONZALEZ-LAHOZ J, SORIANO V: Correlation between lopinavir plasma levels and lipid abnormalities in patients taking lopinavir/ritonavir. AIDS Patient Care STDS (2003) 17:443-445.
53. SEMINARI E, DANISE A, HASSON H et al.: Relationship between lopinavir troughs and liver function tests. 7th International Congress on Drug Therapy in HIV Infection. Glasgow, United Kingdom (2004).
54. DURAN S, SAVES M, SPIRE B et al.: Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy. AIDS (2001) 15:2441-2444.
55. MARTINEZ E, MOCROFT A, GARCIA-VIEJO MA et al.: Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study. Lancet (2001) 357:592-598.
56. BERNASCONI E, BOUBAKER K, JUNGHANS C et al.: Abnormalities of body fat distribution in HIV-infected persons treated with antiretroviral drugs: The Swiss HIV Cohort Study. J. Acquir. Immune Defic. Syndr. (2002) 31:50-55.
57. MALLON PW, MILLER J, COOPER DA, CARR A: Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS (2003) 17:971-979.
58. BRINKMAN K, SMEITINK JA, ROMIJN JA, REISS P: Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet (1999) 354:1112-1115.
59. BONFANTI P, GULISANO C, RICCI E et al.: Risk factors for lipodystrophy in the CISAI cohort. Biomed. Pharmacother. (2003) 57:422-427.
60. SAVES M, RAFFI F, CAPEAU J et al.: Factors related to lipodystrophy and metabolic alterations in patients with human immunodeficiency virus infection receiving highly active antiretroviral therapy. Clin. Infect. Dis. (2002) 34:1396-405.
61. BUCHER HC, YOUNG J, BATTEGAY M: Protease inhibitor-sparing simplified maintenance therapy: a need for perspective. J. Antimicrob. Chemother. (2004) 54:303-305.
62. QURISHI N, KREUZBERG C, LUCHTERS G et al.: Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet (2003) 362:1708-1713.
63. LIM ML, MIN SS, ERON JJ et al.: Coadministration of Lopinavir/Ritonavir and Phenytoin Results in Two-Way Drug Interaction Through Cytochrome P450 Induction. J. Acquir. Immune Defic. Syndr. (2004) 36:1034-1040.
64. DI CENZO R, PETERSON D, CRUTTENDEN K et al.: Effects of valproic acid coadministradon on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob. Agents Chemother. (2004) 48:4328-4331.
65. BERTZ R, FOIT C, CHIU Y et al.: Mulitple-Dose Kaletra (Lopinavir/ritonavir) Does Not Affect the Pharmacokinetics of the CYP2D6 Probe, Desipramine. Seattle, WA, USA (2002).
66. BOFFITO M, BONORA S, SALES P et al.: Ketoconazole and lopinavir/ritonavir coadministration: boosting beyond boosting. AIDS Res. Hum. Retroviruses (2003) 19:941-942.
67. BONORA S, BOFFITO M, D'AVOLIO A et al.: Pharmacokinetics (PKS) of Rifabutin (RIF) Coadminstered with Lopinavir/ritonavir (LPV/r) in HIV Patients Affected by Tuberculosis (TB). 2nd IAS Conference on HIV Pathogenesis and Treatment. Paris, France (2002).
68. LA PORTE CJ, COLBERS EP, BERTZ R et al.: Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob. Agents Chemother. (2004) 48:1553-1560.
69. CARR R, ANDRE A, BERTZ R et al.: Concomittant Administration of ABT-378/ritonavir (ABT378/r) Results in a Clinically Important Pharmacokinetic (PK) Interaction with Atorvastarin (ATO) but not with Pravastatin (PRA). 40th Interscience Conference on Antimicrobial Agents Chemotherapy Toronto, Canada (2000).
70. VOGEL M, VOIGT E, MICHAELIS HC et al.: Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients. Liver Transpl. (2004) 10:939-944.
71. JAIN AB, VENKATARAMANAN R, EGHTESAD B et al.: Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients. Liver Transpl. (2003) 9:954-960.
72. CLARKE S, MULCAHY F, BERGIN C et al.: Absence of opioid withdrawal symptoms in patients receiving methadone and the protease inhibitor lopinavir-ritonavir. Clin. Infect. Dis. (2002) 34:1143-1145.
73. RAPAPORT S, MAROLODO-CONNELLY L, PATTERSON J, STEVENS R: Lack of methadone dose alterations or withdrawal symptoms with lopinavir/ritonavir (Kaletra). XIV International AIDS Conference. Barcelona, Spain (2002).
74. SOLAS C, POIZOT-MARTIN I, DROGOUL MP et al.: Therapeutic drug monitoring of lopinavir/ritonavir given alone or with a non-nucleoside reverse transcriptase inhibitor. Br. J. Clin. Pharmacol. (2004) 57:436-440.
75. KEARNEY B, MITTAN A, SAYRE J: Pharmacokinetic interaction and long term safety profile of tenofovir DF and lopinavir/ritonavir. 43rd Interscience Conference on Antimicrobial Agents Chemotherapy. Chicago, IL, USA (2003).
76. KRUSE G, STOCKER H, BRESKE A et al.: Trough levels of six different Atazanavir regimens in HIV-infected patients. 5th International Workshop on Clinical Pharmacology of HIV Therapy. Rome, Italy (2004).
77. CORBETT A, DAVIDSON L, PARK J et al.: Dose Separation Strategies to Overcome the Pharmacokinetic Interaction of a Triple Protease Inhibitor Regimen Containing Fosamprenavir Lopinavir, and Ritonavir. 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, USA (2004).
78. BERTZ R, FOIT C, ASHBRENNER E et al.: Assessment of the Steady-State Pharmacokinetic Interaction of Lopinavir/ritonavir with Either Indinavir or Saquinavir in Healthy Subjects. 42nd Intescience Conference on Antimicrobial Agents and Chemotherapy. San Diego, CA, USA (2002).
79. WALMSLEY S, LEITH J, KATLAMA C et al.: Pharmacokinetics and Safety of Tipranavir/ritonavir Alone or in Combination with Saquinavir (SQV), Amprenavir (APV), Or Lopinavir (LPV): Interim Analysis of BI 1182.51. XV International AIDS Conference. Bangkok, Thailand (2004).