Protease-inhibitor boosting in the treatment-experienced patient.

Highly active antiretroviral therapy (HAART) consisting of protease inhibitor (PI)-containing regimens has revolutionized the treatment options for HIV-infected individuals. However, even with successful treatment, virus is not completely eliminated, and virologic failure can occur because of treatment complexity, tolerability and side-effect issues, and suboptimal pharmacokinetics. Ritonavir-boosted PI therapies (i.e. combinations of low-dose ritonavir with a primary PI) can effectively enhance the pharmacokinetics of the primary PI by reducing its first-pass metabolism and postabsorptive clearance, thereby increasing potency. Boosted PI regimens may also simplify treatment by reducing regimen complexity and pill burden. For treatment-experienced patients, the higher PI concentrations achieved with ritonavir boosting may improve activity against PI-resistant virus. This article reviews the principles of PI boosting, its advantages and disadvantages, and the clinical experience with this strategy in treatment-experienced populations.

[1]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[2]  A. Hsu,et al.  Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. , 1998, Clinical pharmacokinetics.

[3]  R Rode,et al.  Ritonavir and saquinavir combination therapy for the treatment of HIV infection. , 1999, AIDS.

[4]  J. Gerber.  Using pharmacokinetics to optimize antiretroviral drug-drug interactions in the treatment of human immunodeficiency virus infection. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[5]  F. Hecht,et al.  Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population , 2000, AIDS.

[6]  S. Penzak,et al.  Hyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment. , 2000, Scandinavian journal of infectious diseases.

[7]  R. Manfredi,et al.  Disorders of lipid metabolism in patients with HIV disease treated with antiretroviral agents: frequency, relationship with administered drugs, and role of hypolipidaemic therapy with bezafibrate. , 2001, The Journal of infection.

[8]  A. Hsu,et al.  Saquinavir and ritonavir pharmacokinetics following combined ritonavir and saquinavir (soft gelatin capsules) administration. , 2001, British journal of clinical pharmacology.

[9]  G. Moyle.  Use of HIV protease inhibitors as pharmacoenhancers. , 2001, The AIDS reader.

[10]  Dale J. Kempf,et al.  Virtual Inhibitory Quotient Predicts Response to Ritonavir Boosting of Indinavir-Based Therapy in Human Immunodeficiency Virus-Infected Patients with Ongoing Viremia , 2002, Antimicrobial Agents and Chemotherapy.

[11]  P. Sax,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. , 2002, The Journal of infectious diseases.

[12]  R. Zeldin,et al.  Open-label study of a twice-daily indinavir 800-mg/ritonavir 200-mg regimen in HIV-infected adults failing a protease inhibitor regimen. , 2002, Journal of acquired immune deficiency syndromes.

[13]  V. Soriano,et al.  Salvage Treatment with Lopinavir/Ritonavir (Kaletra) in HIV-Infected Patients Failing All Current Antiretroviral Drug Families , 2002, HIV clinical trials.

[14]  Joel E Gallant,et al.  Association between adherence to antiretroviral therapy and human immunodeficiency virus drug resistance. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  K. Squires,et al.  Results of a Phase 2 Clinical Trial at 48 Weeks (AI424-007): A Dose-Ranging, Safety, and Efficacy Comparative Trial of Atazanavir at Three Doses in Combination with Didanosine and Stavudine in Antiretroviral-Naive Subjects , 2003, Journal of acquired immune deficiency syndromes.

[16]  Michael Giordano,et al.  Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results , 2003, AIDS.

[17]  S. Becker.  The role of pharmacological enhancement in protease inhibitor-based highly active antiretroviral therapy , 2003, Expert opinion on investigational drugs.

[18]  D. Haas,et al.  Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial , 2003, AIDS.

[19]  G. Plosker,et al.  Saquinavir: a review of its use in boosted regimens for treating HIV infection. , 2003, Drugs.

[20]  C. Cooper,et al.  A review of low-dose ritonavir in protease inhibitor combination therapy. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[21]  F. Gutiérrez,et al.  Lopinavir Plasma Concentrations and Changes in Lipid Levels During Salvage Therapy with Lopinavir/Ritonavir‐Containing Regimens , 2003, Journal of acquired immune deficiency syndromes.

[22]  Z. Fox,et al.  Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial. , 2003, The Journal of infectious diseases.

[23]  A. Hsu,et al.  Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. , 2004, The Journal of infectious diseases.