Lopinavir/ritonavir in the treatment of HIV-1 infection: a review

REVIEW Lopinavir/ritonavir in the treatment of HIV-1 infection: a review Ashish Chandwani 1 Jonathan Shuter 2 Division of Infectious Diseases, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY, USA; 2 AIDS Center and Division of Infectious Diseases, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY, USA 1 Abstract: Lopinavir/ritonavir is the first and only coformulated HIV-1 protease inhibitor (PI). Large clinical trials have demonstrated lopinavir/ritonavir’s clinical efficacy in both antiretroviral-naïve and -experienced patients. The immunologic and virologic benefits of treatment with this agent have been proven in HIV-infected adults, adolescents, and children. Smaller studies support the use of lopinavir/ritonavir monotherapy as a therapeutic option in certain patients. The drug is characterized by a high genetic barrier to resistance, and appears to be more forgiving of non-adherence than earlier, unboosted PIs. The most frequent side effects observed are diarrhea, nausea, and vomiting. These gastrointestinal adverse effects are generally mild to moderate. Metabolic derangements, including hyperlipidemia and glucose intolerance, have also been observed in lopinavir/ritonavir recipients. As the menu of available antiretroviral agents continues to expand, lopinavir/ritonavir remains a proven and effective drug for the treatment of HIV infection. Keywords: lopinavir/ritonavir, protease inhibitor, HIV, antiretroviral, Kaletra® Highly active antiretroviral therapy (HAART) has revolutionized the management of HIV-1 infection. Antiretroviral therapy has improved steadily in terms of efficacy, tolerability, and dosing convenience since the advent of HAART in 1995. Lopinavir/ ritonavir (Kaletra®) was the sixth drug in the HIV-1 protease inhibitor (PI) class to be approved by the US Food and Drug Administration (FDA). Approved in September 2000 in the US (April 2001 in Europe) for the treatment of HIV infection in adults and children older than 6 months of age, it was the first, and only, PI to be coformulated. It has been widely and effectively used in both antiretroviral naïve and experienced HIV-infected patients around the world. The current tablet formulation of lopinavir/ ritonavir was approved by the FDA in October 2005, and the capsule formulation was phased out in the US 6 months later in favor of the new tablet. This article will review the pharmacologic and clinical aspects of lopinavir/ritonavir in the management of HIV infection. Historical aspects Correspondence: Jonathan Shuter Montefiore Medical Center AIDS Center, 111 East 210th Street, Bronx, NY 10467, USA Tel +1 718 920 7845 Fax +1 718 405 0610 Email The availability of PIs changed the landscape of HIV therapy. Treatment with these agents produced virologic and immunologic improvements not previously seen with the nucleoside reverse transcriptase inhibitors (NRTIs) that were the standard of care (Sham et al 1998). They offered, for the first time, the possibility of long-term survival to persons living with HIV/AIDS (PLWHAs) (Deeks et al 1997; Sham et al 1998; Rana and Dudley 1999). However, all of the early PIs had limited bioavailability, high protein binding, large pill burdens, and short half-lives producing low trough levels (ie, nadir drug levels at the end of a dosing interval) and requiring frequent dosing. They were also associated with significant side effects that compromised adherence, Therapeutics and Clinical Risk Management 2008:4(5) 1023–1033 © 2008 Dove Medical Press Limited. All rights reserved 1023 Chandwani and Shuter a soft-gelatin capsule containing 133.3 mg of lopinavir and 33.3 mg of ritonavir, and it required storage in a refrigerator. The recommended adult dosage of the original formulation was 3 capsules taken twice daily (or 6 tablets once daily in antiretroviral-naïve patients). A new tablet formulation of lopinavir/ritonavir which used proprietary melt-extrusion technology (Meltrex™) was approved by the FDA in 2005. The new formulation consisted of a stable, solid dispersion of the drugs within a tablet. The new Kaletra® tablets each contain 200 mg lopinavir and 50 mg ritonavir. This formulation provides a lower pill burden, similar bioavailability, decreased effect of food on absorption of the drug, and an elimination of the refrigeration requirement (Klein et al 2007). In April 2005, the FDA issued an additional approval for once-daily lopinavir/ritonavir in adult patients with no prior antiretroviral treatment. An oral solution of lopinavir/ ritonavir containing 80 mg lopinavir and 20 mg ritonavir per ml is available and must be taken with food. Since 2007 a lower-dose tablet formulation of lopinavir/ritonavir (100 mg/25 mg) has been available in the US (available in the EU since early 2008) for the pediatric population. The introduction of lopinavir/ritonavir to the developing world has been accompanied by some controversy. Initiatives begun in recent years to make HAART available in resource poor areas have placed pressure on drug manufacturers to supply their medications at reduced cost. Current World Health Organization (WHO) guidelines recommend lopinavir/ritonavir, boosted fosamprenavir, or boosted atazanavir as the anchor drugs in second line regimens (World Health Organization 2006). WHO notes lopinavir/ritonavir’s co-formulation and heat stability as advantages over the and thus promoted the development of drug resistance (Deeks et al 1997; Sham et al 1998). Virologic failure was extremely common in those who did not maintain very high levels of adherence (Paterson et al 2000), and the outlook for patients who failed their first PI-based regimen was bleak (Gulick et al 2000; Hammer et al 2003). In 1997, Abbott Laboratories unveiled its new protease inhibitor, ABT-378, later to be named lopinavir, at the 4th Conference on Retroviruses and Opportunistic Infections. It was developed in an attempt to retain activity despite mutations in the HIV-1 protease gene. Lopinavir was found to be 3 to 4 times more active against HIV than ritonavir. Administered alone, lopinavir exhibits poor bioavailability. However, its blood levels are dramatically increased by low doses of ritonavir, a potent inhibitor of cytochrome P450 3A4. Coformulated lopinavir/ritonavir was the first combination pill to contain a drug (lopinavir) not available separately. Lopinavir/ritonavir (Kaletra®) received accelerated FDA approval for the treatment of HIV infection in combination with other agents for both antiretroviral naïve and experienced patients. The approval was based upon analyses of plasma HIV RNA and CD4+ lymphocyte count outcomes in a controlled study of treatment of HIV infection with lopinavir/ritonavir and in smaller uncontrolled doseranging studies of lopinavir/ritonavir of 72 weeks duration (FDA/Center for Drug Evaluation and Research). Lopinavir was not the first PI to take advantage of ritonavir boosting, but the (...truncated)