Protease inhibitor combination
| Clinical Use|
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services include lopinavir/ritonavir (given twice daily or once daily), in combination with tenofovir/emtricitabine or abacavir/lamivudine, as "alternative" regimens for initial antiretroviral therapy.
Regimens containing lopinavir/ritonavir have been shown to achieve effective viral suppression in initial and subsequent therapy.
Lopinavir/ritonavir, used with stavudine and lamivudine as initial treatment, was significantly more effective in achieving virologic suppression than the combination of nelfinavir + stavudine + lamivudine (HIV RNA <50 copies/mL in 67% vs 52% at 48 weeks; p < .001).(1)
In a study comparing lopinavir/ritonavir with ritonavir-boosted fosamprenavir, the 2 boosted protease inhibitors, given in combination with abacavir + lamivudine, provided comparable rates of virologic suppression and similar increases in CD4 cell counts. At 48 weeks, by intent-to-treat analysis, the proportion of subjects with HIV RNA <50 copies/mL was 65% in the lopinavir/ritonavir group and 66% in the fosamprenavir + ritonavir group. CD4 count increases were 191 cells/µL and 176 cells/µL, respectively.(3)
In a randomized comparison between lopinavir/ritonavir and efavirenz, each given with 2 nucleoside analogues, lopinavir/ritonavir recipients had lower rates of virologic suppression to <50 copies/mL at 48 weeks (77% for lopinavir/ritonavir and 89% for efavirenz recipients; p = .003), though greater increases in CD4 cell counts (285 and 241 cells/µL, respectively; p = .01). A third treatment group was given efavirenz + lopinavir/ritonavir, without nucleoside analogues; 83% of subjects in this group had virologic suppression to <50 copies/mL.(4)
Following failure of initial treatment with 2 nucleoside analogues and a protease inhibitor other than lopinavir/ritonavir, a majority of patients with no prior NNRTI use experienced suppression of viral load for 48 weeks after switching to a regimen containing lopinavir/ritonavir, nevirapine, and 1 new nucleoside analogue.(5)
In a study of individuals with extensive nucleoside analogue and protease inhibitor experience (but no prior NNRTI experience) and virologic recurrence on treatment, changing to a regimen including lopinavir/ritonavir and efavirenz resulted in viral load suppression at week 24 in the majority of participants.(6)
| Adverse Effects|
The most common symptomatic side effects of lopinavir/ritonavir are diarrhea and nausea. Common laboratory abnormalities include elevated cholesterol and triglyceride levels; liver toxicity and hyperglycemia are also observed. As with other protease inhibitors, lopinavir/ritonavir may contribute to abnormalities of body fat distribution. It is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with lopinavir/ritonavir is initiated.
Lopinavir/ritonavir is classified as an FDA Pregnancy Category C drug.
| Interactions with Other Drugs|
The ritonavir component of lopinavir/ritonavir is a potent inhibitor of cytochrome P450 3A (CYP3A) and CYP2D6, as well as an inducer of other hepatic enzyme systems. Coadministration with lopinavir/ritonavir therefore causes clinically significant alterations in serum levels of several other antiretrovirals, and of a variety of drugs including certain cholesterol-lowering agents, rifabutin, antiarrhythmics, sedative-hypnotics, erectile dysfunction agents, oral contraceptives, methadone, recreational substances, and others.
Drugs that affect metabolism by CYP3A can affect lopinavir levels. For example, some antiretrovirals, including efavirenz, nevirapine, and fosamprenavir, as well as other medications such as rifampin decrease lopinavir levels significantly.
Information on drug interactions should be consulted, as dosage adjustments are frequently required, and some combinations are clearly contraindicated.
Resistance to lopinavir is associated with the selection of several resistance mutations.
| Implications of lopinavir resistance for treatment with other antiretrovirals|
Resistance to lopinavir is seldom identified in the setting of viral rebound on lopinavir-containing initial regimens. In patients with preexisting mutations associated with protease inhibitors, new resistance mutations may emerge, and these likely would decrease the efficacy of other protease inhibitors. Genotypic or phenotypic analysis may be useful in predicting the response to protease inhibitors following failure of regimens containing lopinavir/ritonavir.
| Implications of resistance to other antiretrovirals for lopinavir treatment|
While no single mutation appears to confer high-level resistance to lopinavir, resistance mutations selected by other protease inhibitors, in particular L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V, can contribute to resistance. The probability of lopinavir/ritonavir treatment failure increases with each additional mutation.(7)
Genotypic or phenotypic testing may be useful in predicting the likelihood of response to lopinavir/ritonavir following failure of regimens containing other antiretrovirals.
|| || Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002 Jun 27;346(26):2039-46.|
|| || Hicks C, King MS, Gulick RM, et al. Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naive patients: 4 year follow-up study. AIDS. 2004 Mar 26;18(5):775-779.|
|| || Eron J Jr, Yeni P, Gathe J Jr, et al; KLEAN study team. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet. 2006 Aug 5;368(9534):476-82.|
|| ||Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection: ACTG 5142. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto. Abstract THLB0204. |
|| || 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 Infect Dis. 2002 Mar 1;185(5):599-607.|
|| ||Becker S, Brun S, Bertz R, et al. ABT-378/ritonavir (ABT-378/r) and Efavirenz: 24 Week Safety/Efficacy Evaluation in Multiple PI Experienced Patients. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto. Abstract 697.|
|| || King MS, Rode R, Cohen-Codar I, et al. Predictive genotypic algorithm for virologic response to lopinavir-ritonavir in protease inhibitor-experienced patients. Antimicrob Agents Chemother. 2007 Sep;51(9):3067-74.|