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Lopinavir/Ritonavir (Kaletra, Aluvia)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Adult Dosing
Pediatric Dosing
Prescribing Notes
Clinical Use
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
Resistance
Implications of lopinavir resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for lopinavir treatment
References
Related Resources
DHHS Guidelines
Characteristics of PIs
Drug Interactions with PIs
Interactions among PIs
Interactions between NNRTIs, Maraviroc, Raltegravir, and PIs
Drugs That Should Not Be Used with PIs, NNRTIs, or CCR5 Antagonists
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Insert)
Lopinavir/ritonavir (Kaletra)
Class

Protease inhibitor combination

Background
U.S. Manufacturer

Abbott Laboratories

Approval

The coformulation of lopinavir + ritonavir (lopinavir/ritonavir) received FDA approval in 2000 for treatment of HIV in adults and children age 6 months or older. In 2008, it received approval for use in infants. Approval was based on a study (1) showing comparable rates of viral suppression at 24 weeks of initial treatment in individuals receiving lopinavir/ritonavir + stavudine + lamivudine compared with those receiving nelfinavir + stavudine + lamivudine. Subsequent follow-up of a noncontrolled study showed that viral load suppression with this lopinavir/ritonavir combination persists through 4 years.(2) A tablet formulation of lopinavir/ritonavir received FDA approval in November 2005.

Formulation and Dosing

Lopinavir/ritonavir is available in tablet and oral liquid formulations. The capsule formulation has been phased out. Two tablet formulations are available: 200 mg lopinavir + 50 mg ritonavir or 100 mg lopinavir + 25 mg ritonavir (the latter is for pediatric dosing). The liquid formulation contains 80 mg lopinavir + 20 mg ritonavir per mL. The liquid formulation is 42% ethanol by volume.

Lopinavir/ritonavir is approved for twice-daily dosing; it also is approved for once-daily dosing in treatment-naive adults. For treatment-experienced patients, only the twice-daily option is recommended.

Adult Dosing
Tablets
(200 mg lopinavir/50 mg ritonavir)
400/100 mg BID
OR
800/200 mg QD*

Abbreviations: BID = twice daily; QD = once daily

* QD dosing is recommended only for treatment-naive adults. Lopinavir/ritonavir should not be administered once-daily in regimens that include efavirenz, nevirapine, amprenavir, fosamprenavir, or nelfinavir.

Oral solution not recommended for adults.

Pediatric Dosing
Age / WeightOral Solution
(80 mg lopinavir/
20 mg ritonavir per mL)
Tablets
(100 mg lopinavir/
25 mg ritonavir)
Age 14 days to 6 months
16/4 mg/kg BID, or 300/75 mg/m2 BIDUse oral solution
Age 6 months to 18 years
7-15 kg(12/3 mg/kg BID#)
7 to 10 kg1.25 mL BIDTablets are not recommended; use oral solution
>10 to <15 kg1.75 mL BIDTablets are not recommended; use oral solution
15-40 kg(10/2.5 mg/kg BID#)
15 to 20 kg2.25 mL BID
2 tablets BID
(100/25 mg formulation)
OR
1 tablet BID
(200/50 mg formulation)
>20 to 25 kg2.75 mL BID
2 tablets BID
OR
1 tablet BID
(200/50 mg formulation)
>25 to 30 kg3.5 mL BID
3 tablets BID
(100/25 mg formulation)
>30 to 35 kg4 mL BID
3 tablets BID
(100/25 mg formulation)
>35 to 40 kg4.75 mL BID
4 tablets BID
(100/25 mg formulation)
OR
2 tablets BID
(200/50 mg formulation)
>40 kg400/100 mg BID (same as adult dosage)
>40kg5 mL BID
4 tablets BID
(100/25 mg formulation)
OR
2 tablets BID
(200/50 mg formulation)

Abbreviations: wt = weight; BID = twice daily

# Approximately equivalent to lopinavir/ritonavir 230/57.5 mg/m2.

Prescribing Notes
Lopinavir/ritonavir oral solution should be taken with food; the tablets may be taken with or without food.
Lopinavir/ritonavir interacts with a number of antiretroviral medications, including other protease inhibitors, efavirenz, and nevirapine; dosage adjustments may be required. See Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing for lopinavir/ritonavir with other antiretrovirals.
No dosage adjustment is necessary in renal insufficiency.
Please consult product labeling for detailed dosing information.
FDA Pregnancy Category C.
Clinical Use
Combinations

Regimens containing lopinavir/ritonavir plus 2 nucleoside analogues have been shown to achieve effective viral suppression in initial and subsequent therapy (see "Use in Initial vs Subsequent Therapy").

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, fosamprenavir, and tipranavir, as well as other medications such as rifampin decrease lopinavir levels significantly.

Information on drug interactions should be consulted, as dose adjustments are frequently required, and some combinations are clearly contraindicated.

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. The guidelines designate lopinavir/ritonavir (in combination with zidovudine plus lamivudine) as the "preferred" regimen for pregnant women.

Regimens containing lopinavir/ritonavir have been shown to be effective as initial 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)

The effectiveness of regimens containing lopinavir/ritonavir in patients with prior NNRTI experience and failure of a protease inhibitor-containing regimen is unknown.

Factors Affecting Adherence

The most common symptomatic side effects of lopinavir/ritonavir are diarrhea and nausea. Common laboratory abnormalities include elevated cholesterol and triglyceride levels; liver toxicity is 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.

Resistance

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, and the implications of lopinavir resistance for treatment with other protease inhibitors are unknown. 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 has been found to confer high-level resistance to lopinavir, resistance mutations selected by other protease inhibitors can contribute to resistance.(7) If 5 or more protease resistance mutations are present at baseline, the probability of lopinavir/ritonavir treatment failure increases with each additional mutation.(8)

Regimens containing lopinavir/ritonavir and an NNRTI may be effective as subsequent regimens in individuals without prior NNRTI experience. Following failure of other protease inhibitors, the effectiveness of lopinavir/ritonavir used without an NNRTI, or in NNRTI-experienced individuals, is unclear. Genotypic or phenotypic testing may be useful in predicting the likelihood of response to lopinavir/ritonavir following failure of regimens containing other antiretrovirals.

References
1.   Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, Johnson M, Johnson D, Lalonde R, Japour A, Brun S, Sun E. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection.N Engl J Med. 2002 Jun 27;346(26):2039-46.
2.   Hicks C, King MS, Gulick RM, White Jr AC, Eron Jr JJ, Kessler HA, Benson C, King KR, Murphy RL, Brun SC. 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.
3.   Eron J Jr, Yeni P, Gathe J Jr, Estrada V, DeJesus E, Staszewski S, Lackey P, Katlama C, Young B, Yau L, Sutherland-Phillips D, Wannamaker P, Vavro C, Patel L, Yeo J, Shaefer M; 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.
4.  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.
5.   Benson CA, Deeks SG, Brun SC, Gulick RM, Eron JJ, Kessler HA, Murphy RL, Hicks C, King M, Wheeler D, Feinberg J, Stryker R, Sax PE, Riddler S, Thompson M, Real K, Hsu A, Kempf D, Japour AJ, Sun E. 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.
6.  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. Abstract 697. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 2000; Toronto.
7.   Kempf DJ, Isaacson JD, King MS, Brun SC, Xu Y, Real K, Bernstein BM, Japour AJ, Sun E, Rode RA. Identification of genotypic changes in human immunodeficiency virus protease that correlate with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease inhibitor-experienced patients. J Virol. 2001 Aug;75(16):7462-9.
8.   Kempf DJ, Isaacson JD, King MS, Brun SC, Sylte J, Richards B, Bernstein B, Rode R, Sun E. 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 Sep;7(3):165-74.