A Once-Daily Lopinavir/Ritonavir-Based Regimen Is Noninferior to Twice-Daily Dosing and Results in Similar Safety and Tolerability in Antiretroviral-Naive Subjects Through 48 Weeks

Gathe, Joseph; Silva, Barbara A. da; Cohen, Daniel E.; Loutfy, Mona; Podzamczer, Daniel; Rubio, Rafael; Gibbs, Sara; Marsh, T. David; Naylor, Christian; Fredrick, Linda; Bernstein, Barry

doi:10.1097/qai.0b013e31819c2937

Cited by 74 publications

(36 citation statements)

References 17 publications

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“…LPV/r has also been studied and is registered in the USA at the dose 800/ 200 q.d in treatment-naïve patients. Although this dose has been demonstrated to be "non-inferior" to 400/100 b.i.d [32,33], it is still to some extent a matter of contention whether it is equally efficacious [34]. A published PK/PD analysis on the relation between LPV concentration and effect in patients receiving these doses, as well as 800/200 q.d., states that no relation between drug concentration and antiretroviral effect was observed within the range of LPV exposures investigated [35].…”

Section: Discussionmentioning

confidence: 99%

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

Josephson

Andersson

Flamholc

et al. 2009

Eur J Clin Pharmacol

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Section: Discussionmentioning

confidence: 99%

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

Josephson

Andersson

Flamholc

et al. 2009

Eur J Clin Pharmacol

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“…Hypertriglyceridemia and hypercholesterolemia have been reported in patients treated with the conventional dose of LPV/r. 21,27 However, during pregnancy, there is an increase of TG in the first trimester. 28 Lipids are used as an energy source for the fetus, and as precursors for bile acids and steroid hormones.…”

Section: Changes In Laboratory Testsmentioning

confidence: 99%

“…When using the conventional dose of LPV/r in men and non-pregnant women, diarrhea occurs in 39-57% of patients and nausea occurs in 11-15% of patients during the 1st year. 21,22 Among patients who were exposed to HIV while receiving a prophylactic ART regimen with LPV/r at the conventional doses of tenofovir and emtricitabine, there was a 78% incidence of diarrhea and 59% incidence of nausea during the first 28 days of use. 23 The lower rates of occurrence of diarrhea during pregnancy may be attributed to the constipation that occurs during pregnancy because of the progestational effect.…”

Section: Gi Eventsmentioning

confidence: 99%

A Randomized Controlled Trial to Assess Safety, Tolerability, and Antepartum Viral Load with Increased Lopinavir/Ritonavir Dosage in Pregnancy

Bonafé

Costa

Vaz

et al. 2013

AIDS Patient Care and STDs

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HIV mother-to-child transmission (MTCT) is significantly reduced if antepartum viral load (apVL) is < 50 copies/mL. Pharmacokinetic studies suggest increasing the dosage of lopinavir/ritonavir (LPV/r) in pregnancy. It is important to assess tolerance, safety, and rate of patients presenting a apVL < 50 copies/mL when treating with increased dose of LPV/r during pregnancy. Confirmed HIV-infected pregnant women with a fetus at a gestational age of 14-33 weeks were randomly assigned to receive LPV/r 400/100 or 600/150 mg b.i.d. plus two nucleoside analogues (NRTIs). Treatment was discontinued in the case of alanine transaminase (ALT) of grade III elevation or higher, glucose, or triglycerides. Thirty-two women were randomized to the LPV/r 400/ 100 mg dose, and 31 women were randomized to the 600/150 mg dose. Overall, 9.4% of the women receiving the conventional dose, and 17.2% receiving the increased dose, discontinued treatment because of adverse events ( p = 0.29). The rates of gastrointestinal (GI) symptoms, laboratory abnormalities, preterm delivery, and low birth weight were similar in both groups. There were no cases of HIV MTCT. Among the women with a baseline VL > 50 copies/mL assigned to the conventional dose group, 45% (95% confidence interval [CI] 62.5-27.5%) had a apVL > 50 copies/mL compared with 10.5% (95% CI 21.6-0.6%) of those assigned to the increased dose group ( p = 0.01). There was no significant difference found for the patients with a baseline VL < 50 copies/mL. In pregnant women with a baseline VL > 50 copies/mL, it may be warranted to initiate LPV/r dosing at 600/ 150 mg, whereas the conventional dose is sufficient for pregnant women with a baseline VL < 50 copies/mL.

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“…However, the lopinavir AUC 0-12 and C 12 for patients taking 3 tablets BD plus NNRTIs are similar to those for patients taking 2 tablets BD without NNRTIs in whom lopinavir and ritonavir exposures were similar to that observed for studies in resource-rich settings (4). Low plasma C 12 values for patients taking 2 tablets BD plus NNRTIs may increase the risk of virological failure, although these levels are similar to the C trough values seen for patients taking 800/200 mg (4 tablets) four times a day (QD), which has shown good efficacy in patients without lopinavir resistance (6). Nevertheless, the fact that levels were lower than both those for patients taking 4 capsules BD with NNRTIs and those for patients taking 2 tablets BD without NNRTIs supports the most recent licensing information that a dose increment above 2 lopinavir-ritonavir tablets BD with concurrent NNRTIs should be considered.…”

Section: Discussionmentioning

confidence: 99%

“…Only the C max for the group receiving 2 lopinavir-ritonavir tablets BD with efavirenz was formally bioequivalent to 4 lopinavir-ritonavir capsules BD. Comparison of data for the group receiving 3 lopinavir-ritonavir tablets BD with NNRTI to data for the group receiving 2 lopinavirritonavir tablets BD without NNRTIs showed that the levels were generally similar those for the group receiving 3 tablets (50) 9 (45) 11 (55) 5 (28) 6 (33) 7 (39) 7 (35) 4 5 (25) 2 (10) 5 (25) 8 (44) 3 (17) 7 (39) 10 (50) 6 5 (25) 4 (20) 4 (20) 2 (11) 3 (17) 3 (17) 3 (15) 8 1 (5) 1 (6) Geometric mean C 12 (g/ml) (%CV) ͓range͔ 2.9 (189) ͓0.1-13.8͔ No. of patients (%) with C 12 (g/ml) of: Ͻ1 3 (15) 3 (15) 8 (40) 4 (22) 5 (28) 1-Ͻ5…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetics of Lopinavir-Ritonavir with and without Nonnucleoside Reverse Transcriptase Inhibitors in Ugandan HIV-Infected Adults

Kityo

Walker

Dickinson

et al. 2010

Antimicrob Agents Chemother

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We evaluated the pharmacokinetics of lopinavir-ritonavir with and without nonnucleoside reverse transcriptase inhibitors (NNRTIs) in Ugandan adults. The study design was a three-period crossover study ( respectively, and the apparent oral clearance (CL/F) values were reduced by 58% and 1%, respectively. For nevirapine, the geometric mean lopinavir AUC 0-12 (%CV) values were 112.9 g ⅐ h/liter (30%), 68.1 g ⅐ h/liter (53%), and 61.5 g ⅐ h/liter (52%), respectively, with corresponding GMR values of 1.66 (90% CI, 1.46 to 1.88; P < 0.001) and 0.90 (90% CI, 0.77 to 1.06; P ‫؍‬ 0.27), respectively, and the CL/F was reduced by 57% and 7%, respectively. Higher values for the lopinavir concentration at 12 h (C 12 ) were observed with 3 tablets and efavirenz-nevirapine (P ‫؍‬ 0.04 and P ‫؍‬ 0.0005, respectively), and marginally lower C 12 values were observed with 2 tablets and efavirenz-nevirapine (P ‫؍‬ 0.08 and P ‫؍‬ 0.26, respectively). These data suggest that 2 tablets of lopinavir-ritonavir BD may be inadequate when dosed with NNRTIs in Ugandan adults, and the dosage should be increased by the addition of an additional adult tablet or a half-dose tablet (100/25 mg), where available.When efavirenz (a CYP450 inducer) and lopinavir-ritonavir (metabolized by CYP450) are coadministered, a decrease in lopinavir plasma concentrations has been observed (8). In theory, this could lead to subtherapeutic lopinavir concentrations, the development of virological failure, and, potentially, the emergence of resistance mutations, particularly in the absence of viral load monitoring. Therefore, an increase from the standard dose of 3 capsules (400 mg of lopinavir/100 mg of ritonavir [400/100 mg]) to 4 capsules (533/133 mg) twice daily was recommended during the coadministration of lopinavir-ritonavir capsules (Kaletra) with nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-infected patients.A solid formulation of lopinavir-ritonavir tablets (Aluvia tablets; based on Meltrex technology) is now approved for the treatment of HIV infection. Each tablet contains 200 mg/50 mg lopinavir-ritonavir, so the standard dose is 2 tablets (rather than 3 capsules) twice daily (BD). The tablets are preferred to the capsules because of heat stability, a lack of a food effect, and lower pill burden. However, there are few data on the pharmacokinetic (PK) interactions between NNRTIs and lopinavir-ritonavir tablets, particularly in African populations, and the previously recommended 533/133-mg twice-daily capsule dose cannot be achieved with 200/50-mg tablets. In the United States, original recommendations for lopinavir-ritonavir tablets with NNRTIs were 400/100 mg twice daily, but a dose of 600/150 mg twice daily was to be considered if decreased lopinavir susceptibility was suspected. In Europe, a dose of 600/150 mg twice daily with close monitoring was recommended. These recommendations were based on two healthy-volunteer studies that found that the administration of lopinavir-ritonavir tablets at 400/100

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A Once-Daily Lopinavir/Ritonavir-Based Regimen Is Noninferior to Twice-Daily Dosing and Results in Similar Safety and Tolerability in Antiretroviral-Naive Subjects Through 48 Weeks

Cited by 74 publications

References 17 publications

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

A Randomized Controlled Trial to Assess Safety, Tolerability, and Antepartum Viral Load with Increased Lopinavir/Ritonavir Dosage in Pregnancy

Pharmacokinetics of Lopinavir-Ritonavir with and without Nonnucleoside Reverse Transcriptase Inhibitors in Ugandan HIV-Infected Adults

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