Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Protease Inhibitors (PIs)
Last Updated: May 22, 2018; Last Reviewed: May 22, 2018
|Lopinavir/Ritonavir (LPV/r, Kaletra)
For additional information see Drugs@FDA: https://www.accessdata.fda.gov/scripts/cder/daf/
|Pediatric Oral Solution:
|Dosing Recommendations||Selected Adverse Events|
|Neonatal Dose (Aged <14 Days):
Infant Dose (Aged 14 Days–12 Months):
Adult Dose (Aged >18 Years):
Note: These drugs induce lopinavir metabolism and reduce lopinavir plasma levels. Increased LPV/r dosing is required with concomitant administration of these drugs.
- Metabolism: Cytochrome P (CYP) 3A4 is the major enzyme responsible for metabolism. There is potential for multiple drug interactions with lopinavir/ritonavir (LPV/r).
- Before administration, a patient’s medication profile should be carefully reviewed for potential drug interactions with LPV/r. In patients treated with LPV/r, fluticasone (a commonly used inhaled and intranasal steroid) should be avoided and an alternative used. Drug interactions with anti-tuberculous drugs are common and may require dose adjustments or regimen change.
- More common: Diarrhea, headache, asthenia, nausea and vomiting, rash, insulin resistance,1 and hyperlipidemia, especially hypertriglyceridemia,2 possibly more pronounced in girls than boys.3 These adverse events may be exacerbated by the higher dose of ritonavir used for boosting with lopinavir (200 mg) compared with atazanavir and darunavir (100 mg).
- Less common (more severe): Fat maldistribution.
- Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting diabetes mellitus, hemolytic anemia, spontaneous and/or increased bleeding in hemophiliacs, pancreatitis, elevation in serum transaminases, and hepatitis (life-threatening in rare cases). PR interval prolongation, QT interval prolongation, and Torsades de Pointes may occur.
- Special populations—neonates: LPV/r should not be used during the immediate postnatal period in premature infants because an increased risk of toxicity in premature infants has been reported. These toxicities in premature infants include transient symptomatic adrenal insufficiency,4 life-threatening bradyarrhythmias and cardiac dysfunction (including complete atrioventricular block, bradycardia, and cardiomyopathy),5-7 lactic acidosis, acute renal failure, central nervous system depression, and respiratory depression. These toxicities may be from the drug itself and/or from the inactive ingredients in the oral solution, including propylene glycol 15.3% and ethanol 42.4%.7 Transient asymptomatic elevation in 17-hydroxyprogesterone levels has been reported in term newborns treated at birth with LPV/r.4
LPV/r is Food and Drug Administration (FDA)-approved for use in children. Because there is a risk of toxicity, LPV/r should not be administered to neonates before a postmenstrual age of 42 weeks and a postnatal age of at least 14 days. Ritonavir acts as a pharmacokinetic (PK) enhancer by inhibiting the metabolism of lopinavir and thereby increasing the plasma concentration of lopinavir.
Clinical trials of treatment-naive adults have shown that regimens containing LPV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) are comparable to a variety of other regimens including regimens that contain atazanavir, darunavir (at 48 weeks), fosamprenavir, saquinavir/ritonavir, or efavirenz. Studies have also shown that regimens containing LPV/r plus two NRTIs are superior to regimens containing nelfinavir and inferior to regimens containing darunavir (at 192 weeks).8-16
LPV/r has been studied in both antiretroviral (ARV)-naive and ARV-experienced children and has demonstrated durable virologic activity and acceptable toxicity.17-25
Children have lower drug exposure than adults when treated with doses that are directly scaled for body surface area. The directly scaled dose approximation of the adult dose in children is calculated by dividing the adult dose by the usual adult body surface area of 1.73 m2. For the adult dose of LPV/r 400 mg/100 mg, the appropriate pediatric dose would be approximately LPV/r 230 mg/57.5 mg per m2. However, younger children have enhanced lopinavir clearance and need higher drug doses to achieve drug exposures similar to those in adults treated with standard doses. To achieve a Ctrough similar to that observed in adults, the pediatric dose needs to be increased 30% over the dose that is directly scaled for body surface area. Lopinavir exposures in infants19,24,26 are compared to those in older children17 and adults27 in Table A below.
|Adults27||Children17||Children17||Infantsa at 12 Months24||Infants 6 Weeks–6 Months19||Infants 14 Days to <6 Weeks26|
|Dose LPV||400 mg||230 mg/m2||300 mg/m2||300 mg/m2||300 mg/m2||300 mg/m2|
|a Data generated in a study that was cited but not reported in final manuscript. Data in table source: personal communication from Edmund Capparelli, PharmD (April 18, 2012)
Note: Values are means; all data shown performed in the absence of non-nucleoside reverse transcriptase inhibitors (NNRTIs).
Key to Acronyms: AUC = area under the curve; LPV = lopinavir
Models suggest that diet, body weight, and postnatal age are important factors in lopinavir PK, with improved bioavailability as dietary fat increases over the first year of life28 and with clearance slowing by age 2.3 years.29 A study from the U.K. and Ireland compared outcomes of LPV/r treatment with either a 230 mg/m2/dose or a 300 mg/m2/dose in children aged 5.6 to 12.8 years at the time of LPV/r initiation. Study findings suggested that the higher doses were associated with improved long-term viral load suppression.30
Pharmacokinetics and Dosing
12 Months to 12 Years (Without Concurrent Nevirapine, Efavirenz, Fosamprenavir, or Nelfinavir)
Lower trough concentrations have been observed in children receiving LPV/r 230 mg/57.5 mg both per m2 of body surface area when compared to LPV/r 300 mg/75 mg per m2 of body surface area per dose twice daily (see table).16 Therefore, some clinicians choose to initiate therapy in children aged 12 months to 12 years using LPV/r 300 mg/75 mg per m2 of body surface area per dose twice daily (when given without nevirapine, efavirenz, fosamprenavir, or nelfinavir) rather than the FDA-recommended LPV/r 230 mg/57.5 mg per m2 of body surface area per dose twice daily.
For infants receiving LPV/r 300 mg/75 mg per m2 of body surface area per dose twice daily, immediate dose reduction at age 12 months is not recommended; many practitioners would allow patients to “grow into” LPV/r 230 mg/57.5 mg per m2 of body surface area per dose twice daily dose as they gain weight over time. Some would continue the infant dose (300 mg/m2 of body surface area per dose twice daily) while on LPV/r liquid formulation.
14 Days to 12 Months (Without Concurrent Nevirapine, Efavirenz, Fosamprenavir, or Nelfinavir)
The PK of the oral solution at approximately LPV/r 300 mg/75 mg per m2 body surface area per dose twice daily was evaluated in infants aged <6 weeks26 and infants aged 6 weeks to 6 months.19 Even at this higher dose, Ctrough levels were highly variable but were lower in infants than in children aged >6 months. Ctrough levels were lower in infants aged ≤6 weeks than in infants aged 6 weeks to 6 months. By age 12 months, lopinavir area under the curve (AUC) was similar to that found in older children.24 Because infants grow rapidly in the first months of life, it is important to optimize lopinavir dosing by adjusting the dose at frequent intervals. Given the safety of doses as high as 400 mg/m2 body surface area in older children and adolescents,20 some practitioners anticipate rapid infant growth and prescribe doses somewhat higher than the 300 mg/m2 body surface area dose to allow for projected growth between clinic appointments.
Pharmacokinetics and Dosing with Concurrent Nevirapine, Efavirenz, Fosamprenavir, or Nelfinavir
In both children and adults, the lopinavir Ctrough is reduced by concurrent treatment with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or concomitant fosamprenavir or nelfinavir. Higher doses of lopinavir are recommended if the drug is given in combination with nevirapine, efavirenz, fosamprenavir, or nelfinavir. In 14 children treated with LPV/r 230 mg/57.5 mg per m2 body surface area per dose twice daily plus nevirapine, the mean lopinavir Ctrough was 3.77 ± 3.57 mcg/mL.17 Not only are these trough plasma concentrations lower than those found in adults treated with standard doses of LPV/r, but the variability in concentration is much higher in children than in adults.17,31 In a study of 15 children with HIV aged 5.7 to 16.3 years who were treated with LPV/r 300 mg/75 mg per m2 body surface area per dose twice daily plus efavirenz 14 mg/kg body weight per dose once daily, there was a 34-fold interindividual variation in lopinavir trough concentrations. Five of 15 children (33%) had lopinavir 12-hour trough concentrations less than 1.0 mcg/mL, the plasma concentration needed to inhibit wild-type HIV.32 A PK study in 20 children aged 10 to 16 years who were treated with LPV/r 300 mg/75 mg per m2 body surface area twice daily plus efavirenz 350 mg/m2 body surface area once daily showed only one patient (6.6%) with sub-therapeutic lopinavir trough concentrations,33 perhaps because the trial used an efavirenz dose that was approximately 11 mg/kg body weight33 instead of the 14 mg/kg body weight dose used in the trial discussed above.32
Once-daily dosing of LPV/r 800 mg/200 mg administered as a single daily dose is FDA-approved for treatment of HIV in therapy-naive adults aged >18 years. However, once-daily administration cannot be recommended for use in children in the absence of therapeutic drug monitoring (TDM), although this approach may be successful in select, closely monitored children.34 There is high interindividual variability in drug exposure and trough plasma concentrations below the therapeutic range for wild-type virus, as demonstrated in studies of ARV-naive children and adolescents.35-38 The currently available tablet formulation of LPV/r has lower variability in trough levels than the previously used soft-gel formulation.38,39 An international, randomized, open-label trial designed to demonstrate noninferiority in viral suppression between once-daily and twice-daily LPV/r dosing in children (median [IQR] age of 11 years [with a range of 9–14 years]) was unsuccessful, and more children on once-daily dosing had viral loads ≥50 copies/mL within 48 weeks.40
Dosing and Its Relation to Efficacy
LPV/r is effective in treatment-experienced patients with severe immune suppression,41,42 although patients with greater prior exposure to ARVs may be slower to reach undetectable viral load concentrations42,43 and may have less-robust CD4 T lymphocyte (CD4) percentage responses.44 Twice daily doses of lopinavir used in treatment-experienced patients were 230 mg to 300 mg/m2 body surface area in 39% of patients, 300 mg to 400 mg/m2 body surface area in 35%, and greater than 400 mg/m2 body surface area per dose in 4%.44
More important than viral resistance to lopinavir is the relationship of the drug exposure to the susceptibility of the HIV-1 isolate (EC50). The ratio of Ctrough to EC50 is called the inhibitory quotient (IQ), and in both adults and children treated with LPV/r, viral load reduction is more closely associated with IQ than with either the Ctrough or EC50 alone.45-47 A study of the practical application of the IQ to guide therapy using higher doses of LPV/r in children and adolescents to reach a target IQ of 15 showed the safety and tolerability of doses of LPV/r 400 mg/100 mg per m2 body surface area per dose twice daily (without fosamprenavir, nelfinavir, nevirapine, or efavirenz) and LPV/r 480 mg/120 mg per m2 body surface area per dose twice daily (with nevirapine or efavirenz).20 Results of a modeling study suggest that standard doses of LPV/r may be inadequate for treatment-experienced children and suggest the potential utility of TDM when LPV/r is used in children previously treated with protease inhibitors.48 A lopinavir plasma concentration of ≥1 mcg/mL is cited as a minimum target trough concentration,49-51 but this concentration may not adequately control viremia in patients with multiple lopinavir mutations.52,53
The poor palatability of the LPV/r oral solution can be a significant challenge to medication adherence for some children and families. Numbing of the taste buds with ice chips before or after administration of the solution, masking of the taste by administration with sweet or tangy foods (e.g., chocolate syrup or peanut butter), or having the pharmacist flavor the solution prior to dispensing are examples of interventions that may improve tolerability. Alternative pediatric formulations are currently being developed.54,55
Do Not Use Crushed Tablets
LPV/r tablets must be swallowed whole. Crushed tablets are slowly and erratically absorbed, and result in significantly reduced AUC, Cmax, and Ctrough compared with swallowing the whole tablet. The variability of the reduced exposure with the crushed tablets (5% to 75% reduction in AUC) means that a dose modification cannot be relied on to overcome the reduced absorption. Crushed tablets cannot be recommended for use.56 In a PK study using a generic adult formulation of LPV/r manufactured in Thailand, 21 of 54 children were administered cut (not crushed) pills and had adequate lopinavir Ctrough measurements.39
Children treated with LPV/r may have less-robust weight gain and smaller increases in CD4 percentage than children treated with NNRTI-based regimens.22,57-61 However, one study did not observe this difference in the effect of LPV/r on CD4 cell count,62 and another study found that the difference did not persist after a year of therapy.25 Some studies found no differences in the weight gain of children treated with LPV/r versus efavirenz.60,63 Switching to efavirenz-based ART at or after age 3 years removed the risk of lopinavir-associated metabolic toxicity, with no loss of virologic control (see Table 16 of Modifying Antiretroviral Regimens in Children with Sustained Virologic Suppression on Antiretroviral Therapy).60,61 Bone mineral density improved when children were treated with efavirenz-containing ART instead of LPV/r-containing ART.64
- Dejkhamron P, Unachak K, Aurpibul L, Sirisanthana V. Insulin resistance and lipid profiles in HIV-infected Thai children receiving lopinavir/ritonavir-based highly active antiretroviral therapy. J Pediatr Endocrinol Metab. 2014;27(5-6):403-412. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24259240.
- Arpadi S, Shiau S, Strehlau R, et al. Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based antiretroviral therapy. Arch Dis Child. 2013;98(4):258-264. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23220209.
- Shiau S, Kuhn L, Strehlau R, et al. Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment. BMC Pediatr. 2014;14:39. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24521425.
- Simon A, Warszawski J, Kariyawasam D, et al. Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal dysfunction among uninfected infants of HIV-infected mothers. JAMA. 2011;306(1):70-78. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21730243.
- Lopriore E, Rozendaal L, Gelinck LB, Bokenkamp R, Boelen CC, Walther FJ. Twins with cardiomyopathy and complete heart block born to an HIV-infected mother treated with HAART. AIDS. 2007;21(18):2564-2565. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18025905.
- McArthur MA, Kalu SU, Foulks AR, Aly AM, Jain SK, Patel JA. Twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir therapy. Pediatr Infect Dis J. 2009;28(12):1127-1129. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19820426.
- Food and Drug Administration. Serious health problems seen in premature babies given Kaletra (lopinavir/ ritonavir) oral solution. Available at http://www.fda.gov/Drugs/DrugSafety/ucm246002.htm. 2011.
- Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346(26):2039-2046. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12087139.
- Eron J, Jr., Yeni P, Gathe J, Jr., et al. 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;368(9534):476-482. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16890834.
- Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372(9639):646-655. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18722869.
- Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008;22(12):1389-1397. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18614861.
- Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008;358(20):2095-2106. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18480202.
- Pulido F, Estrada V, Baril JG, et al. Long-term efficacy and safety of fosamprenavir plus ritonavir versus lopinavir/ritonavir in combination with abacavir/lamivudine over 144 weeks. HIV Clin Trials. 2009;10(2):76-87. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19487177.
- Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr. 2015. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26262777.
- Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naive patients in the ARTEMIS trial. HIV Med. 2013;14(1):49-59. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23088336.
- Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010;53(3):323-332. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20032785.
- Saez-Llorens X, Violari A, Deetz CO, et al. Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 2003;22(3):216-224. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12634581.
- De Luca M, Miccinesi G, Chiappini E, Zappa M, Galli L, De Martino M. Different kinetics of immunologic recovery using nelfinavir or lopinavir/ritonavir-based regimens in children with perinatal HIV-1 infection. Int J Immunopathol Pharmacol. 2005;18(4):729-735. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16388722.
- Chadwick EG, Capparelli EV, Yogev R, et al. Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results. AIDS. 2008;22(2):249-255. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18097227.
- Robbins BL, Capparelli EV, Chadwick EG, et al. Pharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitors. Antimicrob Agents Chemother. 2008;52(9):3276-3283. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18625762.
- Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359(21):2233-2244. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19020325.
- Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med. 2010;363(16):1510-1520. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20942667.
- Reitz C, Coovadia A, Ko S, et al. Initial response to protease-inhibitor-based antiretroviral therapy among children less than 2 years of age in South Africa: effect of cotreatment for tuberculosis. J Infect Dis. 2010;201(8):1121-1131. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20214476.
- Chadwick EG, Yogev R, Alvero CG, et al. Long-term outcomes for HIV-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral therapy. AIDS. 2011;25(5):643-649. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21297419.
- Barlow-Mosha L, Angelidou K, Lindsey J, et al. Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial. Clin Infect Dis. 2016;63(8):1113-1121. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27439527.
- Chadwick EG, Pinto J, Yogev R, et al. Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy. Pediatr Infect Dis J. 2009;28(3):215-219. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19209098.
- Food and Drug Administration (FDA). Lopinavir-ritonavir (Kaletra) product label. 2015; http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021226s042lbl.pdf.
- Nikanjam M, Chadwick EG, Robbins B, et al. Assessment of lopinavir pharmacokinetics with respect to developmental changes in infants and the impact on weight band-based dosing. Clin Pharmacol Ther. 2012;91(2):243-249. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22190064.
- Urien S, Firtion G, Anderson ST, et al. Lopinavir/ritonavir population pharmacokinetics in neonates and infants. Br J Clin Pharmacol. 2011;71(6):956-960. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21564164.
- Donegan K, Doerholt K, Judd A, et al. Lopinavir dosing in HIV-infected children in the United Kingdom and Ireland. Pediatr Infect Dis J. 2013;32(1):45-50. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23076384.
- Verweel G, Burger DM, Sheehan NL, et al. Plasma concentrations of the HIV-protease inhibitor lopinavir are suboptimal in children aged 2 years and below. Antivir Ther. 2007;12(4):453-458. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17668553.
- Bergshoeff AS, Fraaij PL, Ndagijimana J, et al. Increased dose of lopinavir/ritonavir compensates for efavirenz-induced drug-drug interaction in HIV-1-infected children. J Acquir Immune Defic Syndr. 2005;39(1):63-68. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15851915.
- King JR, Acosta EP, Yogev R, et al. Steady-state pharmacokinetics of lopinavir/ritonavir in combination with efavirenz in human immunodeficiency virus-infected pediatric patients. Pediatr Infect Dis J. 2009;28(2):159-161. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19106779.
- Gondrie IPE, Bastiaans DET, Fraaij PLA, et al. Sustained Viral Suppression in HIV-infected Children on Once-daily Lopinavir/Ritonavir in Clinical Practice. Pediatr Infect Dis J. 2017;36(10):976-980. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28475554.
- Rosso R, Di Biagio A, Dentone C, et al. Lopinavir/ritonavir exposure in treatment-naive HIV-infected children following twice or once daily administration. J Antimicrob Chemother. 2006;57(6):1168-1171. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16606636.
- van der Lee M, Verweel G, de Groot R, Burger D. Pharmacokinetics of a once-daily regimen of lopinavir/ritonavir in HIV-1-infected children. Antivir Ther. 2006;11(4):439-445. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16856617.
- la Porte C, van Heeswijk R, Mitchell CD, Zhang G, Parker J, Rongkavilit C. Pharmacokinetics and tolerability of once- versus twice-daily lopinavir/ritonavir treatment in HIV-1-infected children. Antivir Ther. 2009;14(4):603-606. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19578247.
- van der Flier M, Verweel G, van der Knaap LC, et al. Pharmacokinetics of lopinavir in HIV type-1-infected children taking the new tablet formulation once daily. Antivir Ther. 2008;13(8):1087-1090. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19195335.
- Puthanakit T, Chokephaibulkit K, Suntarattiwong P, et al. Therapeutic drug monitoring of lopinavir in human immunodeficiency virus-infected children receiving adult tablets. Pediatr Infect Dis J. 2010;29(1):79-82. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19858772.
- Paediatric European Network for Treatment of A. Once vs. twice-daily lopinavir/ritonavir in HIV-1-infected children. AIDS. 2015;29(18):2447-2457. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26558544.
- Resino S, Bellon JM, Ramos JT, et al. Salvage lopinavir-ritonavir therapy in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 2004;23(10):923-930. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15602192.
- Resino S, Bellon JM, Munoz-Fernandez MA, Spanish Group of HIVI. Antiretroviral activity and safety of lopinavir/ritonavir in protease inhibitor-experienced HIV-infected children with severe-moderate immunodeficiency. J Antimicrob Chemother. 2006;57(3):579-582. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16446377.
- Resino S, Galan I, Perez A, et al. Immunological changes after highly active antiretroviral therapy with lopinavir-ritonavir in heavily pretreated HIV-infected children. AIDS Res Hum Retroviruses. 2005;21(5):398-406. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15929702.
- Larru B, Resino S, Bellon JM, et al. Long-term response to highly active antiretroviral therapy with lopinavir/ritonavir in pre-treated vertically HIV-infected children. J Antimicrob Chemother. 2008;61(1):183-190. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18025025.
- Casado JL, Moreno A, Sabido R, et al. Individualizing salvage regimens: the inhibitory quotient (Ctrough/IC50) as predictor of virological response. AIDS. 2003;17(2):262-264. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12545089.
- Delaugerre C, Teglas JP, Treluyer JM, et al. Predictive factors of virologic success in HIV-1-infected children treated with lopinavir/ritonavir. J Acquir Immune Defic Syndr. 2004;37(2):1269-1275. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15385734.
- Hsu A, Isaacson J, Brun S, et al. Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2003;47(1):350-359. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12499212.
- Rakhmanina N, van den Anker J, Baghdassarian A, Soldin S, Williams K, Neely MN. Population pharmacokinetics of lopinavir predict suboptimal therapeutic concentrations in treatment-experienced human immunodeficiency virus-infected children. Antimicrob Agents Chemother. 2009;53(6):2532-2538. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19258274.
- Moholisa RR, Schomaker M, Kuhn L, et al. Plasma lopinavir concentrations predict virological failure in a cohort of South African children initiating a protease-inhibitor-based regimen. Antivir Ther. 2014;19(4):399-406. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24518130.
- Moholisa RR, Schomaker M, Kuhn L, et al. Effect of Lopinavir and Nevirapine Concentrations on Viral Outcomes in Protease Inhibitor-experienced HIV-infected Children. Pediatr Infect Dis J. 2016;35(12):e378-e383. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27583591.
- Aurpibul L, Teerananchai S, Prasitsuebsai W, et al. Therapeutic Drug Monitoring of Lopinavir in HIV-Infected Children on Second-Line Antiretroviral Therapy in Asia. Ther Drug Monit. 2016;38(6):791-795. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27749514.
- van Zyl GU, van Mens TE, McIlleron H, et al. Low lopinavir plasma or hair concentrations explain second-line protease inhibitor failures in a resource-limited setting. J Acquir Immune Defic Syndr. 2011;56(4):333-339. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21239995.
- Court R, Gordon M, Cohen K, et al. Random lopinavir concentrations predict resistance on lopinavir-based antiretroviral therapy. Int J Antimicrob Agents. 2016;48(2):158-162. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27345268.
- Food and Drug Administration. NDA 205425 tentative approval 2015. Available from http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/205425Orig1s000TAltr.pdf. 2015.
- Kekitiinwa A, Musiime V, Thomason MJ, et al. Acceptability of lopinavir/r pellets (minitabs), tablets and syrups in HIV-infected children. Antivir Ther. 2016. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27128199.
- Best BM, Capparelli EV, Diep H, et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. J Acquir Immune Defic Syndr. 2011;58(4):385-391. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21876444.
- Coovadia A, Abrams EJ, Stehlau R, et al. Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized controlled trial. JAMA. 2010;304(10):1082-1090. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20823434.
- Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med. 2012;366(25):2380-2389. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22716976.
- Lindsey JC, Hughes MD, Violari A, et al. Predictors of virologic and clinical response to nevirapine versus lopinavir/ritonavir-based Antiretroviral Therapy in Young Children With and Without Prior Nevirapine Exposure for the Prevention of Mother-to-child HIV transmission. Pediatr Infect Dis J. 2014;33(8):846-854. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25222305.
- Murnane PM, Strehlau R, Shiau S, et al. Switching to efavirenz versus remaining on ritonavir-boosted lopinavir in HIV-infected children exposed to nevirapine: long-term outcomes of a randomized trial. Clin Infect Dis. 2017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28419200.
- Coovadia A, Abrams EJ, Strehlau R, et al. Efavirenz-Based Antiretroviral Therapy Among Nevirapine-Exposed HIV-Infected Children in South Africa: A Randomized Clinical Trial. JAMA. 2015;314(17):1808-1817. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26529159.
- Dahourou DL, Amorissani-Folquet M, Malateste K, et al. Efavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and Cote d'Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial. BMC Med. 2017;15(1):85. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28434406.
- Achan J, Kakuru A, Ikilezi G, et al. Growth Recovery Among HIV-infected Children Randomized to Lopinavir/Ritonavir or NNRTI-based Antiretroviral Therapy. Pediatr Infect Dis J. 2016;35(12):1329-1332. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27580060.
- Arpadi SM, Shiau S, Strehlau R, et al. Efavirenz is associated with higher bone mass in South African children with HIV. AIDS. 2016;30(16):2459-2467. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27427876.