The FDA has approved a new pediatric dosage form and label changes for atazanavir. Please see the FDA announcement for more information.
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Protease Inhibitors (PIs)
(Last updated: February 12, 2014; last reviewed: February 12, 2014)
Pediatric Oral Solution: 80 mg/20 mg LPV/r per mL (contains 42.4% alcohol by volume and 15.3% propylene glycol by weight/volume) Film-Coated Tablets: 100 mg/25 mg LPV/r, 200 mg/50 mg LPV/r
Neonatal Dose (<14 Days):
No data on appropriate dose or safety in this age group. Do not administer to neonates before a post-menstrual age of 42 weeks and a postnatal age of at least 14 days because of potential toxicities.
Dosing for Individuals not Receiving Concomitant Nevirapine, Efavirenz, Fosamprenavir, or Nelfinavir Infant Dose (14 Days–12 Months):
Once-daily dosing is not recommended.
300 mg/75 mg ritonavir-boosted lopinavir per m2 of body surface area twice daily (approximates 16 mg/4 mg ritonavir-boosted lopinavir per kg body weight twice daily).
Note: This dose in infants aged <12 months is associated with lower lopinavir trough levels than those found in adults; lopinavir dosing should be adjusted for growth at frequent intervals (see text below). (Also see text for transitioning infants to lower mg per m2 dose).
Pediatric Dose (>12 Months to 18 Years):
Once-daily dosing is not recommended.
300 mg/75 mg ritonavir-boosted lopinavir per m2 of body surface area per dose twice daily (maximum dose 400 mg/100 mg twice daily except as noted below). For patients with body weight <15 kg, this approximates 13 mg/3.25 mg ritonavir-boosted lopinavir per kg body weight twice daily; and for patients with body weight ≥15 to 45 kg this dose approximates 11 mg/2.75 mg ritonavir-boosted lopinavir per kg body weight twice daily. This dose is routinely used by many clinicians and is the preferred dose for treatment-experienced patients with possible decreased lopinavir susceptibility (see text below).
230 mg/57.5 mg ritonavir-boosted lopinavir/m2 of body surface area per dose twice daily can be used in antiretroviral (ARV)-naive patients aged >1 year. For patients <15 kg, this dose approximates 12 mg/3 mg ritonavir-boosted lopinavir per kg body weight given twice daily and for patients ≥15 kg to 40 kg, this dose approximates 10 mg/2.5 mg ritonavir-boosted lopinavir per kg body weight given twice daily.
Weight-Band Dosing for 100 mg/25 mg Ritonavir-Boosted Lopinavir Pediatric Tablets for Children/Adolescents
Recommended number of 100-mg/25-mg ritonavir-boosted lopinavir tablets given twice daily
300 mg/m2/dose given twice daily
230 mg/m2/dose given twice daily
Body Weight (kg)
15 to 20 kg
>20 to 25 kg
>25 to 30 kg
>30 to 35 kg
>35 to 45 kg
4a or 5b
a Four of the 100 mg/25 mg ritonavir-boosted lopinavir tablets can be substituted by 2 tablets each containing 200 mg/50 mg ritonavir-boosted lopinavir in children capable of swallowing a larger size tablet.
b In patients receiving concomitant nevirapine, efavirenz, fosamprenavir, or nelfinavir, for body weight >45 kg, the Food and Drug Administration (FDA)-approved adult dose is 500 mg/125 mg ritonavir-boosted lopinavir twice daily, given as a combination of 2 tablets of 200/50 mg ritonavir-boosted lopinavir and 1 tablet of 100 mg/25 mg ritonavir-boosted lopinavir. Alternatively, 3 tablets of 200/50 mg ritonavir-boosted lopinavir can be used for ease of dosing.
Adult Dose (>18 Years):
800 mg/200 mg ritonavir-boosted lopinavir once daily, or
Do not use once-daily dosing in children or adolescents, or in patients receiving concomitant therapy with nevirapine, efavirenz, fosamprenavir, or nelfinavir, or in patients with three or more lopinavir-associated mutations (see Special Instructions for list).
In Patients with Three or more Lopinavir-Associated Mutations (see Special Instructions for list):
Dosing for Individuals Receiving Concomitant Nevirapine, Efavirenz, Fosamprenavir, or Nelfinavir. Note: These drugs induce lopinavir metabolism and reduce lopinavir plasma levels; increased ritonavir-boosted lopinavir dosing is required with concomitant administration of these drugs.
Once-daily dosing should not be used.
Pediatric Dose (>12 Months to 18 Years):
300 mg/75 mg ritonavir-boosted lopinavir per m2 of body surface area per dose twice daily. See table for weight-band dosing when using tablets.
Adult Dose (>18 Years):
Food and Drug Administration (FDA)-approved dose is 500 mg/125 mg ritonavir-boosted lopinavir twice daily, given as a combination of 2 tablets of 200/50 mg ritonavir-boosted lopinavir and 1 tablet of 100 mg/25 mg ritonavir-boosted lopinavir. Alternatively, 3 tablets of 200/50 mg ritonavir-boosted lopinavir can be used for ease of dosing. Once-daily dosing should not be used.
Ritonavir-boosted Lopinavir in Combination with Saquinavir Hard-Gel Capsules (Invirase) or in Combination with Maraviroc:
Saquinavir and maraviroc doses may need modification (See sections on SQV and MVC).
Possible increased bleeding in patients with hemophilia
PR interval prolongation
QT interval prolongation and torsades de pointes
Risk of toxicity—including life-threatening cardiotoxicity—is increased in premature infants (see Major Toxicities below).
Ritonavir-boosted lopinavir tablets can be administered without regard to food; administration with or after meals may enhance GI tolerability.
Ritonavir-boosted lopinavir tablets must be swallowed whole. Do not crush or split tablets.
Ritonavir-boosted lopinavir oral solution should be administered with food because a high-fat meal increases absorption.
The poor palatability of ritonavir-boosted lopinavir oral solution is difficult to mask with flavorings or foods (see Pediatric Use).
Ritonavir-boosted lopinavir oral solution can be kept at room temperature up to 77ºF (25ºC) if used within 2 months. If kept refrigerated (2º to 8ºC or 36º to 46ºF) ritonavir-boosted lopinavir oral solution remains stable until the expiration date printed on the label.
Once-daily dosing is not recommended because of considerable variability in plasma concentrations in children aged <18 years and higher incidence of diarrhea.
Use of ritonavir-boosted lopinavir once daily is specifically contraindicated if three or more of the following lopinavir resistance-associated substitutions are present—L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V—because higher lopinavir trough concentrations may be required to suppress resistant virus.
Cytochrome P (CYP) 3A4 inhibitor and substrate.
Dosing of ritonavir-boosted lopinavir in patients with hepatic impairment: ritonavir-boosted lopinavir is primarily metabolized by the liver. Caution should be used when administering lopinavir to patients with hepatic impairment. No dosing information is currently available for children or adults with hepatic insufficiency.
In the co-formulation of ritonavir-boosted lopinavir, the ritonavir acts as a pharmacokinetic enhancer, not as an ARV agent. It does this by inhibiting the metabolism of lopinavir and increasing lopinavir plasma concentrations.
Metabolism: CYP450 3A4 (CYP3A4) is the major enzyme responsible for metabolism. There is potential for multiple drug interactions.
Before administration, a patient’s medication profile should be carefully reviewed for potential drug interactions with lopinavir/ritonavir. In patients treated with lopinavir/ritonavir, fluticasone (a commonly used inhaled and intranasal steroid) should be avoided and an alternative used.
More common: Diarrhea, headache, asthenia, nausea and vomiting, rash, and hyperlipidemia, especially hypertriglyceridemia
Less common (more severe): Fat maldistribution
Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing 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: Ritonavir-boosted lopinavir should not be used in 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,1 life-threatening bradyarrhthymias and cardiac dysfunction,2-4 and lactic acidosis, acute renal failure, central nervous system depression, and respiratory depression.4 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%.4 Transient asymptomatic elevation in 17-hydroxyprogesterone levels has been reported in term newborns treated at birth with ritonavir-boosted lopinavir.1
Ritonavir-boosted lopinavir is Food and Drug Administration (FDA)-approved for use in children. Ritonavir acts as a pharmacokinetic (PK) enhancer by inhibiting the metabolism of lopinavir and thereby increasing the plasma concentration of lopinavir.
There is some controversy about the dosing of ritonavir-boosted lopinavir in children. 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 400/100 mg ritonavir-boosted lopinavir, the appropriate pediatric dose would be approximately 230/57.5 mg ritonavir-boosted lopinavir 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 similar Ctrough 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 infants5-7 are compared to those in older children8 and adults9 as shown in the table below.
Infants at 12 Months7,a
6 weeks–6 months5
a Data generated in study cited but not reported in final manuscript; data in table according to an e-mail 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 life10 and with clearance slowing by age 2.3 years.11 A study from the UK and Ireland in children aged 5.6 to 12.8 years at the time of ritonavir-boosted lopinavir initiation that compared outcomes in children treated with 230 mg/m2/dose versus 300 mg/m2/dose suggests that the higher doses were associated with long-term viral load suppression.12
Pharmacokinetics and Dosing
Aged 6 Months to 12 Years (Without Concurrent Nevirapine, Efavirenz, Fosamprenavir, or Nelfinavir)
Lower trough concentrations have been observed in children receiving 230 mg/57.5 mg ritonavir-boosted lopinavir per m2 of body surface area when compared to the 300 mg/75 mg ritonavir-boosted lopinavir per m2 of body surface area per dose twice-daily dose. (see table and Verweel, Burger, 2007) Therefore, some clinicians choose to initiate therapy in children aged 6 months to 12 years using 300 mg/75 mg ritonavir-boosted lopinavir per m2 of body surface area per dose twice daily (when given without nevirapine, efavirenz, fosamprenavir, or nelfinavir) rather than the drug label-recommended 230 mg/57.5 mg ritonavir-boosted lopinavir per m2 of body surface area per dose twice daily.
For infants receiving 300 mg/75 mg ritonavir-boosted lopinavir 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” the 230 mg/57.5 mg ritonavir-boosted lopinavir per m2 of body surface area per dose twice daily dosage 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.
Aged 6 Weeks to 6 Months (Without Concurrent Nevirapine, Efavirenz, Fosamprenavir, or Nelfinavir)
The PK of the oral solution at approximately 300 mg/75 mg ritonavir-boosted lopinavir per m2 body surface area per dose twice daily was evaluated in infants younger than age 6 weeks6 and infants aged 6 weeks to 6 months.5
Even at this higher dose, pre-dose (Ctrough) levels were highly variable but were lower in infants than in children older than age 6 months and were lowest in the youngest infants aged 6 weeks or younger compared with those ages 6 weeks to 6 months. By age 12 months, lopinavir AUC was similar to that found in older children.7 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,13 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 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 230 mg/57.5 mg ritonavir-boosted lopinavir per m2 body surface area per dose twice daily plus nevirapine, the mean lopinavir Ctrough was 3.77 ± 3.57 mcg/mL.8 Not only are these trough plasma concentrations lower than those found in adults treated with standard doses of ritonavir-boosted lopinavir, but the variability in concentration is much higher in children than adults.8,14 In a study of 15 HIV-infected children 5.7 to 16.3 years treated with the combination of 300 mg/75 mg ritonavir-boosted lopinavir 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 inter-individual variation in lopinavir trough concentrations, and 5 of 15 (33%) children had lopinavir 12-hour trough concentrations less than 1.0 mcg/mL, the plasma concentration needed to inhibit wild-type HIV.15 A PK study in 20 children aged 10 to 16 years treated with the combination of ritonavir-boosted lopinavir 300 mg/75 mg per m2 body surface area twice daily plus efavirenz 350 mg/m2 body surface area once daily showed only 1 (6.6%) patient with sub-therapeutic lopinavir trough concentrations,16 perhaps because of the use of a lower efavirenz dose of approximately 11 mg/kg body weight,16 compared to efavirenz 14 mg/kg body weight in the Bershoeff trial.15
Once-daily dosing of ritonavir-boosted lopinavir 800 mg/200 mg administered as a single daily dose is FDA-approved for treatment of HIV infection in therapy-naive adults older than age 18 years. However, once-daily administration cannot be recommended for use in children in the absence of therapeutic drug monitoring (TDM). There is high inter-individual 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.17-20 Compared with the soft-gel formulation of ritonavir-boosted lopinavir, the tablet formulation has lower variability in trough levels20,21 but the Panel remains concerned about the long-term effectiveness of once-daily ritonavir-boosted lopinavir in children.
Dosing and Its Relation to Efficacy
Ritonavir-boosted lopinavir is effective in treatment-experienced patients with severe immune suppression,22,23 although patients with greater prior exposure to ARVs may have slower reductions in virus load to undetectable concentrations23,24 and less robust response in CD4 percentage.25 Twice daily doses of lopinavir used in this cohort were 230 to 300 mg/m2 body surface area in 39% of patients, 300 to 400 mg/m2 body surface area in 35%, and greater than 400 mg/m2 body surface area per dose in 4%.25
More important than viral resistance to lopinavir is the relationship of the drug exposure (trough plasma concentration measured just before a dose, or Ctrough) 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 ritonavir-boosted lopinavir, virus load reduction is more closely associated with IQ than with either the Ctrough or EC50 alone.26-28 A study of the practical application of the IQ to guide therapy using higher doses of ritonavir-boosted lopinavir in children and adolescents to reach a target IQ of 15 showed the safety and tolerability of doses of 400 mg/100 mg ritonavir-boosted lopinavir per m2 body surface area per dose twice daily (without fosamprenavir, nelfinavir, nevirapine or efavirenz) and 480 mg/120 mg ritonavir-boosted lopinavir per m2 body surface area per dose twice daily (with nevirapine or efavirenz).13 Results of a modeling study suggest that standard doses of ritonavir-boosted lopinavir may be inadequate for treatment-experienced children and suggest the potential utility of TDM when ritonavir-boosted lopinavir is used in children previously treated with protease inhibitors.29
The poor palatability of the 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, chocolate syrup, or peanut butter, for example, or by flavoring the solution by the pharmacist prior to dispensing, are examples of interventions that may improve tolerability.
Do Not Use Crushed Tablets
Ritonavir-boosted lopinavir 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.30 In a PK study using a generic adult formulation of ritonavir-boosted lopinavir manufactured in Thailand, 21 of 54 children were administered cut (not crushed) pills and had adequate lopinavir Ctrough measurements.21
Compared with children treated with NNRTI-based regimens, those treated with ritonavir-boosted lopinavir may have less robust weight gain and smaller increases in CD4 percentage.31-33 The poor weight gain associated with ritonavir-boosted lopinavir is not understood, but may be related to aversion to the taste of the liquid formulation or decreased appetite.
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. Jul 6 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. Nov 30 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. Dec 2009;28(12):1127-1129. Available at http://www.ncbi.nlm.nih.gov/pubmed/19820426.
Boxwell D, Cao K, et al. Neonatal Toxicity of Kaletra Oral Solution—LPV, Ethanol, or Propylene Glycol?- Abstract #708. Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI). 2011. Boston, MA.
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. Jan 11 2008;22(2):249-255. Available at http://www.ncbi.nlm.nih.gov/pubmed/18097227.
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. Mar 2009;28(3):215-219. Available at http://www.ncbi.nlm.nih.gov/pubmed/19209098.
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. Mar 13 2011;25(5):643-649. Available at http://www.ncbi.nlm.nih.gov/pubmed/21297419.
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. Mar 2003;22(3):216-224. Available at http://www.ncbi.nlm.nih.gov/pubmed/12634581.
Food and Drug Administration (FDA). Lopinavir-ritonavir (Kaletra) product label. 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021226s030lbl.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. Feb 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. Jun 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. Jan 2013;32(1):45-50. Available at http://www.ncbi.nlm.nih.gov/pubmed/23076384.
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. Sep 2008;52(9):3276-3283. Available at http://www.ncbi.nlm.nih.gov/pubmed/18625762.
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. May 1 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. Feb 2009;28(2):159-161. Available at http://www.ncbi.nlm.nih.gov/pubmed/19106779.
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. Jun 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. Jan 2010;29(1):79-82. Available at http://www.ncbi.nlm.nih.gov/pubmed/19858772.
Resino S, Bellon JM, Ramos JT, et al. Salvage lopinavir-ritonavir therapy in human immunodeficiency virus-infected children. Pediatr Infect Dis J. Oct 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. Mar 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. May 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. Jan 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. Jan 24 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. Oct 1 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. Jan 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. Jun 2009;53(6):2532-2538. Available at http://www.ncbi.nlm.nih.gov/pubmed/19258274.
Best BM, Capparelli EV, Diep H, et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. J Acquir Immune Defic Syndr. Dec 1 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. Sep 8 2010;304(10):1082-1090. Available at http://www.ncbi.nlm.nih.gov/pubmed/20823434.
Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med. Oct 14 2010;363(16):1510-1520. Available at http://www.ncbi.nlm.nih.gov/pubmed/20942667.
Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med. Jun 21 2012;366(25):2380-2389. Available at http://www.ncbi.nlm.nih.gov/pubmed/22716976.