Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Protease Inhibitors (PIs)

Darunavir

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Darunavir (DRV) is primarily metabolized by cytochrome P450 (CYP) 3A4. Both ritonavir (RTV) and cobicistat (COBI) are inhibitors of CYP3A4, thereby increasing the plasma concentration of DRV. Coadministration of DRV plus RTV (DRV/r) or DRV plus COBI (DRV/c) with drugs that are highly dependent on CYP3A clearance creates potential for multiple drug–drug interactions and may be associated with suboptimal efficacy or serious and/or life-threatening events.
• Coadministration of several drugs, including other protease inhibitors (PIs) and rifampin, is contraindicated with DRV/r and DRV/c. A study involving adults with HIV suggested that etravirine (ETR) may reduce serum DRV concentrations by induction of CYP3A5, which is more commonly expressed in individuals of African descent.¹ Before administering DRV with a pharmacokinetic (PK) enhancer (boosting agent), a patient’s medication profile should be carefully reviewed for potential drug interactions.
• When twice-daily DRV/r was used in combination with tenofovir disoproxil fumarate (TDF) in 13 patients with HIV aged 13 to 16 years, both TDF and DRV exposures were lower than those found in adults treated with the same combination.² No dose adjustment is recommended when using DRV/r with TDF, but caution is advised and therapeutic drug monitoring (TDM) may be useful.³ Data from the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) protocol P1058A indicate that coadministering once-daily DRV/r with once-daily or twice-daily ETR in children, adolescents, and young adults aged 9 years to <24 years did not have a significant effect on DRV plasma concentrations.⁴ When DRV/r was coadministered with ETR twice daily in pediatric patients, target concentrations for both DRV and ETR were achieved.⁵ DRV PK were not affected when DRV was coadministered with rilpivirine (RPV) in a study of adolescents and young adults.⁶ DRV/r coadministration increased RPV exposure twofold to threefold; close monitoring for RPV-related adverse events is advisable.

Major Toxicities

• More common: Diarrhea, nausea, vomiting, abdominal pain, headache, and fatigue.
• Less common: Skin rash, including erythema multiforme and Stevens-Johnson syndrome; fever and elevated levels of hepatic transaminases; lipid abnormalities; and crystalluria.
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting diabetes mellitus, and spontaneous bleeding in hemophiliacs. Hepatic dysfunction, particularly in patients with underlying risk factors, such as hepatitis B or hepatitis C virus coinfection.

Resistance

The International Antiviral Society–USA maintains a list of updated HIV drug resistance mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Approval

DRV/r is approved by the U.S. Food and Drug Administration (FDA) as a component of antiretroviral (ARV) therapy in treatment-naive and treatment-experienced children aged ≥3 years. Because RTV oral solution is no longer commercially available, use of  DRV/r is limited to children weighing ≥20 kg who can use the RTV 100-mg powder packet or 100-mg tablet.

DRV is approved by the FDA to be administered with COBI (Tybost) boosting in pediatric patients weighing ≥40 kg. The fixed-dose combination (FDC) DRV/c (Prezcobix) is approved by the FDA for use in pediatric patients weighing ≥25 kg to <40 kg at a dose of DRV 675 mg/COBI 150 mg and for use in people weighing ≥40 kg at a dose of DRV 800 mg/COBI 150 mg. The latest FDA label for COBI (Tybost) includes additional recommended dosing for children weighing ≥25 kg to <30 kg. DRV/c/emtricitabine (FTC)/tenofovir alafenamide (TAF) (Symtuza) is approved by the FDA for use in pediatric patients weighing ≥40 kg.

A pediatric formulation of Symtuza (DRV 675 mg/COBI 150 mg/FTC 200 mg/TAF 10 mg) is being developed as a scored tablet (to enable splitting) for use in the European Union; this formulation is not approved by the FDA). This FDC was found to be bioequivalent to coadministration of all of the individual formulations of each component of the FDC. The swallowability and acceptability of a placebo tablet (size 21 × 11 × 7 mm) matching this pediatric fixed-dose formulation has been studied in an open-label randomized crossover PK bioequivalence clinical trial in 24 virologically suppressed children with HIV aged 6 years to <12 years of age weighing 25 kg to <40 kg.^7,8 Participants were also taking their stable antiretroviral therapy (ART) regimen. Twenty-three of 24 (95.8%) participants were able to swallow the whole and the split tablets after one or two attempts; >70% of participants rated the tablets to be acceptable or good, and whole tablets were favored over split tablets.

Efficacy in Clinical Trials

In an international, multisite clinical trial (TMC114-TiDP29-C228) that enrolled treatment-experienced children aged 3 years to <6 years, 17 (81%) of 21 children who received DRV/r twice daily had viral loads <50 copies/mL at Week 48.^9-11

A randomized, open-label, multicenter pediatric trial¹¹ that evaluated twice-daily DRV/r among 80 treatment-experienced children aged 6 years to <18 years reported that 66% of patients had plasma HIV RNA <400 copies/mL and 51% had HIV RNA <50 copies/mL at Week 24.

Once-daily DRV/r has been investigated in a small study involving 12 treatment-experienced children aged 6 to 12 years who had maintained HIV viral loads <50 copies/mL for at least 6 months.¹² All but one child continued to have undetectable viral loads during a median of 11.6 months of follow-up (range 0.5–14.2 months). The remaining child had detectable viral load measurements between 20 copies/mL and 200 copies/mL on three occasions during a 3-month period before, again, becoming undetectable without a change in regimen.

In one study, 12 participants aged 12 to 17 years received DRV/r once daily.¹³ After 48 weeks, all but one participant had viral loads <50 copies/mL.

The SMILE (Penta-17-ANRS 152) trial released results¹⁴ showing that a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)–sparing regimen of integrase strand transfer inhibitor (INSTI) plus boosted DRV was non-inferior to the standard of care (SOC) (i.e., 2 NRTI + boosted PI/non-nucleoside reverse transcriptase inhibitor) at 48 weeks in maintaining virologic suppression among children and adolescents with HIV aged 6 to 18 years. Eight (5%) of 158 participants in the INSTI+DRV/r arm and 12 (7.5%) of 160 in the SOC arm had HIV viral loads ≥50 copies/mL at 48 weeks post-enrollment; difference of −2.5% (95% CI, −7.6% to 2.5%), meeting the non-inferiority margin of 10%. Safety was similar between the arms. There were small significant differences between the two arms in CD4 T lymphocyte (CD4) cell count mean change from baseline, high-density lipoprotein (HDL) cholesterol, weight, and body mass index (BMI): CD4 and HDL decreased more in the INSTI+DRV/r arm than in the SOC arm, and weight and BMI had greater increases in the INSTI+DRV/r arm than the SOC arm over the 48 weeks. The difference between the INSTI+DRV/r experimental arm compared to SOC in mean CD4 count change and mean HDL change from baseline were −48.3 cells/mm³ (95% CI, −93.4 to −3.2; P = 0.036) and −4.1 mg/dL (95% CI, −6.7 to −1.4; P = 0.003), respectively. The differences in weight and BMI between the INSTI+DRV/r experimental arm and the SOC were 1.97 kg (95% CI, 1.1–2.9; P < 0.001) and 0.66 kg/m2 (95% CI, 0.3–1.0; P < 0.001)], respectively.

Observational Data

An observational cohort¹⁵ of children and youth <25 years of age on DRV-based ART in nine countries in sub-Saharan Africa found that, over a median duration of follow-up of 28.3 months, 771 (87.9%) were alive at the end of follow-up for the study, 29 (3.6%) died, and 69 (8.5%) moved away or were lost to follow-up; 809 participants had final outcomes. Males were marginally less likely to be retained in care than females (adjusted hazard ratio 0.85, 95% CI 0.72–1.0), and adolescents aged 15 to 19 years were more likely to die than children younger than 10 years (adjusted subdistribution hazard ratio 4.20, 95% CI, 1.37–12.87).

Pharmacokinetics and Dosing

Pharmacokinetics in Children Aged 3 Years to <6 Years

Twenty-one children aged 3 years to <6 years and weighing 10 kg to <20 kg received twice-daily DRV/r oral suspension. These children had experienced virologic failure on their previous ARV regimens and had fewer than three DRV resistance mutations, confirmed by genotypic testing.^9.10,16 The DRV area under the curve from 0 to 12 hours (AUC_0–12h), measured as a percent of the adult area under the curve (AUC) value,^9,10,17 was 128% overall: 140% in children weighing 10 kg to <15 kg and 122% in children weighing 15 kg to <20 kg.

The CHAPAS-4 trial included a PK substudy¹⁸ in a subset of 104 of children aged 3 to 15 years weighing ≥14 kg and receiving a failing first-line ART. The children were randomized to either TAF/FTC (dosed according to World Health Organization–recommended weight bands) or SOC dual-NRTI treatment, in combination with dolutegravir (DTG) or a boosted PI, and had plasma PK data collected at steady-state. TAF was administered in combination with DTG (n = 18), DRV/r (n = 34), or lopinavir/ritonavir (n = 20), and the measured geometric mean (CV%) TAF AUC from dose to the time of the last measurable concentration (AUC_last) for those combinations was 284.5 (79), 232.0 (61), and 210.2 (98) ng·hour/mL, respectively, similar to reference values in adults taking TAF 10 mg in conjunction with a boosted PI (adult dosing recommended by the European Medicines Agency). One hundred percent of the children had TAF AUC_last >55 ng·hour/mL, the predefined target value associated with favorable virologic efficacy in adults. In combination with atazanavir/ritonavir (n = 32), TAF AUC_last was higher, at 511.4 (68) ng·hour/mL, and TAF C_max was 86% higher than the C_max in adults taking TAF 25 mg with boosted PI. In all of these combinations, tenofovir geometric mean (CV%) area under the concentration–time curve from dose to 24 hours after dose and C_max was below the exposures observed in adults taking TAF 25 mg once daily in conjunction with boosted PI (TAF 25 mg dosing for adults is recommended by the FDA, except in the case of the FDC DRV/c/FTC/TAF, in which case the dose is 10 mg of TAF). This study provided reassurance that in children aged 3 to 15 years, TAF can achieve safe and well-tolerated exposures when used in conjunction with DRV/r. See the Tenofovir Alafenamide section for more information.

Pharmacokinetics in Children Aged ≥6 Years

Initial pediatric PK evaluation of DRV tablets and RTV oral solution or tablets was based on a Phase 2 randomized, open-label, multicenter study that enrolled 80 treatment-experienced children and adolescents aged 6 years to <18 years and weighing ≥20 kg.¹⁹ Part 1 of the trial used a weight-adjusted dose of DRV (9 mg/kg to 15 mg/kg) and RTV (1.5 mg/kg to 2.5 mg/kg) twice daily, approximating the standard adult dose of DRV/r 600 mg/100 mg twice daily on a per-weight basis. This dose resulted in inadequate drug exposure in the pediatric population studied, with a 24-hour AUC (AUC_24h) that was 81% of the AUC_24h observed in adults and a pre-dose concentration (C_0h) that was 91% of the C_0h observed in adults. A pediatric dose that was 20% to 33% higher than the directly scaled adult dose was needed to achieve a drug exposure that was similar to that found in adults, and this was the dose selected for Part 2 of the study. The higher dose used for the safety and efficacy evaluation was DRV 11 mg/kg to 19 mg/kg and RTV 1.5 mg/kg to 2.5 mg/kg twice daily. This dose resulted in a DRV AUC_24h of 123.3 mcg·h/mL (range 71.9–201.5 mcg·h/mL) and a C_0h of 3,693 ng/mL (range 1,842‍–‍7,191 ng/mL), representing 102% and 114% of the respective values in adults. Doses were given twice daily and were stratified into body-weight bands of 20 kg to <30 kg and 30 kg to <40 kg. The current weight-band doses of twice-daily DRV/r for treatment-experienced pediatric patients weighing >20 kg to <40 kg were selected using the findings from the safety and efficacy portion of this study (see Table A below).

A small study that involved 12 treatment-experienced children aged 6 to 12 years examined the PKs and efficacy of DRV/r once daily administered in combination with abacavir and lamivudine.¹² All participants had maintained HIV plasma viral loads <50 copies/mL for at least 6 months prior to beginning this regimen. The weight-based doses used for once-daily DRV/r were based on a prior modeling study:²⁰ 600 mg/100 mg for patients weighing 15 kg to 30 kg, 675 mg/100 mg for patients weighing 30 kg to 40 kg, and 800 mg/100 mg for patients weighing >40 kg. The geometric mean AUC_0–24h was below the study target of 80% of the value seen in adults (63.1 mg·h/L vs. 71.8 mg·h/L), but the trough values that were observed at 23.1 hours to 25.1 hours after the previous dose exceeded the trough plasma concentration recommended for treatment-experienced adults (0.55 mg/L).²¹ One child developed neuropsychiatric symptoms (anxiety and hallucinations) and was removed from study. This child did not have an excessive exposure to DRV; the AUC_0–24 was 47.8 mg·h/L.

A population PK sub-study was done as part of the SMILE trial²², examining the protein binding and PK of DRV among virologically suppressed adolescents on an INSTI and DRV/r. A total of 443 plasma PK samples from 152 adolescents were incorporated. The median unbound-to–total concentration ratio was 5.4%; DRV displays a total protein binding in plasma of 94.5% (73.7% bound to alpha-1 glycoprotein and 20.8% bound to albumin). A significant impact of alpha-1 glycoprotein concentrations on DRV clearance was observed. The simulations showed that 86.8% of DRV total trough concentrations (C_trough) were above 0.55 mg/L (10 x protein binding–adjusted EC₅₀) for wild-type HIV-1, and 86.8% of DRV unbound C_trough were above 0.0243 mg/L (10 x PA EC₉₀) for wild-type HIV-1. Overall, individual C_trough in adolescents given DRV/r 800 mg/100 mg daily were in line with those observed in adults given DRV/r 800/100 mg daily. This provided reassuring evidence of satisfactory exposures in adolescents given an adult dosing regimen of DRV/r.

Dosing

Pharmacokinetic Enhancers

DRV should not be used without a PK enhancer (boosting agent). RTV may be used as a boosting agent in children and adults. COBI may be used as a boosting agent in children weighing ≥40 kg and adults.

A study that enrolled 19 Thai children used the RTV 100-mg capsule twice daily as the boosting dose for twice-daily DRV 375 mg (in children weighing 20 kg to <30 kg), 450 mg (in children weighing 30‍ kg to 40 kg), and 600 mg (in children weighing ≥40 kg).²³ The DRV exposures with RTV 100 mg twice daily were similar to those obtained in the studies with lower (<100 mg) doses of liquid RTV.^19,23 The tolerability and PK data from this small study support the use of RTV 100 mg for boosting using either the powder or tablet formulation in children weighing ≥20 kg, particularly in instances where the lower-dose formulations are unavailable or a child does not tolerate the liquid RTV formulation. No data are available on the safety and tolerability of using the RTV 100-mg tablet or powder formulation in children weighing <20 kg.

Data on the dosing of DRV/c are available primarily for adult patients.²⁴ Data on once-daily use of the FDC tablet DRV/c 800 mg/150 mg (Prezcobix) showed bioavailability that was comparable to the bioavailability observed with the use of DRV/r 800 mg/100 mg once daily.²¹

In an open-label switch study, eight adolescent patients with a median age of 14 years (range 12‍–‍17 years) who received DRV/c had DRV exposures (AUC_tau) that were similar to those observed in adults, except for a lower trough concentration at the end of the dosing interval (C_tau). The median DRV C_tau (494 ng/mL) was above the protein binding-adjusted half-maximal inhibitory concentration for wild-type virus (55 ng/mL). Adolescent patients in this study received the adult dose of COBI 150 mg daily. DRV dosing was based on weight, with patients who weighed ≥40 kg receiving DRV 800 mg once daily and patients who weighed 30 kg to <40 kg receiving DRV 675 mg once daily. In this small sample, 95.5% of patients had HIV RNA <50 copies/mL at Week 12. COBI appeared to be well tolerated with no discontinuations due to adverse events.²⁵

Frequency of Administration

In February 2013, the FDA approved the use of once-daily DRV for treatment-naive children and for treatment-experienced children without DRV resistance-associated mutations (see Table B below). Population PK modeling and simulation were used to develop recommendations for once-daily dosing in younger pediatric subjects aged 3 years to <12 years and weighing 10 kg to <40 kg.^10,26 Currently, limited data exist on the efficacy of once-daily DRV/r dosing in treatment-naive or treatment-experienced children aged <6 years. Therefore, the Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV (the Panel) generally recommends dosing DRV/r twice daily in children aged ≥3 years to <12 years (see Once-Daily Administration in Children Aged <12 Years and Weighing <40 kg below). The Panel recommends that once-daily DRV/r be used only in treatment-naive and treatment-experienced adolescents weighing ≥40 kg who do not have mutations that are associated with DRV resistance. If DRV and RTV are used once daily in children aged <12 years, the Panel recommends conducting a PK evaluation of plasma concentrations of DRV and closely monitoring viral load.

Table B. U.S. Food and Drug Administration–Approved Once-Daily Dosing for Pediatric Patients Aged ≥3 Years and Weighing >20 kg Who Are Treatment Naive or Treatment Experienced With No Darunavir Resistance-Associated Mutations

Note: The Panel generally recommends dosing DRV plus RTV twice daily in children aged ≥3 years to <12 years.

Once-Daily Administration in Children Aged <12 Years and Weighing <40 kg

During the TMC114-C228 trial, the researchers investigated once-daily dosing of DRV for 2 weeks; DRV PKs were evaluated in treatment-experienced children aged 3 years to <12 years as part of a substudy. After the conclusion of the substudy, the participants switched back to a twice-daily regimen.^21,26 The DRV/r dose for once-daily use, which was based on PK simulation and which did not include a relative bioavailability factor, was DRV 40 mg/kg coadministered with approximately 7 mg/kg of RTV for children weighing <15 kg and DRV/r 600 mg/100 mg once daily for children weighing ≥15 kg.^26,27 The PK data obtained from 10 children aged 3 to 6 years in this substudy (see Table C below) were included as part of the population PK modeling and simulation that was used to determine the FDA-approved dose for once-daily DRV/r in children aged 3 years to <12 years.

In a small study in which DRV/r was administered once daily to 12 treatment-experienced children aged 6 to 12 years,¹² the geometric mean AUC_0–24h achieved was below the study target of 80% of the value seen in adults (63.1 mg·h/L vs. 71.8 mg·h/L). Trough values exceeded the plasma concentration that is recommended for treatment-experienced patients (0.55 mg/L). Despite the FDA dosing guidelines, the Panel generally recommends dosing DRV/r twice daily in children aged ≥3 years to <12 years. The Panel makes this recommendation because of the small data set used for once-daily DRV/r PK modeling and the limited amount of data on the use of once-daily DRV/r in children aged <12 years.

Once-Daily Administration in Adolescents Aged ≥12 Years and Weighing ≥40 kg

A substudy of once-daily dosing of DRV/r 800 mg/100 mg demonstrated that DRV exposures in 12 treatment-naive adolescents (aged 12–17 years and weighing ≥40 kg) were similar to those seen in adults treated with once-daily DRV (see Table D below).¹³ After 48 weeks, 83.3% of patients had viral loads <50 copies/mL and 91.7% had viral loads <400 copies/mL.¹³ Interestingly, no relationship was observed between DRV AUC_0-24h and C_0h and virologic outcome (HIV RNA <50 copies/mL) in this study. DRV exposures were found to be similar to those observed in adults with once-daily dosing in another study in which a single dose of DRV 800 mg with RTV 100 mg was administered to 24 subjects with a median age of 19.5 years (range 14–23 years).²⁸ However, DRV exposures were slightly below the lower target concentrations in adolescent patients aged 14 to 17 years (n = 7) within the cohort, suggesting that higher doses may be needed in younger adolescents. A single case report involving a highly treatment-experienced adolescent patient suggests that using an increased DRV dose with standard RTV boosting and employing TDM can lead to virologic suppression.

The efficacy of once-daily DRV has been established within a limited number of studies in small cohorts of adolescents that reported long-term data on virologic and immunologic outcomes.^13,29

References

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