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 Liverpool 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.
• Coadministration of emtricitabine (FTC)/tenofovir alafenamide (TAF) plus DRV/c in children aged 2 years to <12 years weighing 14 kg to <40 kg had a favorable safety profile without any bone or renal toxicities or adverse weight effects (in an interim analysis at 24 weeks).7
• In a drug–drug interaction study in healthy adults without HIV, coadministration of DRV/c with bictegravir (BIC) was associated with increases in BIC exposures (74% increase in area under the concentration time curve over the dosing interval [AUCtau], 52% increase in maximum plasma concentration [Cmax], and 111% increase in trough concentration [Ctrough]) compared with BIC administration alone, with no effect on median time to reach maximum concentration.8

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.
• In utero exposure risks: An analysis of data from the French National Health Data System from 2012 to 2022, including data on 9,035 live single-born children born to mothers with HIV who were all prenatally exposed to antiretroviral (ARV) drugs, found that the incidence⁹ of neurodevelopmental disorders among exposed children was higher than in the general population, even after matching for five sociodemographic criteria (ZIP code, social vulnerability indicator, salary, maternal age, year of birth) and gestational age, (hazard ratio [HR] 1.24, 95% confidence interval [CI], 1.04–1.47). The relative contributions of maternal HIV infection as opposed to maternal treatment could not be separated, as all children were coexposed to both HIV and its treatment. However, the combination of DRV/r/TDF/FTC was associated with a significantly higher incidence of neurodevelopmental disorders compared to other PIs with TDF/FTC (log rank, P < 0.001).

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 therapy (ART) 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 aged ≥ 3 years weighing ≥15 kg at a dose of DRV 600 mg/COBI 90 mg, for use in pediatric patients weighing <20 kg ≥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. DRV/c FTC/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. In healthy adults, this FDC was found to be bioequivalent to coadministration of all of the individual formulations of each component of the FDC.¹⁰ In another bioequivalence study, 32 healthy adult participants received either a single dose of the DRV/c 600 mg/90 mg FDC tablet dispersed in water or the separate formulations (DRV 100 mg/mL at a dose of DRV 600 mg/COBI 90 mg), after a ≥7 day washout period. The geometric mean ratios for DRV C_max and AUC over the dosing interval of the dispersed DRV 600-mg/ COBI 90-mg FDC tablet versus the separate formulations fell within the prespecified 80% to 125% bioequivalence limits. 

The swallowability and acceptability of a placebo tablet (size 21 × 11 × 7 mm) matching this pediatric fixed-dose formulation of Symtuza 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.^11,12. Participants were also taking their stable 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. In a separate study¹⁰ in children with HIV aged ≥3 years and weighing ≥15 kg to <25 kg, the acceptability of a single dose of dispersed DRV 600-mg/COBI 90-mg FDC tablet was evaluated. According to independent observers, 83% (10/12) of the children were able to swallow the dispersion completely and rated the dispersed FDC tablet as “OK” to “very easy” to swallow.

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.^13-15

A randomized, open-label, multicenter pediatric trial¹⁵ 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.¹⁷ After 48 weeks, all but one participant had viral loads <50 copies/mL.

The SMILE (Penta-17-ANRS 152) trial released results¹⁸ 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., two NRTIs + 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.

Because of concerns about a potential interaction between DRV/r and dolutegravir (DTG), the SMILE trial (PENTA 17-ANRS152) also assessed the safety, efficacy, and drug interactions of once-daily dual therapy, using DTG 50 mg combined with DRV/r (100 mg/800 mg), both once daily, in virologically suppressed adolescents aged 12 years and older. Unbound DTG concentrations were measured and used in this study. There was a slight effect—DTG clearance was 12.1% lower (and corresponding DTG trough 14.3% higher) when unbound DRV AUC from time zero to 24 hours postdose (AUC_0–24h) was higher than 4.7 mg h/L. However, the key finding of this analysis was that there was a clinicially negligible impact of DRV/r on DTG concentrations at steady-state.¹⁹ In a separate modeling paper, there was no clinically relevant interaction identified between DRV/r and the clearance of DTG at steady-state, and the influence of unbound DRV exposures on unbound DTG concentrations was quite small.

Observational Data

An observational cohort²⁰ 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 HR 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 HR 4.20, 95% CI, 1.37–12.87).

In another retrospective study²¹ in India, people aged ≥13 years who experienced virological failure on first-line ART and were transitioned to second-line ART (dual NRTI + RTV-boosted PI) between September 2015 and October 2018 were followed for 5 years. Overall, 219 individuals switched to RTV-boosted PI-based second-line ART after 68 (median) months (interquartile range [IQR] 68) of first-line ART exposure and were followed up for 57 (median) months (IQR 48). The incidence of virological failure was 6.9% at 36 months and 15.9% at 60 months. Drug resistance analysis revealed 17.4% lopinavir (LPV) resistance, 34.8% atazanavir resistance, and DRV cross-resistance in only three sequences. The conclusion was that PIs are quite resilient when used as second-line ART and there was a low incidence of virologic failure that was caused by PI resistance.

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.^13,14,22 The DRV area under the curve from 0 to 12 hours (AUC_0–12h), measured as a percent of the adult AUC value,^13,14,22 was 126% overall: 143% in children weighing 10 kg to <15 kg and 121% in children weighing 15 kg to <20 kg.

The CHAPAS-4 trial²³ examined efficacy and safety of second-line ARV treatment, including DRV/r. The study randomized African children aged 3 to 15 years who had failed first-line treatment to either TAF/FTC (dosed according to World Health Organization [WHO]–recommended weight bands) or SOC dual-NRTI treatment, in combination with DTG or a boosted PI. Out of 919 children, 232 children received DRV/r. There was favorable safety (8.6% of children experienced Grade 3 or 4 adverse events with DRV/r, as compared to 11.5% with LPV/r [P = 0.31]). In terms of efficacy criteria of having an HIV viral load <400 copies/mL at 96 weeks, DRV/r failed to meet the pre-specified superiority criteria for comparison to LPV/r and ATV/r (combined analysis) but had numerically higher efficacy (88.3% as compared to 82.5%, adjusted difference 5.6 percentage points; 95% CI, 0.3–11.0; P = 0.04 [prespecified threshold, P = 0.03]).

The CHAPAS-4 trial included a PK substudy²⁴ in a subset of 104 of children aged 3 to 15 years weighing ≥14 kg and receiving a failing first-line ART; plasma PK data were collected at steady-state. TAF was administered in combination with DTG (n = 18), DRV/r (n = 34), or LPV/r (n = 20), and the measured geometric mean (coefficient of variation [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). All 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%) AUC_0-24h 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.²⁵ 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.²⁵ 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 an AUC_0-24h that was 81% of the AUC_0-24h 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_0-24h 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.¹⁶ 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:²⁷ 600 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).²⁸ 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_0–24h was 47.8 mg·h/L.

A population PK sub-study was done as part of the SMILE trial²⁹, 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 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.

The PK substudy of the CHAPAS-4 study also included an analysis of DRV exposures³⁰ in a subset of 59 CHAPAS-4 participants, with median age 10.9 (range 3.8–14.7) years and weight 26.0 (14.5–47.0) kg. The observed DRV geometric mean (%CV) AUC_0–24h 94.3(50) mg•h/L and C_max, 9.1(35) mg/L were both above exposures seen in adults, but the C_trough, 1.5(111) mg/L, was comparable to adult exposures. Children with higher levels of alpha-1-acid glycoprotein were observed to have decreased apparent clearance of DRV, likely due to binding of DRV. Population PK methods were used to simulate the WHO-recommended 600/100 mg DRV/r dose for children in the 25 kg to 34.9 kg weight band, achieving exposures in the range of adult exposures. The conclusion of this PK substudy was that either the simulated dose (600 mg/100 mg) or the CHAPAS-4 studied dose (800 mg/100 mg) had acceptable exposures and could be used in the 25 kg to 34.9 kg weight band, depending on tablet availability.

An analysis of genotypic resistance in children in the CHAPAS-4 study was reassuring. At the 2025 Conference on Retroviruses and Opportunistic Infections (CROI), Week 96 data from this trial were presented on resistance that emerged on study and associations between baseline resistance and ultimate virological failure. Sequencing for resistance (defined using the Stanford algorithm) was performed on baseline samples and on participants who had a week 96 viral load of 400 copies/mL or greater. Intermediate or high-level resistance to the anchor drug was seen at week 96 in: 0/29 LPV/r, 1/26 (4%) ATV/r, 0/18 DRV/r and 2/9 (22%) DTG (all of whom were taking zidovudine as one of their NRTIs).

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).³¹ 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.^26,31 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.³² 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.²⁸

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.³³

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.^14,34 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.^28,34 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.^34,35 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,¹⁶ 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).¹⁷ After 48 weeks, 83.3% of patients had viral loads <50 copies/mL and 91.7% had viral loads <400 copies/mL.¹⁷ 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).³⁶ 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.^17,37

References

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