Antiretroviral Therapy in Children and Adolescents: A Look Into Modern Single Tablet Regimens

Abstract

Single tablet regimens (STRs) have simplified antiretroviral therapy (ART) over the years in the adult human immunodeficiency virus (HIV) population. However, there is still a prevalent need to simplify regimens in children and adolescents living with HIV. Finding the optimal regimen requires a multi-factorial approach due to their complex pharmacokinetic profiles throughout childhood and the challenges and limitations of medication non-adherence in the pediatric population. These challenges include pill size, available formulations, palatability, and caregiver health literacy, which can all affect the proper administration of medications. The complexity of this population implies the importance of customizing everyone's antiretroviral regimen so that the patient and family can successfully adhere to the therapy. The current recommendations for ART in the adult and pediatric populations are similar, yet the use of STRs are limited. The goal of this review was to assess current data on available STRs and determine their utility as ART in the pediatric population.

Introduction

Although highly successful therapies have changed treatment algorithms for adults living with human immunodeficiency virus (HIV), the approval of novel agents in the pediatric population has been lagging. Cases of perinatal HIV infections have decreased 54% from 141 cases reported in 2014 to only 65 cases in 2018 in the United States.¹ With fewer children diagnosed with HIV, there has been less incentive to research and develop treatment options for the pediatric population.^2,3 Pharmacokinetic changes throughout childhood also pose a challenge to drug development and research. However, a need for proper HIV prevention and treatment for children and adolescents prevails despite the decreasing infection rates in the pediatric population.^2,4–6

A complicating factor in pediatric HIV treatment is the complex, multifaceted problem of medication non-adherence. Along with the psychosocial, behavioral, and socioeconomic factors that can influence adherence in adult patients, pediatric patients face additional barriers, such as having to rely on others for their care due to their young age.^7–9 This can include multiple caregivers for the child with different degrees of health literacy, understanding of the disease, and the importance of medication adherence.⁷ The social stigma that still exists for those infected with HIV can be especially difficult for a child and can lead to bullying.^4,7 Large pill burden for HIV regimens can be particularly difficult in school age children, especially if it requires dosing during school hours. It often requires the student to obtain medication from the school nurse, which can lead to increased social stigma among the child's peers and fear of disclosure of their diagnosis.^7,10,11 One population within pediatrics particularly non-adherent is the adolescent age group. Specifically looking at medication adherence, there is a transition of control in responsibility between the parent and the child. During this rebellious stage, the adolescent may decide to not take the medication in a fight for autonomy.^9–11 Other challenges in pediatric medication adherence include large pill size, palatability, limited data on safety and efficacy, and difficulty in weight-based dose adjustments with currently available products.^{4,6,7,10,12,13} Treatment approach, therefore, should be individualized with all factors considered to effectively achieve and maintain virologic suppression while improving quality of life.

Pharmacotherapy and regimen characteristics can have a big impact on achieving specific treatment goals. With advances in antiretroviral therapy (ART), HIV has become a chronic disease that can be managed with life-long medication therapy. For successful HIV management, adherence is crucial to control the viral load, restore immune function, and prevent long-term complications. In the past, HIV treatment required taking multiple tablets, multiple times per day, but the advancement in ART has now made treatment as simple as taking 1 single tablet daily. Single tablet regimens (STR) are the mainstay of ART therapy for adults and adolescents as it decreases pill burden, improves adherence, and increases the likelihood of achieving higher levels of viral suppression.^14–17 Unfortunately, this modernization of therapy has yet to reach the pediatric population. Major clinical trials of novel STRs with robust pharmacokinetic, efficacy, and safety data exclude the pediatric population.

Currently, the recommended initial antiretroviral (ARV) regimen is the same in adults and children. The regimen may contain a dual (possibly single) nucleoside reverse transcriptase inhibitor (NRTI) backbone plus an integrase strand transfer inhibitor (INSTI), a non-NRTI, or a protease inhibitor based on patient factors.^18,19 Many STRs are available in 2- to 3-drug combinations for regimen simplification. The goal of this review was to describe the role of STRs in the pediatric population, literature available to support their use, and challenges that need to be addressed to make safe and effective STRs available to children and adolescents.

Methods

Manuscripts and abstracts were systematically searched between January 2020 and December 2020, using PubMed/MEDLINE, EMBASE, and conference proceedings. Combinations of the following search terms were used: HIV, single tablet regimen, pediatric, child, and adolescent. The article selection was also filtered to only include articles in the English language, prospective trials, and study population ages <18 years. Studies were screened by abstract review for relevance and those with an active comparator and outcomes assessing efficacy and safety endpoints of treatments were included. Because of the scarcity of data in the pediatric population, conference proceedings and abstracts of ongoing studies were included in the qualitative synthesis. Refer to Figure for the study selection process.

Figure.

Study selection process

STR Use in Pediatrics

Antiretroviral therapy should be initiated in all pediatric patients living with HIV regardless of age, weight, or sexual maturity.¹⁹ In addition, rapid initiation of ART (i.e., immediate initiation on the day of or within 7 days of HIV diagnosis) is recommended for all children living with HIV.¹⁹ The selection of ART should be individualized based on current guidelines and patient factors including age, weight, cognitive developmental stage, and other variables that may influence adherence (e.g., ability to swallow or tolerate unpleasant taste). Recommendations should also take into consideration convenience in administration for the patient and their family as well as the latest efficacy and safety data.

The FDA has recommendations on which STRs can be used in children or adolescents based on certain criteria (Table 1).^20–29 Children must weigh ≥25 kg to be considered for any STR. Based on the CDC's weight-for-age reports, children are estimated to reach 25 kg between ages 5 and 10 years with a vast majority of adolescents aged ≥12 years generally meeting the minimum weight requirement.³⁰ If HIV was acquired perinatally, patterns of postnatal growth in these children are documented to lag behind uninfected children or those who acquire HIV later in their lives.^31,32 These differences can be significant and long-lasting, and therapeutic decisions should be made depending on an individual patient's growth and sexual maturity.

Table 1.

Available STRs Approved for HIV Treatment in Pediatric Populations^20–29

STR	Active Components	Dosing	Tablet Size* (Crushable†)	FDA Requirements	DHHS Recommendations‡
Integrase strand transfer inhibitor (INSTI)-based regimens
Biktarvy	BIC/FTC/TAF (50/200/25 mg)	One daily	15 (NR)	≥ 25 kg	Preferred regimen for ages ≥12 yr with SMRs of 1–3; alternate for ages ≥6 yr to <12 yr
Genvoya	EVG/COBI/FTC/TAF (150/150/200/10 mg)	One daily with food	19 (NR)	≥ 25 kg	Preferred regimen for ages ≥3 yr
Stribild	EVG/COBI/FTC/TDF (150/150/200/300 mg)	One daily with food	20 (Possibly; bioequivalence met in healthy adults when given with breakfast or enteral nutrition)	> 12 yr and ≥ 35 kg	NR in children with SMRs of 1–3
Triumeq	DTG/ABC/3TC (50/600/300 mg)	One daily	22 (May crush; add to small amount of semi-solid food/liquid and consume immediately)	≥ 40 kg and HLA-B*5701 negative	Preferred regimen for ≥3 yr and ≥ 25 kg
Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens
Atripla	EFV/FTC/TDF (600/200/300 mg)	One daily, preferably at bedtime on an empty stomach	20 (Unk; EFV bioequivalence was not met in pharmacokinetic studies in healthy adults)	≥12 yr and ≥ 40 kg	—
Complera	RPV/FTC/TDF (25/200/300 mg)	One daily with food	19 (NR)	≥ 35 kg	Alternate regimen for ≥12 yr with SMRs of 1–3§
Odefsey	RPV/3TC/TAF (25/200/25 mg)	One daily with food	15 (NR)	≥ 35 kg	Alternate regimen for ≥12 yr with SMRs of 1–3§
Symfi	EFV/3TC/TDF (600/300/300 mg)	One daily preferably at bedtime on an empty stomach	23 (NR/Unk)	≥ 40 kg	—
Symfi Lo	EFV/3TC/TDF (400/300/300 mg)	One daily preferably at bedtime on an empty stomach	21 (NR/Unk)	≥ 35 kg	TDM recommended for children with SMRs 1–3 who weigh ≥40 kg
Boosted protease inhibitor (PI)-based regimens
Symtuza	DRV/COBI/FTC/TAF (800/150/200/10 mg)	One daily with food	22 (Unk; decrease in TAF bioavailability in healthy adults)	≥ 40 kg	Alternate regimen for ages ≥12 yr with SMRs of 1–3

BIC, bictegravir; DHHS, Department of Health and Human Services; INSTI, integrase strand transfer inhibitor; NR, not recommended; SMR, sexual maturity rating; STR, single tablet regimen; TDM, therapeutic drug monitoring; Unk, unknown

^* Largest dimension of the tablet in millimeters.

^† For more information, refer to Information on Crushing and Liquid Drug Formulations from Toronto General Hospital.

^‡ DHHS recommendations on weight and age requirements are same as the FDA unless otherwise noted.

^§ For post-pubertal adolescents aged ≥12 years with SMRs of 4–5, refer to the DHHS Adult and Adolescent Antiretroviral Guidelines.¹⁸

^¶ Due to RPV component, patients must have initial viral loads of ≤100,000 copies/mL.

^# EFV dosing may be too low and close monitoring is recommended to prevent virologic failure.

Newborns or infants have limited ART options because of their inability to swallow tablets. Some fixed-dose combinations (FDC) are recommended to use, as first-line treatment, once children are ≥3 years of age and ≥25 kg.¹⁹ Until then, each component of the drug regimen must be administered individually. The LPV/r is available in combination as an oral suspension for neonates aged postmenstrual age of ≥42 weeks and postnatal age of ≥14 days, but a complete regimen requires 2 NRTIs in addition to LPV/r.^19,33 Suspensions, powders, or chewable tablets are available for other ARV agents.

For children ≥3 years of age and weighing ≥25 kg, the Department of Health and Human Services (DHHS) guidelines recommend 2 NRTIs plus DTG or EVG/COBI.¹⁹ DTG/ABC/3TC and EVG/COBI/FTC/TAF are 2 STR options for initial therapy. Dolutegravir was recently approved by the FDA for use in children ≥4 weeks old and ≥3 kg, but the STR DTG/ABC/3TC cannot be used in patients <25 kg because doses of ABC and 3TC in the STR co-formulation are considered too high.¹⁹ Same as in adults, screening for HLA-B*5701 allele is recommended before initiation of ABC-containing regimens. EVG/COBI/FTC/TAF must be taken with food, and the COBI component is a CYP3A4 inhibitor that can potentially result in drug-drug interactions.

For adolescents ≥12 years of age and weighing ≥25 kg, the STR, bictegravir (BIC)/FTC/TAF, is the preferred regimen for initial therapy. It has a favorable toxicity profile, can be taken with or without food, and has minimal drug interactions. Although crushing or splitting the tablet has not been studied and is not recommended at this time, BIC/FTC/TAF has 1 of the smallest pill size compared with other STRs available making it an ideal choice for children.³⁴ BIC/FTC/TAF is also an alternative regimen for children ages ≥6 years and <12 years who weigh ≥ 25 kg. The alternative regimen designation was given to this age group because evidence demonstrates higher variability in serum concentrations compared with those ≥12 years old, which could potentially put some children at a higher risk for subtherapeutic drug concentrations.^19,35 There are several other STRs as alternate regimens for those who are ≥ 12 years of age but with higher weight cut offs and specific food requirements (Table 1). The RPV/TAF/FTC is recommended for adolescents ≥12 years of age but weighing ≥35 kg instead of ≥25 kg and initial viral load ≤100,000 copies/mL. The DRV/COBI/TAF/FTC is yet another option but with an even higher weight requirement of ≥40 kg. Both RPV/TAF/FTC and DRV/COBI/TAF/FTC have food requirements, but RPV/TAF/FTC has a specific recommendation to administer the medication with a meal of at least 500 calories due to the RPV component.¹⁹

In adolescents, sexual maturity rating (SMR) or Tanner stage becomes an important factor in selecting ART.³⁶ The rating scale ranges from I to V, with V conferring highest adolescent sexual maturity (i.e., pubic hair growth, breast enlargement and menarche in females or penis growth and pubic hair of adult distribution in males). The growth and maturation of pediatric patients can have different implications in pharmacokinetics and pharmacodynamics with different drugs. For instance, EFV exposure is affected by age, development of liver enzymes, and polymorphisms. Pharmacokinetic studies report highly variable plasma concentrations of EFV in children suggesting a significant risk of underdosing in the pediatric population.^37–39 A prospective cohort trial that studied EFV exposure in children 3 to 36 months of age showed that over 80% of infants and young children who were extensive metabolizers for CYP2B6 had rapid clearance of EFV and thus at risk for underdosing. Meanwhile, 19% of infants and children who were poor metabolizers for CYP2B6 had approximately 4-fold higher EFV exposures than extensive metabolizers putting them at greater risk for side effects.^39,40 Hepatic enzyme activity reaches adult levels in infants 6 to 12 months old and then the activity tends to exceed adult levels at 1 to 4 years of age.⁴¹

Children also have a higher rate of bone turnover, which could predispose them to bone toxicity more than adults.⁴² Such developmental changes along with the inherent interpatient variability in hepatic metabolism make EFV pharmacokinetics difficult to predict. The DHHS recommends therapeutic monitoring of EFV in patients with SMRs 1 to 3 who weigh ≥40 kg and are receiving EFV 400 mg/TDF/3TC because the lower EFV dose may not achieve therapeutic levels.¹⁹ SMR is also a relevant factor when considering the impact drug-related adverse events will have during that developmental stage. For example, TDF is associated with decreased bone mineral density (BMD).^43,44 Several studies have demonstrated that TDF-containing regimen lead to approximately 1% to 3% greater BMD loss than regimen containing other NRTIs.⁴⁵ A randomized controlled trial (n = 1443) demonstrated that switching from TDF to TAF-containing regimen resulted in BMD improvement in the TAF group as demonstrated by the T-score for hip (+1.5% vs −0.3%, p < 0.001) and lumbar spine (+1.6% vs −0.4%, p < 0.001).⁴⁶ Because approximately 80% of adult bone mass accrues during puberty, the use of TDF is not favored in those with SMRs 1 and 2 compared with those with more advanced pubertal development.^19,47

The TDF was also associated with more renal toxicity compared with TAF. A meta-analysis of 26 ARV initiation or switch studies, which included 9322 adults and children, showed that there were 10 cases of proximal renal toxicity in those receiving TDF (n = 2962) but none reported in those receiving TAF (n = 6360). Individuals taking TDF-based regimen were also more likely to discontinue therapy due to a renal adverse event.⁴⁸ Therefore, the DHHS guidelines recommend monitoring renal function with creatinine and using a renal dipstick in patients receiving TDF-based regimen.¹⁹

Modernizing Pediatric ART

The EFV/FTC/TDF was the first STR approved for use in adolescents in 2010. The approval brought a major change in the treatment of HIV with its simplified 1-tablet daily regimen. EFV/FTC/TDF, however, is no longer used as initial treatment mainly due to its CNS side effects from the EFV component and low genetic barrier to resistance. In children, seizures and cerebellar dysfunction have been reported with EFV use and the incidence of rash appears to be higher in children than adults.^19,24 CNS side effects can be reduced if the dose is taken at bedtime on an empty stomach and following such specific dosing instruction could potentially be inconvenient to the patient or the caregiver. EFV/FTC/TDF also contains TDF, which could lead to bone and renal toxicities. Although EFV/FTC/TDF is listed as an option for patients who are ≥12 years and ≥40 kg, its use has been phased out by regimens with improved tolerability, easier dosing recommendations, and higher barriers of resistance. The DHHS guidelines do not list EFV/TDF/FTC as 1 of the preferred or alternative regimen for initial therapy in any pediatric age group.¹⁹

Tenofovir is an adenosine analog and is often an attractive choice as 1 of the 2 NRTIs in the initial regimen. Tenofovir has less metabolic side-effects compared with older NRTIs (e.g., didanosine, stavudine) and the longest half-life in the NRTI class allowing desirable therapeutic drug concentrations for antiviral activity.^42,49 Because of emerging data that TAF has a lower risk for bone and renal toxicity compared with TDF, recent trials are more focused on regimens that contain TAF instead of TDF, such as EVG/COBI/FTC/TAF and BIC/FTC/TAF (Table 2).^35,50–56 Recently, the Antiretroviral Pregnancy Registry reported that sufficient number of first-trimester exposures have been monitored to detect at least a 2-fold increase in the risk of birth defects. Thus far, no significant pattern or such increase in birth defects has been found with TAF.⁵⁷

Table 2.

Clinical Trials of Antiretroviral Therapy (ART) Regimens and Evidence of Safety and Efficacy in the Pediatric Population^34,49–55

Study Drug (Strength)	Study Design	Key Eligibility Criteria	Pharmacokinetics/Safety and Efficacy Results	Key Findings
NCt201881320 (2019)
BIC/FTC/TAF (50/200/25 mg)	Type: Phase 2/3, prospective, single-arm, open-label, 2-part study35,50–52,56 Time frame: 48 wk Countries: United States, Thailand, Uganda, South Africa Endpoints: PK parameters (AUCtau, Ctau,), efficacy (VL <50 c/mL) at wk 24 and 48, and safety (AEs), palatability and acceptability	Cohort 1 (n = 50): 12 to <18 yr, ≥35kg, VL <50 c/mL for ≥6 mo before screening, CD4 ≥200 cells/μL Cohort 2 (n = 50): 6 to <12 yr, ≥25 kg, VL <50 c/mL for ≥6 mo before screening, CD4 ≥200 cells/μL	Statistical analysis for Cohort 1 and Cohort 2 (n = 100): BIC AUCtau: children and adolescents consistent with adult phase 3 trials; BIC Ctau: lower in adolescents relative to adults but >11-fold above paEC95; BIC Ctau: similar in children relative to adults Therapeutic plasma concentrations: all components achieved AE: Most common was abdominal discomfort (2%); withdrew due to grade 2 insomnia and anxiety (n = 1) VL <50 c/mL: 24 wk: 100% of 100; 48 wk: 99% (74/75)	Efficacy: BIC/FTC/TAF maintained virologic suppression Safety: Well tolerated by children and adolescents for 48 wk Other: All 100 participants reported BIC/FTC/TAF as palatable and acceptable in shape and size
BIC/FTC/TAF (30/120/15 mg)	Type: Phase 2/3, prospective, single-arm, open-label study51,52 Time frame: 48 wk Countries: United States, Thailand, South Africa Endpoints: PK parameters (AUCtau, Ctau,), efficacy (VL <50 c/mL) at wk 24 and 48, and safety (AEs, laboratory tests, eGFR), palatability and acceptability	Cohort 3 (n = 12): Ages ≥2 yr, weight ≥14 to <25 kg, VL <50 c/mL for ≥6 mo before screening, CD4 ≥200 cells/μL, eGFR ≥90 mL/min/1.74 m2	Data reported from baseline to wk 24: BIC AUCtau: children were consistent with adult phase 3 trials BIC Ctau: was lower in adolescents relative to adults but >11-fold above paEC95 Therapeutic plasma concentrations: all components achieved VL <50 c/mL: AE: All 12 participants achieved AE: Three participants experienced drug-related AE consisting of neutropenia, abdominal pain, irritability, and social avoidant behavior. All AEs were mild to moderate in severity. No AE led to study discontinuation Median changes in eGFR: ranged from 0.5 to −27.5 mL/min/1.73 m2, which was not considered clinically significant and consistent with the effects of BIC on renal creatinine transporter Ability to swallow tablet: All children aged 3 years were able to swallow the tablet whole (n = 3). Some children needed to split tablets in half: n = 2 at baseline, n = 3 at wk 4 and n = 1 at wk 24	Safety and efficacy: results of low-dose BIC/FTC/TAF were comparable with the results in adults and children weighing ≥25 kg. Overall, the STR was well tolerated and children as young as 3 yr demonstrated ability to swallow the tablet whole. A few participants had to split tablets to administer the medication.

Table 2.

Clinical Trials of Antiretroviral Therapy (ART) Regimens and Evidence of Safety and Efficacy in the Pediatric Population^34,49–55

Study Drug (Strength)	Study Design	Key Eligibility Criteria	Pharmacokinetics/Safety and Efficacy Results	Key Findings
NCT01854775 (2017)
EVG/COBI/FTC/TAF (150/150/200/10 mg)	Type: Open-label, multicenter, 2-part, single-arm study53–55 Time frame: 48 wk Countries: United States, Thailand, Uganda (and South Africa for Cohort 1) Endpoints: PK parameters (AUC, AUCtau, AUClast), efficacy (VL <50 c/mL), and safety (AEs)	Cohort 1 (n = 50): Ages 12 to <18 yr, VL ≥1000 c/mL, CD4 ≥100 cells/μL, eGFR ≥90 mL/min/1.74 m2, weight ≥35 kg, HIV-1 genotype sensitive to all components of the study drug, and treatment-naïve Cohort 2 (n = 23): Ages 6 to 11 yr, weight ≥ 25 kg, VL <50 c/mL for ≥ 6 mo, CD4 count ≥ 100 cells/μL, and no history of resistance to any component of the study drug	Data reported is from baseline to wk 48: Drug exposures: all components were similar relative to adults Virologic suppression (VL <50 c/mL): 46 (92%) achieved at wk 48. Three participants experienced virologic failure; 1 was due to poor adherence and was lost to follow-up after wk 12 AE: Most common AE were nausea (20%), abdominal pain (12%), and vomiting (10%). Four participants (8%) had a serious adverse event; 1 was deemed related to study drug (intermediate uveitis). No AE lead to discontinuation of regimen Data reported are from baseline to wk 24: Drug exposures: all components were modestly higher than those reported in adults Virologic suppression: All participants maintained virologic suppression at 24 wk AE: No adverse serious AEs were reported and none lead to study discontinuation	Overall well tolerated and achieved plasma pharmacokinetic exposures similar in adults in virologically suppressed participants. Plasma concentrations of EVG/COBI/FTC/TAF were higher than in adults, but within the observed variability in the adult trials. The study drug was well tolerated and effective in achieving virologic suppression. From the AEs reported and PK data, TAF component appears to have a favorable bone and renal safety profile.

AE, adverse event; AUC, area under the plasma concentration versus time curve; AUC_last, area under the plasma concentration curve from time zero to the last quantifiable concentration; AUC_tau, area under the plasma concentration versus time curve over the dosing interval; BIC, bictegravir; C_tau, trough plasma concentration; eGFR, estimated glomerular filtration rate; paEC₉₅, protein-adjusted 95% effective concentration; PK, pharmacokinetic; STR, single tablet regimen; VL, viral load (HIV-1 RNA)

The use of EVG/COBI/FTC/TAF has been studied in children and adolescents (NCT01854775).⁵³ This was a phase 2/3, multicenter, 48-week, single-arm, open-label trial that involved 50 treatment-naïve adolescents.⁵⁴ The goal of this study was to assess efficacy and safety while monitoring pharmacokinetic parameters of EVG/COBI/FTC/TAF in adolescents between ages 12 and 18 years who weighed ≥35 kg. This was the first clinical trial investigating the effects of TAF in an STR in children. Phase 3 clinical trials in adults demonstrated that switching therapy from EVG/COBI/FTC/TDF to EVG/COBI/FTC/TAF led to improved bone and renal toxicity.⁴⁶ Hence, this study focused on safety outcomes related to bone and renal toxicities to assess whether EVG/COBI/FTC/TAF would have similar safety and efficacy outcomes in children as seen in adults. Primary endpoints included AUC concentration at the end of the dosing interval (AUC_tau) for EVG and the AUC from time zero to the last quantifiable concentration for TAF.

Bone toxicity was assessed by measuring BMD and height-for-age Z-scores, whereas renal toxicity was assessed by monitoring estimated glomerular filtration rate (eGFR) and proteinuria. Two participants discontinued: 1 withdrew consent and 1 was lost to follow-up. Forty-eight participants completed the trial where 24 were evaluated for intensive pharmacokinetic monitoring to assess exposure of EVG and TAF. At week 48, 46 out of 48 participants achieved viral suppression (HIV-1 RNA <50 copies/mL). Most common adverse events were gastrointestinal-related: nausea (20%), abdominal pain (12%), and vomiting (10%). Four participants (8%) had a serious adverse event, but only 1 was deemed related to study drug (intermediate uveitis). There were no significant adverse events or abnormal laboratory values suggesting bone or renal toxicity. Changes in BMD and Z-scores from baseline to week 48 were minimal. In fact, 64% of participants who had lived with prolonged periods of untreated HIV had positive gains in BMD. Overall, the results of the trial were similar to the findings in the phase 3 studies completed in adults supporting the use of EVG/COBI/FTC/TAF in treatment-naïve adolescents. In 2015, EVG/COBI/FTC/TAF was FDA approved for the use in adolescents ages ≥12 years who weigh ≥35 kg, regardless of SMR.

The investigators then evaluated the pharmacokinetic parameters, safety, and efficacy of EVG/COBI/FTC/TAF in a second cohort to explore the potential of extending its use to even younger patients. This cohort enrolled 23 virologically suppressed children between ages 6 and 11 years weighing ≥25 kg.^54,55 This report included the analysis from baseline (before switching to EVG/COBI/FTC/TAF) up to week 24. At week 24, all participants tolerated the medication well and maintained virologic suppression. No serious adverse events or event-related discontinuations were observed throughout the study. Overall bone renal safety profiles were favorable with no significant differences in eGFR, proteinuria, BMD, and Z-scores relative to the findings in adult trials. Plasma levels of drug components were reportedly higher than that of adults, but within range of variability seen in adults. In 2017, the indication of EVG/COBI/FTC/TAF was extended to include children weighing ≥25 kg.

Subsequently, BIC/FTC/TAF co-formulation was approved in 2018 for the treatment of HIV in adults. BIC, a novel, unboosted, potent INSTI, demonstrated high ARV activity, higher barrier to resistance compared with first generation INSTIs (raltegravir and EVG), good tolerability, and low potential for drug-drug interactions. BIC/FTC/TAF was studied in adolescents and children in a phase 2/3, open-label, multicenter, multicohort, single-arm trial (NCt201881320).^35,50,51,56 The design was sequential, as with many pediatric trials, where a study is conducted with adolescents first to evaluate pharmacokinetic parameters in that age group and then proceeding to assess younger children. The first cohort included 50 participants ages 12 to <18 years and ≥35 kg, whereas the second cohort included 50 participants ages 6 to <12 years and ≥25 kg. Participants were all virologically suppressed for at least 6 months prior to the start of the trial and were switched from their previous ARV regimen to BIC/FTC/TAF. Both cohorts were assessed for safety and efficacy, and pharmacokinetic parameters were monitored. In addition, participants were asked about palatability and acceptability of tablet size and shape. The statistical analysis that was based on preliminary data included both cohorts. At week 24, all 100 participants maintained viral suppression.⁵⁰ At the time these data were reported, the investigators had 48-week virologic outcome data for 75 participants where 74 out of the 75 participants maintained virologic suppression. BIC, overall, was well tolerated with 1 study-drug related discontinuation in the 6 to <12 years age group due to moderate insomnia and anxiety. Pharmacokinetic parameters were reported at weeks 24 and 48. When the cohort was analyzed as a whole, BIC exposure, measured as AUC_tau, was similar in adolescents and children relative to adults at week 48. In children aged 6 to <12 years and ≥25 kg, however, AUC_tau was 77% higher and C_tau was 22% lower compared with the adult reference data at week 24, which may indicate faster clearance of BIC in children.^35,50,56 BIC concentrations were still above effective concentration despite these differences. Exposures of FTC and TAF were within expected range and similar to the results seen in EVG/COBI/FTC/TAF trials. All participants responded that BIC/FTC/TAF was palatable and acceptable in size and shape.

NCt201881320 also evaluated a third cohort, which included children aged ≥2 years who weigh ≥14 kg but <25 kg but with a “low-dose” formulation of BIC/FTC/TAF. Low-dose BIC/FTC/TAF STR contained 60% of the active ingredients in the full-strength STR with BIC 30 mg, FTC 120 mg, and TAF 15 mg. Twelve participants were enrolled in the study to examine pharmacokinetic parameters and evaluate for safety and tolerability.^51,52 At week 24, BIC AUC_tau was similar in this cohort relative to adults. C_tau was lower when compared with adults but levels were still approximately 12 times higher than 95% effective concentration for wild-type virus.⁵² Exposures of FTC and TAF were within expected ranges based on historical data in adults. Three participants experienced drug-related adverse events, which included episodes of neutropenia, abdominal pain, irritability, and social avoidant behavior. Laboratory results showed decreased neutrophils in 2 participants and increased creatinine in 1 participant. All adverse events were mild to moderate in severity and low-dose BIC/FTC/TAF was well tolerated. Pharmacokinetic parameters of DRV/COBI/TAF/FTC is undergoing evaluation in children aged ≥3 years weighing ≥14 to <25 kg, 6 to <12 years weighing ≥25 to <35 kg, and 12 to <18 years weighing ≥25 kg.⁵⁸

Discussion

There are limited studies evaluating the use of STR for the management of HIV in children and adolescents. However, there have been improvements in the pediatric ART regimen and optimization in the adult regimen. The recent approval of BIC/FTC/TAF use in adolescents has promising implications for younger patients as BIC/FTC/TAF is 1 of the smallest STRs available without meal requirements for administration. Another advancement in pediatric HIV care is the approval of FTC/TAF for pre-exposure prophylaxis in addition to FTC/TDF.^59,60 FTC/TAF is indicated in HIV-negative adolescents weighing ≥35 kg and could potentially be a safer alternative to FTC/TDF in male or trans-gender female patients. One caveat to FTC/TAF is that it is not indicated for patients who are at risk of acquiring HIV from vaginal sex because the effectiveness in this population has not been validated. Therefore, FTC/TDF continues to be the recommended pre-exposure prophylaxis option for patients at risk for acquiring HIV from receptive vaginal sex. With the approval of FDCs with convenient dosing and administration, clinicians will have more opportunity to provide medications for HIV prevention or treatment in children and adolescents.

Still, there are too few effective, safe, and convenient formulations available for pediatric patients. There are numerous barriers to pediatric-friendly HIV medication therapy that need to be addressed. First, FDC formulations are limited to tablets. Many STRs have too large of a pill size to swallow by pediatric patients and pose a choking hazard. For instance, although DTG/ABC/3TC and EVG/COBI/FTC/TAF are approved for use in ages ≥3 years and ≥25 kg, both are too large and not feasible for younger children to swallow whole. The DTG/ABC/3TC may be crushed because this does not affect dissolution or absorption.³⁴ With other STRs, it is less certain whether they can be crushed and the limited pharmacokinetic data that exist are in healthy adults. If crushed, there is a possibility of improper preparation or administration, which can result in underdosing.^4,19 Crushed tablets may also be difficult to tolerate if they have an unpleasant taste. The DHHS guidelines suggest masking the offending taste of medications with flavoring syrup or food when non-adherence is due to poor palatability.¹⁹ A study in Thailand with 30 participants showed that 80% of caregivers reported easier medication administration to their children when a flavoring agent was added to crushed tablets or liquid ARVs.⁶¹ This is not always possible with LPV/r because the taste cannot be masked with flavoring. Pill-swallowing training can be beneficial and increase ART adherence in HIV-infected children.^4,19 One study showed pill-swallowing training in 23 patients aged 4 to 21 years was associated with improved adherence at 6 months post-training.⁶²

Another limitation is that STRs have minimum weight or age cut offs that prevent their use. Children who do not meet minimum weight or age requirements often start their treatment with twice daily regimens. Lack of combination formulations results in individual administration of each component of the regimen, which can result in pill or volume burden.⁷ For instance, the DTG component in DTG/ABC/3TC is typically dosed once daily and it comes as a small tablet or suspension, which is ideal for younger patients. However, as with adults, a combination of drugs is recommended to treat children requiring multiple administrations for each ARV.

Pediatric trials often enroll a small number of participants, and many recommendations are based on underpowered studies.³⁹ Consequently, safety and efficacy data for treatment options may not be as robust compared with the adult population. The complexity of pharmacokinetics in children complicates the extrapolation of population pharmacokinetic profiles due to the variation of properties in age and weight.^2,4 Furthermore, although age-specific pharmacokinetic data can be used to predict efficacy, safety data are more difficult to predict. Reports of unanticipated events are low due to small sample size, making it challenging to interpret whether an adverse event is truly study-drug related. Additionally, a child's inability to communicate can prevent them from reporting adverse events they experience. As a result, study findings may not reflect safety outcomes completely or accurately.

With very few children acquiring HIV perinatally, there has been a decreasing interest to study ART in the pediatric population as a whole. Pharmaceutical companies may be discouraged from pursuing treatments in children or adolescents because there is a smaller market for profit, although there are higher risks for liability and more strict regulatory requirements compared with adults.⁶³ Clinical trials may be more costly or slow in progression when recruiting from a smaller population. However, youth aged 13 to 24 made up 21% of the 37,832 new HIV diagnoses in the United States in 2018.⁶⁴ This population was least likely of any age group to be retained in care and achieve viral suppression. These statistics demand a need for improved pharmacotherapy for younger patients along with better screening and education and more research, and incentives to conduct such investigations, is necessary to provide this population with simple, tolerable, effective, and safe treatment options.

One possible area of research is the use of 2-drug regimens (2DRs) in the pediatric population. To minimize the potential for long-term drug-related toxicities and simplify treatment regimens, 2DRs are recommended by the DHHS guidelines as initial and/or switch therapy for adult patients as of October 2018. The 2DR STRs, DTG/RPV and DTG/3TC, are not approved by the FDA for the use in the pediatric population. The individual components of these STRs are approved for use with varying age and weight cut offs. The STR DTG/ABC/3TC contains DTG and 3TC, so the safety and pharmacokinetic data could be extrapolated for DTG/3TC use, but efficacy of using DTG/3TC as a complete regimen needs to be evaluated in children. The DHHS does not recommend either 2DR as a complete regimen for adolescents and children at the time of this review, but there is an ongoing pharmacokinetic study evaluating the use of DTG/3TC in children between 6 months and 12 years weighing at least 6 kg.^19,65 The individual components of these STRs are approved for use with varying age and weight cut offs. Studies evaluating 2DRs in children and adolescents would be beneficial to reduce pill burden and drug-related adverse events. These tablets are also smaller in size, making them easier for younger children to swallow.

Another area of research is the use of the use of long-acting formulations in the pediatric population. Cabotegravir/RPV intramuscular injections is a promising ART option if approved. Given the 4-week dosing intervals or longer, long-acting injectable regimens could significantly ease administration and improve adherence. Currently, More Options for Children and Adolescents is an ongoing study assessing pharmacokinetics, safety, acceptability, and tolerability of long-acting injectable cabotegravir/RPV in children and adolescents.⁶⁶

Conclusion

HIV can have a profound and lasting impact on pediatric patients' health and quality of life. Acquiring HIV during early stages of growth predisposes children and adolescents to the development of resistance to ARVs. Although FDCs have simplified the management of HIV and improved medication adherence, the availability of pediatric-friendly STR options is limited and inadequate, especially in those <12 years of age or <25 kg. Development of combination ART with novel formulations and convenient administration while maintaining efficacy and safety is a priority in pediatric HIV treatment.

ABBREVIATIONS

2DR

2-drug regimen

3TC

lamivudine

ABC

abacavir

ART

antiretroviral therapy

ARV

antiretroviral

AUC

area under the curve

AUC_tau

area under the plasma concentration versus time curve over the dosing interval

BIC

bictegravir

BMD

bone mineral density

CDC

Centers for Disease Control and Prevention

CNS

central nervous system

COBI

cobicistat

DHHS

Department of Health and Human Services

DRV

darunavir

DTG

dolutegravir

EFV

efavirenz

eGFR

estimated glomerular filtration rate

EVG

elvitegravir

FDA

US Food and Drug Administration

FDC

fixed-dose combination

FTC

emtricitabine

HIV

human immunodeficiency virus

INSTI

integrase strand transfer inhibitor

LPV/r

lopinavir/ritonavir

NRTI

nucleoside reverse transcriptase inhibitor

RPV

rilpivirine

SMR

sexual maturity rating

STR

single tablet regimen

TAF

tenofovir alafenamide

TDF

tenofovir disoproxil fumarate,

VL

viral load