Integrase Strand Transfer Inhibitor Use in Children with Perinatal HIV-1 Infection: A Narrative Review

Abstract

Integrase strand transfer inhibitors (INSTIs), including raltegravir (RAL), dolutegravir (DTG), elvitegravir (EVG), bictegravir (BIC), and cabotegravir (CAB), are increasingly used, given excellent data on their efficacy, effectiveness, and tolerability profile in adults, while data in children are accumulating. To review the most recent evidence on the efficacy, effectiveness, safety, and resistance of INSTIs in children, a quick narrative review of the available literature data was performed using the MEDLINE/PubMed and Scopus databases, including only English-language studies, published between 2009 and 2022. Six studies (259 children) on RAL use, 17 studies (3,448 children) on DTG, 2 studies (73 children) on EVG, and 1 study (102 children) on BIC were retrieved. Results on efficacy and effectiveness were close to those reported in adult studies, suggesting similarities between children and adult population. Resistance to RAL was detected in four studies, ranging between 5.0% to 35.3% of participants. In four studies resistance to DTG occurred in 12.4% to 22% of children. Adverse events to RAL have been uncommon reported. In studies on EVG, 8% to 74% of children developed uveitis, nausea, or abdominal pain. In DTG studies, the proportion of weight gain ranged from 10% to 87%, and neuropsychiatric effects ranged 1% to 16% of participants. One BIC study reported adverse events >10% of participants. The evidence supports high efficacy and low toxicity of INSTIs in pediatric and adolescent populations.

Introduction

Since the introduction of combined antiretroviral therapy (ART) in 1996, substantial improvements in the management of HIV-1 infection have occurred.¹ A steady increase in life expectancy for people living with HIV over the years has been reported and this condition is now considered a chronic disease.¹ Several drugs with improved efficacy, tolerability and toxicity profiles, and more practical formulations have been developed over years.² The most recent available antiretroviral class is the integrase strand transfer inhibitor class (INSTIs). INSTIs block the activity of the HIV-1 integrase, a key enzyme in viral replication, which catalyzes the covalent integration of viral cDNA into the host genome.³ Currently available INSTIs include raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), bictegravir (BIC), and, a more recently licensed, promising, long-acting injectable molecule: cabotegravir (CAB). DTG, EVG, and BIC are all available as co-formulated as a single-tablet regimen.⁴

In adults, INSTIs have shown favorable pharmacokinetic (PK) and pharmacodynamic properties, which contribute to both their efficacy and ease of use, and are now recommended by current U.S. guidelines for both treatment-naive and treatment-experienced patients.⁵ Interestingly, INSTIs allow a rapid virologic suppression compared with other antiretroviral molecules,⁶ and a rapid and sustained suppression within 4 weeks after initiation in treatment-naive individuals have been demonstrated for all oral INSTIs.⁴ Moreover, INSTIs have displayed a higher genetic barrier to resistance compared with nucleoside and nucleotide analog reverse transcriptase inhibitors (NRTIs) and non-nucleoside analog reverse transcriptase inhibitors (NNRTIs).²

However, recently, the potential cross-resistance due to mutations Q148H and R263K has been reported and has to be further investigated.⁷ Differently from protease inhibitors (PIs), INSTIs have a minimal impact on lipid profile, and no evidence of lipodystrophy or increased risk for cardiovascular disease.⁸ Finally, the possibility to use most INSTIs within a single-table regimen allows to increase adherence to therapy.⁹ Nevertheless, rare virological failures related to suboptimal adherence and emergence of resistant mutations have been reported.¹⁰

Although generally well tolerated, several adverse events have been reported with the use of INSTIs. Reported adverse events of RAL include nausea, muscle pain, tenderness, weakness, dizziness, severe skin reactions, and increase in liver enzymes.¹¹ The most commonly reported adverse events are diarrhea and immune reconstitution inflammatory syndrome for EVG; nausea, dizziness, liver toxicity, and weight gain for DTG; diarrhea, nausea, and fatigue for BIC; and fatigue, fever, headache, and nausea for CAB.¹¹

Moreover, the use of DTG at the time of conception or during the first 3 months of pregnancy was of concern for the potential neural tube defects (NTDs).¹² However, in a recent meta-analysis, adverse birth outcomes were observed in 33.2% of DTG-managed pregnancies and 35.0% of efavirenz (EFV)-managed pregnancies.¹³ Similarly, a recent large study conducted in Botswana suggested that the prevalence of NTDs in infants exposed to DTG was not statistically different than in those receiving other antiretrovirals.¹²

Currently, most INSTIs are licensed for use in children in many countries (Tables 1 and 2).^14,15

Table 1.

Integrase Strand Transfer Inhibitor Approval by Food and Drug Administration¹⁴

	Approval date	Approved age and/or weight
RAL (Isentress^®)	2011	>2 years and weight ≥10 kg
	2013	4 weeks to 2 years and weight ≥3 kg
	2017	≥37 weeks to 2 years and weight ≥2 kg
DTG (Tivicay^® oral tablets)	2013	≥12 years and weight ≥40 kg
DTG (Tivicay tablets for oral suspension)	2020	≥4 weeks and weight ≥3 kg
DTG/ABC/3TC (Triumeq^®)	2014	Weight ≥40 kg
DTG/ABC/3TC (Triumeq^®)	2022	Weight ≥25 kg (oral tablets) and >10–25 kg (oral suspension)
EVG/c/FTC/TAF (Genvoya^®)	2015	≥12 years and weight ≥35 kg
EVG/c/FTC/TAF (Genvoya^®)	2017	Weight ≥25 kg
BIC/FTC/TAF (Biktarvy^®)	2019	Weight ≥25 kg
BIC/FTC/TAF (Biktarvy^®)	2021	≥2 years and weight ≥14 to <25 kg

3TC, lamivudine; ABC, abacavir; BIC, bictegravir; c, cobicistat; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; TAF, tenofovir alafenamide fumarato.

Table 2.

Integrase Strand Transfer Inhibitor Approval by European Medicine Agency¹⁵

	Approval date	Approved age and/or weight
RAL (Isentress)	2013	>2 years (CT); ≥6 years and weight ≥25 kg (adult tablet)
RAL (Isentress)	2014	≥4 weeks to 2 years
DTG/3TC (Dovato^®)	2019	>12 years at least 40 kg
EVG/c/FTC/TDF (Stribild^®)	2017	≥12 years and ≥35 kg
DTG (Tivicay)	2014	≥6 years and weight ≥14 kg (oral tablets); ≥4 weeks and weight ≥3 kg (oral suspension)
DTG/ABC/3TC (Triumeq)	2014	>12 years and weight ≥40 kg
EVG/c/FTC/TAF (Genvoya)	2015	>12 years and weight ≥35 kg
EVG/c/FTC/TAF (Genvoya)	2017	>6 years and ≥25 kg

CT, chewable tablets.

Although data regarding the use of INSTIs in children are accumulating, a comprehensive and updated review of the available literature is lacking. Two previous available reviews date back to 2015 and 2019.^16,17 Therefore, hereby, we reviewed and summarized the most recent evidence on the efficacy/effectiveness, PKs, safety, and resistance data of INSTIs in neonates, children, and adolescents.

Methods

A narrative review of the literature was performed by means of MEDLINE/PubMed database, including English-language studies, published from 2009 to 2022. Every type of article was included. Keywords were identified for each topic and entered into the search engine. An example of search strategy is dolutegravir[Title/Abstract] AND (children[Title/Abstract] OR pediatr*[Title/Abstract] OR newborn[Title/Abstract] OR neonate[Title/Abstract]). The search was repeated substituting “dolutegravir” with “raltegravir,” “elvitegravir,” “bictegravir,” “cabotegravir,” “INSTI resistance,” “adverse events,” and “integrase inhibitors.” Titles and abstracts were screened for applicability. References of relevant studies and review articles were also searched for additional references.

When multiple studies reported the same results from ongoing trial (i.e., IMPAACT P1066 study),^16,18
–20 only the most recent and/or comprehensive publications were considered, to avoid duplications. Selected articles were evaluated, and the following data were extracted: author, year, number of study, mains results, and possible biases. Main results were then summarized in paragraphs for each considered INSTI drug. Exclusion criteria were as follows: studies in adults/pregnancy; non-English language; and not full text available. Finally, data from pertinent abstracts from the Conference on Retroviruses and Opportunistic Infections (CROI), International AIDS Society (IAS), and International workshop on HIV pediatrics in the previous 4 years were included, since several relevant data might have not been published in articles.

Results

Studies about RAL included one prospective observational study,²¹ three clinical trials,^18,22,23 and two retrospective studies.^24,25 Studies about DTG included five clinical trials,^{7,26

–32} six retrospective studies,^33

–38 three prospective observational studies,^39
–41 and two systematic reviews.^20,42 Studies about EVG included two clinical trials.^17,26 Studies about BIC included one clinical trial.⁴³

Raltegravir

A total of six studies (295 children) on RAL were included in these studies^22,28 (Table 3).

Table 3.

Summary of Studies Analyzed in the Review on Pharmacokinetics, Efficacy/Effectiveness, and Adverse Events of Raltegravir

Author (year)	Country	Number of participants (n)	Median age or range (years)	Study design and objective	Type of study	Main results	No. of patients with undetectable viremia (%)	Discontinuation of treatment (%)	Main adverse events	Conclusions/notes
Patten (2020)²¹	Africa, Asia, South America	62	14.3	RAL as a third-line replacement for PIs	Prospective study	17% of children with UVL had a rebound (>1,000 copies/mL)	After 2 years of follow-up: 70% reached VL <400 copies/mL	34%	Three children interrupted due to adverse events	Good virological and immunological outcomes, despite frequent prior triple-class failure. Long-term adherence was challenging due to pill burden
Thuret (2009)²⁴	France	12	15	Virological effectiveness in nonvirologically suppressed children	Retrospective study	RAL-based regimen+DRV and etravirine had high virological efficacy with no treatment interruptions	After a 12-month median follow-up, viral load was <400 copies/mL in 11 (<50 in 6).	None	No RAL-related adverse event >grade 2 was observed
Briz (2012)²⁵	Spain	19	16	Virological effectiveness of RAL in ART-experienced children	Retrospective study	Despite multiple resistances, high virological effectiveness was achieved	After a median follow-up of 80 weeks: 21% had VL <400 copies/mL and 68% had VL <50 copies/mL	15.8% (3/19) due to poor adherence and simplification of therapy	Two skin rash	No acquired resistance occurred during treatment
Nachman (2018)¹⁸ Dehority (2015)¹⁶ Collins (2018)¹⁹ Kolakowska (2019)²⁰ [IMPAACT P1066]	United States, South Africa, Brazil, Botswana, Argentina	153	14.9 years for cohort received adult tablets, 5.4 years for chewable tablets, 35.7 weeks for oral granules	Virological efficacy of RAL in ART-experienced children	Phase I/II, open-label, multicenter trial	At 240 weeks of follow-up, 49% had virological failure	At 240 weeks 77% of children receiving chewable tablets, 87% of those receiving oral granules and 44% among those who received adult tablets had VL <400 copies/mL	1/122 (0.8%) of children at 240 weeks	Two allergic rash, one transient elevation of liver function enzymes	Adherence data were available from 23 patients receiving adult tablets. At the time of VF, 70% had a compliance >90%. These data suggest that excellent adherence was not a predictor of VF
Meyers (2019)²² [IMPAACT P1101]	South Africa	26	2–12	Multicenter study on PK RAL-rifampicin interactions	Phase I/II, open-label trial	Twice-daily administration of 12 mg/kg of the chewable RAL formulation safely achieved PK targets	At week 8, 79% had VL <50 copies/mL	One participant discontinued treatment due to adverse events	One hepatitis
Clarke (2020)²³ [IMPAACT P1110]	South Africa	50	Since birth to 6 weeks	Noncomparative study. Collect PK data of oral RAL	Phase I, multicenter, noncomparative trial	Recommended dose of 1.5 mg/kg from birth to day 7; 3 mg/kg twice daily from day 8 to day 28; 6 mg/kg twice daily after the first 4 weeks until 6 weeks	Not reported	Discontinuation in two infants: one due to a weight loss and one infant due to a parental decision	Cohort 1: four infants had grade 3 or 4 adverse events. Cohort 2: 31% and 43% had grade 3 or 4 adverse events at 6 and 24 weeks of life, respectively	The neonatal dosing regimen of RAL was safe and well tolerated in term infants

ART, antiretroviral therapy; DRV, darunavir; PIs, protease inhibitors; PK, pharmacokinetic; UVL, undetectable viral load; VF, virological failure.

A multicenter prospective observational study analyzed data from children and adolescents enrolled in the global consortium International epidemiology Databases to Evaluate AIDS, in Africa, South America, and Asia from 1994 to 2017. Data from ART-experienced children switched to INSTI based-ART regimens were analyzed (Table 3). Overall, 62 children were included (median age = 14.3 years).²¹ Among the 53 children with available viral load (VL) measurements within 1 year of starting RAL, 70% displayed VL <400 copies/mL, but 17% of them experienced a rebound to VL >1,000 copies/mL, with a median rebound time from RAL initiation of 391 days.²¹

Before starting RAL-based regimens, 40 of 62 patients underwent resistance testing and 2 cases of INSTI resistance were found. At 2 years of follow-up, 34% of children had stopped treatment; among the 15 patients whose reasons for discontinuation were recorded, 6 children stopped because the drug was no longer available, 4 because of treatment failure (virological, immunological, or due to resistance), 3 because of adverse events, 1 because of the patient's decision, and 1 to switch to a more effective treatment.²¹

In a French case series, 12 adolescents with a median age of 15 years, who had experienced virological failure on previous ART regimens, were recruited and received RAL-based regimen (400 mg twice daily) along with an NRTI and a PI (Table 3). At 12 months of follow-up, 11 of 12 (92%) had VL <400 copies/mL and 6 of 12 (50%) had VL <50 copies/mL. No RAL-related severe adverse event was detected.²⁴

In a Spanish retrospective observational study among 19 children (median age = 16 years), the virological effectiveness of RAL was evaluated. All participants were ART experienced and had experienced virological failure due to multiple resistances to previous ART regimens. At the end of follow-up (80 weeks), 21% of participants displayed VL <400 copies/mL and 68% had VL <50 copies/mL. Two children had skin rash as an adverse effect and no acquired resistance to RAL occurred during treatment.²⁵

In the IMPAACT P1066 trial (phase I/II open label, multicenter), virological efficacy of RAL at 48 and 240 weeks of follow-up in children 4 weeks to 18 years of age was evaluated: cohort 1 (age 12 to 18 years) and cohort 2A (6 to <12 years) received the 400 mg adult tablet formulation (twice per day), cohort 2B (6–12 years) and cohort 3 (2 to <6 years) received a dose of 6 mg/kg with the chewable tablet formulation (twice per day), and cohort 4 (6 months to <2 years) and cohort 5 (4 weeks to <6 months) received the granules for suspension formulation, at ∼6 mg/kg per dose.¹⁸

At 48 weeks, a total of 152 children were enrolled and 142 children (93.4%) were still on treatment with RAL.¹⁸ At 240 weeks, 121 patients were still on treatment and patients receiving chewable tablets or oral granules had sustained efficacy (VL <400 copies/mL) of 77% and 87%, respectively (Table 3). By contrast, patients who received adult tablets (52% of all participants) had virological success of 44% at week 240.¹⁹ In addition, of the 36 participants with virological failure by week 48, 34 had a genotypic analysis performed: 35.3% had developed RAL-resistant mutations with the following amino acid substitutions: Y143R, Q148H/R, and N155H. Multiple other resistances were detected during follow-up.¹⁶

At 240 weeks of follow-up, 49% of participants had virological failure, and of these, 32% had resistance to RAL,¹⁸ in particular, development of resistance was noted in 38% of patients who experienced virological rebound after initial suppression. During this study, one participant experienced a transient elevation of liver function enzymes, but this did not lead to treatment discontinuation.²⁰ Two participants (1%) had serious clinical adverse events possibly related to the study drug, both had allergic rashes, and one discontinued the study because of this drug-related event.¹⁸

In a multicenter, phase I/II open-label study (IMPAACT P1101) conducted in South Africa in 26 participants 2–12 years of age with HIV-1 co-infection and TB, the PK interaction of rifampicin was evaluated. All 26 participants enrolled had previously had ART treatment and it was found that twice-daily administration of 12 mg/kg of the chewable RAL formulation safely achieved the PK targets.²² At week 8, 19 of the 24 participants (79%) had VL <50 copies/mL.²² Few cases of adverse events have been reported, notably one case of hepatitis and a rise in transaminases, and in rare cases, treatment had to be discontinued.

The phase I, multicenter, noncomparative IMPAACT P1110 study in South Africa investigated RAL granules for oral suspension in full-term infants weighing at least 2 kg exposed to HIV-1.²³ The PK parameters of 50 infants recruited were analyzed in two cohorts: in cohort 1, sixteen mother-infant pairs (10 infants born to RAL-naive mothers and 6 infants born to RAL-exposed mothers), and the PK parameters of 15 infants were available (Table 3). In cohort 2 there were 36 mother-infant pairs (26 from RAL-naive mothers and 10 from RAL-exposed mothers), of which, PK data were available for 35.²³

The study showed that RAL can be administered in a safe and well-tolerated dose of 1.5 mg/kg from birth to day 7; 3 mg/kg twice daily from day 8 to day 28; and 6 mg/kg twice daily after the first 4 weeks until the sixth week of life. These variations in optimal doses are due to the fact that RAL is metabolized by uridine diphosphate glucuronyl transferase (UGT1A1), which has low activity immediately at birth followed by a rapid increase during the first few weeks of life.²³ RAL was discontinued in two infants due to weight loss and one infant due to parent's decision. In cohort 1, four infants, and in cohort 2, twenty six infants had grade 3 or 4 adverse events. The most common adverse events were decreased hemoglobin, decreased neutrophil count, increased bilirubin, and dyspnea. Adverse events were considered unrelated to RAL.

In one study, PK parameters of RAL in children 2–12 years of age and in infants (4 weeks to 2 years) during concomitant treatment with rifampicin were assessed. The area under curve (AUC) 0–12 h and Ctrough parameters in children receiving 12 mg/kg every 12 h and in infants (doubling the dose of chewable tablets) were within the predefined target range.⁴²

Elvitegravir

A total of two studies^44,45 on EVG were retrieved, overall including 73 children (Table 4). Some of these results have also been reported in a narrative review.¹⁷

Table 4.

Summary of Studies Analyzed in the Review on Pharmacokinetics, Efficacy/Effectiveness, and Adverse Events of Elvitegravir

Author (year)	Country	Number of participants	Median age or range (years)	Study design and objective	Type of study	Main results	No. of patients with undetectable viremia (%)	Discontinuation of treatment (%)	Main adverse events
Gaur (2016)⁴⁵	South Africa, Thailand, Uganda, and United States	50	12–18	Virological efficacy of EVG ART-experienced adolescents	Single-arm, open-label trial	High virological efficacy has been achieved	92% of participants had VL <50 copies/mL at 48 weeks	4%	8% had uveitis, nausea, vomiting, and abdominal pain
Natukunda (2017)⁴⁴	Uganda, United States, and Thailand	23	10	Virological efficacy of EVG in ART-experienced children	Single-arm, open-label trial	Virological efficacy was achieved by all participants	All participants maintained VL <50 copies/mL at week 24	None	74% had abdominal pain and vomiting

VS, virological suppression.

In the first study, a single-arm, open-label trial, 50 treatment-naive adolescents (12–18 years) were included and followed up for 48 weeks.⁴⁵ Participants received a once-daily single tablet regimen containing elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (EVG/c/FTC/TAF); 96% of children completed the treatment until the end of follow-up, 92% had VL <50 copies/mL at 48 weeks, and 8% developed serious adverse events (uveitis, nausea, vomiting, and abdominal pain), even if none of the participants discontinued the treatment for this reason.⁴⁵

In the second study, 23 children, 6 to 11 years of age (weighting ≥25 kg), were enrolled and received a fixed-dose oral formulation of EVG/c/FTC/TAF once daily.⁴⁴ The study was a single-arm, open-label study conducted in Uganda, United States, and Thailand, and only virologically suppressed children were enrolled (Table 4). All participants maintained virological suppression (VL <50 copies/mL) at week 24; 74% of participants experienced mild to moderate adverse events, most commonly abdominal pain or vomiting.⁴⁴

Dolutegravir

A total of 17 studies were analyzed,^{7,20,26
–28,30,32
–34,38,39,40
–42,46} overall including 3,448 children (Table 5).

Table 5.

Summary of Studies Analyzed in the Review on Pharmacokinetics, Efficacy/Effectiveness, and Adverse Events of Dolutegravir

Author (year)	Country	Number of participants	Median age or range (years)	Study design and objective	Type of study	Main results	No. of patients with undetectable viremia (%)	Discontinuation of treatment (%)	Main adverse events	Conclusions/notes
Viani (2015)²⁶ Viani (2020)²⁷ Vavro (2022)²⁸ [IMPAACT P1093]	United States	23	12–18	Short- and long-term PK and safety parameters	Phase I/II, open-label, multicenter, noncomparative trial	VF due to adherence levels <90%	At week 48, 61% had VL <50 copies/mL. After 144 weeks, 35% had VL <50 copies/mL	31% within 144 weeks of follow-up	No adverse event was probably or definitely related to DTG
Levy (2020)³⁹	United States	141	17	Virological and safety outcomes after initiation INSTI in ART-experienced children	Prospective study	Among participants without pre-INSTI VS, 46% achieved VS after a median of 3 months, among those with pre-INSTI VS, 51% remained virologically suppressed after a median of 11 months	Among participants not suppressed at baseline, undetectable viremia was 40% at 12 months, among those suppressed at baseline 93.3%	One participant	No adverse event was detected	>50% of children and young adults with detectable viremia before INSTI did not achieved VS, while 50% of those with previous VS showed transient viremia
Frange (2019)³³	France	84	5–17	Virological effectiveness of DTG in children ART-experienced (91.7%)	Retrospective study	Despite 2 transient virological rebound, VL returned <50 copies/mL without change in ART	UVL in group 1 was 93.9% and in group 2 was 84.3% at 24 months	One patient due to adverse events	Dizziness and sleep disturbances
Bruzzese (2018)⁴⁰	Italy	6	17	Virological effectiveness of DTG in ART-experienced adolescents	Prospective study	Virological effectiveness and treatment adherence were maintained at a 24-week follow-up	Three patients experienced VL <40 copies/mL in 4 weeks, one patient in8 weeks, two patients, maintained VS	None	None	One month after DTG, patient enrolled because of severe dyslipidemia and hyper-transaminasemia showed a complete normalization of laboratory values
Yeoh (2021)³⁴	Australia	17	14	Weight gain in ART-experienced children receiving DTG or TAF	Retrospective study	Viral blips occurred in two children (<200 copies/mL)	VS (<100 copies/mL) after switching to DTG was maintained in 63% at 1 year	Not reported	87.5% of participants who switched to DTG experienced weight gain, compared to 100% of those who switched to TAF	Suboptimal adherence was observed in three children
Moore (2021)⁷ Turkova (2021)⁴⁷ Gunaratne (2021)²⁹ Rabie and Frigati (2020)³⁰ Bollen (2020)³¹ [ODYSSEY trial]	Uganda, Zimbawe, South Africa, Thailandia, Europe	707	12	Efficacy and safety comparison of DTG +2NRTI vs. SOC	Open-label, multicenter, randomized trial	>25 kg switch to the adult FCT dose; 20 to <25 kg switch to DTG 30 mg DT or DTG 50 mg FCT and 14 to <20 kg switch to DTG 25 mg DT	At 96 weeks, VL <50 copies/mL was achieved by 81% of children in the DTG arm and 76% in the SOC arm week	4% in the DTG arm and 9% in the SOC arm changed ART regimen during follow-up;2 in the DTG arm and 21 in theSOC arm changed ARTdue to treatment failure	10% with DTG and 11% with SOC	62 Children receiving DTG: ≥20 kg (50 mg FCT) and 20–25 kg (30 mg DT) remained in the reference values of adults receiving DTG 50 mg twice daily
Venter (2020)³²	South Africa	1,053	>12	Virological efficacy in participants without ART for ≥6 months	Phase III, randomized trial	Virological efficacy was greater in regimens containing DTG	79% in the TAF/F/DTG group, 78% in the TDF/F/DTG had VL <50 copies/mL at 96 weeks	3% of participants in the TDF/F/EFV group discontinued due to liver dysfunction and rash	Participants in the TAF/F/DTG group had more weight gain than the other two treatment groups
Jacobs (2020)⁴²		13	6–18	PK parameters of DTG received with rifampicin	Systematic review	DTG can be administered twice daily (instead of once daily) in children >6 years of age	Not reported	Not reported	Not reported	Limited options for ART in children <3 years receiving rifampicin-based TB therapy
Abo (2019)³⁵	Europe	54	15	Virological effectiveness of INSTIs and characterization of resistance in ART-experienced adolescents	Retrospective study	One mutation (E157Q) against RAL and two mutations in reverse transcriptase	83% of participant in a median of 26 days	Two-thirds of patients who received DTG (33%)	16% had adverse events (neuropsychiatric and gastrointestinal)	26 Discontinuations of INSTI, of which 9 were caused by adverse events. In two children adverse events leading to discontinuation were neutropaenia and hypertension
Briand (2017)³⁶	France	50	18	Virological effectiveness and adverse events in ART-experienced adolescents	Retrospective study	82% remained virologically suppressed; 58% achieved VL <50 copies/mL	78% of patients had UVL at the last visit (10 months)	One participant due to adverse events	2/50 with neuropsychiatric adverse events
Frange (2018)⁴⁶	France	84	5–18	Characterization of resistance and effectiveness	Retrospective study	Prevalence of INSTI-related TDR was 5%	VL <50 copies/mL in 93.9% of patients 5–12 years of age and 84.3% of patients 12–18 years of age	1.2%	Dizziness, sleep disturbances	In newly diagnosed children with an E157Q mutation, the preferred choice was DTG, rather than RAL or EVG
Salou (2020)⁴¹	Africa	259	Among adolescents, a median age of 11 years, among children 4 years	Characterization of resistance in children who switched to DTG-based regimens	Prospective study	Minor mutations associated with DTG resistance were observed in 12.4%	Not reported	Not reported	Not reported	36.4% of adolescents and 23.6% of children had VL >1,000 copies/mL
Thivalapill (2021)³⁸	Sub-Saharian Africa	460	10–19	Analysis to estimate the rate of BMI increase with DTG	Retrospective study	The rate of change in BMI was about 1.2 kg/m² per year, a difference of 0.8 kg/m² per year	Not reported	Not reported	19% of those receiving DTG had an increase in BMI	Rate of change of BMI was influenced by gender

BMI, body mass index; DT, dispersible tablets; FCT, film-coated tablets; INSTIs, integrase strand transfer inhibitors; SOC, standard of care; TDF/F/EFV, tenofovir disoproxil fumarate/emtricitabine/efavirenz; TDR, transmitted drug resistance.

The IMPAACT 1093 phase I/II, multicenter, open-label, noncomparative study conducted in United States in children with a median age of 15 years aimed to study tolerability, safety, efficacy, and PK of DTG in combination with an optimal baseline regimen.²⁶ Results are reported in three main studies published in 2015,²⁶ 2020,²⁷ and 2022.²⁸

In the first 2015 report, 23 adolescents (ART-experienced, but INSTI naive), 12–18 years of age, were included and received a DTG dose of ∼1 mg/kg once daily. At 48 weeks, 96% of the children were still on treatment, and of these, 74% had VL <400 copies/mL and 61% had VL <50 copies/mL.²⁶ Results at 144 weeks of follow-up were published in the 2020 report.²⁷ Among the 23 adolescents initially recruited, 69% children were still on treatment, 43% of them had VL <400 copies/mL, and 35% had VL <50 copies/mL. Discontinuations were not due to adverse events or drug intolerance, but due to suboptimal adherence, and most participants who experienced virological failure had adherence levels <90%.²⁷ No adverse event was judged to be DTG related (Table 5).

In the third 2022 report, the results of resistance characterization of 36 children with virological failure, 8/36 (22%) children presented with resistance-associated integrase mutations. Six children developed mutations during the course of treatment (specifically G118R and R263K/R), while in two children with a single polymorphic INSTI-associated substitution (E157Q or L74I), it could not be determined whether the emergence had occurred during the study period.²⁸

The District of Columbia cohort study, a multicenter observational study, recruited 141 ART-experienced adolescents (of which 65% <18 years); the objective was to assess whether virologically suppressed adolescents from previous ART regimens (35% of the cohort) had episodes of detectable viremia (VL ≥20 copies/mL) and how many of those not virologically suppressed (65% of the cohort) at the start of INSTI achieved undetectable viral load (UVL).³⁹ The 55% of participants were receiving DTG-based regimens, 8% RAL, and 37% were receiving EVG: among participants without pre-INSTI viral suppression (VS) 46% achieved VS after a median of 3 months, while among those with pre-INSTI VS, 51% remained virologically suppressed after a median of 11 months (Table 5).

Sixty-seven percent of participants continued with the same regimen until the end of follow-up, while 13% continued the same INSTI, but changed the backbone, 9% changed INSTI, and 7% switched to a non-INSTI regimen. One participant permanently discontinued his INSTI-based regimen. Among virologically suppressed pre-INSTI participants, it was noted that virological failure was more likely among participants starting EVG than those receiving DTG.

Among participants who were not virologically suppressed before starting the INSTI regimen, it was noted that, after starting INSTI, participants 13–24 years of age were less likely to achieve virological suppression than those 0–12 years of age and participants receiving EVG than those receiving RAL.³⁹ The 6% of participants showed resistance to INSTI before the start of treatment. Resistance to INSTI was found in two participants by genotypic testing after starting treatment with INSTI (mutation E138A): one participant was receiving RAL, while the other was receiving EVG.³⁹

In a retrospective study, 84 children and adolescents (5–17 years of age) were recruited and virological effectiveness of DTG was evaluated³³; DTG was administered at doses of 25 mg for children who weighed <30 kg and 50 mg for children who weighed at least 30 kg. The primary endpoint of the study was the achievement of an UVL in 3 months; 91.7% of participants were ART experienced, including three INSTI experienced. Twenty-eight patients (62.2%) achieved virological suppression within 3 months of starting DTG, with virological success maintained thereafter. Follow-up was performed for an average of 24 months. At the last visit, UVL (<50 copies/mL) in groups 1 (5–11 years) and 2 (12–17 years) was 93.9% and 84.3% of participants, respectively. Two children (in the 12–17-year group) experienced a transient virological rebound, but VL returned <50 copies/mL without change in ART.³³

A prospective observational Italian study was conducted, in 2015, including six ART-experienced adolescents with a median age of 17 years⁴⁰ (Table 5). Participants started a DTG-based regimen combined with other antiretrovirals, and it was found that three adolescents displayed HIV VL <40 copies/mL within the first 4 weeks, one patient reached complete VS after 8 weeks of treatment, and two patients, who already had UVL with the previous ART regimen, maintained suppressed HIV load after switch to DTG.⁴⁰ At a median follow-up of 24 months, there was no adverse event or treatment failure.⁴⁰

A retrospective Australian observational study included 17 ART-experienced children (median age = 14 years), who were switched to receive DTG (8 children) or TAF (9 children). HIV viral suppression (<100 copies/mL) was maintained in 5/8 children (63%) receiving DTG and 6/9 (67%) receiving TAF at 12 months; viral blips occurred in two children (<200 copies/mL) and suboptimal adherence was observed in three children.³⁴ Interestingly, 100% of patients who switched to TAF and 87.5% of who switched to DTG had an increase in body mass index (BMI) z-score within 12 months after treatment change.³⁴

ODYSSEY is an open-label, multicenter, randomized trial conducted in South Africa, Europe, and Thailand, involving 707 participants, aimed to evaluate the virological or clinical efficacy of DTG +2 NRTIs compared to standard of care (SOC) at 96 weeks in children and adolescents starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The median age of children was 12.2 years.⁷ Children and adolescents (≥4 weeks to <18 years) weighing at least 14 kg were recruited. Forty-four percent of participants received first-line ART, while 56% received second-line ART (Table 5).

At 96 weeks, VL <50 copies/mL was achieved by 81% of children in the DTG arm and 76% in the SOC arm. Virological failure (VL >400 copies/mL) was observed in the ODYSSEY A cohort in 7% of participants receiving DTG and 19% of those in the SOC arm, and in the ODYSSEY B cohort in 16% of children in the DTG arm and 20% of those in the SOC arm.⁷

Resistance to DTG was developed in 18% of participants with treatment failure on DTG in the ODYSSEY B cohort (the four mutations found were Q148R, Q148K, G118RS, and G118RS+R263K), while among participants receiving first-line therapy (ODYSSEY A cohort), none of those in the DTG arm experienced resistance after treatment failure.⁴⁷ Serious adverse events occurred equally in both arms, 10% with DTG and 11% with SOC, respectively. More participants experienced serious adverse events in the ODYSSEY A cohort (15% in the DTG arm and 17% in the SOC arm) than in the ODYSSEY B cohort (6% and 7%, respectively).⁴⁷ At 96 weeks, BMI measures were slightly higher in children receiving DTG, while low-density lipoprotein cholesterol levels were lower in those receiving DTG than in the SOC arm.²⁹

Three PK studies were conducted at ODYSSEY study sites in 62 African children with HIV, 6–18 years of age, who weighed 20 kg to <40 kg: DTG exposure (expressed as AUC0–24 h) in children weighing 20 kg or more (receiving 50 mg film-coated tablets) and in children weighing between 20 and 25 kg [receiving 30 mg dispersible tablets (DTs)] was found to remain within the reference values of adults receiving DTG 50 mg twice daily^30,31 (Table 5). The ODYSSEY PK studies also show that 30 mg DTs in children weighing between 20 kg and <25 kg is an alternative option for those unable to swallow tablets.³¹

A randomized phase III trial was conducted in South Africa, in 1,053 children not virologically suppressed, older than 12 years, to compare three groups of patients receiving TAF/FTC/DTG (50 mg once daily), or tenofovir disoproxil fumarate (TDF)/FTC/DTG (50 mg once daily), or TDF/FTC/EFV, respectively. At week 96, 79% of participants in the TAF/FTC/DTG group, 78% of the participants in the TDF/FTC/DTG, and 74% of participants in the TDF/FTC/EFV group had achieved a VL <50 copies/mL.³² Regarding adverse events, mean weight gain was greatest in the TAF/FTC/DTG group and 3% of participants in the TDF/FTC/EFV group discontinued due to treatment-related adverse events, of which liver dysfunction and rash were the most common ones.³²

In a systematic review, the PK parameters of DTG received in combination with rifampicin were observed in three studies (Table 5). Co-administration of DTG and rifampicin was studied in 13 children, 6–18 years of age, receiving either 25 mg or 50 mg of DTG twice daily, and PK parameters during treatment and after discontinuation of rifampicin were found to be similar. It was concluded that DTG can be administered twice daily (instead of once daily) in children >6 years of age.⁴² Accordingly, the 2018 World Health Organization (WHO) guidelines recommend that children >20 kg with HIV and TB co-infection and treated with rifampicin-containing regimens, should receive an additional 50 mg of DTG 12 h after receiving their main ART regimen (two NRTIs).⁴⁸

A retrospective cohort study was conducted in Europe, in 56 children on the virological effectiveness of INSTIs; 37.5% of patients received RAL, 51.8% DTG, and 10.7% EVG. The median age at the start of INSTI-based therapy was 15 years and 98% of children were ART experienced. At baseline, 24 children had a detectable VL, and 83% of these achieved virological suppression in a median of 26 days.³¹ Eight children had subsequent viral failure with INSTI due to poor adherence. One child developed an E157Q mutation with potential resistance to RAL and two children acquired previously undocumented resistance mutations in reverse transcriptase [M184I not responding to DTG/abacavir (ABC)/lamivudine (3TC) and M184V and T215Y unresponsive to darunavir (DRV) plus EVG/c/FTC/TAF].³¹ Adverse events reported were mainly neuropsychiatric and gastrointestinal and were documented in 16% of patients, leading to discontinuation of INSTI in two-thirds of patients receiving DTG.³¹

However, these results differ from those of Briand et al. who conducted a multicenter retrospective study in France, including 50 treatment-experienced adolescents (median age = 18 years, range = 15.5–20.2), receiving DTG. Two out of 50 cases developed with neuropsychiatric adverse events, only one of which required discontinuation of therapy.³⁵ Also, 17/50 patients were suppressed at baseline, of whom 100% achieved UVL <50 copies/mL at last follow-up (10 months). A further 33 adolescents were enrolled, who were not virologically suppressed at baseline and 67% achieved UVL (Table 5). Overall, 78% (39/50) of patients had VL <50 copies/mL at the last visit.³⁶

In France, a retrospective study included 84 children and adolescents and a transmitted drug resistance (TDR) analysis was performed. Median follow-up was 24 months. VL <50 copies/mL in 93.9% of patients 5–12 years of age (n = 33), and 84.3% of patients 12–18 years of age (n = 51). One patient discontinued treatment due to severe DTG-related adverse events (dizziness and sleep disturbances).³⁷ Overall, the prevalence of INSTI-related TDR was 5%. The polymorphic E157Q mutation in the integrase gene conferred resistance to RAL, EVG, and DTG administered once daily and intermediate resistance to DTG when administered twice daily. Susceptibility to DTG may be less affected by this substitution, then in children with an E157Q mutation, the preferred choice was DTG, rather than RAL or EVG.⁴⁶

A prospective observational study conducted in Africa, including 259 children and adolescents, showed that 36.4% of adolescents (mean age = 11 years) and 23% of children (mean age = 4 years) had virological failure, defined as a VL >1,000 copies/mL,⁴¹ at 9 months. Genotypic testing for drug resistance was conducted in 76% of children and 67.5% of adolescents, and minor mutations (E157Q, T97A, and V151VA) associated with DTG resistance were observed in 22 (12.4%) patients.

In addition, 31% of adolescents with VL >1,000 copies/mL who switched to a second-line DTG/zidovudine (AZT)/3TC-based regimen were on DTG monotherapy because they had developed mutations predicting high or intermediate resistance to 3TC and AZT. 24% of children were regimen-sensitive and the remaining patients were on dual DTG/AZT therapy due to the development of resistance to 3TC. Study results showed that up to 50% of adolescents and almost all children in virological failure on first-line and 30% of those on second-line regimens will be on functional DTG monotherapy due to accumulated resistance against NRTIs.⁴¹

A retrospective observational study compared the BMI of 460 virologically suppressed (<200 copies/mL) and ART-experienced, but INSTI-naive South African adolescents (10–19 years of age) before and after switching to a DTG-containing regimen; 10.9% of participants were taking an ABC/3TC/DTG regimen and 89.1% were taking TDF/3TC/DTG (Table 5). After DTG, the rate of change in BMI was ∼1.2 kg/m² per year, a difference of 0.8 kg/m² per year. The sex of the adolescent changed the relationship between DTG and rate of change in BMI: the rate increased by 1.1 kg/m² in females and by 0.6 kg/m² per year in males.³⁸

In a report by the National Collaborative UK and Ireland ART children and adolescent (CHIPS) study, among the 406 children who received an INSTI, low rates of toxicity and no change in BMI score with DTG were observed, but an increase in these adverse events with RAL was found.²⁰

Bictegravir

One study was retrieved regarding BIC use in children⁴³ (Table 6). In this single-arm, open-label study, 102 children and adolescents, 6 to <18 years of age, with HIV-1 were enrolled in 22 hospital-based clinics in South Africa, Thailand, Uganda, and the United States; all participants weighed at least 25 kg and were virologically suppressed (<50 copies/mL).⁴³ Participants received the fixed-dose regimen of coformulated BIC 50 mg, FTC 200 mg, and TAF 25 mg once daily. VL <50 copies/mL was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48 and no resistance emerged during treatment.

Table 6.

Summary of Studies Analyzed in the Review on Pharmacokinetics, Efficacy/Effectiveness, and Adverse Events of Bictegravir

Author (year)	Country	Number of participants	Median age or range (years)	Design and objective of the study	Type of study	Main results	No. of patients with undetectable viremia (%)	Discontinuation of treatment (%)	Main adverse events	Conclusions/notes
Gaur (2021)⁴³	South Africa, Thailand, Uganda, and United States	102	6–18	PK analysis for dose confirmation and comparison with data in adults	Phase II/III, single-arm, open-label, multicenter trial	At 48 weeks, BIC had Ctau within the parameters considered safe and effective	VS (VL <50 copies/mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48	One discontinued due to adverse events	Grade 2 insomnia and anxiety, upper respiratory tract infection (26%), and diarrhea (11%)	The single-tablet regimen based on BIC/FTC/TAF is currently recommended by FDA as first-line treatment for adolescents and as an alternative regimen in children

Ctau, plasma trough concentration.

The most common adverse events were upper respiratory tract infection (26%) and diarrhea (11%). One 7-year-old participant discontinued the study at week 20 due to grade 2 insomnia and anxiety and was considered to be treatment related. Grade 3 laboratory abnormalities were found in 21 participants and grade 4 abnormalities in 2 participants, but were transient.⁴³

Conference on Retroviruses and Opportunistic Infections

We reported data from main abstracts from the CROIs in 2018–2021.^{49

–56} Overall eight studies were reported, including 3,980 children and adolescents.

The REALITY study randomized 1,550 patients from Africa to two NRTI+NNRTI (Std)+RAL (n = 775) versus Std (n = 775). Participants were ART-naive adults and children ≥5 years of age. After 12 weeks, 470/667 of participants (69%) with Std+RAL and 334/685 of participants (49%) with Std had VL <50 copies/mL. The major mutations detected were R263K, T97A, L74M, or N155H (7% of sequenced participants at week 12). At 48 weeks, 527/654 of participants (81%) with Std+RAL and 495/642 of participants (77%) with Std had VL <50 copies/mL. Important mutations for RAL have occurred in a very small number of participants, it was uncertain whether they were transmitted or emergent mutations, as no sequencing was performed at baseline⁴⁹ (Table 7).

Table 7.

Summary of Abstracts Analyzed in the Conferences CROI, IAS, and International Workshop on HIV Pediatrics on Pharmacokinetics, Efficacy/Effectiveness, and Adverse Events of INSTIs

Author (year)	Number of participants	Median age or range (years)	Design and objective of the study	Type of study	Main results	No. of patients with undetectable viremia	Discontinuation of treatment (%)	Main adverse events	Conclusion/notes
Kityo (2018)⁴⁹	1,550	13	Virological efficacy and resistant mutations in two randomized groups receiving Std vs. SOC	Randomized trial (REALITY)	The major mutations detected were R263K, T97A, L74M, or N155H	After 12 weeks, 69% with Std+RAL and 49% with Std had VL <50 copies/mL. At 48 weeks, 81% with Std+RAL and 77% with Std had VL <50 copies/mL	Not reported	Not reported	Important mutations detected for RAL were uncertain whether they were transmitted or emergent mutations, as no sequencing was performed at baseline
Ruel (2019)⁷⁶	20	22 months	PK, safety and efficacy of DTG in children 6 months to 6 years of age	Ongoing phase I/II open-label trial	VL <400 copies/mL was reported in 80% of participants at 4 weeks	VL <50 copies/mL in 8/20 (40%)	None	Three cases of adverse events (neutropenia, lipase elevation, and diarrhea)
Gaur (2019)⁵²	100	Cohort 1 (weight ≥35 kg): 15 yearsCohort 2 (weight ≥25 kg): 10 years	Effectiveness and safety of BIC/FTC/TAF in adolescents	Prospective study	Data at 48 weeks support the use of BIC/FTC/TAF 50/200/25 mg in adolescents and children 6 to <18 years of age and weighing ≥25 kg	100% had VL <50 copies/mL at 24 weeks and 98% (74/75) at 48 weeks	One participant discontinued due to insomnia and anxiety	Abdominal pain was reported in 2% of participants
Giacomet (2020)⁵³	14	16.1	Evaluate effects of DTG on body composition and glycolipid metabolism in ART-experienced children	Retrospective study	The mean blood concentration of glucose and HDL-cholesterol did not change significantly during 12 months of follow-up	Not reported	Not reported	Not reported	DTG-based regimen was not associated with BMI modifications, but a significant increase in adolescents's trunk fat was observed
Dirajilal-Fargo (2020)⁵⁴	51	15–21	Determine whether there was a greater increase in BMI in the first 2 years on INSTIs compared with the 2 years before INSTI initiation	Retrospective study	Similar to adults there was a greater increase in BMI following the switch to INSTI	Not reported	Not reported	Not reported
Iyer (2021)⁵⁵	2,245	8	Effectiveness of DTG-based regimen in children at 3 years of follow-up	Retrospective study	DTG-based regimens were associated with a lower probability of detectable viremia (VL >1,000 copies/mL) than non-DTG-based regimens	Not reported	Not reported	Not reported
Collins (2019)⁵⁷	1,741	Children who received DTG were 15.2 years, of which those who received RAL was 13.1 and those who received EVG was 14.4	Evaluated the effectiveness and safety of DTG, RAL, and EVG at 6 and 12 months of follow-up in ART-experienced and ART-naive children	Retrospective study	Among children virologically suppressed at baseline, VS was maintained in 92% of those receiving DTG, 100% of those receiving RAL, and 80% of those receiving EVG	91% of those receiving DTG, 82% of those receiving RAL, and 88% of those receiving EVG had VL <50 copies/mL	Discontinuation was detected in 4.9% of cases with DTG and 11.3% of cases with RAL	An increase in BMI was noted with RAL, but not in children who received DTG and EVG	17% of the participants were INSTI experienced, 9% of the children who received DTG and 10% of those who received RAL were ART naive
Rakhmanina (2019)⁵⁸	52	10	Efficacy of the adult formulation of EVG/c/FTC/TAF in virologically suppressed children 6–12 years of age and weighing ≥25 kg	Prospective, single-arm, open-label trial	In children weighing ≥25 kg, EVG/c/FTC/TAF (150/150/200/10 mg) was well tolerated and safe	All participants in treatment at 96 weeks of follow-up (19/52) had VL <50 copies/mL	Not reported	None
ODYSSEY trial team (2021)⁶¹	85	1.4	Efficacy and safety comparison of DTG arm vs. SOC arm in children ≤14 kg	Open-label, multicenter, randomized trial	Efficacy, adherence, and safety were higher in DTG arm	At 96 weeks, 77% of DTG arm had VL <50 copies/mL vs. 50% of SOC arm	Not reported	19 Children in the DTG arm had grade 3 or 4 adverse events vs. 21 children in the SOC arm	In the DTG arm 97.6% children, remained on treatment, and in the SOC arm 86%
Natukunda (2021)⁶³	122	Cohort 1: 12–18 yearscohort 2: 6–12 yearscohort 3: >2 years	Efficacy of BIC/FTC/TAF (50/200/25 mg) in virologically suppressed children 6–18 years of age and >25 kg and of the low-dose formulation (30/120/15 mg) in children >2 years of age and weight 14–25 kg	Open-label trial	BIC/FTC/TAF proved safe and effective in virologically suppressed children	In cohorts 1–2 VL <50 copies/mL was detected in 99% of participants at 96 weeks and in cohort 3 in 91% at 24 weeks of follow-up	In cohort 2, one child discontinued at week 20 due to adverse events	Three cases of abdominal pain, two of neutropenia, one child had insomnia and anxiety of grade 2
Anugulruengkitt (2021)⁶⁴	129	Cohort 1: 12–18 yearsCohort 2: 6–12 yearsCohort 3: ≥2 years	Efficacy of EVG/c/FTC/TAF in children ≥2 years of age and ≥14 kg	Open-label trial	In ART-naive or ART-experienced children EVG/c/FTC/TAF maintained high rates of VS in all three cohorts	VL <50 copies/mL was reported in 97.8% of cases in cohort 1, in 100% of cases in cohort 2 at 96 weeks, and in cohort 3 in 96.3% at 48 weeks of follow-up	Not reported	One child in cohort 1 had a grade 2 autoimmune uveitis	Cohort 1 included ART-naive adolescents weighing ≥35 kg; cohort 2 included children weighing ≥25 kg; cohort 3 included children weighing ≥14 kg
Compagnucci (2021)⁶²	318	14.7	Efficacy and safety of INSTI+DRV arm vs. SOC arm in virologically suppressed adolescents	Randomized trial (SMILE)	In virologically suppressed children, switching to INSTI+DRV was not inferior virologically	At 48 weeks, 8 children in the INSTI+DRV arm vs. 12 in the SOC arm had VL >50 copies/mL	Not reported	13 Children in the INSTI+DRV arm vs. 19 in the SOC arm had grade 3 or 4 adverse events
Bacha (2021)⁶⁵	1,703		Effectiveness of DTG-based regimen after switching from a backbone regimen with two NRTIs in ART-experienced children and adolescents	Retrospective study	After switching to DTG VS (VL <1,000 copies/mL) improved from 86.8% to 92.9%. Among nonvirologically suppressed children, 84% achieved VS	Not reported	Not reported	Not reported	In a cohort of children receiving PI/TDF/3TC after switching to DTG 92.3% were virologically suppressed
Gill (2021)⁶⁶	3,107	5–14	Effectiveness in 2,009 children weighing ≥20 kg switching from various ART regimens to DTG (81% of total)	Retrospective study	Study showed progress in switching to DTG-based regimes in ART-experienced children	Data were available from 85 children, of whom 80% had VL <50 copies/mL after 2.9 months	Not reported	Not reported
Kouamou (2021)⁶⁷	184	15	Effectiveness of DTG in ART-experienced children and adolescents	Retrospective study	High rates of VS were observed in children and adolescents on DTG	After 7 months VS (VL <1,000 copes/mL) was observed in 95% of the participants	Not reported	Not reported	Children switched from a PI-based regimen had more virological failure than those from a NNRTI-based regimen
Barlow-Mosha (2021)⁶⁹	229	12.3	Comparing vitamin B12 and folate rates among children in DTG arm vs. SOC arm	Open-label, multicenter, randomized trial	At week ≥96, mean concentration of folate in the DTG arm> SOC arm. Vitamin B12 levels were similar between two arms	Not reported	Not reported	Not reported	The risk of NTDs was unlikely to be due to the decrease in folate and vitamin B12 levels caused by DTG
Van de Ven (2021)⁷⁰	4,052	0–14	Evaluation of pediatric optimized regimens (LPV/r or DTG) in children	Retrospective study	The proportion of children on the optimal regimen increased from 9% to 87% over 3 years	VS among children receiving LPV/r showed an increase to 76%, compared to 89% of children on DTG-based regimen	Not reported	Not reported
Mutisya (2021)⁷¹	6,559	11	Evaluation of improvement of VS in ART-experienced children	Retrospective study	Among children receiving DTG, the probability of VS was three times higher than in other ART regimens	VL <1,000 copies/mL was in 86.1%	Not reported	Not reported	Older children, longer duration of ART, DTG-based regimen and adherence are key elements for high VS
Gill (2021)⁷²	3,107	>5	Virological effectiveness in children switched to DTG-based regimen	Retrospective study	At the end of follow-up, 75% received DTG, 29% children treated with DTG switched to other regimens within 6 months	68 children (80%) had VL <50 copies/mL	Not reported	Not reported	Virological data of 85 children were available after 3 months
Brooks (2021)⁷³	21	7–10	Evaluation of PK, safety, and tolerability of DT formulation of ABC/DTG/3TC in ART-experienced children >14 kg	Phase I/II, multisite, open-label study (IMPAACT 2019)	PK targets were achieved in children≥14 kg and these formulations were well tolerated	Not reported	<2 Children	One child had two severe adverse events (grade 2), one child had one adverse event of grade 1	These results reassure on the dosage of these formulations in children weighing ≥14 kg
Ruel (2020)⁵⁹	51	4 weeks to 6 years	Safety and tolerability of DTG DT in children	Open-label, phase I/II study (IMPAACT P1093)	None adverse event wwasere assessed as related to DTG	At 24 weeks, 41% of infants 4 weeks to 6 months years of age, 67% of those 6 months to 2 years of age, and 63% of those 2–6 years of age had VL <50 copies/mL	None	49% experienced a grade 3 or higher adverse events
Bacha (2020)⁶⁰	681	13.9	Virological effectiveness after switching to DTG-based regimen from NNRTI-based regimen and PI	Retrospective study	After 10 months, 84.1% of the children with documented VL were suppressed (VL <1,000 copies/mL), compared to 76.1% (448/589) of VL before DTG	84.1% (VL <1,000 copies/mL)	Not reported	Not reported	66.0% received DTG (449/681), 23.9% (163/681) received ABC/3TC/DTG, and 10.1% (69/681) received AZT/3TC/DTG

CROI, Conference on Retroviruses and Opportunistic Infections; HDL, High Density Lipoprotein; IAS, International AIDS Society; LPV/r, lopinavir/ritonavir; NNRTI, non-nucleoside analog reverse transcriptase inhibitors; NRTI, nucleoside analog reverse transcriptase inhibitors; NTDs, neural tube defects; Std, NRTI+NNRTI.

A study simulated the PK of DTG in infants ≥4 weeks of age through a physiology-based pharmacokinetics (PBPK) model to determine an appropriate dosing regimen. The PBPK model was designed by incorporating neonatal maturation characteristics and physiological and anatomical growth data; multiple doses of DTG were simulated in 100 healthy newborns. The result was that an appropriate dose in neonates was between 2 and 4 mg, which corresponds to a plasma exposure comparable to that observed in pediatric patients.⁵⁰

A study evaluated the PK, safety, and efficacy of DTG in children 6 months to 6 years of age. The 20 children recruited were parted into two cohorts (cohort 1: >6 months to 2 years and cohort 2: 2–6 years) and according to weight, an increasing dosage was assigned. Follow-up was 4 weeks and median age was 22 months. VL <400 copies/mL was reported in 16/20 (80%) participants and VL <50 copies/mL in 8/20 (40%). Three cases of adverse events (neutropenia, lipase elevation, and diarrhea) were reported, but no case of treatment discontinuation.⁵¹

In a prospective study on BIC, cohort 1 recruited 50 adolescents (18 years of age) virologically suppressed at baseline and weighing ≥35 kg, and cohort 2 recruited 50 children (6 to <12 years) weighing ≥25 kg. In cohort 1, the median age was 15 years, and in cohort 2, it was 10 years. All participants had VL <50 copies/mL at 24 weeks and 98% (74/75) at 48 weeks. Abdominal pain was reported as an adverse event in 2% of participants and one participant discontinued due to insomnia and anxiety⁵² (Table 7).

A retrospective observational study was conducted to evaluate the effects of DTG on body composition and glycolipid metabolism in children. Fourteen ART-experienced children were recruited (mean age = 16.1 years) and the follow-up was 12 months. The mean blood concentration of glucose and high density lipoprotein-cholesterol did not change significantly during the follow-up. The study showed that a DTG-based regimen induced a significant improvement in blood lipid concentration, but did not interfere with glucose metabolism, and induced a significant increase in trunk fat without alterations in BMI and body fat percentage.⁵³

One observational study enrolled 51 adolescents with a median age of 18 years (IQR = 15–21), and resulted that, similar to adults, there was a greater increase in BMI following the switch to INSTI. The results support the need for continuous monitoring of BMI trends and potential cardiometabolic implications in patients receiving INSTIs.⁵⁴

A PK study used the PBPK model to identify an adequate dose of BIC in infants. The results of the study involved starting infants on a dose of 5 mg once daily, increased to 7.5–10 mg once daily after day 11.⁵⁶

A retrospective study recruited 2,245 children with a median age of 8 years in Lusaka, Zambia. DTG-based regimens were associated with a lower probability of detectable viremia (VL >1,000 copies/mL) than non-DTG-based regimens after 3 years of follow-up. Data on adherence to therapy were not available.⁵⁵

IAS: International workshop on HIV pediatrics

We reported data from main abstracts from the conferences IAS and International workshop on HIV pediatrics in 2019–2021.^{57

–73} Overall 17 studies, including 468,068 children and adolescents, were reported.

A UK/Ireland study recruited 1,741 children and evaluated the effectiveness of DTG, RAL, and EVG at 6- and 12-month follow-up⁵⁷; 17% of the participants were INSTI experienced, 9% of the children DTG, and 10% of those who received RAL were ART naive. The median age of children who received DTG was 15.2 years; of those, 13.1 received RAL and 14.4 received EVG. In total, 216 children received DTG (71%), 93 children (31%) received RAL, and 29 children (10%) received EVG.

Among children virologically suppressed at baseline, after 12 months, virological suppression was maintained in 92% (46/50) of those receiving DTG, 100% (14/14) of those receiving RAL, and 80% (4/5) of those receiving EVG. Overall, 91% (72/79) of those receiving DTG, 82% (42/51) of those receiving RAL, and 88% (7/8) of those receiving EVG had VL <50 copies/mL. Discontinuation was detected in 4.9% of cases with DTG and 11.3% of cases with RAL. An increase in BMI was noted with RAL, but not in children who received DTG and EVG.⁵⁷

A prospective, single-arm, open-label study evaluated the efficacy of the adult formulation of EVG/c/FTC/TAF in virologically suppressed children 6–12 years of age and weighing ≥25 kg. Fifty-two children with a median age of 10 years were enrolled, and all participants (19/52) maintained VL <50 copies/mL at the 96-week follow-up⁵⁸ (Table 7).

IMPAACT P1093, an open-label phase I/II study, evaluated the safety, tolerability, and efficacy of the DT of DTG in 51 children, 4 weeks to <6 years of age. DTG was dosed according to age and weight range (3 to <6 kg: 5 mg; 6 to <10 kg: if <6 months 10 mg, if ≥6 months 15 mg; 10 to <14 kg: 20 mg, and 14 to <20 kg: 25 mg). At 24 weeks, 41% of infants 4 weeks to 6 months of age, 67% of those 6 months to 2 years of age, and 63% of those 2–6 years of age had VL <50 copies/mL. Forty-nine percent experienced a grade 3 or higher adverse event, none was assessed as related to DTG and none resulted in discontinuation of treatment.⁵⁹

A retrospective study conducted in Tanzania recruited 681 children, of whom 66.0% received DTG (449/681), 23.9% (163/681) received ABC/3TC/DTG, and 10.1% (69/681) received AZT/3TC/DTG. ART-naive children were 12.6% (86/681), while 62.4% (425/681) switched from an NNRTI-based regimen and 25.0% (170/681) switched from a PI-based regimen. The median age was 13.9 years. After 10 months, 84.1% (499/593) of children with documented VL were suppressed (VL <1,000 copies/mL), compared to 76.1% (448/589) of VL before DTG.⁶⁰

A substudy was conducted within the ODYSSEY study of 85 children weighing ≤14 kg, of whom 42 children received DTG and 43 received SOC.⁶¹ The median age was 1.4 years. At 96 weeks of follow-up, 11 children who were in the DTG arm and 21 children in the SOC arm had virological failure. At 96 weeks, 77% of children receiving DTG had VL <50 copies/mL compared to 50% of those in the SOC arm; and 19 children in the DTG arm had grade 3 or 4 adverse events compared to 21 children in the SOC arm. In the DTG arm, 41/42 (97.6%) children remained on treatment, and 37/43 (86%) in the SOC arm.⁶¹

SMILE was a randomized trial that evaluated the efficacy and safety of INSTI+DRV versus SOC in children. A total of 318 participants in Africa, Europe, Thailand, and Latin America were recruited, of whom, 158 were in the INSTI+DRV arm (DTG = 153; EVG = 5) and 160 in the SOC arm. The mean age was 14.7 years. At 48 weeks of follow-up, 8 children in the INSTI+DRV arm versus 12 in the SOC arm had VL >50 copies/mL; 13 children in the INSTI+DRV arm versus 19 in the SOC arm had grade 3 or 4 adverse events. Weight gain was reported more frequently in the INSTI+DRV arm.⁶²

An open-label study evaluated the efficacy of BIC/FTC/TAF (50/200/25 mg) in two cohorts of 100 virologically suppressed children (cohort 1: 12–18 years and >35 kg and cohort 2: 6–12 years and >25 kg) and the efficacy of the low-dose formulation (30/120/15 mg) in cohort 3 of 22 virologically suppressed children >2 years of age and weighing between 14 and 25 kg. In cohorts 1 and 2, virological suppression (VL <50 copies/mL) was detected in 99% of participants (95/96) at 96 weeks of follow-up, and in cohort 3, in 91% (20/22) at 24 weeks of follow-up.⁶³ Regarding adverse events, three children had abdominal pain, two children had neutropenia, and one child in cohort 2 discontinued at week 20 due to insomnia and anxiety (grade 2) (Table 7).

One study evaluated the efficacy of EVG/c/FTC/TAF in children ≥2 years of age and ≥14 kg. Cohort 1 included 50 ART-naive adolescents 12–18 years of age, who weighed ≥35 kg; cohort 2 included 52 children 6–12 years of age, who weighed ≥25 kg; and cohort 3 included 27 children ≥2 years of age, who weighed ≥14 kg and received a low-dose formulation. VL <50 copies/mL was reported in 97.8% of cases in cohort 1, in 100% of cases in cohort 2 at 96 weeks, and in 96.3% of cases in cohort 3 at 48 weeks of follow-up. No participant discontinued treatment due to adverse events.⁶⁴

A retrospective study in Tanzania recruited experienced ART children and adolescents. A total of 1,703 participants received DTG, of whom 37.2% switched from a backbone regimen with two NRTIs to a single regimen with DTG. Virological suppression (VL <1,000 copies/mL) improved from 86.8% to 92.9% after switching to DTG. Among nonvirologically suppressed children, 84% achieved virological suppression after switching to DTG. A cohort of children receiving PI/TDF/3TC was also included (54.2% were previously virologically suppressed) and after switching to DTG, 92.3% were virologically suppressed.⁶⁵

A retrospective study observed effectiveness results in children 5–14 years of age and weighing ≥20 kg, switching from various ART regimens to DTG. A total of 3,107 children were included, of whom 81% switched to DTG. Data were available from 85 children, of whom 80% had VL <50 copies/mL 2 months after receiving DTG-based regimen.⁶⁶

A retrospective observational study recruited 184 experienced ART children and adolescents (median age was 15 years), who received DTG-based regimen. Before switching to DTG, 76% were virologically suppressed (VL <1,000 copies/mL), and after a median follow-up of 7 months, virological suppression was observed in 95% of the participants⁷¹ (Table 7).

A study simulated the PK of DTG in a population of 450,000 children <5 years of age from 30 countries; 39% of the children were below the minimum exposure target. Malnutrition caused lower exposure to DTG; in fact, among children with severe malnutrition (5%), 43% were below adult exposure levels.⁶⁸

In a subgroup of 229 children >6 years of age in the ODYSSEY study, folate and vitamin B12 levels among those receiving DTG-based regimen were compared to SOC. The median age was 12.3 years; 114 received DTG and 115 received SOC. At week ≥96 of follow-up, the mean concentration of folate was higher in the DTG arm than in the SOC arm, while vitamin B12 levels were similar between two arms. These results suggest that among children born to mothers receiving DTG in pregnancy, the risk of NTDs was unlikely to be due to the decrease in folate and vitamin B12 levels caused by DTG.⁶⁹

A retrospective study in Tanzania evaluated the use of pediatric optimized regimens [lopinavir/ritonavir (LPV/r) or DTG]. Children 0–14 years of age were recruited over 3 years. The proportion of children on the optimal regimen increased from 392 children (9%) in 2018 to 4,052 children (87%) in 2020. Virological suppression among children receiving LPV/r-based regimen showed a lower increase from 66% to 76%, compared to 89% of children on DTG-based regimen.⁷⁰

A retrospective study evaluated the improvement of virological suppression in ART-experienced children in Kenya. The study recruited 6,559 children, with median age of 11 years. Virological suppression (VL <1,000 copies/mL) was 86.1%. In particular, children receiving DTG were three times more likely to have virological suppression than other ART regimens.⁷¹

A retrospective study evaluated virological effectiveness in children 0–14 years of age in Mozambique, who switched to DTG-based regimen. Of 3,107 children ≥5 years of age, 2,488 (80%) changed ART regimens; of those who changed regimens 2,009 (81%) switched to DTG. However, 711/2,488 (29%) children treated with DTG switched to other regimens within 6 months. At the last visit, 75% (2,311/3,092) of children received DTG. Virological data of 85 children were available after 3 months of therapy and 68 (80%) had VL <50 copies/mL.⁷²

IMPAACT 2019 is a phase I/II, multisite, open-label study evaluating the PK, safety, and tolerability of an immediate-release formulation and a DT formulation of ABC/DTG/3TC in ART-experienced children <12 years of age and weighing >14 kg in Botswana, South Africa, Thailand, and the United States. One child had two adverse events of grade 2 and another child had one event of grade 1; no child discontinued treatment due to adverse events.⁷³

Summary of virological outcome across studies

Data on the efficacy/effectiveness of RAL showed a UVL in 79% of children at the 8-week follow-up,²² 69% at 12 weeks,⁴⁹ and in 92% or 81%–82% at 12 months.^24,49,57 Percentages were still sustained in studies with longer follow-up, 68% at 20 months,²⁵ 70% at 24 months,²¹ and 77% at 60 months.¹⁷ Of particular interest is one study in infants, 4 weeks to 6 months of age, who received the granule formulation for oral suspension displaying sustained efficacy UVL in 87% of participants at 60 months.¹⁷

In the studies on EVG, VL <50 copies/mL was detected in 100% of participants at 24 weeks,⁴⁴ 88% to 96.3% in a 12-month follow-up,^57,64 and 97.8% to 100% in a 24-month follow-up.^58,64

In the various studies on DTG, percentages of participants with UVL (VL <50 copies/mL) were found to be 83% within the first months of treatment,³⁵ 80% at 3 months,^66,72 78% at the 10-month follow-up,³⁶ and 61% of participants at 1 year.²⁶ In a long-term follow-up (96 weeks), the proportion of participants with VL <50 copies/mL was in a range from 35%²⁷ to 93.9%.³³ Considering studies with VL <1,000 copies/mL, the range of virological efficacy was 84.1%–95%.^60,67 Of interest was a trial in children 4 weeks to 6 years of age, in which virological efficacy (VL <50 copies/mL) at 3 months ranged from 41% to 67%.⁵⁹

In the BIC study, VL <50 copies/mL was maintained at week 24 in a range from 91% to 100% and by 98% of participants at week 48.^43,52,63 In a long-term follow-up (96 weeks), VL <50 copies/mL was detected in 99% of children.⁶³

Summary of discontinuation rates across studies

Discontinuation rates, mainly due to suboptimal treatment adherence, adverse events, or unavailability of the drug, largely vary across studies. One study reports 34% of RAL discontinuation rate at the 2-year follow-up,²¹ in most cases because the drug was no longer available. IMPAACT 1066 study reported 0,8% (1/122) of discontinuations.¹⁹ Moreover, other authors report only few discontinuations due to adverse events.^18,22

For DTG, 31% of participants interrupted treatment in one study,⁴⁰ caused by suboptimal adherence to therapy, and discontinuation rates due to drug toxicity ranged from 2% to 33%.^28,39 The discontinuation rate was 4% in one study on EVG use,⁴⁵ and considering BIC studies, only one case of treatment discontinuation due to adverse events was reported among 102 children.⁴³ In the abstracts from the CROI, IAS, and International workshop on HIV pediatrics, a range of discontinuation from <1% to 11.3% was detected, especially in studies on BIC <1%,^52,63 in one study on RAL 11.3%, and in one study⁶³ on DTG 4.9% of children discontinued.⁵⁷

Summary of drug resistance rates across studies

Resistance to RAL was most notably detected in the IMPAACT P1066 clinical trial,¹⁸ where genotypic analysis was performed in patients with virological failure at 48 weeks and 35.3% of these developed mutations resistant to RAL (amino acid substitutions: Y143R, Q148H/R, and N155H).⁷⁵ In this study, at 240 weeks, among patients with virological failure (49%), resistance to RAL was detected in 32% of cases; resistance was also detected in 38% of patients who had virological rebound after initial suppression (Table 8).

Table 8.

Summary of INSTI Resistance-Related Mutations Reported in Pediatric Studies

	Type of study	No. of participants with mutations resistant to INSTI (%)	Type of mutations
RAL	IMPAACT P1066^18,86	At 48 weeks, 35.3% were resistant to RAL, at 240 weeks 32%	Y143R, Q148H/R, N155H
DTG	IMPAACT P1093²⁸	22%	6 mutations during treatment: G118R and R263K/R 2 mutations not correlated with certainty: E157Q or L74I
	Prospective study³⁹	6% showed resistance to INSTI before the start of treatment⁸	2 mutation E138A: one receiving RAL, one receiving EVG
	ODYSSEY trial⁴⁷	18% in ODYSSEY B cohort, 0% in ODYSSEY A cohort	Q148R, Q148K, G118RS, G118RS+R263K
	Retrospective study³⁵	5.3% (3/56)	One E157Q mutation with potential resistance to RAL.Two resistance mutations in reverse transcriptase: M184I not responding to DTG/ABC/3TC; M184V and T215Y unresponsive to DRV plus EVG/c/FTC/TAF
	Retrospective study⁴⁶	5% prevalence of TDR	E157Q mutation conferred resistance to RAL, EVG and DTG once daily and intermediate resistance to DTG twice daily
	Prospective study⁴¹	12.4%	Minor mutations: E157Q, T97A, V151VA
CROI 2018	REALITY study⁴⁹	7% of sequenced participants	R263K, T97A, L74M or N155H

In a retrospective study of RAL, genotypic testing for resistance was performed and an E157Q mutation with potential resistance was found, and previously undocumented reverse transcriptase resistance mutations (M184I mutation, not responsive to DTG/ABC/3TC) were acquired in treatment-experienced children.³⁵ However, a retrospective study in France performed an analysis of TDR and the prevalence of INSTI-related TDR was 5%.⁴⁶ A multicenter observational study found the E138A mutation resistant to RAL and EVG in two participants³⁹ (Table 8).

With regard to DTG, resistance emerged during the IMPAACT P1039 in six participants with the G118R and R263K/R mutations, and in two participants, a single polymorphic substitution (E157Q or L74I) was identified during the study,⁷ but whether the onset occurred during the study period could not be determined. However, none of these was receiving DTG in a fixed-dose combination. In the ODYSSEY study, among participants receiving DTG in the ODYSSEY B cohort, 18% developed resistance to DTG (the four mutations found were Q148R, Q148K, G118RS, and G118RS+R263K)⁴⁷ (Table 8). Another observational study reported 12.4% of participants with resistance to DTG, but 31% of ART-experienced adolescents with detectable viremia were on DTG monotherapy due to high or intermediate resistance to 3TC and AZT, while 24% were susceptible to the regimen and the rest on dual DTG/AZT therapy due to resistance to 3TC.⁴¹

The most common INSTI resistances associated with high levels of reduced virological response to RAL are T66K, G140S/A/C, Y143C/R/H, Q148H/R/K, and N155H and to EVG are T66A/I/K, E92Q, G140S/A/C, S147G, Q148H/R/K, and N155H.⁷⁴ Susceptibility to RAL is reduced with mutations E92Q, G118R, and E148K/A/T and to EVG with mutations G118R, E148K/A/T, and R263K. Mutations Q148H/R/K reduce susceptibility to DTG and BIC (Table 9).

Table 9.

Major Integrase Inhibitor Resistance Mutations⁷⁴

	66 T	92 E	118 G	138 E	140 G	143 Y	147 S	148 Q	155 N	263 R
RAL	AIK	Q	R	KAT	SAC	RCH		HRK	H	K
EVG	AIK	Q	R	KAT	SAC		G	HRK	H	K
DTG	K	Q	R	KAT	SAC			HRK	H	K
BIC	K	Q	R	KAT	SAC			HRK	H	K

Summary of adverse events rates across studies

Drug adverse events are infrequent, similar to those reported in adults, but the rates vary between molecules. Adverse events such as rash, weight gain, and transient increase in liver enzymes have been reported associated with RAL in rare cases.^18,22,25 In DTG studies, cases of leukopenia, increased bilirubin, neutropenia, increased BMI (ranging from 10% to 87.5% of participants), and neuropsychiatric effects (e.g., anxiety, depression, insomnia) were reported in up to 16% of participants.^{29,32,34,35,40,51} Cases of uveitis, nausea, vomiting, and abdominal pain were reported by up to 8% and up to 74% of participants in studies on EVG.^44,45

Finally, upper respiratory tract infections (26%), diarrhea (10%), headaches, flu-like symptoms, and neuropsychiatric effects (grade 2 insomnia and anxiety) were reported with BIC.⁴³ Studies from CROI, IAS, and International workshop on HIV pediatrics reported that one study⁷⁶ on DTG had 15% of children with adverse events (neutropenia, increased lipase, and diarrhea), another trial⁶¹ on DTG reported 45.2% of participants with grade 3/4 adverse events, and the IMPAACT P1093 study reported grade 3 adverse events in 49% of children⁵⁹; one study on EVG reported adverse events in <1% of cases,⁶⁴ and two studies on BIC reported 2% and 4.9% of adverse events, respectively.^52,67

However, in most cases, these adverse events were mild to moderate and did not lead to discontinuation of treatment.

Discussion

In this narrative review, data from the available literature on the use of INSTIs in children were collected and summarized.

Data on the efficacy/effectiveness INSTI showed excellent virological outcomes with all the considered INSTI at several follow-up periods. Proportion of children with UVL ranged from 69% to 79% in short-term follow-up (8–12 weeks)^22,49 and between 77% and 92% in long-term follow-up (60–12 months)^19,24 for RAL, and from 96.3% at 12 months to 100% at 24 months⁶⁴ for EVG. UVL ranged from 78% to 83% in short-term follow-up (1–10 months),^35,36 and from 35% to 93.9% in 2 years of follow-up²⁷ for DTG. VL <1,000 copies/mL was detected in a range from 84.1% to 95% of children.^60,71 In children 4 weeks to 6 years of age, VL <50 copies/mL at 3 months ranged from 41% to 67% of participants.⁵⁹ For BIC, proportion of children with UVL ranged from 91% to 100% at 24 weeks of follow up and 99% of children at 96 weeks of follow up.⁶³

Results on efficacy and effectiveness were close to those reported in adult studies, suggesting similarities between children and adult population. As examples, UVL has been reported in 51% (235/462) of participants (ART experienced and INSTI naive),⁷⁷ in 81.5% ART-naive adults at 96 weeks of follow-up,⁷⁸ and 71% of participants at 240 weeks.⁷⁹ Similarly, the virological efficacy of EVG has been reported in several studies in adults, with one study reporting that 87.6% of 348 participants (ART naive) had VL <50 copies/mL at 48 weeks⁸⁰ and 80.2% at 144 weeks of follow-up.⁸¹

In a further study, 93% of 866 ART-naive adults had VL <50 copies/mL at 144 weeks.⁸² A study on the efficacy of DTG shows 88% of participants out of 414 with virological suppression (VL <400 copies/mL) at 48 weeks.⁸³ Another study reported 93% of 477 participants had VL <50 copies/mL after 10 months of follow-up.⁵¹ In two BIC studies, the virological efficacy rates (VL <50 copies/mL) at 48 weeks were 92.4% in 320 ART-naive adults⁸⁴ and 89% in 314 participants.⁸⁵

Overall, treatment discontinuation was mainly caused by suboptimal adherence, rarely by adverse events or unavailability of the drugs. Discontinuation ranged from <1% to 34% of participants, and no relevant difference was reported between the various INSTIs.^21,34

Drug adverse events were infrequent, similar to those reported in adults, but the rates vary between molecules. Notably, in most cases, adverse events were mild to moderate and did not lead to discontinuation of treatment.^{24,26
–28,35,44,49,67}

Study limitations

Our literature review may have some possible limitations, including the fact that some references might have been missed. Moreover studies are etherogenous both in settings and designs.

Conclusion

Data regarding the use of INSTIs in children are difficult to interpret as there are no comparative studies, and the ages and drugs used for the backbone vary between studies. For this reason, the U.S. guideline recommendations are based on extrapolation of adult data, which have shown that INSTI-containing regimens have superior efficacy compared to PI- and NNRTI-containing regimens, and on studies involving adolescents not on ART. Pediatric U.S. guidelines⁸⁶ recommend DTG plus NRTI as the preferred ARV regimen for infants and young children (age ≥4 weeks and weight ≥3 kg).

RAL is an alternative regimen for infants ≥4 weeks of age due to its twice-daily dosing requirement and lower barrier to resistance than other NRTIs. EVG/c/FTC/TAF is recommended as an alternative INSTI-based regimen for children and adolescents weighing ≥25 kg with creatinine clearance ≥30 mL/min, but is not recommended as the preferred INSTI regimen due to the lower resistance barrier of EVG compared to BIC or DTG. BIC/FTC/TAF regimen is recommended as the preferred INSTI regimen not only for children ≥6 years of age and weighing ≥25 kg but also for children ≥2 years of age and weighing ≥14 kg.⁸⁶

Our review includes data complexively from 51 studies (475,966 children and adolescents). The evidence supports high efficacy and low toxicity of INSTIs in pediatric and adolescent populations and their role as preferred ART agents as recommended by the WHO and U.S. guidelines recommendations. However, more data are needed, especially in younger children and with long follow-up.

Author's Contributions

M.F. wrote, revised, and edited. E.C. supervised the revision. M.F. and E.C. drafted and proofread. E.C. and L.G. designed the study. E.P. and L.G. supported, approved, and agreed with the article.

Footnotes

Author Disclosure Statement

The authors declare no conflict of interests.

Funding Information

No funding was received for this study.

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	66 T	92 E	118 G	138 E	140 G	143 Y	147 S	148 Q	155 N	263 R
RAL	AIK	Q	R	KAT	SAC	RCH		HRK	H	K
EVG	AIK	Q	R	KAT	SAC		G	HRK	H	K
DTG	K	Q	R	KAT	SAC			HRK	H	K
BIC	K	Q	R	KAT	SAC			HRK	H	K

	66 T	92 E	118 G	138 E	140 G	143 Y	147 S	148 Q	155 N	263 R
RAL	AIK	Q	R	KAT	SAC	RCH		HRK	H	K
EVG	AIK	Q	R	KAT	SAC		G	HRK	H	K
DTG	K	Q	R	KAT	SAC			HRK	H	K
BIC	K	Q	R	KAT	SAC			HRK	H	K

	66 T	92 E	118 G	138 E	140 G	143 Y	147 S	148 Q	155 N	263 R
RAL	AIK	Q	R	KAT	SAC	RCH		HRK	H	K
EVG	AIK	Q	R	KAT	SAC		G	HRK	H	K
DTG	K	Q	R	KAT	SAC			HRK	H	K
BIC	K	Q	R	KAT	SAC			HRK	H	K