Optimising Paediatric HIV Treatment: Recent Developments and Future Directions

Abstract

Treatment options for children living with HIV have historically been less effective, less practical and more difficult to implement compared with those for adults, as the research and development of new drugs for children has lagged behind. Significant progress has been achieved in response to the paediatric HIV epidemic over the last decade. Several optimised paediatric antiretroviral formulations are currently available or in development, including fixed-dose combination tablets containing a complete World Health Organization-recommended regimen. Despite these advancements, virological suppression rates in children are generally lower than in adults. Even when oral fixed-dose combinations with the optimal target profiles are developed, for some children virological suppression is not achievable for reasons such as adherence challenges, intolerance, toxicity and genotypic resistance. New safe, effective, well-tolerated antiretroviral agents from existing and novel classes, as well as innovative administration strategies are essential. To achieve the UNAIDS target of virological suppression in 95% of children receiving antiretroviral therapy, concerted efforts are required. This includes identifying priority drugs in line with latest developments, focusing drug development studies on these priorities, ensuring a timely technical knowledge transfer between originator and generic companies, accelerating regulatory approvals and facilitating procurement and implementation in countries. Success in these efforts depends on collaboration among all stakeholders, including communities, researchers, pharmaceutical companies, guideline and policymakers, governments, funders, regulators and healthcare providers. This review outlines which paediatric antiretroviral therapies are currently available, those which are under development and the future directions of paediatric HIV treatment.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40272-024-00656-4.

Key Points

Significant success has been achieved in the response to the paediatric HIV epidemic over the last decade.

Although paediatric treatment has been optimised, virological response rates in children still lag behind adults, highlighting the need for new antiretroviral agents and innovative administration strategies.

Continued efforts should be made to identify, develop and implement optimised paediatric treatment in order to achieve UNAIDS targets of ending paediatric AIDS.

What has Been Achieved?

Over the past decade, significant progress has been made in addressing the paediatric HIV epidemic. Since 2013, the number of children living with HIV has decreased from 2.2 million to 1.4 million in 2023, mainly owing to improved measures for preventing mother-to-child transmission. Additionally, the proportion of children who received antiretroviral therapy (ART) increased from 30 to 57%. Despite these improvements, the disparity in ART coverage between children and adults has widened from 9% in 2013 to 20% in 2023. The primary reason that children living with HIV are not started on ART is because of missed diagnoses: only 66% were diagnosed in 2023, substantially lower than the 87% diagnosis rate among adults and well short of the first UNAIDS 95% cascade-of-care target [1, 2]

Thanks to targeted efforts to end the AIDS epidemic among children, 86% of diagnosed children aged under 15 years received ART in 2023, a rate comparable to 89% among adults. However, for the third UNAIDS treatment target of 95% virological suppression among those who started ART, only 84% of children on ART achieved it, compared with 94% of adults [1]. This underscores the urgent need for treatment optimisation in children and adolescents living with HIV.

The World Health Organisation (WHO) treatment recommendations for people living with HIV have continuously evolved (Electronic Supplementary Material [ESM]). In 2013, adults gained access to a triple fixed-dose combination (FDC) of efavirenz (EFV), tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) or emtricitabine (FTC). However, children could only receive this FDC once they reached 35 kg [3]. Young children were particularly disadvantaged, as EFV was unsuitable because of highly variable exposures <3 years of age [4]. Although the WHO recommended lopinavir/ritonavir (LPV/r) for this age group, [3] which has been shown to be superior to nevirapine (an antiretroviral in the same class as EFV), [5, 6] the liquid LPV/r paediatric formulation had poor palatability, required a cold-chain and twice-daily administration. LPV/r was also associated with dyslipidaemia and had drug–drug interactions with frequently used drugs, including rifamycin-containing tuberculosis treatment and anticonvulsants, [7] making it a suboptimal option. Overall, paediatric formulations have historically been generally less palatable and more difficult to use compared with those for adults.

In more recent years, ART drugs with higher efficacy and better safety and resistance profiles have been developed. Recognising the delays in paediatric drug development, the WHO-led Paediatric Drug Optimization (PADO) initiative was established in 2013 to determine medium-term and long-term drug development goals (Table 1). This initiative has expedited the development of several prioritised ART drugs, including paediatric formulations of dolutegravir (DTG) and the FDCs of DTG/abacavir (ABC)/3TC, which have received approval and are now being rolled out. Additionally, paediatric FDCs such as DTG/tenofovir alafenamide fumarate (TAF)/FTC and darunavir/ritonavir (DRV/r) are approaching the final stages of development [8]. This review focuses on recent developments in paediatric HIV treatment and outlines future directions for drug optimisation and accelerated development.

Table 1.

PADO meetings

The mid-term priorities (3–5 years) are in dark blue, the long-term priorities are in light blue

LPV/r lopinavir/ritonavir, ABC abacavir, 3TC lamivudine, EFV efavirenz, ATV/r atazanavir/ritonavir, NVP nevirapine, DRV/r darunavir/ritonavir, RAL raltegravir, DTG dolutegravir, F/TAF emtricitabine/tenofovir alafenamide, XTC emtricitabine or lamivudine, AZT zidovudine, FTC emtricitabine, DT dispersible tablet, CAB cabotegravir, PNP postnatal prophylaxis

Where are We Now and What is Around the Corner?

Currently Available ART

Standard ART recommendations for children include an anchor drug from one of three ART classes (integrase strand transfer inhibitor [INSTI], protease inhibitor [PI] or non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). Integrase strand transfer inhibitors are preferred anchor drugs for children starting first-line and second-line ART, provided there was no previous treatment failure on INSTI-based regimens. Robust evidence from the ODYSSEY and CHAPAS-4 trials, showing superiority of DTG compared to other anchor drugs, supported by real-world data, [9, 10] reinforced this recommendation.

Dolutegravir is currently the most widely used INSTI in children, available as dispersible 5 mg tablets and generic 10 mg scored tablets for children aged ≥28 days and weighing ≥3 kg. An additional benefit of DTG is its ability to facilitate co-treatment of children with HIV/tuberculosis co-infection, as the interaction with rifampicin can be managed by administering DTG twice daily, doubling the daily dose [11].

For the NRTI backbone, ABC, zidovudine (ZDV) or tenofovir (TDF for children weighing at least 30 kg or TAF from 14 kg), combined with 3TC or FTC are recommended by the WHO [12]. Dual NRTI FDCs available for children in low-to-middle income countries (LMICs) include dispersible ABC/3TC 120/60 mg and 60/30 mg tablets for children weighing 3 to <25 kg, [13] and dispersible ZDV/3TC 60/30 mg tablets, for children weighing 3 to <20 kg. FTC/TAF 120/15 mg can be used for children weighing 14 to <25 kg, [14] though it is not yet produced by generic companies despite PADO recommendations (Table 1), and therefore not widely available in LMICs.

For adolescents with virological failure on a ABC-based first-line backbone, TDF is commonly recommended. For children in LMICs where TAF is not available in paediatric formulations, and there are concerns of using TDF in children because of renal and bone toxicity, the options are limited to twice-daily ZDV, which is associated with reduced efficacy [15]. Recycling ABC may be an option for children experiencing treatment failure [10, 16]. However the efficacy of this approach has not been confirmed in a study specifically to address this question.

In 2023, a paediatric dispersible FDC of abacavir (ABC)/3TC/DTG 60/30/5 mg (pALD) was approved for children weighing 6 to <25 kg [17] and is now available as a generic formulation. This FDC includes a complete WHO-recommended once-daily regimen and offers enhanced palatability and ease of administration and storage, and avoids unintentional monotherapy or dual therapy resulting from individual component-drug intolerance or stock-outs. A recently presented population-pharmacokinetic (PK) modelling and simulation study supports the potential use of one pALD tablet once daily in children weighing 3 to <6 kg [18]. Children weighing ≥25 kg could use the adult DTG/ABC/3TC formulation, but the large tablet size is potentially challenging for some children. In high-resource settings, children weighing ≥14 kg can be switched to a FDC based on bictegravir (BIC), an INSTI, combined with TAF/FTC (BIC/FTC/TAF 30/120/15 mg), which is a smaller tablet than DTG/ABC/3TC [19].

Children experiencing treatment failure on DTG require boosted PI-based ART, especially if INSTI resistance is identified. Current options include LPV/r, atazanavir/ritonavir (ATV/r) and DRV/r. In the CHAPAS-4 trial, DRV/r showed a trend to superiority in virological suppression (<400 c/mL) compared with LPV/r and ATV/r arms combined (adjusted difference 5.6% [95% confidence interval 0.3, 11.0]; p = 0.04) [20]. Of note, DRV/r is not recommended for children aged <3 years because of toxicity observed in animal studies [21]. A novel paediatric fixed-dose combination of DRV/r (120/20 mg) has been developed and will be suitable for children aged ≥3 years and weighing at least 10 kg [22]. Lopinavir/ritonavir remains the only boosted PI option for children aged <3 years, as paediatric ATV/r, although invited for WHO prequalification, is not yet available. [23]

Around the Corner

DTG/FTC/TAF and DRV Paediatric Formulations

The UNIVERSAL project [24] is evaluating the dosing, pharmacokinetics, and short-term safety and efficacy of ARV drugs for two paediatric FDCs, DTG/FTC/TAF 5/15/1.88 mg and DRV/r 120/20 mg, [25, 26] which are being developed by CHAI and generic companies specifically for children in LMICs. The DTG/FTC/TAF dispersible tablet is intended for children from 4 weeks of age weighing 3 to <20 kg. Children weighing ≥20 kg will be able to receive the adult DTG/FTC/TAF 50/200/25 mg formulation, allowing an aligned regimen from 3 kg into adulthood, harmonising treatment with adults, who primarily receive TDF/3TC/DTG in LMICs. Darunavir/ritonavir 120/20 mg for second-line ART is being assessed for children from 3 years of age. Darunavir/ritonavir will ideally be paired with TAF combined with 3TC or FTC, as TAF has been shown to be virologically superior over the ‘standard of care’ backbones (ZDV/3TC or ABC/3TC) and demonstrates a favourable safety profile in children weighing over 3 kg, including when combined with a boosted PI [27]. Notably, a study on the pharmacokinetics of TAF and tenofovir co-administered with DTG and boosted PIs in children showed that plasma exposures of tenofovir were higher when TAF was given with a boosted PI (DRV/r, ATV/r or LPV/r) than with DTG, but levels did not exceed the reference values for adults. This provides reassurance regarding the co-administration of the same TAF dose with boosted and unboosted anchor drugs [28]. The paediatric FTC/TAF 120/15 mg tablet available for children weighing 14 to <25 kg [14] and suitable for combination with DRV/r, is currently only available from the innovator company. However, there is hope that generic production will commence if FTC/TAF is included in the WHO guidelines as a preferred NRTI backbone for children. Furthermore, a paediatric FTC/TAF 15/1.88 mg tablet for oral suspension is also under development, [29] which would be suitable for younger children unable to swallow tablets, providing flexibility in combining with different anchor drugs.

Oral Two-Drug Regimens

With modern highly efficacious and safe ARV drugs, treatment based on two drugs can be as effective as standard three-drug regimens [30]. Potential benefits of oral two-drug regimens include reduced long-term toxicity, a smaller tablet size and reduced costs.

Adult phase III trials and real-world data provide robust evidence for oral, two-drug, DTG-based regimens, showing excellent efficacy and safety in ART-naïve and virologically suppressed ART-experienced populations [31–36]. DTG/3TC is currently being assessed in children with virological suppression aged 2 to <15 years in the multicentre, phase III, D3/Penta 21 randomised trial, [37] which is investigating a novel paediatric dispersible formulation (DTG/3TC 5/30 mg) and the adult formulation (50/300 mg). The DANCE trial, a single-arm study in ART-naïve adolescents aged 12 to <18 years, showed 88% virological suppression at 96 weeks and no safety concerns [38]. However, the lack of a comparison group limits conclusions on efficacy. DRAGON (NCT05674656), a phase I/II single-arm study, is evaluating the pharmacokinetics, safety and tolerability of DTG/RPV in children with virological suppression aged 6 to <12 years. SMILE and D2EFT randomised controlled trials (RCTs) have demonstrated potential for the NRTI-sparing two-drug combination of DTG and DRV/r in adolescents who are virologically suppressed and in adults requiring post-nucleoside reverse transcriptase inhibitor second-line ART, respectively [39, 40]. A significant evidence gap remains for ART-naïve children, with no two-drug regimen studies initiated yet in children aged <12 years.

Paediatric Pipeline

Even if the intended range of oral FDCs with an optimal target profile (Box 1) is developed to provide INSTI or boosted PI with ABC or TAF-based backbones for all ages and weights for first/subsequent-line treatments, there will remain children for whom virological suppression is not achievable for reasons including persistent adherence challenges, intolerance, toxicity and genotypic resistance. Even within trial conditions, virological suppression above 95% was not achieved in children and adolescents receiving first-line or second-line DTG-based ART. For example, at week 96, 88% of participants in the ODYSSEY trial had an HIV viral load of <400 copies/mL, and a similar rate of 92% was observed in the CHAPAS-4 trial [20, 41].

Box 1.

Target profile of an ideal antiretroviral drug regime

• High efficacy and safety

o High genetic barrier resistance

• Practical

o Once daily or less frequent

o Dosing based on weight bands

o Good stability: no cold chain requirement, long shelf-life

o Easy to store

o For oral options: small tablets that are easy to swallow or fixed-dose combination that can be dispersed

o Long acting for those with adherence difficulties and treatment fatigue

o For long-acting injectable options: frequency ≥3 monthly

o Components of antiretroviral drugs same as recommended for adults for harmonization

o Combined formulation with a complete regimen to enhance adherence and avoid unintentional monotherapy as a result of individual drug stock-outs or non-adherence to one of the components

• Available options for HIV/hepatitis B virus coinfection and suitable dose adjustment for tuberculosis co-treatment

o Good drug interaction profile

• Good acceptability/tolerability

o Good palatability for oral options

o Minimal local-site reactions for long-acting injectable options

New safe, effective, well-tolerated agents from existing and novel classes with innovative administration strategies are essential to reach the third UNAIDS treatment target of above 95% virological suppression [42]. Several agents are already authorised or in phase III trials in adults and/or adolescents, which could potentially be valuable additions to the range currently available for children (Table 2).

Table 2.

Long-acting antiretroviral formulations and their stage of development for adults and children

Regimen	Adult stage of development	Paediatric stage of development
CAB/RPV	IM injection, every 1 or 2 months Approved for adults who are virologically suppressed [43–45]	MOCHA (NCT03497676): treatment with IM CAB/RPV every 8 weeks, with or without oral lead-in phase  - Phase I/II trial in children aged 12 to <18 years who are virologically suppressed  - Results support the use of CAB/RPV every 1 or 2 months in this population [49] and show high acceptability and tolerability [141] LATA (NCT05154747): treatment with IM CAB/RPV every 8 weeks  - Phase III trial in children aged 12–19 years who are virologically suppressed  - Ongoing, no results available yet CRAYON (NCT05660980): treatment with IM CAB/RPV every 4 weeks or every 8 weeks, with or without oral lead-in phase  - Phase I/II trial in children aged 2 to <12 years who are virologically suppressed  - Ongoing, no results available yet CREATE (NCT06336434)  - Modelling study, setting the foundation for a model-predicted dose for long-acting injectables in neonates  - Ongoing, no results available yet
CAB	IM injection, every 2 months Approved for adults and adolescents weighing ≥35 kg as PrEP [142]	PBPK modelling  - To establish a neonatal CAB dosing regimen for neonates [143]
LEN	Subcutaneous injection, every 6 months Approved for adults with MDR HIV-1 infection, in combination with other antiretroviral drugs [63, 64]	CAPELLA (NCT04150068): treatment with subcutaneously administered LEN twice yearly, in combination with optimised background therapy  - Phase II/III trial in adults and adolescents aged ≥12 years with MDR HIV  - Results show that patients with MDR HIV-1 infection who received LEN had a greater reduction in viral load from baseline compared to those who received placebo [144] GS-US-621-6463 (NCT06532656): treatment with orally administered BIC/LEN, once daily  - Phase II/III trial in children aged 2 to <18 years who are virologically suppressed  - Ongoing, no results available yet PURPOSE 1 (NCT04994509): prohylaxis with subcutaneously administered LEN twice yearly  - Phase III trial in cisgender female individuals aged 16–25 years who are HIV-1 negative  - Results show 100% efficacy in HIV prevention when dosing lenacapavir twice yearly [73] PURPOSE 2 (NCT04925752): prohylaxis with subcutaneously administered LEN twice yearly  - Phase III trial in cisgender male individuals, transgender male individuals, transgender female individuals and gender non-binary persons aged ≥16 years who are HIV-1 negative  - Results show 99.9% efficacy in HIV prevention when dosing lenacapavir twice yearly [74]
ISL	Oral, weekly Phase III studies completed in heavily treatment-experienced adults and children weighing ≥35 kg, as a single agent and in combination with DOR (NCT04233216) and treatment-naïve adults, in combination with DOR (NCT04233897) Oral, monthly Phase III study has been completed in cisgender man and transgender women as PrEP (NCT04652700)	ILLUMINATE HTE (NCT04233216): treatment with orally administered ISL and DOR, separately and combined, once daily, in combination with optimised background therapy   - Phase III trial in adults and children weighing ≥35 kg with MDR HIV  - Completed, no results available yet IMPOWER-022 (NCT04644029): prophylaxis with orally administered ISL once monthly as PrEP in cisgender women  - Phase III trial in adults and adolescents aged 16–45 years who are HIV-1 negative  - Ongoing, no results available yet IMPOWER-024 (NCT04652700): prophylaxis with orally administered ISLr once monthly as PrEP in men and transgender women  - Phase III trial in adults and adolescents aged ≥16 years who are HIV-1 negative  - Completed, no results available yet
FTR	Oral, twice daily Approved for adults with MDR HIV-1 infection, in combination with other antiretroviral drugs [81, 82]	SHIELD (NCT04648280): treatment with orally administered FTR in combination with optimised background therapy  - Phase I/II trial in children aged 6–17 years with MDR HIV-1 infection  - Ongoing, no results available yet
bNAbs	Several bNAbs are in phase II development for HIV treatment and prevention in adults	IMPAACT P1112 (NCT02256631): prophylaxis with VRC01, VRC01LS and VRC07-523LS, administered subcutaneously, while also receiving SOC ART  - Phase I trial in infants aged 0–5 days who are HIV-1 exposed  - Results show that VRC01 subcutaneously as single or monthly doses is safe and well tolerated in very young infants and is suitable for further study to prevent HIV transmission in infants [107]  - Results show that VRC01LS (at 0–5 days and 12 weeks) was well tolerated with pharmacokinetics that support further studies of more bNAbs as adjunct treatment with antiretroviral drugs to prevent HIV-1 transmission [105]  - Studies on VRC07-523LS (at 0–5 days and 12 weeks) are still ongoing, no results available yet IMPAACT P2008 (NCT03208231): HIV clearance with VRC01, administered subcutaneously at 0, 2, 6 and 10 weeks, while also receiving SOC ART  - Phase I/II trial in infants aged 0–12 weeks with confirmed HIV-1 infection  - Results show that VRC01 was well tolerated, however HIV-1 RNA and DNA did not differ from the comparative arm (SOC) and baseline VRC01 resistance was frequent [145] PedMab [146]: prophylaxis with VRC07-523LS and CAP256V2LS, separately and in combination, administered subcutaneously  - Phase I trial in infants aged up to 72 hours who are HIV exposed  - Results show that a single dose of CAP256V2LS administered within 72 hours of birth was safe, efficacy studies ongoing [147]  - Studies on VRC07-523LS are still ongoing, no results available yet IMPAACT 2037 [148]: prophylaxis with PGT121.414.LS alone or in combination with VRC07-523LS, administered subcutaneously at 0 and 12 weeks, while also receiving SOC ART  - Phase I trial in infants aged up to 72 hours who are HIV-1 exposed  - Ongoing, no results available yet IMPAACT 2039 [149]: cure with HIVconsvX Vaccines and bNAbs  - Phase I/II trial in infants aged 5–11 years living with HIV who started ART <12 months ago  - In development Tatelo Study (NCT03707977): treatment with VRC01LS and 10-1074, administered intravenously every 4 weeks while remaining on ART  - Phase I/II trial in children aged 96 weeks to 7 years with confirmed HIV-1 infection  - Results show that VRC01LS and 10-1074 were safe and well tolerated among children receiving ART [150]

ART antiretroviral therapy, bNAbs broadly neutralising antibodies, CAB cabotegravir, DOR doravirine, EMA European Medicines Agency, FDC fixed-dose combination, FTR fostemsavir, IM intramuscular, ISL islatravir, LEN lenacapavir, MDR multi-drug resistant, PBPK physiologically based pharmacokinetic, PIP Paediatric Investigation Plan, PK pharmacokinetic, PrEP post-exposure prophylaxis, RPV rilpivirin, SOC standard of care

Cabotegravir/Rilpivirine

This long-acting (LA) INSTI/nucleoside reverse transcriptase inhibitor injectable combination given intramuscularly every 1 or 2 months is licensed for adults and adolescents aged ≥12 years and weighing ≥35 kg who are virologically suppressed [43–45]. This approval is based on excellent safety and efficacy outcomes in phase III adult trials [46–48], and the phase I/II MOCHA trial in adolescents aged 12 to <18 years [49, 50]. LATA, a phase III RCT of individuals aged 12–19 years with virological suppression in Africa switching to cabotegravir/rilpivirine (CAB/RPV) versus continuing standard of care, [51] has recently completed recruitment. Additionally, the CRAYON study, a phase I/II CAB/RPV single-arm trial is currently underway in children aged 2 to <12 years [52]. Recent results of the phase III CARES trial in adults in Africa [53] showed excellent safety and high rates of sustained virological suppression over 48 weeks after switching from oral ART to LA drugs compared with continuing oral therapy. Despite a high proportion of participants with baseline archived resistance mutations (CAB 16%, RPV 14%), only 2/255 (1%) participants on CAB/RPV experienced virological failure. These findings suggest CAB/RPV could be a viable option in LMICs despite high RPV pre-treatment archived resistance; however, the 96-week results are needed to confirm that baseline resistance to RPV and CAB does not significantly impact treatment efficacy and the true significance of the described archived resistance (compared to documented RPV resistance pretreatment or at virological rebound) requires further consideration. Because of the high prevalence of RPV pre-treatment resistance in many LMICs [54–57] and the requirement for cold-chain storage and transportation, RPV has not been prioritised for roll out in these settings [58, 59]. Ideally, CAB could be paired with alternative LA agents without these disadvantages, such as lenacapavir (LEN). Unfortunately, there are no large clinical trials currently evaluating LA CAB and LEN in adults, and none is planned for children.

Interim results from LATITUDE, a phase III RCT in adults with adherence challenges have also been recently presented [60]. The trial was stopped early because of the superiority of CAB/RPV for secondary efficacy outcomes compared with oral treatment. Observational studies showing encouraging rates of virological suppression in people initiating CAB/RPV with viraemia led to an update to the International Antiviral Society-USA adult guidelines to consider its off-label use in this context provided specific criteria are fulfilled [61]. For now, the place of CAB/RPV in paediatric treatment remains to be determined but it has great promise in all settings in suppressed switch and hopefully also for those with adherence challenges. Although generic formulations are not yet in development, a voluntary licence was granted for patents relating to LA CAB for pre-exposure prophylaxis (PrEP) [62]. Generic formulations of LA CAB/RPV for treatment, however, are not yet in development.

Lenacapavir

Lenacapavir, a first-in-class capsid inhibitor given subcutaneously 6 monthly, is authorised for adults with multidrug-resistant (MDR) HIV [63, 64]. Oral LEN is being investigated in phase II trials, evaluating weekly administration with islatravir (ISL), [65, 66] and daily administration with BIC, both in adults who are virologically suppressed [67, 68]. Observational data on LEN/CAB with or without RPV in a small cohort of adults with adherence challenges have recently been reported [69]. A phase II trial of oral and subcutaneous LEN for first-line treatment has been completed in adults [70]. A phase II/III trial of individuals aged 2 to <18 years with virological suppression switching to daily administration of an oral LEN/BIC FDC will start soon [71]. Studies of SC LEN for treatment in children are planned, but not yet underway [72]. The recently announced results of PURPOSE 1 and PURPOSE 2, phase III RCTs, demonstrated 100% and 99.9% efficacy and superiority of twice-yearly subcutaneous LEN compared with daily TDF/FTC for HIV prevention in cisgender women and adolescent girls aged 16–25 years (PURPOSE 1) and cisgender men, transgender men, transgender women and gender non-binary individuals aged ≥16 years who have sex with partners assigned male at birth (PURPOSE 2) [73, 74]. If made available in LMICs, this drug could revolutionise HIV prevention in adolescents who struggle with adherence to daily oral PrEP [75].

Islatravir

Islatravir is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI). Good efficacy of once-daily oral ISL in combination with doravirine (DOR) was demonstrated in adults who were virologically suppressed in a phase III adult trial; [76, 77] however, a safety signal of reduced total lymphocyte and CD4 counts resulted in a pause in the ISL development programme. After demonstration that toxicity was dose dependent, trials with lower ISL doses have now restarted [78]. Preliminary results of the phase II trial of weekly oral LEN/ISL mentioned above [65, 66] have been presented. There are no ongoing trials of ISL in children. Once-weekly oral dosing is a promising strategy to improve adherence in children. Other agents with potential for once-weekly administration are in earlier phases of development [79, 80].

Fostemsavir

Fostemsavir is a first-in-class oral attachment inhibitor, dosed twice daily in combination with an optimised background regimen and authorised for adults with MDR HIV [81, 82] based on results of the phase III BRIGHTE trial [83]. SHIELD, a phase I/II trial in children aged at least 6 years and weighing ≥20 kg is underway [84]. Twice-daily oral dosing of FTR may pose a challenge in children with adherence difficulties but it may still play a role for highly treatment-experienced children in future paediatric treatment guidelines.

Broadly Neutralising Antibodies

Broadly neutralising antibodies (bNAbs) directed against epitopes of the trimeric HIV-1 envelope protein, have emerged as a promising option for enhancing the treatment, prevention and potential cure of paediatric HIV. These antibodies neutralise HIV and interact with the immune system, enhancing antibody-dependent cellular cytotoxicity, opsonisation, innate activation and antigen presentation. Some combinations, such as 10-1074 and 3BNC117, have been shown to reduce the proviral reservoir [85, 86]. In neonates, bNAbs may provide protection against HIV acquisition, and play a role in postnatal prophylaxis.

Administered intravenously or subcutaneously, bNAbs may offer several potential benefits. Their long half-lives (currently around 12 weeks) could mitigate challenges related to daily adherence and administration. They have a small injection volume, and for infants at risk of vertical transmission of HIV, they offer the possibility of integration with postnatal care and immunisation programmes. Young infants living with HIV, who have high mortality and low virological suppression rates, [87] may benefit from bNAbs as an adjunctive treatment [88–94]. So far, bNAbs have shown modest antiviral activity in adults, but have demonstrated good safety and tolerability, with no interactions with ARV drugs or cross-resistance [95–98]. They have also been shown to increase long-term viral suppression and delay rebound during treatment interruption [85, 96, 99–104]. In children, phase I or IIa trials have evaluated VRC01, VRC01-LS, VR07-523-LS and 10-1074 in participants who are virologically suppressed, confirming good safety [105–107].

The main limitations of the current bNAb combinations are suboptimal efficacy because of global and within-host diversity of HIV strains and rapid development of high-level resistance. A phase II trial in children with virological suppression demonstrated that post-ART interruption, only 44% of participants maintained suppression through 24 weeks of monthly bNAb-only treatment (VRC01LS and 10-1074) [106]. Efficacy of bNAbs for prevention and treatment is not yet comparable to current highly effective ART [108]. Results from new trials with different triple combinations, multi-specific bNAbs and combinations with LA small molecules, such as LEN, are awaited. Although current production is complex and costly, health economics studies suggest that bNAbs could be cost effective in various implementation settings [109, 110]. Despite a number of ongoing challenges, the potential benefits of bNAbs make them compelling agents for paediatric research.

What Other Formulations Should be Developed in the Future for Children?

Additional novel administration strategies for LA formulations are being investigated to maximise convenience by reducing dosing frequency, easing administration and improving acceptability.

Micro-Array Patches

Micro-array patches (MAPs) are a promising intradermal delivery system for the paediatric population. Physiologically based pharmacokinetic (PBPK) modelling suggests CAB and ISL MAPs have potential for children. However, CAB MAP may require weekly administration, and ISL, while having favourable predicted efficacy with a monthly schedule, has a dose-dependent association with reduced lymphocyte/CD4 counts, [76, 77] presenting a challenge for further development. Lenacapavir showed an unfavourable  PBPK profile and a high number of MAPs needed. Key barriers for MAP development include the need for a large surface area, frequent administration and high costs [111].

Implants

Antiretroviral (ARV) drug delivery through implant administration could generate a dosing frequency that ranges from months to years. Implantable systems for the delivery of ARV drugs in young children are currently being developed [112]. Unfortunately, a phase I study of TAF implants in adults showed sub-optimal tolerability, mostly due to implant-site reactions [113].

Oral Dispersible Films

Antiretroviral drug delivery via oral dispersible films holds promise for neonates and young children, as it offers easier administration and avoids dosing errors and issues with incomplete oral administration. Dolutegravir 5 mg and 10 mg oral dispersible films have recently been approved by the US Food and Drug Administration for the treatment of children with HIV from 4 weeks of age, weighing ≥3 kg [114]. The DTG 5 mg oral dispersible film is currently being studied in the PETITE-DTG study in term neonates (NCT05590325).

Drug Development for Neonates

The development of age-appropriate ARV formulations for both treatment and prevention in neonates has been slow and significantly lags behind other age groups. Only a handful of formulations are available for use in neonates, and few have been licensed (Table 3). To address the lack of data on appropriate dosing for neonates, PK modelling and simulation studies have increasingly been used. One example is a study of an ABC liquid formulation (20 mg/mL) that led to the inclusion of WHO dosing guidance for ABC from birth [115]. Notably, out of the currently used ARV in neonates (ZDV, raltegravir, LPV/r, FTC, maraviroc, 3TC, NVP and ABC), only 3TC and ABC are currently recommended for first-line ART in adults or older children, highlighting an urgent need to address this discrepancy.

Table 3.

Antiretroviral dosing guidance availability for HIV treatment and prevention in neonates by the US FDA, the WHO and the US DHHS

Antiretroviral	FDA dosing guidance	WHO dosing guidance	DHHS dosing guidance
Zidovudine	For preterm and newborns from ≥37 week gestational age [151]	For infants <4 weeks of age [12]	For <30 weeks gestational age [152]
Raltegravir	From ≥37 weeks gestational age weighing ≥2 kg [153]	For infants weighing ≥2 kg [12]	For ≥37 weeks gestational age [154]
Ritonavir-boosted lopinavir	From ≥14 days of age [155]	From ≥14 days of age [12]	From ≥14 days of age [156]
Emtricitabine	From birth [157]	No guidance available	From birth [158]
Maraviroc	For infants weighing ≥2 kg [159]	No guidance available	For infants weighing ≥2 kg [160]
Lamivudine	For infants aged ≥3 months [161]	For infants <4 weeks of age [12]	From ≥32 weeks gestational age [162]
Nevirapine	For infants aged ≥14 days [163]	For infants <4 weeks of age [12]	From ≥32 weeks gestational age [162]
Abacavir	For infants aged ≥3 months [164]	For infants <4 weeks of age [12]	From ≥37 weeks gestational age [152]

DHHS Department of Health and Human Services, FDA Food and Drug Administration, WHO World Health Organization

There are even less available data to guide dosing in preterm neonates. Lamivudine has a current dosing recommendation down to 32 weeks gestation; however, it is based on limited evidence with no PK data available in preterm neonates with a gestational age <36 weeks. To better understand the impact of renal clearance on 3TC, a modelling and simulation study combining neonatal and infant PK data has recently been performed, confirming the current 3TC recommendation of 2 mg/kg twice daily for neonates with a gestational age ≥32 weeks. Predictions also supported a 3TC dose of 2 mg/kg daily from birth in preterm neonates with a gestational age ≥27 weeks [116].

The recently conducted PETITE study evaluated the pharmacokinetics, safety and acceptability of the novel ‘4-in-1’ granule formulation of the ABC/3TC/LPV/r 30/15/40/10 mg FDC in term neonates [117]. Unfortunately, LPV/r concentrations were found to be too low, preventing its use in this age range. In a second stage of the PETITE study, once-daily ABC/3TC 30/15 mg (one quarter of a ABC/3TC 120/60 mg dispersible tablet) and two sachets of twice-daily LPV/r 80/20 mg granules were shown to achieve targeted exposures in term neonates from birth, and was safe and well tolerated [118]. While no safety issues were reported in the PETITE study initiating the ABC/3TC dispersible tablets from birth, a subsequent population PK modelling analysis of the PETITE data highlighted that the ABC/3TC exposures would likely be above target exposure in term neonates during the first week of life; thus, continued safety surveillance of ABC/3TC FDC from birth is warranted [119].

The results of the ongoing PETITE-DTG and IMPAACT 2023 (NCT05406583) PK and safety studies evaluating the safety and pharmacokinetics of DTG formulations in term neonates are eagerly awaited [120, 121]. Based on PK modelling and simulation of single doses of DTG in neonates, these studies are currently evaluating a DTG dosing schedule of DTG 5 mg administered every other day for the first 2 weeks of life, followed by administration of DTG 5 mg daily. Multi-doses of both the DTG dispersible tablets and the recently approved DTG 5 mg oral dispersible film are under investigation in the PETITE-DTG study, while the IMPAACT 2023 study is evaluating DTG 5 mg dispersible tablets as well as a 0.5 mg/kg oral suspension.

There is increased interest in capitalising on novel, LA, ARV drug and delivery platforms to optimise these for infant postnatal prophylaxis, including during the breastfeeding period [58, 122]. Long-acting cabotegravir (CAB) is an exciting option for infant HIV postnatal prophylaxis and was highlighted as a priority product at the latest WHO PADO-HIV meeting [58]. PBPK modelling of IM LA-CAB in neonates predicted that a dose of 20 mg administered to term neonates weighing 2–5 kg will result in sufficient exposure [111]. A recent case report of a pregnant woman taking LA CAB/RPV showed a substantial placental transfer of CAB with cord blood drug concentrations comparable to those of the mother [123]. Additional data of CAB in neonates will be available as infant washout data from the CREATE study assessing LA-CAB/RPV in pregnant women living with HIV [124]. Lenacapavir for postnatal prophylaxis would be an exciting option to develop, and bNAbs are also promising, although the optimal combination of bNAbs is yet to be determined. Aligning LA-based postnatal prophylaxis with immunisation schedules could potentially ensure high uptake and facilitate better implementation.

Discussion and Conclusions

The 95–95–95 targets, adopted by UN Member States in June 2021, aim to close HIV testing and treatment gaps and improve outcomes for all subpopulations, including children, to end the AIDS epidemic by 2030 [42]. In 2023, only 84% of the children receiving ART achieved virological suppression, failing short of the third 95% target. Combined efforts should focus on paediatric treatment optimisation to close this gap.

The paediatric HIV treatment landscape has evolved towards more effective once-daily regimens with fewer side effects and greater tolerability. However, even with the current best-available DTG-based treatments, virological suppression rates remain below the desired level in children, [20, 41] highlighting the urgent need for novel delivery methods as alternatives to the oral route and LA drugs.

The relatively small number of children living with HIV compared with adults results in a fragmented low-volume market, which discourages pharmaceutical investment in developing these formulations [125]. A unified approach across stakeholders is needed to minimise the risk of stockouts of key paediatric formulations in LMICs. Aligning paediatric and adult regimens could help with drug production and supply. The PADO consultations prioritise the most important ARV drugs for short-term and long-term development to overcome challenges in the fragmented paediatric market and ensure children are not left behind [8, 126–128]. As new formulations are prioritised and developed for a rapid roll-out, a timely update to guidelines, agile programmatic adaptation, and horizon scanning are essential to ensure that these options are introduced as quickly as possible and do not become obsolete too rapidly, which could potentially result in drug wastage and a reduction in the cost effectiveness of programmatic delivery. One of the organisations working on timely access to new formulations in LMICs is the Medicines Patent Pool, which ensures drug patents from innovator companies become available to generic companies against minimal royalties, facilitating the selling of these products at a low price in LMICs only [129].

The delay between adult and paediatric approvals remains unacceptably large. For instance, DTG was approved for adults over a decade ago, yet appropriate dosing for term neonates and preterm infants is still lacking. Industry-led and academia-led trials should ideally implement simultaneous enrolment of children across different weight bands, [130] and inclusion of adolescents in adult licensing studies will also potentially speed up access to novel treatment options [131].

Antiretroviral formulations and dosing information for ARV drugs remain limited particularly for young infants. In 2021, a consultative process convened by WHO and the IMPAACT Network called for urgent action to ensure novel drugs and strategies are investigated in neonates as soon as possible [132]. Dose finding for neonates should commence early, parallel to drug evaluations in children, utilising recent advances in modelling and simulation approaches and employing the same paediatric formulations in development for children. This would accelerate access to the latest, most optimal treatments for this critically underserved population. Broadly neutralising antibodies for prophylaxis or treatment, including for premature and low birthweight neonates, are a promising area of drug development and have been identified as a research priority by WHO-led PADO [58]. A recent WHO technical consultation meeting brought together a multidisciplinary group of stakeholders, including research leads, paediatric immunologists, WHO methodologists, ethicists and civil society, to review development status, data gaps and challenges for using bNAbs in preventing vertical HIV transmission [133]. The field is quickly evolving with promising new strategies and advancements for paediatric HIV.

Long-acting agents have high potential to transform the treatment and prevention of HIV in children and adolescents [134]. Recent adult studies on CAB/RPV LA injectables have clearly demonstrated significant potential in LMICs and among people with adherence challenges [53, 135]. However, this regimen has not been identified as a priority treatment for LMICs by the WHO-led Conference on Antiretroviral Drug Optimization (CADO)/PADO initiatives, owing to cold-chain requirements and a low resistance threshold for RPV [59]. Consequently, it has not been prioritised for voluntary licensing to enable generic production for LMICs [136]. Other potentially highly effective LA combinations for children and adolescents include injectable CAB and LEN, [69] and oral LEN and ISL; [65] however, no paediatric studies employing these combinations have yet been initiated. Lenacapavir has recently been shown to be highly effective for PrEP in adult and adolescent cisgender women, [137] but the path to future access to LEN in LMIC remains unclear. Although LEN and ISL have been identified as long-term priorities by WHO-PADO, CAB for treatment was not. To accelerate access to LA injectable treatment options in LMICs, strong advocacy on priority prevention and treatment regimens from CADO/PADO, guideline development groups and the community is required.

To speed up access to optimal paediatric ART formulations, the Global accelerator for paediatric formulations (GAP-f) was created [138]. The GAP-f is a WHO-led network that brings together expert groups and stakeholders to close paediatric treatment gaps by streamlining efforts at different steps of the pathway of paediatric drug prioritisation, development, manufacture and uptake. Continued efforts from everyone involved and concerned about ensuring children have timely access to better drugs are essential. This includes identifying and adjusting priority drugs in line with the latest developments, focusing drug development studies on these priorities, timely technical knowledge transfer between originator and generic companies, and strong political leadership for ringfencing investments in evidence-based paediatric prevention and treatment. These efforts should be synergistic to enable an efficient shift from paediatric drug prioritisation and drug development research to implementation across all geographic settings, in order to move closer to ending paediatric AIDS by 2030.

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Declarations

Funding

Anne Kamphuis received funding from the UNIVERSAL project, which is part of the EDCTP2 Programme supported by the European Union (grant number RIA2019PD-2882-UNIVERSAL). Anna Turkova receives core funding from the UK Medical Research Council (grants MC_UU_00004/03). No other funding was received for the preparation of this article, the open access fee was paid by Radboudumc.

Conflicts of Interest/Competing Interests

Alasdair Bamford is chair of the Penta/EACS Paediatric HIV Treatment Guidelines Working Group and has received fixed-term consultancy fees from the WHO-hosted Global Accelerator for Paediatric Formulations (GAP-f). Adrie Bekker is part of the WHO-led Paediatric Antiretroviral Working Group. Adrie Bekker is co-chief investigator of the PETITE studies, funded by UNITAID, and has received advisory board funding from ViiV Healthcare. Angela Colbers received research grants from ViiV Healthcare, Gilead, Merck and PENTA foundation, all paid to the institution. Alexandra Compagnucci is chief investigator of the SMILE trial, funded by Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. Alfredo Tagarro is researcher of the EPIICAL study funded by ViiV and a COVID-19 research grant from Pfizer, both paid to his institution, and received honoraria for webinars from Gilead and Biomerieux. Anna Turkova is co-chair of the WHO-led Paediatric Antiretroviral Working Group. Anna Turkova is chief investigator for the D3 trial (ISRCTN17157458) funded by ViiV Healthcare. Francis Ateba Ndongo is a civil servant for Cameroon, principal investigator for the UNIVERSAL-2 study, without any other funding received for the preparation of this article or any conflict of interest directly related to the content of this article. Pauline Amuge is a member of the WHO-led Paediatric Antiretroviral Working Group, and an independent TSC member for the SHIELD trial. Pauline Amuge has no financial conflict of interest. Tim R. Cressey is co-lead of the WHO-GAP-f Clinical Research Working Group and has received fixed-term consultancy fees from the Penta-ID. Tim R. Cressey is co-chief investigator of the SHIELD Study, funded by ViiV Healthcare, and co-chief investigator of the PETITE studies, funded by UNITAID. Anna Turkova, Alfredo Tagarro, Tim R. Cressey, Alasdair Bamford and Angela Colbers are members of the Penta-ID Scientific Steering Committee. Aminata Diack, Hilda Mujuru and Marc Lallemant have no conflicts of interest that are directly relevant to the content of this article.

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Authors’ Contributions

ACol, AK and ATu were responsible for the concept and outline of the paper. AK led the first draft of the manuscript, with input from Aba, ACol, AK, Ata and ATu. All other co-authors critically reviewed the manuscript.