Paediatric European Network for Treatment of AIDS (PENTA) Guidelines for Treatment of Paediatric HIV-1 Infection 2015

Optimizing Health in Preparation for Adult Life

A Bamford; A Turkova; H Lyall; C Foster; N Klein; D Bastiaans; D Burger; S Bernadi; K Butler; E Chiappini; P Clayden; M Della Negra; V Giacomet; C Giaquinto; D Gibb; L Galli; M Hainaut; M Koros; L Marques; E Nastouli; T Niehues; A Noguera-Julian; P Rojo; C Rudin; HJ Scherpbier; G Tudor-Williams; SB Welch

Disclosures

HIV Medicine. 2018;19(1):e1-e42. 

In This Article

Which Art Regimen to Start as First-line Therapy

  • Children should start effective (at least three drugs) ART, usually a dual or triple NRTI backbone together with either a ritonavir-boosted PI or an NNRTI.

  • Children exposed to NVP during failed PMTCT (or in whom perinatal NVP exposure cannot be excluded) should be started on a boosted PI-containing regimen, as transmitted resistance may lead to failure of NVP-containing ART.

  • Children aged < 3 years not exposed to NVP during failed PMTCT may be initiated on either NVP or ritonavir-boosted lopinavir (LPV/r)-containing ART. We recommend that NVP should be given together with three NRTIs (ABC, 3TC and ZDV) in all infants and in children aged 1–3 years with VL > 100 000 copies/ml or signs of CNS involvement as an induction-maintenance strategy, unless any of these drugs are contraindicated (such as ABC in HLA B*5701-positive children).

  • In children aged > 3 years, either NNRTI or boosted PI-based ART is acceptable for initial therapy. Factors such as availability of age-appropriate formulations, palatability, dosing frequency and adherence should be considered when choosing NNRTIs or boosted PIs.

  • The preferred NNRTI is NVP in children aged < 3 years not exposed to NVP during failed PMTCT, and EFV in children aged > 3 years. The preferred PI in children aged < 6 years is LPV/r, in children aged 6−12 years it is ATV/r, and in children aged > 12 years it is ATV/r or DRV/r.

  • INSTI-based ART may be an alternative regimen in children over age 12 years.

  • The preferred first-line NRTIs are ABC/3TC in children aged < 12 years and TDF/FTC or ABC/3TC (if VL < 100 000 copies/ml) in children aged > 12 years.

  • Age, HLA B*5701 genotype, previous drug exposure, resistance profile, coinfections, available formulations and likely adherence should be taken into account when choosing a first-line regimen.

  • See Table 4 for details of recommended first-line ART regimens.

General Principles of Treatment

To achieve long-term virological suppression requires high levels of ART adherence. Children's doses should be checked for age and weight or surface area at each visit, and this should be done frequently during periods of rapid growth, especially infancy. Doses should be rounded up (not down) to convenient syrup volumes or tablet formulations, and parents should be given careful instructions on dosage, timing, administration, repeating doses if there is vomiting within 1 hour after taking medication, and seeking medical attention rather than discontinuing if drugs are refused or side effects are suspected. Supervised initiation of therapy in hospital or at home with visiting nurses may be appropriate for some children and families, particularly newly diagnosed infants. When drugs show comparable toxicity and efficacy profiles, clinicians should be aware of pricing, drug availability and national policies.

The standard first-line treatment regimen remains two NRTIs with either an NNRTI or a boosted PI (see Table 4). Although transmitted viral resistance remains rare in children, it may lead to suboptimal response to the first-line treatment.[19] Therefore, pretreatment resistance genotyping should be performed.

NNRTI or Boosted PI for First-line ART?

Boosted PIs have a higher barrier to viral resistance, but have more potential drug interactions and cause higher rates of dyslipidaemia, while NNRTIs are often more palatable although virological failure frequently results in whole-class resistance. Recent studies have produced discordant results on whether or not NNRTI- and boosted PI-based regimens are equally effective, especially in the youngest children. This discordance has resulted in conflicting recommendations for first-line drug regimens and merits consideration.

Infants and young children (< 3 years old). Infected infants exposed to NVP during failed PMTCT (or in whom perinatal NVP exposure cannot be excluded) should be started on a boosted PI-containing regimen, as transmitted resistance may lead to failure of NVP-containing ART.[64,65] LPV/r should not be administered to premature neonates or to term neonates below 2 weeks of postnatal age because of the increased risk of toxicities reported in premature and very young babies.[66,67]

International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1060 suggested better efficacy for LPV/r than for NVP in children aged below 3 years, even without prior NVP exposure. Children randomized to an NVP-containing regimen were twice as likely as those on an LPV/r-based regimen to reach a composite endpoint of: virological failure, treatment discontinuation or death at 24 weeks of follow-up (40.8% versus 19.3%, respectively; P < 0.001).[68] Transmitted NVP resistance, emergence of NVP resistance because of high VL in infancy and possible low NVP levels during lead-in dosing[69] may have played a role. A composite endpoint at only 24 weeks, and the low-income setting, make it difficult to extrapolate the results in terms of longer outcomes and generalizability to higher income settings.

In contrast, PENTA 9/Pediatric AIDS Clinical Trials Group (PACTG) 390 (PENPACT-1), a randomized trial conducted in resource-rich settings, showed no difference between first-line NNRTI – and boosted PI-based regimens in virological outcomes in children aged 0.1–17.8 years (median age 6.5 years).[70] An underpowered subanalysis by individual drug in children younger than 3 years of age found no difference in virological outcome between children on NVP- and LPV/r-containing ART regimens (G. Tudor-Williams, unpublished results). In agreement with PENPACT-1, the Prevention of Malaria and HIV Disease in Tororo, Uganda (PROMOTE) study, a small open-label RCT in Uganda of children aged 0.4–5.9 (median 3.1) years not exposed to NVP, showed comparable results at 48 weeks in terms of virological suppression, CD4 gain and severe adverse events for NNRTI- and LPV/r-containing ART regimens.[71]

The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study, of children under 1 year of age commencing ART at a median age of 3.6 months, showed no difference in virological suppression or CD4 response between children receiving NNRTI-based ART (mostly NVP) and those receiving LPV/r-based ART over a median of 5.9 years of follow-up. The power to detect small differences was low as comparatively few infants started boosted PI-based ART. However, in this cohort study, children on an NNRTI-based four-drug regimen (NNRTI + 3 NRTIs) had significantly better virological suppression and CD4 gain at 12 months after ART initiation when compared with either PI- or NNRTI-based three-drug regimens.[42] The initial rapid virological suppression and immune reconstitution on an NVP-based four-drug regimen compared with a three-drug regimen have been confirmed in ARROW, although differences in virological/immunological outcomes were not sustained following a switch to three-drug therapy at 36 weeks from ART initiation[72] (see Section 6.5).

The evaluation of virological outcomes in real-life clinical settings in the national cohort of HIV-infected children in the UK/Ireland [Collaborative HIV Paediatric Study (CHIPS)] showed similar rates of VL suppression by 12 months for different first-line regimens in children aged < 3 years (NVP + 2 NRTIs; NVP + 3 NRTIs; LPV/r + 2 NRTIs).[73] However, three-drug NVP-based regimens were associated with faster progression to virological failure long term, while four-drug NVP-based regimens had the lowest risk of failure.

In practice, the poor palatability of boosted LPV/r liquid formulation precludes its use in many young children, and NVP remains a first-line option in infants and young children not exposed to NVP perinatally. NVP has good palatability, high cerebrospinal fluid (CSF) penetration and a favourable lipid profile. Taking the above into consideration, either NVP- or LPV/r-containing ART may be initiated in children younger than 3 years of age. However, in view of the above-mentioned evidence and the fragility of NVP at high VLs, we recommend that NVP should be accompanied by three NRTIs, as an induction-maintenance strategy, in infants and young children with VL > 100 000 copies/ml or signs of CNS involvement, including neurodevelopmental delay (Table 4). Earlier viral suppression and greater early CD4 responses with the use of four-drug induction with a triple NRTI backbone[42,71] may have potential benefits in terms of reduced viral reservoirs and reduced risk of CNS compartmentalization. Early detection of treatment failure should be picked up by regular monitoring of viral response in the first few months following treatment initiation.

Children > 3 years of age. As mentioned above, PENPACT-1 found no difference in clinical, virological or immunological outcomes between NNRTI- and PI-based regimens.[70] The virological outcome analysis in the CHIPS cohort study showed that in children aged > 3 years overall virological suppression by 12 months was high (> 93%) and there was no difference between NNRTI- and PI-based regimens. However, the progression to virological failure was different between regimens: in the first 2 years on therapy, it was slowest for EFV + 2 NRTIs or NNRTI + 3 NRTIs and fastest for NVP + 2 NRTIs. After 2 years on therapy, the risk was similar for EFV and NVP three-drug ART, and remained lowest for NNRTI four-drug ART, although the number of children on the latter regimen was small.[73]

Either NNRTI- or boosted PI-containing regimens are acceptable for initial therapy in children above 3 years of age. Issues to consider when choosing an NNRTI or boosted PI regimen include the availability of age-appropriate formulations, palatability, dosing frequency and adherence. For EFV and NVP, single point mutations in the reverse transcriptase gene rapidly lead to virological failure and whole-class resistance. Families should be counselled carefully about these issues before starting ART. If predicted adherence is questionable, as is often seen in teenagers, a more forgiving PI-based regimen should be initiated with a possibility of subsequent simplification to an NNRTI FDC one-tablet-once-daily regimen when virological suppression is sustained and adherence is established.

Which NNRTI?

The choice for the first-line NNRTI-based therapy in children is either EFV or NVP. Until recently, only NVP was licensed for children < 3 years of age because of very poor bioavailability of EFV syrup in this age group. The US Food and Drug Administration (FDA) have recently approved EFV capsule sprinkles for children as young as 3 months of age, based only on the results of a paediatric pharmocokinetic (PK) population model including three open-label paediatric studies and a PK comparison study in adults.[74,75] Variable EFV exposure in young children, as shown in a recent study of EFV PK in children under 3 years old,[76] and lack of experience with EFV sprinkle formulation in children may prevent its widespread use. While waiting for the results of further studies, EFV sprinkles should only be considered as an alternative regimen to NVP in this age group and PK monitoring is currently recommended. Pharmacogenetics may be a useful adjunct in the future as testing for cytochrome P450 2B6 (CYP2B6) polymorphisms has been shown to predict adequate dosing.[76]

As seen in adult studies,[77] two recent retrospective paediatric cohort studies, in resource-limited and resource-rich settings, comparing EFV and NVP showed that EFV was associated with superior virological outcomes[78,73] although in the UK/Ireland CHIPS cohort, the benefit of EFV-based regimens over NVP-based regimens in terms of virological failure was very modest after 2 years of therapy.[73] In the ARROW trial, a nonrandomized comparison of NNRTI-based regimens showed favourable short-term VL suppression with EFV; however, long-term suppression depended on age, and was better with EFV in children aged < 10 years, and with NVP in those aged > 10 years.[79] A recent systematic review and meta-analysis which included data on nearly 4000 children showed a lower frequency of severe adverse events and treatment discontinuations with EFV than NVP, although EFV use was associated with higher rates of CNS adverse events.[80] Overall, these data support the use of EFV as the preferred NNRTI in children aged > 3 years. However, for children with neurodevelopmental and psychiatric comorbidities, NVP may be a better choice in view of potential CNS side effects associated with EFV.

In summary, the preferred NNRTI is NVP in children aged < 3 years, and EFV in children aged > 3 years.

Which Boosted PI?

PI use in children should be ritonavir-boosted to optimize efficacy. Consideration of which PI should be used is based on balancing pill burden, toxicity, experience, available paediatric data and available formulations for a given age group.

LPV/r [Kaletra (AbbVie, North Chicago, IL, USA)] is the only combined PI/ritonavir liquid or tablet formulation for children and the only PI licensed for children aged < 3 years in Europe. It must be given twice daily.[81] ATV/r, a once-daily PI, is licensed for children aged > 6 years in Europe, and is the preferred boosted PI in this age group. DRV/r is licensed for children aged > 3 years in the USA (treatment-naïve and treatment-experienced) and Europe (treatment-experienced aged > 3 years; treatment-naïve > 12 years). Paediatric studies with once-daily administration of DRV/r have not been conducted in children aged 6–12 years. It is therefore recommended that DRV/r be used twice daily in children aged < 12 years while awaiting new data. In view of this, we recommend DRV/r as an alternative first-line PI in children in this age group (6–12 years), especially when there is known transmitted PI resistance or intolerance precluding use of other PIs. Both ATV/r and DRV/r are acceptable first-choice PIs in older children (> 6 years old for ATV/r and > 12 years old for DRV/r) because of their favourable virological outcomes and the availability of once-daily treatment (Table 4). Fosamprenavir/r (fAPV/r), a twice-daily PI, is licensed for children from age 6 years in Europe. Although fAPV/r is approved by the FDA in children aged > 4 weeks, it is not recommended for children aged < 6 months because of low drug exposure in this age group.[82] In view of limited paediatric experience, the adverse effect on lipids, the twice-daily regimen and meal requirements, it is not recommended for first-line therapy in children.

Some PIs (ATV and fAPV) may be used unboosted in special circumstances where ritonavir is not tolerated, but this is not recommended because of reduced efficacy. Where possible, doses of unboosted PIs should be monitored by TDM.

In summary, the preferred PI for children less than 6 years old is LPV/r, for children 6–12 years old it is ATV/r, and for children > 12 years old it is ATV/r or DRV/r (Table 4).

Choice of NRTI Backbone

Factors to consider when choosing the dual NRTI combination:

  • the potential for resistance and cross-resistance (and hence future therapy options);

  • tolerability and toxicity;

  • dosing frequency;

  • age-appropriate formulations including FDCs.

3TC and ABC are the preferred first-line NRTIs in children < 12 years of age. Superiority of ABC over ZDV has previously been reported in children.[83] Starting with ABC and 3TC also has the advantage of preserving (and even increasing) susceptibility to ZDV for future options in cases of virological failure, whereas starting on ZDV may lead to accumulation of thymidine analogue-associated mutations (TAMs) affecting subsequent susceptibility to ABC.[84,85] Both ABC and 3TC can be given once daily to children over 3 months old, which is supported by PK data in PENTA 13 and PENTA 15, and virological outcomes in ARROW.[71,86–88] 3TC and ABC both have palatable liquid formulations, and scored breakable tablets have recently become available. Children over 30 kg can be given the adult fixed dose combined pill [Kivexa (ViiV Healthcare, Middlesex, UK)]. As a consequence of inferior 96-week virological efficacy of ABC/3TC compared with TDF/FTC in adults with VL ≥ 100 000 copies/ml,[2] an ABC/3TC backbone is recommended as an alternative rather than the preferred backbone in older children with very high VLs (Table 4).

ZDV is recommended as a substitute for ABC in children with the HLA genotype B*5701, as they have an increased risk of severe hypersensitivity reactions to ABC. ZDV is also recommended alongside ABC and 3TC in infants and in young children with high VLs receiving NVP (see Section 6.3 above). It should be given twice daily. It is not recommended as first-line treatment in other situations, but remains an important component of neonatal PEP.

TDF has been licensed for children aged > 2 years by the FDA and European Medicines Agency (EMA); however, the long-term risk of renal and bone toxicity remains a possible concern (see Section 9 on drug toxicity). As a result of limited long-term safety data in young children and unresolved concerns over the effects on bone and kidneys with prolonged use, TDF is recommended as a preferred first-line NRTI only in older children (aged > 12 years or weight > 35 kg) with no underlying renal insufficiency or other risk factors significantly affecting bone and renal health. Some clinicians prefer to wait until after puberty because of uncertain effects on bone health (Table 4). TDF is also recommended as a first-line NRTI in all children aged > 2 years with HBV coinfection (see Section 10 on coinfections). It is available in co-formulated tablets with FTC as mentioned above.

FTC is chemically very similar to 3TC and they are interchangeable. FTC has been co-formulated with TDF [Truvada (Gilead, Forest City, CA, USA)] and TDF and EFV (Atripla, Bristol-Myers Squibb, New York, NY, USA and Gilead), which may be used in older children (see below). It is also included with TDF in the more recently developed FDCs based on the second-generation NNRTI rilpivirine (RPV) [Eviplera (Gilead and Janssen Therapeutics, Titusville, NJ, USA)] and the INSTI elvitegravir (EVG) [Stribild (Gilead)].

Where possible, once-daily and fixed dose formulations should be used to reduce pill burden and potentially improve adherence.

In view of well-documented toxicities, stavudine (d4T) is no longer recommended for treatment of HIV-infected children in Europe. However, its efficacy is acknowledged and it is accepted that, in rare circumstances, it may be the only option available. Didanosine (ddI) is no longer recommended for first-line therapy because of the high risk of toxicities and the availability of safer options (see Section 9 on toxicity). Children arriving in Europe from other regions on d4T or ddI should be changed to another regimen if possible.

NRTI-only Regimens

Triple NRTI therapy has been shown to have inferior virological and immunological outcomes and a high risk of selection for resistance mutations in ART-naïve adult patients.[89] The ARROW study showed that children on a three-NRTI maintenance regimen with 3TC, ABC and ZDV had inferior virological outcomes at week 144 and more ZDV-related neutropenia, but no difference in disease progression or immunological outcomes when compared to NNRTI plus 3TC and ABC.[71] Based on these data, triple-NRTI regimens are not recommended except in special circumstances when significant drug interactions or toxicity risks prevent the use of NNRTI- or PI-containing ART (e.g. for concomitant TB treatment; see Section 10 below).

Integrase Inhibitors (INSTIs)

RAL, a twice-daily INSTI, in combination with two NRTIs is now a first-line options for adults[2,5] and is licensed for treatment-experienced children from 4 weeks of age. Dolutegravir (DTG), a second-generation INSTI, has recently been licensed for treatment-naïve adults and children > 12 years of age. An international paediatric trial of its use in ART-naïve and -experienced children is planned (the PENTA 20 trial). EVG, a once-daily INSTI, requires boosting with ritonavir or cobicistat. It is a component of the FDC Stribild and is now recommended as another preferred regimen for ART-naïve adult patients in the USA and Europe.[2,5]

Given the evidence on the efficacy and safety of RAL and DTG derived from studies of treatment-naïve adults and treatment-experienced children,[90,91] RAL- and DTG-containing regimens can now be recommended as alternative first-line ART in children older than 12 years. In children younger than 12 years, there are no data on the use of either drug in treatment-naïve children. Their first-line use should therefore be restricted to specific circumstances (transmitted resistance and intolerance).

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