Prescribing information and weight-based dosing of available ARV formulations for infants and children
This annex contains information on ARV drugs for which there are paediatric indications, formulations or sufficient information and evidence to provide guidance on prescribing and dosing for infants, children and adolescents. WHO has undertaken the work to develop and update simplified guidance on ARV drugs for children through the Paediatric Antiretroviral Working Group.1
For simplification and ease of implementation, doses are expressed by weight band rather than per kilogram or per square metre of body surface area. When this simplified weight-band dosing was developed, the expected body surface area of children from low- and middle-income countries in each weight band was carefully considered. The primary source of information for the guidance provided is the manufacturer’s package insert. This was supplemented with data from other clinical studies as well as expert paediatric pharmacology consultations. For ARV drug fixed-dose combinations, a dose-modelling tool (1) was used to predict the dose delivered for each component drug against the recommended dosing schedule. In some cases, the dose for a component in a particular weight band may be somewhat above or below the target dose recommended by the manufacturer. This is inevitable given the limitations imposed by a fixed-dose combination, but care was taken to minimize the number of children that would receive more than 25% above the maximum target dose or more than 5% below the minimum target dose. Pharmacokinetic efficacy and safety studies have also confirmed the overall safety of this dosing approach. For simplification, ARV drugs no longer considered preferred or alternative options for children have been removed from the dosing guidance.
In the context of increasing implementation of HIV virological testing at birth, and the shift towards treating infants earlier in an effort to reduce early mortality, these guidelines include additional weight-based dosing guidance for term infants less than four weeks old, including those weighing 2–3 kg. However, there is limited experience with initiating treatment for neonates living with HIV younger than two weeks and a paucity of pharmacokinetic data to fully inform accurate dosing for most drugs in neonates, who are undergoing rapid growth and maturation in renal and liver function. Limited pharmacokinetic data for preterm infants are available for AZT, NVP, 3TC and ABC; there is considerable uncertainty of appropriate dosing for NVP, RAL, 3TC and ABC for preterm and low-birth-weight infants. In addition, LPV/r solution should not be given to infants younger than two weeks old or to preterm infants until they have reached 42 weeks of gestational age, because of the risk of adverse effects that may occur in this population. The management of HIV treatment for preterm neonates remains challenging because of the lack of appropriate pharmacokinetic, safety and dosing information as well as suitable formulations.
Dosing for postnatal prophylaxis for infants exposed to HIV is also included here. These guidelines provide simplified dosing to administer enhanced or extended prophylaxis with NVP 50 mg scored dispersible tablets, which provide an alternative to NVP syrup. Finally, alternative ARV drugs were considered to address special situations in which stock-outs of NVP or AZT may affect the ability to effectively provide postnatal prophylaxis (including for enhanced and extended prophylaxis).
Since the WHO ARV drug guidelines were revised in 2018, integrase strand transfer inhibitors (INSTIs) have been included more prominently among the preferred regimens recommended by WHO, and DTG-based regimens have been recommended for all children with approved DTG dosing. At the time of this update in July 2021, the United States Food and Drug Administration and the European Medicines Agency have approved DTG for treatment-naive or treatment-experienced INSTI-naive children who are at least four weeks old and weigh at least 3 kg (2,3). These approvals were granted based on data generated by the IMPAACT P1093 registration trial (4) as well as the multicountry Odyssey trial (5), which also investigated the pharmacokinetics of DTG among children co-treated for TB.
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In November 2020, the United States Food and Drug Administration approved the first generic DTG 10 mg scored dispersible tablet. DTG dispersible tablets should be ideally dispersed in water or swallowed whole. Crushing, chewing or mixing with other foods or liquids can be considered as long as the entire tablet is ingested. DTG dispersible tablets are not bioequivalent to DTG film-coated tablets; 30 mg of DTG dispersible tablet is equivalent to 50 mg of DTG film-coated tablets (6).
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For infants who received RAL-containing ART for limited duration (such as no more than three months) and without evidence or suspicion of treatment failure, the Paediatric Antiretroviral Working Group concluded that switching to standard (once-daily) weight-appropriate DTG was reasonable while encouraging the generation of direct evidence to evaluate this approach. Of note, although DTG can be dosed twice daily for treating adults with suspected INSTI resistance, this approach cannot be safely extrapolated to children given differences in pharmacokinetics. Alternative regimens should be considered and, if possible, informed by appropriate HIV drug resistance testing.
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This annex includes guidance on dose adjustment for children receiving a DTG formulation during rifampicin-based TB co-treatment. For all weights and ages with approved DTG dosing, the United States Food and Drug Administration recommended administering the weight-based DTG dose twice daily if taken with rifampicin based on its customary approach of extrapolating drug–drug interaction data from adults. Direct pharmacokinetic data for children support the use of DTG twice daily for children weighing more than 25 kg (7). The DTG dose will need to remain twice daily for two weeks after the last dose of rifampicin has been given since the enzyme-inducing effect of rifampicin slowly fades away after discontinuing the drug. The Paediatric Antiretroviral Working Group highlights the need to continue to collect confirmatory evidence in lower weight bands but, as reflected in the dosing table, endorses immediate uptake of twice-daily dosing of DTG when taken with rifampicin for all children (at least four weeks old and weighing at least 3 kg) and to be continued for two weeks after cessation of rifampicin-based TB treatment.
RAL granules were added in 2018 with the goal of providing a suitable formulation to deliver RAL to neonates. Because of concerns about the complexity of administering the granule formulation, the Paediatric Antiretroviral Working Group endorsed the 25-mg chewable tablets as dispersible tablets for infants and children older than four weeks and weighing at least 3 kg. This decision was largely based on in vitro data on solubility and bioequivalence between RAL chewable tablets and granules (8) and considering the limited availability of alternative formulations for this age group. In this update of the dosing guidance, we also recommend appropriate dose adjustment for of RAL during rifampicin-based TB treatment, to be continued for two weeks after completion of rifampicin-based TB treatment.
In this 2021 update, we confirm dosing information for children for tenofovir alafenamide (TAF), fixed-dose combinations containing TAF were included for children weighing 25 kg or more with a 25-mg dose when used with unboosted regimens. This aligns with dosing approved by United States Food and Drug Administration (9). Studies to investigate dosing for children weighing less than 25 kg are ongoing, and more information will be made available as soon as approval is extended.
This dosing annex and the simplified dosing schedule will be regularly reviewed and updated as additional data and new formulations become available. Updated information on ARV drug dosing in children and rationale for dose simplification is available on the newly developed paediatric ARV dosing dashboard (10).
ARV drugs and formulations are available from several manufacturers, and the available dosage strengths of tablets, capsules and liquid formulations may vary from the information provided here. Several optimal dosage forms for children are currently being developed but have not yet received regulatory approval at the time these updated guidelines were published. National programme managers should ensure that products planned for use have received stringent regulatory approval and are of appropriate quality and stability. The current list of WHO prequalified drugs is available (11). The United States Food and Drug Administration has a current list of approved and tentatively approved ARV drugs (12). The policy of the Global Fund to Fight AIDS, Tuberculosis and Malaria on procurement and quality assurance is available (13).