New approaches for paediatric dosing: abacavir in newborns, doubling dolutegravir with rifampicin

8mg/kg of abacavir given twice daily to normal- and low-birth-weight newborns with HIV in South Africa was safe and effective according to presentations in a session on new approaches to paediatric dosing at the Conference on Retroviruses and Opportunistic Infections (CROI 2020) last week. Another study supported the doubling of the dose of dolutegravir for children with HIV/TB co-infection who are taking rifampicin.

Background

World Health Organization (WHO) guidelines recommend abacavir in liquid form as part of the preferred first-line regimen in children aged 28 days and above, but there is no approved dose for children under three months of age. A recent report from the United Kingdom concerning abacavir prescribed at 2 to 8mg/kg in routine care in infants under three months of age had no safety concerns.

Currently recommended regimens for newborns with HIV are zidovudine+lamivudine+raltegravir; zidovudine+lamivudine+nevirapine; and zidovudine+lamivudine+lopinavir/ritonavir. Increased access to early infant HIV diagnosis necessitates data to guide dosing for newborns.

Drug metabolism is reduced in newborns. No pharmacokinetic (how the drug is absorbed, distributed, metabolised and excreted) data for abacavir are available for infants of normal- (less than 2.5 to 4kg) or low-birth weight (under 2.5kg). Women living with HIV are at increased risk of delivering low-birth-weight infants.

IMPAACT sub-study

Dr Tim Cressey presented findings from a sub-study looking at abacavir safety and pharmacokinetic (PK) data in South African normal- and low-birth-weight infants with HIV starting antiretroviral therapy (ART) comprising abacavir+lamivudine+lopinavir/ritonavir within the first three months of life. All infants had previously received nevirapine.

Infant characteristics and safety data were collected before starting the regimen and seven times after. Blood was sampled at five visits, usually once before and twice after a dose.

Data and characteristics from 25 infants, with a majority (18) of low birth weight were analysed. Median gestational age at birth was 36 (27-39) weeks with a median birth weight of 2.25 (1.36-3.32) kg. Median age at study entry was 6 (1.5-11) weeks.

The clinician chose the abacavir dose. The median dose was 10mg/kg twice daily, ranging from 6 to 13mg/kg.

Corresponding median abacavir PK parameters for CL/F (drug clearance determining dose-rate) were 0.67, 0.79 and 1.03 L/hr/kg, at weeks 2, 10 and 24 respectively. The AUC _0-12 (overall amount of drug in the blood after a dose) was 16.9, 10.7 and 9.8, mg.hr/L, respectively. 

This shows that exposure to abacavir was higher during the first three months of life compared with older children, but rapidly decreased as the infants developed.

The 14 grade 3/4 adverse events were assessed as unrelated to abacavir.

Dr Cressey concluded that abacavir dosed at 8mg/kg twice daily was well tolerated in infants under three months of age.

IeDEA Southern Africa study

A second study also looked at abacavir safety and efficacy, this time among infants in nine South African observational cohorts from the IeDEA Southern Africa collaboration.

Infants under three months of age who started ART between 2006 and 2017 were included. In this real-life retrospective study, the authors looked at the proportion discontinuing abacavir and the proportions with viral suppression at six and 12 months compared to those who started zidovudine-containing regimens.

Of 1275 infants starting ART, 931 got abacavir (10% of whom were under 28 days old) and 344 got zidovudine (almost 50% under 28 days old). At baseline, median CD4 % was 26.9 (19.0-37.0) for those on abacavir compared to 33.4 (21.0-49.1) for infants on zidovudine.  (In young children CD4 percentage is used rather than CD4 count to assess HIV progression, with a lower percentage indicating greater damage to the immune system.) Median viral load was 6.0 and 5.0 (log₁₀) respectively.

Abacavir discontinuations and viral load suppression at 6 and 12 months were not significantly different in infants starting ART aged < 28 days and ≥ 28 days, or in infants weighing < 3 and ≥ 3kg. Fewer discontinued abacavir compared to zidovudine.

Eight per cent of infants discontinued abacavir at a median of 13 months. Reasons were available for 41% and included transferring to another clinic, treatment failure, stockouts, hypersensitivity and lipodystrophy.

ODYSSEY trial

The TB medication rifampicin reduces the efficacy of dolutegravir, known as the induction effect of rifampicin. In HIV/TB co-infected adults on dolutegravir-based ART this interaction can be overcome by doubling the dolutegravir dose (50mg twice a day instead of once daily). Until now, no data have been available to support this strategy in children.

Dr Hylke Waalewijn presented findings on behalf of the ODYSSEY Trial Team showing that dolutegravir (50mg) given twice daily with rifampicin was safe and sufficient to overcome the induction effect in children aged 6 to 18.

The authors undertook a PK sub-study to look at the effect and safety of rifampicin on dolutegravir plasma concentrations in children, taking either a twice-daily weight appropriate dolutegravir dose with rifampicin, or oncedaily dolutegravir without rifampicin.

Safety analysis included 31 children with a median age of 12.2 (5.9-17.6) years. Just over half were male and were followed for a median of 31 (28-40) weeks. There were 13 adverse events, which independent reviewers determined to be unlikely to be linked to dolutegravir.

PK analysis included 17 children. Doubling the dolutegravir dose combined with rifampicin resulted in AUC_0-24  and C_max (highest concentration of drug in the blood measured after a dose) that were comparable to dolutegravir given without rifampicin.

The inducing effect of rifampicin increased clearance of dolutegravir as expected: CL/F: 1.36 and 2.05 for dolutegravir 25 and 50mg, respectively.

Results were comparable for both younger and older children.

Waalewijn concluded that the data support doubling the dose of dolutegravir for children treated for TB with rifampicin. He added that embedding PK and drug interaction sub-studies in phase II/III paediatric trials accelerates getting key data to treat children in a timely manner.

Full image credit: 'South Sudan: Anniversary of the World's Newest Country'. Child receiving tuberculosis medicine in South Sudan with support from the Global Fund to Fight AIDS, Tuberculosis and Malaria and UNDP. UNDP South Sudan/Brian Sokol. Available at www.flickr.com/photos/unitednationsdevelopmentprogramme/7479902506 under a Creative Commons licence CC BY-NC-ND 2.0.