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New approaches to dosing newborns with abacavir

8mg/kg of abacavir given twice daily to normal- and low-birth-weight new-borns 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). Another study supported the doubling of the dose of dolutegravir for children with HIV/TB co-infection who are taking rifampicin.

World Health Organisation (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 UK concerning abacavir prescribed at 2 to 8mg/kg in routine care in infants under three months of age had no safety concerns.

Dr Tim Cressey and researchers at the Chiang Mai University Thailand, Stellenbosch University South Africa, Harvard TH Chan School of Public Health, University of the Witwatersrand, NIH Rockville, NIH Bethesda, Perinatal HIV Research Unit Soweto, Frontier Science & Technology Research Foundation, University of Cape Town, Boston University, and University of California San Diego, 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.

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

A second study by researchers at the University of Cape Town, Stellenbosch University, Tygerberg Hospital, University of the Witwatersrand, Desmond Tutu HIV Foundation, Africa Health Research Institute, Kheth'Impilo, and the Institute of Social and Preventive Medicine in Switzerland also looked at abacavir safety and efficacy, this time among infants in nine South African observational cohorts from the IeDEA Southern Africa collaboration.

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 and researchers at Radboud University Medical Centre, University of Zimbabwe, Baylor College of Medicine Children's Foundation Kampala, Stellenbosch University, MRC Clinical Trials Unit at University College London, University of the Witwatersrand, Joint Clinical Research Centre Uganda, 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.

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.

Abstract 1
Abacavir (ABC) is licensed for infants >3 months of age while WHO recommends use in HIV-infected children 4 weeks of age and 3 kg. ABC is metabolized in the liver via UDPGT and ADH enzymes, and information describing ABC disposition during the first few months of life is lacking. We describe ABC pharmacokinetic (PK) and safety data in HIV-infected normal and low birth weight (LBW) infants initiating ABC within the first 3 months of life.
IMPAACT P1106 is an opportunistic, multi-arm study of PK and safety in LBW infants conducted in South Africa on antiretroviral and antituberculosis medicines. Arm 5 included HIV-infected infants receiving ABC, lamivudine and lopinavir/ritonavir. Plasma samples for ABC PK assessment were collected pre-dose (C0), 1.5- and 4-hours post-dose at study weeks 2, 10, and 24, with C0 samples at weeks 6 and 16. ABC concentrations were measured by LC-MS/MS and ABC PK parameters estimated using a population approach. Adverse events (AE) were evaluated from entry to week 24.

Twenty-five infants (18 LBW) were included in the analysis. Median entry age was 44 days (range 11 to 78 days). Twelve (48%) infants were male and 22 (88%) black African. Median ABC dose was 10 (6-13) mg/kg BID and ABC concentrations were available for 24 (195 observations) infants with median (range) birth weight 2190 g (1360-3260) and median gestational age 36 weeks (32-37). ABC plasma concentrations were described by a 1-compartment model. Infant body weight (BW) and post-menstrual age (PMA=gestational age+postnatal age [PNA]) influenced ABC PK parameters. ABC oral clearance (CL/F) increased by 2% per PMA week. Infant characteristics and ABC PK parameters per PK visit are shown in Table 1. One infant died of unknown cause 3 days after entry. Fourteen infants had Grade 3/4 AEs, among which most common were gastroenteritis (n=4) and respiratory infection (n=4) and all of which improved except for malnutrition (n=1), underweight (n=1) and a respiratory infection (n=1) present at the last study visit. No hypersensitivity was reported. All AEs were assessed as unrelated to ABC, except for one possibly related Grade 2 alanine aminotransferase where all antiretrovirals were stopped for 2 weeks until resolution then restarted without further complications.
ABC was well tolerated in LBW infants. ABC exposures were relatively high compared to older infants during the first 3 months of life but decreased rapidly as infants matured.

Authors
Tim R Cressey, Adrie Bekker, Mae Cababasay, Jiajia Wang, Firdose Nakwa, Elizabeth Smith, Jack Moye, Avy Violari, Mark Cotton, Bobbie Graham

Abstract 2
World Health Organization guidelines recommend abacavir as part of the preferred first line antiretroviral treatment (ART) regimen in children aged >28 days. However, there is no approved dose under 3 months of age, and with increasing access to early infant HIV diagnosis, more data are necessary to guide dosing recommendations in neonates. We describe the safety and effectiveness of abacavir in young infants in 9 South African cohorts participating in the IeDEA collaboration.
We included all infants who initiated ART (≥3 antiretroviral drugs from ≥2 classes) before 3 months of age, between 2006–2017. In those who received abacavir we described characteristics at abacavir initiation; the proportion who discontinued abacavir; and viral load suppression at 12 months. We compared infants who started abacavir aged <28 days with older infants, and those who weighed <3 kg with those who weighed ≥3 kg, in terms of abacavir discontinuations and viral load suppression, using Chi-squared or Fisher’s exact tests.

Of 1847 infants who started ART aged <3 months, 931 (50%) received abacavir: 96 were aged <28 days. At abacavir start, median (interquartile range, IQR) age was 67 days (48 to 80), CD4 percentage was 26.9 (19.0 to 37.0), viral load was 1 000 000 copies/mL (146 036 to 3 792 175), and weight was 4.2 kg (3.2 to 5.0). ART regimens included lamivudine and ritonavir-boosted lopinavir in 858 infants (92%), lamivudine and nevirapine in 9 (1%) and other antiretrovirals in 64 (7%). In those with 1 months follow-up after abacavir initiation, 61/789 (8%) infants discontinued abacavir permanently, at a median of 13.3 months (IQR 6.4 to 26.8). There were no significant differences in the proportion of discontinuations by age or weight category (p=0.6 and 0.9 respectively, Table 1). Reasons for discontinuation were documented in 20 infants (33%): non-compliance or transfer out in 11, treatment failure in 6, and hypersensitivity in 1. Viral load was measured at 12 months in 353/527 infants with 12 months follow up. The proportion of infants with viral load <400 copies/mL was 15/27 (56%) and 188/326 (58%) in those who started abacavir aged <28 days and 28 days to 3 months respectively (p=0.8); and 17/24 (71%) and 67/111 (60%) in those who weighed <3 kg and 3 kg respectively (p=0.4).
Half of the infants who started ART before three months of age in our cohort received abacavir. Our data suggest that abacavir may be used safely in infants <28 days old or who weigh <3 kg.

Authors
Renee De Waal, Helena Rabie, Karl Technau, Brian Eley, Nosisa Sipambo, Mark Cotton, Andrew Boulle, Robin Wood, Frank Tanser, Geoffrey Fatti

Abstract 3
Adults with HIV/TB co-infection on dolutegravir (DTG)-based antiretroviral therapy (ART) can overcome the induction effect of rifampicin (RIF) by doubling the DTG dose (50mg twice(BID) instead of once(QD) daily. We undertook a pharmacokinetic (PK) substudy nested within the ongoing ODYSSEY randomised controlled trial (#NCT02259127) to evaluate DTG PK in HIV/TB co-infected children while receiving DTG BID+RIF and DTG QD.
Children aged 6-<18 years receiving DTG BID+RIF were eligible; we aimed to include 6 children aged 6-<12 years and 6 children 12-<18 years
. A 12h PK curve was constructed for children on DTG BID in the last month of RIF treatment and subsequently, a 24h PK curve on DTG QD ≥4 weeks after stopping RIF. Geometric mean ratios (GMRs) were estimated comparing DTG PK parameters between the 2 periods and individual Ctrough levels below EC90 (0.32 mg/L) were summarised. All children who received DTG BID+RIF aged ≥6 years were followed for serious adverse events(SAEs), grade 3/4 clinical/laboratory adverse events(AEs) and any AEs resulting in ART modification from start of DTG BID to 30 days after return to DTG QD.
Of 30 eligible children, 17 were enrolled in the PK substudy; 13/17 participants undertaking PK had 1 evaluable PK curve. 12/13 were black African, median (range) age 12.3 (6.8-16.1) years and 31.3 (19.8-48.5) kg. 12 PK curves were evaluable for DTG BID+RIF (5 on 25mg BID and 7 on 50mg BID) and 11 for DTG QD (5 on 25mg QD and 6 on 50mg QD). GMRs (90% CI) for DTG BID+RIF versus DTG QD (reference) for Ctrough, AUC0-24h and Cmax were 1.59 (1.09-2.33), 1.20 (0.90-1.59), and 0.98 (0.79-1.21), respectively. Oral clearance of DTG with RIF was increased 1.7-fold, with 41% reduction in elimination half-life. Findings were similar in children above and below 12 years old. AUC0-24h GMRs in children 20kg receiving WHO 2019-recommended DTG 50mg dose was 1.00 (0.61-1.62) and 1.47 (0.99-2.19) for children on 25mg dose. One child on DTG 25mg QD without RIF had Ctrough
Twice daily dolutegravir dosing was safe and sufficient to overcome rifampicin enzyme-inducing effect in HIV/TB co-infected children aged 6-<18 years, including in children 20kg receiving new WHO doses (DTG 50mg).

Authors
Hylke Waalewijn, Hilda Mujuru, Pauline Amuge, Mark Cotton, Pauline Bollen, Man Chan, Shabinah Ali, Ebrahim Variava, Shafic Makumbi, Angela Colbers

[link url="http://www.aidsmap.com/news/mar-2020/new-approaches-paediatric-dosing-abacavir-newborns-doubling-dolutegravir-rifampicin"]Full Aidsmap report[/link]

[link url="http://www.croiconference.org/sessions/abacavir-safety-and-pharmacokinetics-normal-and-low-birth-weight-infants-hiv"]CROI 2020 abstract 1[/link]

[link url="http://www.croiconference.org/sessions/abacavir-safety-and-efficacy-young-infants-south-african-observational-cohorts"]CROI 2020 abstract 2[/link]

[link url="http://www.croiconference.org/sessions/adequate-dolutegravir-exposure-dosed-bid-rifampicin-children-6"]CROI 2020 abstract 3[/link]

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