Once a day lamivudine and abacavir, and abacavir hypersensitivity in the ARROW trial
Polly Clayden, HIV i-Base
Simplification of HAART regimens provides benefit for children, caregivers and health workers. To date there are no data on oncedaily use of 3TC and abacavir (ABC) in resource limited settings.
A substudy from the ARROW trial (a randomised trial of monitoring and first-line induction-maintenance strategies) compared the PK of once- v. twice-daily 3TC and abacavir (ABC) (Kivexa). This was a cross-over study performed in 41 Ugandan children aged 3 – 12 years receiving HAART, dosed according to weight bands. The ARROW trial uses scored tablets of ABC/3TC to ensure better accuracy of division and more flexible dosing. Total daily doses were 150+300 mg, 225+450 mg and 300+600 mg for children weighing 12 – 20 kg, 20 – 25 kg and >25 kg, respectively.
PK sampling was performed for twice-daily dosing at steady state (36 weeks) pre-dose, and 1, 2, 4, 6, 8 and 12 hours post dose. Children were then switched to the once-daily dose and further sampling was performed at 4 weeks with an additional sampling at 24 hours.
Daily area under the curve (AUC0-24) and peak level (Cmax) were compared by geometric mean ratios (GMR). GMR with 90% CI within 0.80 – 1.25 was considered to be bioequivalent.
PK parameters were available for 35 and 36 children for 3TC and ABC, respectively. Approximately half were in the younger age group.
The investigators reported that in children 3 – 12 years, AUC0-24 of both 3TC and ABC were bioequivalent with once and twice daily regimens but Cmax was 76% and 64% higher for 3TC and ABC respectively. No grade 3/4 adverse events were reported and no child discontinued after the switch to once-daily dosing.
In this analysis, in contrast to data from European children in PENTA 13, 3TC AUC levels in 3 – 6- and 7 – 12-year-old children were similar for both once- and twice-daily dosing and similar to levels in older children. The investigators noted that many younger children in PENTA 13, whose 3TC levels were lower, received syrups, but ARROW children received tablets. They concluded that these results suggest that once-daily dosing of 3TC and ABC is feasible in resource-limited settings.
The ARROW investigators also showed data describing successful management of hypersensitivity reactions among children in this trial in Uganda and Zimbabwe.
The WHO recommends ABC for paediatric first-line treatment. Hypersensitivity reactions (HSR) occur in 2 – 5% of people receiving ABC in clinical trials and are strongly associated with the presence of the HLA-B*5701 allele. Prospective screening for HLA-B*5701 is sometimes recommended, but this pharmacogenetic test is rarely available in resource limited settings.
Clinical diagnosis and management may be complicated in this setting due to widespread use of NVP and cotrimoxazole and febrile infections.
Health workers and caregivers were trained in recognition and management of ABC-HSR and all suspected HSR underwent independent clinical review. ABC was only discontinued in 7 cases.
The investigators reported that suspected ABC-HSR was rare (3/1 207, 0.2% (95% CI, 0.05 – 0.7%)) in this trial, consistent with reports of a lower prevalence of HLA-B*5701 in black populations. Clinical symptoms (fever, rash) occurred 9 – 13 days after initiation of HAART; 2/3 cases had additional gastrointestinal and respiratory symptoms and required hospitalisation.
ABC-HSR was successfully managed despite co-administration of cotrimoxazole and NVP, and the investigators recommend that ABC can be used safely in resource-limited settings.
This article first appeared in issue 36 of the Journal of HIV Medicine, the journal of the Southern African Clinicians Society.
Unless otherwise stated, all references are to the programme and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19 – 22 July 2009, Cape Town.
19. Musiime V et al. Pharmacokinetics of once versus twice daily lamivudine and abacavir in HIV-1 infected Ugandan children in the ARROW trial. Abstract WEPEB271.
20. Nahirya-Ntege P et al. Successful management of suspected abacavir hypersensitivity reactions among African children in the ARROW (AntiRetroviral Research for Watoto) trial. Abstract TUPEB183.