Did you know about the updated perinatal guidelines?

(I had previously posted this a couple of weeks ago, but took it down since I was waiting for the "thumbs-up" from the powers that be.  Apologies for the re-post.)

New DHHS Perinatal Guidelines: Part I

There had been some controversy about the dosing of zidovudine for prevention of mother-to-child transmission (MTCT) of HIV – one institution had been dosing the medication based on the WHO recommendations (twice-daily) and our institution had been dosing it based on the DHHS guidelines (four-times daily).  There had been discussion on which one was the “right” dosing; however, after reviewing the most recent DHHS recommendations for prevention of perinatal HIV infection¹, we sheepishly concluded that twice-daily dosing would be appropriate.

Pediatric ACTG 076 showed that the administration of intravenous zidovudine to mothers who were HIV-1 infected (and who did not receive antepartum antiretrovirals) in the intrapartum period and the administration oral zidovudine (dosed at 2 mg/kg PO q6h) to the neonate reduced perinatal HIV infection to 8.3% from 25.5%.²  The study took place in the United States and showed a dramatic decrease of perinatal HIV infection; intravenous zidovudine and infant prophylaxis was strongly recommended from then on for MTCT prevention.

Although one of the most prominent studies of MTCT prevention suggested dosing of zidovudine every 6 hours, the recent international studies dosed the neonatal zidovudine at 4 mg/kg PO q12h and has been shown to be effective.  Although there are no head-to-head trials to compare the new dosing regimen to the ACTG 076 dosing, the DHHS has applied the successes from the studies to change the 2010 recommendations to the twice-daily dosing to reduce the burden of frequent administration. 

The q12h dosing also seems practical from the pharmacokinetic viewpoint: one study suggested that the exposure between the two dosing regimens are similar³, zidovudine is primarily metabolized through the glucuronidation pathway and is eliminated through the renal system, which is initially immature in the neonate (t_1/2 = 4 hours vs. 1.5 hours in adults).³  Additionally, the intracellular half-life of zidovudine is much longer than the serum half-life, which drives the pharmacodynamic effect of zidovudine.⁴

DHHS Perinatal Guidelines: Infant Antiretroviral Prophylaxis

Gestational Age	2010	2011
> 35 weeks	2 mg/kg/dose PO q6h	4 mg/kg/dose PO q12h
30-35 weeks	2 mg/kg/dose PO q12h, increase to 2 mg/kg/dose PO q8h at 2 weeks of age	Same
< 30 weeks	2 mg/kg/dose PO q12h, increased to 2 mg/kg/dose PO q8h at 4 weeks age	Same

1.     Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Sep. 14, 2011; pp 1-207. Available at http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf.

2.     Connor EM, Mofenson LM. Zidovudine for the reduction of perinatal human immunodeficiency virus transmission: pediatric AIDS Clinical Trials Group Protocol 076--results and treatment recommendations. Pediatr Infect Dis J. 1995;14:536-41. PMID: 7667060

3.     Moodley D, Pillay K, Naidoo K, et al. Pharmacokinetics of zidovudine and lamivudine in neonates following coadministration of oral doses every 12 hours. J Clin Pharmcol. 2001;41:732-41. PMID: 11452705

4.     Flynn PM, Rodman J, Lindsey JC, et al. Intracellular pharmacokinetics of once versus twice daily zidovudine and lamivudine in adolescents. Antimicrob Agents Chemother. 2007;51:3516-22. PMID: 17664328.