Did you know that another part was also updated?

Perinatal Guidelines: Part II

All children born to HIV-seropositive women are recommended to initiate antiretroviral (ARV) therapy; however, the decision in selecting ARVs for prophylaxis depends on the situation.  There are a few settings to consider for neonatal prophylaxis:

1.    HIV-positive mother who was on antepartum HAART and is virologically controlled

2.    HIV-positive mother was NOT on antepartum HAART (with or without intrapartum IV zidovudine)

3.    HIV-positive mother who was on antepartum HAART but is NOT virologically controlled

4.    HIV-positive mother was has known ARV-resistant virus

In setting 1, neonates should receive 6 weeks of oral zidovudine (AZT); the most recent dosing recommendation was discussed in the previous blog.  In settings 3 and 4, it is highly recommended to contact the National HIV/AIDS Clinicians’ Consultation Center Perinatal HIV Hotline (available at 1.888.448.8765) to discuss the optimal combination of ARVs.  The 2011 Prevention of Mother to Child Transmission has new recommendations for ARV prophylaxis in setting 2.

Previously, it was recommended to provide 6 weeks of AZT, a single-dose of nevirapine (NVP) and 7 days of lamivudine (3TC) to neonates; it was recognized that even a single dose of nevirapine could lead to drug-resistant virus and a “tail” of 3TC could decrease the risk.  However, side effects, such as neutropenia, were more common in this combination of ARVs.

The NICHD HPTN 040/PACTG 1043 sought to compare the efficacy and safety of 3 regimens to prevent intrapartum transmission of HIV-1 in neonates whose mothers did not receive antepartum HAART (but could receive intrapartum IV AZT:

1.    AZT x 6 weeks alone (n = 566)

2.    AZT x 6 weeks with 3 doses of NVP (n = 562)

3.    AZT x 6 weeks with 3TC and nelfinavir (NFV) x 2 weeks (n = 556)

Of the 1684 neonates who were evaluable for the study, 140 neonates were infected with HIV, of which 47 were from intrapartum transmission. The transmission rate in each group: AZT alone group = 4.9%, AZT + NVP = 2.2%, and AZT +3TC/NFV = 2.5%; the rate was considered significantly lower in the patients who received combination therapy compared to AZT alone (p = 0.045 for both).  A high viral load (the median viral load was log ₁₀ 4.17) and drug abuse was associated with intrapartum transmission of HIV; I think that this is particularly interesting since the current guidelines recommend a Cesarean section if the viral load > 1000 copies/mcL and in this study, a majority of women had a natural birth (65%) and transmission was not associated with the mode of birth.  On the other hand, there were a small number of patients with intrapartum transmission and the study may not have been powered to look at this association.  When looking at safety of the ARVs, it was found that group 3 had a significantly higher rate of neutropenia (p < 0.0001); other factors, such as anemia, transaminitis, or thrombocytopenia was similar amongst all groups.

Due to the increased efficacy in comparison to AZT alone, and lesser toxicity in comparison to the 3-drug regimen, it is now recommended to provide 6 weeks of AZT and 3 doses of NVP to the neonate where HIV-seropositive mothers did not receive antepartum HAART.

Of note, the infants included in this study were NOT breastfed; formula was provided to the family through the study.  The ideal ARV regimen for neonates who are breastfed by HIV-seropositive mothers is still under investigation.

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. May 24, 2010; pp 1-117.

2.       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.

3.       Nielsen-Saines K, Watts DH, Santos VV, et al. Phase III randomized trial of the safety and efficacy of three neonatal antiretroviral regimens for preventing intrapartum HIV-1 transmission (NICHD HPTN 040/PACTG 1043). Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); Feb. 27-Mar 3, 2011; Boston, MA.

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.