HPTN 046

Phase III Trial to Determine the Efficacy and Safety of an Extended Regimen of Nevirapine in Infants Born to HIV Infected Women to Prevent Vertical HIV Transmission During Breastfeeding

Study Summary

What was HPTN 046?

A Phase III, randomized, placebo-controlled trial designed to determine the efficacy and safety of an extended daily regimen of nevirapine (NVP) in infants born to HIV-infected women to prevent vertical HIV transmission during breastfeeding.

Who participated in the study?

HIV-1 infected women and their breastfeeding infants.

What happened during the study?

HPTN 046 compared nevirapine (NVP) given to breastfeeding infants born to HIV infected mothers through 6 weeks of age to an extended regimen given through 6 months of age or cessation of breastfeeding, whichever was earliest.


The study found that the overall risk of HIV transmission through breast milk at age 6 months was lower with extended daily infant NVP, 1.1%, compared to 2.4% in infants in the placebo arm who had only 6 weeks of NVP (p=0.048). The study also demonstrated that extended infant NVP is most important for infants of mothers with high CD4+ cell counts (> 350 cells/mm3) who are not receiving antiretroviral therapy for their own health; among these infants, breast milk transmission was much lower with 6 months of NVP, 0.7%, compared to 2.8% of infants in the placebo arm who received only 6 weeks of NVP (p=0.014).

Why was this study important?

Other studies had shown that giving daily infant NVP for 6 weeks, 14 weeks or 6 months to breastfeeding infants reduces HIV transmission through breast milk compared to single dose NVP, but no other study had directly compared 6 weeks of NVP to 6 months of NVP to determine if the longer regimen is better for prevention of HIV transmission through breast milk.

Study Details

Protocol Status: Concluded
Study Purpose:

To evaluate the efficacy and safety of an extended regimen of nevirapine (NVP) from 6 weeks to 6 months or through cessation of breastfeeding, whichever is earliest, for prevention of mother-to-child transmission of HIV through breast milk compared with placebo among infants who are provided nevirapine for the first 6 weeks (through Day 42) of life and are HIV-uninfected at age 6 weeks.

Study Design:

Phase III, multi-site, randomized, double-blind, placebo controlled trial. Stratification: Randomization will be stratified by maternal antiretroviral therapy with two levels based on maternal therapy for treatment of HIV at the point of randomization: mothers receiving antiretroviral therapy (ART) or mothers not receiving antiretroviral therapy (ART).

Study Population:

HIV-1 infected women and their breastfeeding infants.

Study Size:

Approximately 1670 mother/infant pairs will need to be enrolled at birth (within 7 days) in order to randomize the target of 1500 infants at six weeks. In addition, approximately 350 mother/infant pairs originally enrolled under Version 2.0 of the protocol will be followed under Version 3.0.

Study Duration:

Total duration of the study will be approximately 3.5 years. Participants will be enrolled over a period of approximately 18 to 24 months; randomized mothers and infants will be maintained in follow-up through 18 months postpartum.

Treatment Regimen:

Infants eligible under Version 3.0 of the protocol will be enrolled in the study on or before day 7 after birth:
All infants will receive a daily regimen of open-label NVP through 6 weeks (42 days) of life starting at 3 to 7 days after birth.

Infants still eligible at 6 weeks of age will be randomized to one of two study arms and will initiate the daily study drug regimen (NVP or NVP placebo).

Infants enrolled under Version 2.0 of the protocol:
Infants either randomized to the placebo arm and over 6 weeks (> or = to 43 days) of age as of 10 August 2007 or randomized to the NVP arm (regardless of age) will continue the dosing regimen to which they were randomized according to the age-appropriate dose.

Infants who were not randomized (including those enrolled on or after 10 August 2007) or who were randomized to the placebo arm of the study and were under 6 weeks (< 43 days) of age as of10 August 2007 will be provided open-label NVP through six weeks (42 days) of life.

Primary Objectives:

Compare the rate of HIV-1 infection at 6 months in infants determined to be HIV uninfected at 6 weeks in each arm
Evaluate and compare the safety and tolerance in infants in each arm

Secondary Objectives:

Compare the proportion of infants who are alive and free of HIV at 6 months and 18 months of age in the two arms.
Compare the relative rates of HIV infection in infants over 18 months in the two arms.
Compare the infant survival rates (mortality regardless of HIV infection) over 18 months in the two arms.
Determine the frequency and duration of NVP-resistant HIV strains in maternal plasma and breast milk and the relationship with MTCT.
Determine the relationship of maternal plasma and breast milk RNA levels to risk of MTCT.
Determine the frequency, type, and duration of NVP-resistant HIV strains in the plasma of infants who become HIV-infected.
Compare the rates of HIV disease progression, as defined by CD4+ cell count, HIV-1 RNA copy number, and mortality between the two arms in infants who become HIV-infected.
Determine NVP concentrations in infants who become infected with HIV and a sample of HIV uninfected infants as an index of adherence to the NVP regimen.

Key Study Personnel

Philip Andrew, CORE Protocol Specialist
Hoosen Coovadia, Protocol Chair
Wafaie Fawzi, Protocol Co-Chair
Kathleen George, CORE Protocol Specialist
Laura A. Guay, Protocol Co-Chair
Yvonne A. Maldonado, Protocol Co-Chair
Lynne Mofenson, DAIDS Medical Officer
Dhayendre Moodley, Protocol Co-Chair
Sheryl Zwerski, DAIDS Medical Officer