Science alert: HIV drug regimen cuts mother-to-infant transmission

Expanding treatment reduces transmission rate by more than 50%

When HIV is not diagnosed until women go into labor, their infants usually are treated soon after birth with the antiretroviral drug zidovudine to prevent infant infection. Findings from a new study indicate that adding one or two drugs to this standard antiretroviral treatment can reduce the chances by more than 50% that an infant will develop an HIV infection.1

Family planning clinicians know the risk of HIV infection among their female patient population. In 2009, nearly a quarter of diagnoses of HIV infection in the United States were among women and girls ages 13 years and older, statistics from Centers for Disease Control and Prevention (CDC) show.2 Additionally, almost 184,000 women and adolescent girls were living with HIV at the end of 2008, the CDC estimates.

The new study was designed to examine the best post-exposure prophylaxis regimen to give to HIV-exposed infants in situations in which mothers received no antiretroviral treatment during pregnancy, says Karin Nielsen-Saines, MD, MPH, clinical professor of pediatrics in the Division of Infectious Diseases at the David Geffen School of Medicine at the University of California, Los Angeles. In most cases, HIV diagnosis was made only at the time of admission for labor and delivery, says Nielsen-Saines, who served as lead author of the paper.

To perform the prospective randomized study, investigators enrolled 1,684 evaluable infants in Brazil, South Africa, Argentina, and the United States. All infants were HIV-exposed, formula-fed infants born to mothers not receiving antiretroviral therapy prior to labor. In this specific setting, a two-drug regimen consisting of zidovudine for six weeks and three doses of nevirapine, or a three-drug regimen consisting of zidovudine for six weeks and two weeks of a protease inhibitor and a second nucleoside reverse transcriptase inhibitor, lamivudine-3TC, were better in reducing the risk of transmission during labor and delivery. Results were comparable between the two- and three-drug regimen prophylaxis.

What led the research team to look at the addition of the particular drugs (nevirapine, lamivudine, and nelfinavir) to the present standard treatment?

Nevirapine was chosen for one arm based on extensive data on its pharmacokinetics and efficacy when used for prophylaxis, according to Heather Watts, MD, a medical officer in the Pediatric, Adolescent, and Maternal AIDS Branch in the National Institute of Child Health and Human Development. Nevirapine is rapidly absorbed, providing drug levels quickly in the neonate, explains Watts, a coauthor on the current study. An earlier study showed a 47% reduction in transmission when mothers and infants each received a single dose of nevirapine compared to intrapartum and one week of infant zidovudine in a breastfeeding population.3 A study in Malawi showed a greater reduction in transmission with the combination of single dose nevirapine and one week of zidovudine (transmission 15.3%) than with nevirapine alone (transmission 20.9%), again in a breastfeeding population.4

"The three-dose regimen used in our study provided nevirapine levels for 10-14 days in the infants, the period felt to be necessary to interrupt transmission after potential intrapartum exposure to HIV," says Watts. "Studies in non-breastfed infants have shown that 93% of infant infections can be detected by two weeks of age."

The regimen of zidovudine /3TC/nelfinavir was chosen to provide a highly active regimen with three drugs including a protease inhibitor as is used for therapy in adults and children, says Watts. The three-drug regimen was chosen to provide drugs with activity against two viral enzymes, the reverse transcriptase and protease enzymes, she explains. The two extra drugs were given for two weeks.

Lamivudine or 3TC was chosen because it was the most commonly used second agent with zidovudine in combination regimens and had pharmacokinetic data in infants to allow appropriate dosing, says Watts. Nelfinavir was chosen as the protease inhibitor because there were a limited number of protease inhibitor drugs available when the study was designed in 2002, she states.

Nelfinavir was the only drug at the time of study design that had an available formulation (powder to mix with liquids) that could be used in infants and that offered pharmacokinetic data for infants under 3 months of age, says Watts. Even today, the number of protease inhibitors with liquid formulations is limited, and lopinavir/ritonavir is not recommended in newborns because of toxicity, she notes.

The six-week zidovudine regimen was included in all arms since it was the standard of care in the United States and Brazil when the study was designed, says Watts. It remains today as the current standard of care.

Will regimen change?

The current study was restricted to babies who had a high risk of HIV acquisition, says Nielsen-Saines.

The study results are not generalizable to all HIV-exposed infants, only to those born in the special scenario described, she comments. Babies who are born to mothers with a detectable virus load at or close to delivery—even those whose mothers received antiretroviral drugs in pregnancy—also might benefit from the two- or three-drug arm approach, Nielsen-Saines says. Why? Because the infants are also at high risk of HIV acquisition because of the positive maternal virus load. However, for babies who are born to mothers who receive antiretroviral treatment and maintain an undetectable virus load, standard zidovudine prophylaxis for six weeks is still the norm, she states.

"I don't anticipate that this guideline will change anytime soon because investigators are reluctant to conduct a study where zidovudine is not part of the standard prophylactic regimen postpartum," Nielsen-Saines observes. "In our own study, we added drugs to the standard of care (zidovudine), and the zidovudine backbone was not substituted by any other drug."

There is some reluctance to conduct a study in infants where zidovudine, a drug with known post-exposure prophylactic effect, is substituted by a different drug with an unknown or unproven prophylactic effect in infants, Nielsen-Saines says. In the developing world, particularly Sub-Saharan Africa, continuous nevirapine is being used for six weeks postpartum, a practice that addresses the issue of breastfeeding transmission.

"I do not see a push to change to nevirapine prophylaxis in the developed world because that approach has its own set of problems," Nielsen-Saines says. "Therefore, for now, I anticipate we will continue to be delivering zidovudine to infants postpartum, and combination regimens to those whose mothers are at higher risk of HIV transmission, because of absent therapy in pregnancy or failure to respond to therapy."

References

  1. Nielsen-Saines K, Watts H, Veloso VG, et al. Phase III randomized trial of the safety and efficacy of 3 neonatal ARV regimens for prevention of intrapartum HIV-1 transmission: NICHD HPTN 040/PACTG 1043. Presented at the 18th Conference on Retroviruses and Opportunistic Infections. Boston; March 2011.
  2. Centers for Disease Control and Prevention. National Women & Girls HIV/AIDS Awareness Day. Press release. March 7, 2011. Accessed at http://www.cdc.gov/features/womengirlshivaids.
  3. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda:18-month follow-up of the HIVNET 012 randomized trial. Lancet 2003; 362:859-868.
  4. Taha TE, Kumwenda NI, Gibbons A, et al. Short postexposure prophylaxis in newborn babies to reduce mother-to-child transmission of HIV-1: NVAZ randomized clinical trial. Lancet 2003; 362:1,171-1,177.