Longer Preventive Therapy, More Drugs Reduce Risk of Mother-to-Child HIV Transmission

SUMMARY: Infants born to HIV positive women diagnosed at the time of labor were less than half as likely to be infected if they received 2 or 3 antiretroviral drugs rather than zidovudine (Retrovir; AZT) alone, according to a multinational study presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) this month in Boston. A related trial showed that treating infants with nevirapine (Viramune) for 6 months rather than 6 weeks significantly reduced the risk of HIV transmission through breastfeeding.

By Liz Highleyman

Yvonne Maldonado and
Karin Nielsen-Saines
(Photo: Liz Highleyman)

Treating HIV positive pregnant women with zidovudine, or better, a complete combination antiretroviral therapy (ART) regimen, has been shown to dramatically reduce the likelihood of mother-to-child HIV transmission during pregnancy or delivery.

Many women in resource-limited settings are only diagnosed with HIV at the time of labor, however. While they can be given nevirapine or combination therapy at this point, this is typically not enough time to suppress their viral load to undetectable before they give birth. Furthermore, infants also may contract HIV via breast-feeding, but this remains the recommended feeding method if formula and clean water are not accessible and affordable. Therefore, researchers continue to study how best to prevent vertical transmission.

Number of Drugs

Karin Nielsen-Saines and fellow investigators with the NICHD HPTN 040/ PACTG 1043 Study Group (abstract 124LB) conducted a prospective Phase 3 trial to evaluate the safety and efficacy of 3 newborn ART regimens for prevention of HIV transmission during delivery.

The study enrolled 1745 infants in Argentina, Brazil, South Africa, and the U.S. who were born to HIV positive mothers who had not received antiretroviral drugs prior to labor; 1684 infants were evaluated. They were randomly allocated to receive post-exposure prophylaxis using 1 of 3 regimens starting within 48 hours after birth:

	Standard regimen of zidovudine alone for 6 weeks;
	Zidovudine for 6 weeks + 3 doses of nevirapine during week 1;
	Zidovudine for 6 weeks + lamivudine (Epivir; 3TC) and nelfinavir (Viracept) for 2 weeks.

Mothers had a median viral load of about 4 logs and a median CD4 cell count of about 400 cells/mm3. Just over 40% received zidovudine during labor. Babies were tested for HIV using a DNA PCR assay at birth, at 10-14 days, at 4-6 weeks, and at 3-6 months. Infants who were not infected at birth but became so during the first 3 months were presumed to have acquired HIV through exposure to the mother's blood and fluids during delivery. Babies were formula-fed, so were presumed not to be exposed via breast-feeding.

Results

A total of 140 babies were infected with HIV, for an overall mother-to-child transmission rate of 8.3%.

93 newborns (5.5%) were found to have been infected in the womb, a rate that was similar across treatment arms.

47 infants (2.8%) overall were infected during delivery, but here rates differed according to ART regimen:

	24 babies (4.9%) in zidovudine-only arm;
	11 babies (2.2%) in zidovudine + nevirapine arm;
	12 babies (2.5%) in zidovudine + lamivudine + nelfinavir arm.

The 2-drug and 3-drug regimens were both significantly more effective than the zidovudine-only arm, but they did not differ significantly from each other.

In a multivariate analysis, number of antiretroviral drugs and maternal viral load were the only factors found to be significantly associated with perinatal transmission.

Transmission rates did not vary according to maternal age, race, region, CD4 cell count, syphilis coinfection, receipt of prenatal care, baby's gestational age, type of delivery (vaginal vs Cesarean), or use of zidovudine during labor.

With regard to side effects, neutropenia (low white blood cell count) was significantly more common in the 3-drug arm compared with the other 2 groups.

"Neonatal post-exposure prophylaxis with a 2- or 3-antiretroviral-drug regimen is superior to zidovudine alone for prevention of intrapartum HIV transmission among infants born to women not receiving [antiretroviral therapy] before labor," the researchers concluded.

Based on tolerability and ease of use, they suggested that the 2-drug zidovudine + nevirapine regimen may be preferable to the 3-drug combination, but results from forthcoming resistance testing may favor more drugs.

Nielsen-Saines acknowledged after her session that the 3-drug regimen used in this study -- designed in the early 2000s -- might not stand up to a combination of newer antiretroviral agents.

"To reduce mother-to-child HIV transmission, it's best to begin antiretroviral treatment during pregnancy," said co-investigator Heather Watts in a press release issue by the U.S. National Institutes of Health (NIH), a cosponsor of the trial. "However, when treatment during pregnancy isn't possible, our results show that adding 1 or 2 drugs to the current regimen provides another important means to reduce the chance for mother-to-child HIV transmission."

Length of Treatment

In the second study Yvonne Maldonado and fellow investigators with the HPTN 046 Protocol Team (abstract 123LB) evaluated the efficacy of extending nevirapine treatment from the standard 6 weeks to 6 months for infants breast-fed by HIV positive mothers.

Prior studies have found that giving nevirapine for 6 weeks, 14 weeks, or 6 months is superior to single-dose nevirapine, the researchers noted as background, but the optimal length of treatment is unclear.

This study included 1522 infants born to 1505 HIV positive mothers in South Africa, Tanzania, Uganda, and Zimbabwe. About 30% of the women were on combination ART for their own health. The median maternal CD4 cell count was high, at about 540 cells/mm3.

All babies started with 6 weeks of nevirapine; after that, they were randomly assigned to receive continued nevirapine or placebo through 6 months. At 3 months, mothers reported that 95% of infants were exclusively breast-fed, but more than 90% stopped between 6 and 9 months.

Results

Overall, 1.1% of infants in the 6-month nevirapine arm were infected with HIV during the first 6 months of life, compared with 2.4% in the 6-week arm, a difference that just reached statistical significance.

The risk of infection at 6 months fell by 55% in the longer-duration arm.

At 12 months, infection rates were 2.0% in the 6-month arm vs 3.0% in 6-week arm, a difference that was not significant.

There were "virtually no infections" at 6 months among breast-feeding babies born to women taking combination ART, regardless of infant treatment duration (0.5% for 6 months vs 0% for 6 weeks).

Among babies born to women not on ART, however, the 6-month infant prophylaxis regimen lowered the risk of infection by 76% (1.4% vs 3.4%, respectively):

	Among untreated women with < 350 cells/mm3, infant infection rates were 4.8% with 6-month nevirapine vs 8.1% with 6-week treatment;
	Among untreated women with 350 cells/mm3, the corresponding rates were 0.7% vs 2.8%, respectively.

Rates of overall adverse events (83%) and serious adverse events (about 18%) were similar in both duration arms.

"Extending daily infant nevirapine from 6 weeks to 6 months lowered risk of breast-feeding [mother-to-child transmission] at age 6 months, most significantly in mothers with CD4 > 350 not on HAART," the investigators concluded. "[A]fter age 6 months, breast-feeding [mother-to-child transmission] was similar between arms."

Infant mortality was similar in the 2 study arms but about two-thirds of deaths occurred after 6 months of age -- that is, after most infants had stopped breast-feeding.

"These data support the benefits and safety of extended infant nevirapine for women who do not yet require HAART for their own health," the researchers added.

"Extended breast-feeding reduces infant mortality in places that lack safe, clean water by protecting babies from common childhood diseases because breast milk contains protective antibodies from the mother that formula-feeding does not provide," said National Institute of Allergy and Infectious Diseases director Anthony Fauci. "These findings show that giving the infants of HIV-infected mothers an antiretroviral drug daily for the full duration of breast-feeding safely minimizes the threat of HIV transmission through breast milk while preserving the health benefits of extended breast-feeding."

Investigator affiliations: