Six months of nevirapine prophylaxis for breastfeeding infants reduces transmission by 76% if mother not on ART

Extending the use of daily infant nevirapine to six months reduced the risk of breastfeeding mother-to-child transmission by a significant 76% in HIV-positive mothers with CD4 cell counts over 350 and not yet eligible for antiretroviral treatment Yvonne Maldonado reported on behalf of the HPTN 046 study at the Eighteenth Conference on Retroviruses and Opportunistic Infections (CROI) in Boston last week.

While the risk for infant death was similar in both the nevirapine and placebo arms, approximately two-thirds of all deaths happened after six months of age when most infants had stopped breastfeeding. Cessation of breastfeeding was not controlled for in the study.

Previous study findings showed that daily infant nevirapine (extended-dose nevirapine) given to breastfeeding infants for six (SWEN) or 14 weeks (PEPI-Malawi) or six months (BAN) was more effective in reducing mother-to-child transmission (MTCT) compared to single-dose nevirapine.

In the analysis presented Dr Maldonado reported on the incremental protective benefits of extended-dose nevirapine to six months directly compared to six weeks.

In resource-poor settings, MTCT continues to cause significant death and disease. Approximately one third of the estimated 450,000 children infected each year are infected through breastfeeding. Safe alternatives are often not feasible for the majority of women in such settings. The risks for infant death and disease linked to not breastfeeding are greater than the risks associated with HIV infection.

Infant prophylaxis has proven effective in reducing MTCT. While maternal antiretroviral therapy (ART) is also effective in reducing MTCT many women, even if eligible (at CD4 cell counts below 350 cells/mm³), are not able to access treatment in resource-poor settings where coverage is severely limited. Those who do access ART often do so late in pregnancy. Viral suppression can take several weeks. So it is critical to look at the role of infant prophylaxis in reducing MTCT associated with breastfeeding.

HPTN 046 was a randomised, placebo-cotrolled, double-blind trial undertaken in South Africa, Tanzania, Uganda and Zimbabwe.

The multi-site study began in March 2007 with enrolment completed in January 2010. For the first six weeks of life all infants received single-dose nevirapine.

A total of 1522 breastfeeding, uninfected infants born to 1505 mothers were randomised at six weeks of age to get extended nevirapine (759 infants/752 mothers) or placebo (763 infants/753 mothers) for six months.

At the time of randomisation, 29% of mothers were on ART for their own health in each arm (221 in the extended-dose nevirapine and 219 in the placebo). Median maternal CD4 cell counts were 560 cells/mm³ and 528 cells/mm³ in the extended-dose and placebo arms, respectively. At six months the percentages of mothers on ART increased slightly to 31% and 32% in the nevirapine and placebo arms, respectively.

95% of infants were reported to be exclusively breastfeeding at three months; between six and nine months over 90% of all infants stopped breastfeeding. There was no significant difference between the arms.

Extended-dose nevirapine given for six months, compared to six weeks, where the mother was on ART at the time of randomisation, resulted in a 55% reduction in the infection rate (1.1% in the extended-dose nevirapine arm and 2.4% in the placebo arm).

In those mothers not on ART for their own health (CD4 cell counts over 350) the six-month infection rate was 2.4% (1.4% in the extended-dose arm and 3.4% in the placebo arm, p = 0.027).

When treatment stopped at six months the rates of MTCT between 6 and 12 months were similar in both arms.

There were no significant differences in adverse or serious events between the arms.

Dr Maldonado concluded that the benefits of extending the daily dose of nevirapine in breastfeeding infants of mothers with CD4 cell counts over 350 cells/mm³ and not on ART was significant in reducing MTCT.

These results, she added “support the benefits and safety of extended infant nevirapine for women who do not yet require ART for their own health [or cannot access it], a group of women relatively unprotected at this time.”

Adding nevirapine (NVP) or nelfinavir (NFV) and lamivudine (3TC) to the standard regimen of zidovudine (ZDV or AZT) halved the incidence of neonatal mother-to-child transmission among formula-fed infants born to mothers not getting antiretrovirals before labour Karin Nielsen-Saines reported at the same session.

Speaking for the HPTN 040/PACTG 1043 study, an ongoing prospective randomised trial in Brazil, South Africa, Argentina and the United States, she noted that only maternal viral load and treatment arm were significant factors associated with transmission.

Taking toxicity and ease of use into account initial findings suggested that the ZDV+NVP combination might be the preferred regimen.

As the study evaluated the efficacy of post-exposure prophylaxis in the prevention of intrapartum HIV-1 MTCT, only infants to be formula-fed were enrolled. Breastfeeding by HIV-positive women is contraindicated by Brazilian, Argentinian and United States HIV guidelines. In Brazil formula is provided for six months to all patients. In South Africa, patients who chose not to breastfeed and to use formula feed were eligible for enrolment. Infants were followed for the first six months of life.

Safe and effective formula-feeding is not feasible in most resource-poor settings and is associated with high rates of infant disease and death.

The multi-centre three-arm trial began in 2007 for women not on ART during pregnancy primarily because they were not identified as HIV-positive due to poor or absent prenatal care.

Women enrolled into the study were diagnosed through rapid testing during admission for labour and delivery. Women got intravenous ZDV when maternal diagnosis was made during labour. Infants were enrolled into the study within 48 hours of birth, and randomised to three different treatment arms for prevention of intrapartum MTCT.

The primary outcome was infant HIV infection at three months of age among infants not infected at birth.

Among 1684 infants transmission occurred in 3.2% (47) during labour and delivery, 24 (4.9%) of whom were in the ZDV arm (95% CI: 3.3 to 7.2).

Transmission for those in the ZDV + NVP arm was 2.2% (11) (95% CI: 1.2 to 4.0, p = 0.045 compared to the ZDV arm). And for those in the ZDV+NFV+3TC transmission was 2.5% (12) (95% CI: 1.4 to 4.3%, p = 0.045 compared to the ZDV arm).

However, in the ZDV+NFV+3TC arm neutropaenia (low number of white blood cells) was significantly higher than in the other arms (p < 0.001).

In response to a question from the audience Dr Nielsen-Saines noted the study began in 2001-2002 and the choice of ZDV+NFV+3TC was the best available protease inhibitor-based regimen at the time. The decision was made to continue with this regimen when other options became available.

Dr Nielsen-Saines concluded that a two- or three-drug antiretroviral prophylaxis regimen is preferable to standard zidovudine for prevention of mother-to-child transmission during labour and delivery among infants born to HIV-positive mothers not on antiretrovirals before labour.

Resistance testing is in process and will inform the choice for best regimen.

Coovadia H et al. HPTN: efficacy of extended daily infant NVP through age 6 months compared to 6 weeks for postnatal PMTCT of HIV through breastfeeding. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 123LB, 2011.

Nielsen-Saines K 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. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 124LB, 2011.

You can view the abstracts from this research on the official conference website:

Abstract 123LB: www.retroconference.org/2011/Abstracts/42412.htm

Abstract 124LB: www.retroconference.org/2011/Abstracts/42430.htm

You can also watch a webcast of the presentations made at this conference session, including speakers Yvonne Maldonado and Karin Nielsen-Saines.

Webcast from MTCT and HIV in Children.

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