Nevirapine for breastfeeding infants: benefit of 6-week course still evident after one year

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Use of six weeks of extended-dose nevirapine compared to single-dose nevirapine accounted for a 62% reduction in infant mortality and a 46% reduction of HIV transmission or death in breastfed, HIV-exposed infants, according to the final 12-month analysis of the SWEN study.

Saad B. Omer and colleagues reported the final analysis of the Six Week Extended Dose Nevirapine (SWEN) randomised controlled trials in the advance online edition of AIDS.

These results confirm earlier reported analyses of six-week and six-month endpoints of the three SWEN trials.

Glossary

mother-to-child transmission (MTCT)

Transmission of HIV from a mother to her unborn child in the womb or during birth, or to infants via breast milk. Also known as vertical transmission.

not significant

Usually means ‘not statistically significant’, meaning that the observed difference between two or more figures could have arisen by chance. 

antenatal

The period of time from conception up to birth.

endpoint

In a clinical trial, a clearly defined outcome which is used to evaluate whether a treatment is working or not. Trials usually have a single primary endpoint (e.g. having an undetectable viral load) as well as a few secondary endpoints, covering other aspects of treatment safety, tolerability and efficacy.

capacity

In discussions of consent for medical treatment, the ability of a person to make a decision for themselves and understand its implications. Young children, people who are unconscious and some people with mental health problems may lack capacity.

The reduction in risk was only seen in infants born to mothers with CD4 counts above 350 cells/mm3.

Among infants of women with baseline CD4 cell counts below 350 there were no significant differences between single-dose and extended-dose nevirapine in infant death, HIV transmission, and HIV transmission or death.

Evidence of nevirapine resistance, as with other studies, was found in infants infected by six weeks of age: in the Ugandan part of the study 50% of infants who got single-dose nevirapine developed resistance compared to 84% of those who received extended-dose nevirapine prophylaxis.  Similarly in India prevalence was 38% and 92%, respectively.

So recent evidence of the effectiveness of starting ART in infants under 12 weeks of age raises the concern of what regimen to use in infected infants who got extended dose nevirapine, note the authors. They add, the increased risk for nevirapine resistance following extended dose nevirapine prophylaxis must be considered “against the benefit in the prevention of HIV transmission and death in breastfeeding infants of HIV-infected mothers.”

In resource-poor settings mother-to-child transmission of HIV continues to be a major cause of death and disease. Breastfeeding accounts for about a third of the estimated more than 420,000 children infected each year.

Because of the increased risks of death and disease from not breastfeeding compared to the risks of HIV-transmission, the World Health Organization (WHO) recommends that national authorities make a decision to recommend breastfeeding or not, based on local capacity to implement safe formula feeding.

Since safe and affordable replacement options to breastfeeding are severely limited in most resource-poor settings, effective strategies to prevent transmission through breastfeeding are critical.

Maternal ART, when available, can be protective against transmission. Lower maternal CD4 cell counts are associated with a greater probability of MTCT and death. And many women in resource-poor settings present late for antenatal care. For ART to be effective in PMTCT viral loads need to be undetectable. This can take several weeks. Maternal and infant single-dose and infant extended-dose nevirapine offer important alternative means of protection for the infants of HIV-infected breastfeeding mothers.

Infants in Ethiopia, India and Uganda born to HIV-infected mothers were randomised to get single-dose or extended-dose nevirapine. A total of 2067 HIV-positive mothers gave birth to 2037 infants at the three sites.

An analysis of 1890 infants with 987 in the single-dose nevirapine group and 903 in the extended-dose nevirapine group was undertaken. Information about the endpoint status at 12 months was available for 902 (91.3%) and 803 (88.9%), respectively.

Enrolment began in February 2001, August 2002 and July 2004 in Ethiopia, India and Uganda, respectively and the last 12-month follow-up in the respective countries was April 2007, September 2007 and July 2007.

While HIV transmission in the extended-dose group was 8.9% compared to 10.4% in the single-dose group, the difference was not significant (risk ratio: 0.87, (95% CI: 0.65-1.15).

At 12 months there was significant lower cumulative death (close to half) in the extended-dose group compared to the single-dose group (risk ratio 0.53, 95% CI: 0.32-0.85), most notably in infants who were uninfected by six weeks of age.

However, only in infants born to mothers with CD4 cell counts over 350 cells/mm3 were risk ratios for death (RR:0.38, 95% CI: 0.17-0.84) and for HIV transmission or death (RR: 0.54, 95% CI: 0.35-0.85) statistically significant among those who received extended-dose nevirapine.

These findings have clinical and policy implications for exposed but uninfected infants, note the authors.

Unable to account for the higher number of HIV-infected infants at birth in Uganda, the authors suggest this is perhaps due to chance. It may have contributed to an underestimation of the reduction in HIV infection and HIV infection or death.

The authors conclude where access to antiretrovirals is limited and safe replacement feeding is not an option these findings together with results from the PEPI and BAN trials “provide evidence for the use of extended-dose regimens to increase the likelihood of HIV-free survival in infants of HIV-infected breastfeeding women with CD4 cell counts over 350 cells/mm3 [that is not eligible for ART]”.

It is important to note that since the SWEN study was completed a trial comparing 6 months of nevirapine prophylaxis to the 6-week regimen used in the SWEN study has found that the longer course of prophylaxis significantly reduces the risk of HIV transmission from mother to child in the infants of mothers not eligible for antiretroviral treatment for their own health (CD4 counts > 350 cells/mm3 )(see report).

References

Omer, Saad B, for the Six Week Extended Dose Nevirapine (SWEN) Study Team. Twelve-month follow-up of Six Week Extended Dose Nevirapine randomized controlled trials: differential impact of extended-dose nevirapine on mother-to-child transmission and infant death by maternal CD4 cell count. AIDS 25 (6): 767–776, 2011.