Breast milk, HIV suppression and decreased mother to child transmission

13 October 2005. Related: Pregnancy.

Polly Clayden, HIV i-Base

Breast milk HIV-1 transmission contributes to 30-50% of infant infections in Africa. Recently published findings suggest that breast milk HIV suppression can decrease post partum mother to child transmission risk in this setting.

A study published in the September edition of The Journal of Infectious Diseases conducted by Shapiro and colleagues as a sub study of the Mashi trial in Botswana compared breast milk HIV-1 RNA and DNA in breast milk of women receiving and not receiving HAART (nevirapine, 3TC and AZT). [1, 2]

Women in the HAART group received treatment for a median of 98 days at the time of sampling; 23/26 (88%) had whole breast milk HIV-1 RNA l <50 copies/mL, compared with 9/25 (36%) women in the comparitor group who did not receive HAART (p=0.0001).

The authors report that in a multivariate analysis this finding remained significant (p = 0.0006). However they found that the whole milk HIV-1 DNA was not affected by HAART. Of the group of women receiving HAART, 13/26 (50%) had HIV-1 DNA loads <10 copies/106 cells, compared with 15/23 (65%) who did not receive HAART (p= 0.39).

The authors also noted that among the 21 women receiving HAART before delivery through the breastfeeding period (median duration 5.9 months), whose infants received AZT no transmissions occurred at 7 months after delivery.

They found that HAART suppressed cell-free HIV-1 RNA in breast milk and so may therefore reduce mother-to-child transmission (MTCT) of HIV-1 via breast-feeding. However, HAART initiated during pregnancy or early after delivery had no apparent effect on cell-associated HIV-1 DNA loads in breast milk. They wrote: “Clinical trial data is needed to directly measure MTCT rates in women receiving HAART. As the cost of HAART decreases and simplified regimens become available, maternal HAART may be a realistic strategy to maximise MTCT prevention in areas of the developing world where formula feeding is neither safe nor feasible.”

The investigators also report findings from a Mashi PK substudy to measure concentrations of nevirapine, 3TC and AZT in serum and whole breast milk from HIV positive mothers and serum from their uninfected breast feeding infants. [3]

Twenty mother-infant pairs were enrolled. The mothers had been receiving HAART (18 nevirapine/3TC/AZT and 2 nevirapine/3TC/d4T) for at least six weeks and the infants were receiving prophylaxis AZT and had received single dose nevirapine at birth.

The authors report that maternal serum concentrations of nevirapine were high (median, 9534 ng/mL at a median of 4 hours after nevirapine dose). Median breast milk concentrations of nevirapine, 3TC and AZT were 0.67, 3.34, and 3.21 times, respectively, those in maternal serum.

The median infant serum concentration of nevirapine was 971 ng/mL, at least 40 times the IC50 and although lower than therapeutic concentrations similar to peak concentrations after a single 2 mg/kg dose of nevirapine at birth. The median infant serum concentration of 3TC was 28 ng/mL, which is 5% of the IC50, and the median infant serum concentration of AZT was 123 ng/mL, which is 25 times the IC50. Infant serum concentrations of AZT were a median of 2.5 times higher than the maternal concentrations but infants were also receiving AZT prophylaxis. The authors made no comment about the breastfeeding infants of mothers receiving d4T that also received AZT prophylaxis.

The authors report that HIV-1 inhibitory concentrations of nevirapine are achieved in breast-feeding infants of mothers receiving this regimen, exposing infants to the potential risks and benefits including selection of resistant viruses should an infant become infected while breastfeeding. There were no transmissions during the study period.

They conclude that infant antiretroviral exposure to breastfeeding infants may be protective against mother to child transmission. They write: “Further study is needed to better understand the pharmacokinetics of these drugs in both the serum and breast milk of women in the developing world.”

Findings from Chung and colleagues published in the September edition of AIDS compared the effects of single dose nevirapine (HIVNET 012) and short course AZT (Thai-CDC) MTCT prophylaxis regimens on breast milk viral shedding and transmission at 6 weeks in a randomised controlled trial conducted in Nairobi. [4]

From March to October 2003, 76 women electing to breast feed were enrolled. A total of 795 breast milk samples were collected from 60 women over the first 6 weeks postpartum: 391 samples from 30 women in the AZT arm and 404 samples from 30 women in the nevirapine arm. The median number of breast milk samples collected per woman was 14. Breast milk was collected between 1 and 49 days postpartum with half of the total number of samples collected within the first 14 days after delivery.

Between days 3 and 7, mothers receiving nevirapine tended to have lower HIV-1 RNA viral loads in breast milk compared to those receiving AZT (median log10 HIV-1 RNA, 1.98 versus 2.42, p = 0.1). The effects of nevirapine compared to AZT became statistically significant in the second week postpartum (median log10 HIV-1 RNA, 1.78 vs 2.48, p= 0.005), and continued through the third week (median log10 HIV-1 RNA, 1.90 vs 2.97, p= 0.003). After four weeks, there was no statistically significant difference between the two arms.

At week two there were two infants infected in the AZT arm and one infant infected in the nevirapine arm. At 6 weeks, there were eight infants infected in the AZT arm and two infants infected in the nevirapine arm. The cumulative MTCT rate at 6 weeks was 6.8% [95% CI, 0.0-15.9%] in the nevirapine arm vs 30.3% (95% CI, 12.7-47.9%) in the AZT (p= 0.02).

The authors write: “Compared to a peripartum zidovudine regimen, nevirapine was significantly more likely to decrease HIV-1 RNA in breast milk during the first week and through the third week postpartum following single-dose administration, and corresponded with decreased transmission risk at 6 weeks. Sustained breast milk HIV-1 suppression may contribute to the ability of nevirapine to decrease perinatal transmission of HIV-1.”

References:

1. Shapiro R, Ndung’u,T, Lockman S et al. Highly active antiretroviral therapy started during pregnancy or postpartum suppresses HIV-1 RNA, but not DNA, in breast milk. Journ Infect Dis 2005;192:720-727.
2. Clayden P. Mashi Study – late breakers on breastfeeding. HTB Vol 6, No 4 April 2005 p 9-10.
3. Shapiro R, Holland TD, Capparelli E et al. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. Jour Infect Dis 2005;192;720-727.
4. Chung M, Kiarie, J, Richardson B et al. Breast milk HIV-1 suppression and decreased transmission: a randomized trial comparing HIVNET 012 nevirapine versus short-course zidovudine. AIDS: Volume 19(13) 2 September 2005 p 1415-1422.