Treatment of HIV-positive breast-feeding mothers with antiretroviral therapy results in reduced viral loads in breast milk and anti-HIV drug levels sufficient to prevent HIV transmission, according to findings published in the 1st September edition of The Journal of Infectious Diseases.
Although formula feeding is recommended for HIV-positive mothers in the developed world in order to avoid the risk of HIV transmission through breast milk, many mothers in developing countries breast-feed their babies due to the unavailability of milk formula or clean water, because of the elevated risk of disease and death in formula-fed children, or for cultural reasons. It is estimated that over 40% of all HIV transmissions from mothers to their children occur during breast-feeding
The findings from this study suggest that HIV-positive women may be able to reduce the likelihood of transmitting the virus to their child by taking antiretrovirals during breast-feeding, at least where the drugs are available.
Breast milk viral load
Studies are currently underway to investigate how the risk of HIV transmission through breast milk can be minimised using antiretroviral drug regimens. One study, called ‘Mashi’, meaning ‘milk’ in Setswana, examined the levels of HIV in the milk of Botswanan women who had been taking a combination of nevirapine (Viracept), 3TC (lamivudine, Epivir) and AZT (zidovudine, Retrovir) for at least two months.
Breast milk viral loads were compared to those in women who had been taking AZT alone from week 34 of pregnancy plus a single dose of nevirapine during labour. All of the milk samples were taken between two and five months after giving birth, when all of the mothers were still breast-feeding (Shapiro 2005b).
Although there was no difference between the groups at the start of the study, at the time of sampling 23 (88%) of the 26 women taking the three-drug regimen had breast milk viral loads below 50 copies/ml, compared to nine (36%) of the women who were taking AZT monotherapy (p
After controlling for baseline CD4 cell count and viral load, this difference was still statistically significant (p
“The present study has demonstrated that highly active antiretroviral therapy (HAART) effectively suppresses HIV-1 RNA in whole breast milk”, the investigators conclude. “Because the HIV-1 RNA load is associated with the risk of mother-to-child transmission via breast-feeding, HAART may allow HIV-infected women to breast-feed more safely in areas of the world where formula feeding is neither safe nor feasible.”
The investigators also measured the levels of ‘cell-associated’ HIV in the women’s breast milk. Cell-associated HIV, often referred to as ‘pro-viral DNA’, is produced when the virus inserts its genetic material into the host cell’s DNA.
In contrast to free virus, the investigators found no differences in the levels of cell-associated HIV between the two groups of women. Thirteen (50%) of the women taking the three-drug regimen had levels of cell-associated DNA below 10 copies per million cells, compared with 15 (65%) of those taking AZT monotherapy (p = 0.39).
“In contrast to HIV-1 RNA viral load, we did not detect a significant effect of HAART on breast-milk DNA viral load,” the investigators write.
However, they point out that the risk of cell-associated DNA leading to HIV transmission is poorly understood. “The magnitude of cell-associated breast milk HIV-1 transmission is unknown,” they explain. No HIV transmissions were observed in any of the mother-infant pairs during this study.
Drug levels in breast milk
Investigators also measured the levels of nevirapine, 3TC and AZT in the breast milk of 20 of the mothers receiving the three-drug combination (Shapiro 2005a). They found that the median nevirapine level was two-thirds of that in the mothers’ blood, but that levels of 3TC were 3.34 times greater and AZT levels were 3.21 times greater than those in the blood.
When they assessed the drug levels in their babies’ blood, the investigators found that nevirapine levels were a median of 971ng/ml. This corresponds to over 40 times greater than the ‘50% inhibitory concentration’ (IC50) of 24ng/ml. This is the drug concentration that has been shown to inhibit HIV replication by 50%.
Although lower than the levels used to treat HIV infection, the investigators note that this concentration is similar to the level achieved by a single dose of 2mg/kg nevirapine. This is “well above the levels thought to be necessary to provide prophylaxis against HIV infection,” they write.
“When the mother is receiving HAART with these agents, antiretroviral administration to the infant may not be required for the prevention of mother-to-child transmission via breast-feeding,” they conclude.
The researchers note some potential side-effects of antiretroviral drug exposure in the infants. These included three serious cases of neutropenia, a low level of white blood cells, one case of anaemia and one case of severe rash at three days after birth.
“HIV-1 inhibitory concentrations of nevirapine are achieved in breast-feeding infants of mothers receiving these antiretrovirals, exposing infants to the potential for beneficial and adverse effects of nevirapine ingestion,” they write.
In contrast to nevirapine, 3TC levels were only 5% of the IC50, at a median of 28ng/ml. Median AZT levels were 123ng/ml, 25 times this drug’s IC50, but all of the infants were also receiving AZT by mouth.
Although there were no HIV transmissions in this study, the investigators warn that the levels of all three drugs could put any infants who do become infected at risk of developing drug resistance. This could impede their future treatment options if they are not given full doses of antiretrovirals in addition to the low levels in their mothers' milk.
“Further study is needed to understand the impact of maternal antiretroviral treatment on breast-feeding HIV-1 transmission, infant toxicity and HIV-1 resistance mutations among infected infants,” they write.
In an accompanying editorial, Marc Bulterys and co-authors conclude, “the quantities of nevirapine, although perhaps not of 3TC or AZT, that a child ingests through breast milk may not only reduce maternal viral load in breast milk but could potentially also provide infants with drug levels sufficient for prophylaxis against transmission.
“This may be yet another reason to instruct women to practice exclusive breast-feeding of their infants,” they write (Bulterys 2005).
Nevirapine vs. AZT
In a similar study, presented in the 2nd September edition of AIDS, investigators demonstrate that single-dose nevirapine is more likely to decrease breast milk viral loads than twice-daily AZT (Chung 2005).
While both of these regimens are widely implemented in resource-limited settings to prevent the transmission of HIV during childbirth, this study set out to compare the effects on transmission during breast-feeding.
Sixty Kenyan women were randomised to receive either 200mg nevirapine at the onset of labour or to receive 300mg AZT twice daily from week 34 of pregnancy and 300mg every three hours during labour. Babies born to mothers taking nevirapine also received a single dose of nevirapine within 72 hours of birth.
The women randomised to receive nevirapine had lower breast milk viral loads than those receiving AZT in the second and third weeks after childbirth (p
“We found that nevirapine resulted in significantly greater reduction of breast milk HIV-1 RNA and mother-to-child transmission compared to AZT,” the investigators conclude. “Our study suggests that nevirapine exerts at least part of its effect on reducing mother-to-child transmission by lowering breast milk HIV-1, and that this regimen may be superior to short-course AZT in breastfeeding HIV-1 infected mothers.”
Despite their demonstration that short-course therapy with a single drug can still reduce breast milk viral loads and HIV transmissions even after drug therapy has stopped, the investigators’ trial resulted in less dramatic viral load decreases and greater transmission levels than observed with combination therapy in the Mashi study. Although not yet universally available, the comparison of these studies may reflect the superiority of sustained combination therapy in preventing transmission through breast milk and remains a goal to curb the spread of HIV in the developing world.
Bulterys M et al. Combination antiretroviral therapy in African nursing mothers and drug exposure in their infants: new pharmacokinetic and virologic findings. J Infect Dis 192: 709-712, 2005.
Chung MH et al. Breast milk HIV-1 suppression and decreased transmission: a randomized trial comparing HIVNET 012 nevirapine versus short-course zidovudine. AIDS 19: 1415-1422, 2005.
Shapiro RL et al. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. J Infect Dis 192: 720-727, 2005a.
Shapiro RL et al. Highly active antiretroviral therapy started during pregnancy or postpartum suppresses HIV-1 RNA, but not DNA, in breast milk. J Infect Dis 192: 713-719, 2005b.