It
is well known that HIV may be transmitted from mothers
to babies during breast-feeding. While HIV
positive women in developed countries are advised to avoid breast-feeding
for this reason, this recommendation does not hold in resource-poor settings where
clean water and formula may not be readily available. According to the World Health
Organization (WHO), about 150,000 infants each year are infected with HIV through
breast-feeding.
Prophylactic
antiretroviral therapy with AZT
(zidovudine; Retrovir), nevirapine
(Viramune), or combination HAART
for the mother during pregnancy and delivery, plus treatment of the baby for 6
months after birth, has dramatically reduced the rate of mother-to-child transmission.
Researchers
with the Kisumu Breastfeeding Study in Kenya reported data from a study of extended
antiretroviral therapy in breast-feeding mothers (abstract 45aLB).
In
this study, women took AZT/3TC (lamivudine;
Epivir) plus nevirapine
from 34 weeks of gestation through 6 months postpartum; partway through the study,
nevirapine was replaced with nelfinavir (Viracept) in women with a CD4 count >
250 cells/mm3). Infants received a single dose of nevirapine at birth. Women were
advised to exclusively breastfeed for 6 months, then wean rapidly to avoid mixed
feeding of breast milk and other foods.
Infants were tested for HIV using
a polymerase chain reaction (PCR) assay at delivery, at 2, 6, and 14 weeks, and
at 6, 9, 12, and 18 months. Data were available for 502 infants.
Results
•
A total of 29 infants became infected with
HIV by the end of follow-up.
•
3 of these infections occurred after 6 months,
and 2 more after 1 year.
•
Cumulative infant HIV infection rates per
100 infants were 2.4 during the first week after birth, 3.9 at 6 weeks, 4.1 at
3 months, 5.0 at 6 months, 5.9 at 12 months, and 6.7% at 18 months.
•
At 12 months, the infection rate was higher
for girls than for boys (7.4 vs 4.5 per 100 infants, respectively).
•
The cumulative postnatal infection rate fell
to 3.5% after excluding babies who were presumably infected during delivery.
•
Log-rank tests showed no difference in infection
rates according to maternal CD4 count or specific drug regimen (nevirapine vs
nelfinavir).
In
conclusion, the researchers wrote, "Low 12-month infant HIV transmission
rates were achieved using maternal HAART from late pregnancy through 6 months
of breastfeeding. There was no difference in transmission based on maternal CD4
[count] or regimen."
"Further assessment -- adherence to antiretrovirals,
the optimal timing for breastfeeding cessation, HIV-free survival, and drug resistance
in maternal and infant HIV isolates -- is necessary to determine whether HAART
is a feasible, acceptable, safe, and efficacious strategy for prevention of mother-to-child
transmission among breast-feeding women, particularly those not meeting WHO treatment
criteria," they added.
In a related study (abstract 84LB),
the Kisumu team looked at emergence of drug resistance among infants whose mothers
received antiretroviral therapy. Genotypic evidence of resistance was uncommon
immediately following birth, but occurred with increasing frequency over time,
reaching about 66% by 6 months (40% of those exposed to nevirapine; 100% of those
exposed to nelfinavir). The M184V mutation (which confers resistance to 3TC) was
most common, seen in about half the infants, while the NRTI resistance mutations
K65R, D67N, T215Y, and the NNRTI mutations Y181C, K103N, G190A, and K101E were
each detected in a few babies.
"Among infants who became HIV-infected
by the first 6 weeks of life, antiretroviral resistance was initially not detected,
suggesting resistant virus may not have been transmitted from the mother,"
the researchers concluded. "However, resistance emerged during the breast-feeding
period, likely due to the transfer of [antiretrovirals] from breast-milk."
They
added that, "Differing HIV resistance patterns depending on the mothers'
treatment may have implications for the choice of [antiretrovirals] for mothers
during the breastfeeding period and for subsequent treatment of infants who become
HIV-infected."
PEPI-Malawi:
14-week Treatment for Babies
Other
studies presented at the conference showed that longer antiretroviral therapy
for babies can also reduce the risk of mother-to-child transmission through breast-feeding.
Researchers
with the PEPI-Malawi Study (abstract 42LB) evaluated whether extended daily oral
infant antiretroviral prophylaxis with nevirapine alone or nevirapine plus AZT
for 14 weeks, along with early weaning, would reduce postnatal HIV transmission.
In this open-label
study, just over 3000 infants who were uninfected at birth were immediately randomized
to receive 1 of the following regimens:
•
A short control regimen of single-dose nevirapine
plus 1 week of AZT monotherapy;
•
The control regimen plus extended daily nevirapine
through 14 weeks;
•
The control regimen plus extended daily nevirapine
and AZT though 14 weeks.
The
primary endpoint was HIV infection at 9 months in infants who were uninfected
at birth.
Results
•
Breast-feeding frequency was high from birth
through 6 months, then fell off substantially between 6 and 9 months (from about
90% to about 25%).
•
By 14 weeks, there was a significant difference
in rates of HIV infection:
•
10.6% with the control regimen alone;
•
5.2% with extended nevirapine (P < 0.00001
vs control);
•
6.4% in extended nevirapine plus AZT (P <
0.00001 vs control).
•
These differences were still evident at 9
months:
•
HIV infection: 13.0%, 7.2%, and 8.7%, respectively;
•
Mortality: 8.9%, 6.8%, and 6.3%, respectively.
•
There was no significant difference in the
rates of postnatal transmission, HIV infection, or death between the extended
nevirapine and nevirapine/AZT arms.
•
Most infant deaths were due to gastroenteritis
and pneumonia.
•
The frequency of grade 2 (moderate) or higher
adverse events did not differ across treatment arms.
In
conclusion, the investigators wrote, "Daily antiretroviral prophylaxis with
nevirapine or nevirapine/[AZT] for the first 14 weeks of life was safe and significantly
reduced risk of postnatal HIV infection at age 9 months compared to single-dose
nevirapine +1 week [AZT], and significantly increased 9 month HIV-free survival."
SWEN:
6-week Treatment for Babies
Researchers
with the Six Week Extended Dose Nevirapine (SWEN) Study Team conducted related
trials in Ethiopia, India, and Uganda (abstract 43). In these 3 separate
but coordinated controlled trials, a total of nearly 1900 HIV uninfected (by PCR)
infants born to HIV positive breast-feeding mothers were randomly assigned to
receive either:
•
Single-dose nevirapine given to women during
labor and a single dose given to infants immediately after birth;
•
The same regimen, plus infants given once-daily
nevirapine from day 8 through day 24.
Rates
of HIV infection and death were assessed at 6 weeks and 6 months of age. Data
from the 3 trials were pooled and analyzed together using a modified intent-to-treat
analysis excluding infants with missing specimens and those with indeterminate
or confirmed HIV infection at birth.
Results
•
At 6 weeks of age, infants in the extended-treatment
arm had about a 50% lower risk of HIV infection than those in the single-dose
arm (2.5% vs 5.3%), a statistically significant difference (P = 0.009).
•
For the primary endpoint of HIV transmission
by 6 months of age, infants receiving extended nevirapine had a 20% lower risk
of infection than those in the single-dose arm (6.9% vs 9.0%), but this no longer
reached statistical significance (P = 0.164).
•
Mortality rates at 6 months of age in the
2 arms were 1.1% vs 3.6%, respectively (P = 0.016).
•
Looking at a combined endpoint of postnatal
HIV transmission or death, the corresponding rates were 3.7% vs 6.8% (P = 0.008)
at 6 weeks and 8.0% vs 11.6% (P = 0.028) at 6 months.
•
The number of infants who experienced serious
adverse events was similar in both arms.
Based
on these findings, the investigators concluded, "Daily nevirapine from day
8 to 42 of life in breast-fed infants of HIV-infected mothers is feasible, as
safe, and more effective than single-dose nevirapine alone in improving HIV-free
survival at 6 months of age." Taken together, these findings extend the
dramatic reductions in mother-to-child transmission during pregnancy and delivery
brought about by antiretroviral prophylaxis, and offer a way to further limit
transmission for women in resource-limited settings for whom breast-feeding remains
the best option.
2/22/08
References
T
Thomas, R Masaba, R Ndivo, and others. Prevention of Mother-to-Child Transmission
of HIV-1 among Breastfeeding Mothers Using HAART: The Kisumu Breastfeeding Study,
Kisumu, Kenya, 2003-2007. 15th Conference on Retroviruses and Opportunistic Infections
(CROI 2008). Boston, MA. February 3-6, 2008. Abstract 45aLB.
C Zeh, P Weidle,
L Nafisa, and others. Emergence of HIV-1 drug resistance among breastfeeding infants
born to HIV-infected mothers taking antiretrovirals for prevention of mother-to-child
transmission of HIV: the Kisumu Breastfeeding Study, Kenya. CROI 2008. Abstract
84LB.
T Taha, M Thigpen, N Kumwenda, and others. Extended infant post-exposure
prophylaxis with antiretroviral drugs significantly reduces postnatal HIV transmission:
The PEPI-Malawi study. CROI 2008. Abstract 42LB.
J Sastry and others (Six
Week Extended Dose Nevirapine [SWEN] Study Team). Extended-dose nevirapine to
6 weeks of age for infants in Ethiopia, India, and Uganda: a randomized trial
for prevention of HIV transmission through breastfeeding. CROI 2008. Abstract
43.
Antiretroviral
Therapy for Mothers and Infants Lowers Risk of HIV Transmission during Breast-feeding
It
is well known that HIV may be transmitted from 
Researchers
with the Kisumu Breastfeeding Study in Kenya reported data from a study of extended
antiretroviral therapy in breast-feeding mothers (abstract 45aLB). 
Results
Researchers
with the Six Week Extended Dose Nevirapine (SWEN) Study Team conducted related
trials in Ethiopia, India, and Uganda (abstract 43). In these 3 separate
but coordinated controlled trials, a total of nearly 1900 HIV uninfected (by PCR)
infants born to HIV positive breast-feeding mothers were randomly assigned to
receive either:
