Nduati R, John G, Mbori-Ngacha D, Richardson B, Overbaugh J, Mwatha A, Ndinya-Achola J, Bwayo J, Onyango FE, Hughes J, Kreiss J. Effect of Breastfeeding and Formula Feeding on Transmission of HIV-1A Randomized Clinical Trial. JAMA. 2000;283(9):1167-1174. doi:10.1001/jama.283.9.1167
Author Affiliations: Departments of Paediatrics (Drs Nduati, Mbori-Ngacha, and Onyango) and Medical Microbiology (Drs Ndinya-Achola and Bwayo and Mr Mwatha), University of Nairobi, Nairobi, Kenya; Departments of Epidemiology (Dr Kreiss), Medicine (Drs John and Kreiss), Biostatistics (Drs Richardson and Hughes), and Microbiology (Dr Overbaugh), University of Washington, Seattle.
Context Transmission of human immunodeficiency virus type 1 (HIV-1) is known
to occur through breastfeeding, but the magnitude of risk has not been precisely
defined. Whether breast milk HIV-1 transmission risk exceeds the potential
risk of formula-associated diarrheal mortality in developing countries is
Objectives To determine the frequency of breast milk transmission of HIV-1 and
to compare mortality rates and HIV-1–free survival in breastfed and
Design and Setting Randomized clinical trial conducted from November 1992 to July 1998
in antenatal clinics in Nairobi, Kenya, with a median follow-up period of
Participants Of 425 HIV-1–seropositive, antiretroviral-naive pregnant women
enrolled, 401 mother-infant pairs were included in the analysis of trial end
Interventions Mother-infant pairs were randomized to breastfeeding (n = 212) vs formula
feeding arms (n = 213).
Main Outcome Measures Infant HIV-1 infection and death during the first 2 years of life, compared
between the 2 intervention groups.
Results Compliance with the assigned feeding modality was 96% in the breastfeeding
arm and 70% in the formula arm (P<.001). Median
duration of breastfeeding was 17 months. Of the 401 infants included in the
analysis, 94% were followed up to HIV-1 infection or mortality end points:
83% for the HIV-1 infection end point and 93% to the mortality end point.
The cumulative probability of HIV-1 infection at 24 months was 36.7% (95%
confidence interval [CI], 29.4%-44.0%) in the breastfeeding arm and 20.5%
(95% CI, 14.0%-27.0%) in the formula arm (P = .001).
The estimated rate of breast milk transmission was 16.2% (95% CI, 6.5%-25.9%).
Forty-four percent of HIV-1 infection in the breastfeeding arm was attributable
to breast milk. Most breast milk transmission occurred early, with 75% of
the risk difference between the 2 arms occurring by 6 months, although transmission
continued throughout the duration of exposure. The 2-year mortality rates
in both arms were similar (breastfeeding arm, 24.4% [95% CI, 18.2%-30.7%]
vs formula feeding arm, 20.0% [95% CI, 14.4%-25.6%]; P
= .30). The rate of HIV-1–free survival at 2 years was significantly
lower in the breastfeeding arm than in the formula feeding arm (58.0% vs 70.0%,
respectively; P = .02).
Conclusions The frequency of breast milk transmission of HIV-1 was 16.2% in this
randomized clinical trial, and the majority of infections occurred early during
breastfeeding. The use of breast milk substitutes prevented 44% of infant
infections and was associated with significantly improved HIV-1–free
Mother-to-child transmission of human immunodeficiency virus type 1
(HIV-1) may occur in utero, at time of delivery, or through breastfeeding,
but transmission frequency during each period has been difficult to determine.
Breast milk HIV-1 transmission was first described in women newly infected
after delivery through blood transfusion or heterosexual exposure.1,2 Based on meta-analysis, frequency of
breast milk transmission during acute maternal infection was estimated to
be 29% (95% confidence interval [CI] 16%-42%).3
For women with established infection, the additional risk of HIV-1 in breastfed
infants was estimated at 14% (95% CI, 7%-22%).3
Most observational cohort studies are characterized by feeding practice
homogeneity, with women in developed countries using formula and those in
developing countries breastfeeding. More recent observational studies in South
Africa and Brazil had a more equal distribution of feeding practice.4,5 Although these have provided valuable
estimates of transmission risk, choice of feeding modality may be associated
with other factors that influence transmission likelihood. Also, attempts
to measure breast milk transmission rate have been hampered by the difficulty
of distinguishing late in utero, intrapartum, and early breast milk transmission.
Following the first report of breast milk HIV-1 transmission, the Centers
for Disease Control and Prevention issued guidelines recommending that infants
of HIV-1–infected women should not be breastfed, which became the standard
of care in the industrialized world.6 Unfortunately,
most at-risk infants are in the developing world where breastfeeding is a
pillar of child survival, associated with reduced morbidity and mortality
from infectious disease and providing inexpensive nutrition.7
Thus, the World Health Organization's (WHO's) Global Programme on AIDS (acquired
immunodeficiency syndrome) recommended in 1987 and 1992 that in regions where
infectious disease and malnutrition are primary causes of infant mortality,
women should breastfeed irrespective of HIV-1 status.8,9
In 1996, the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommended
that HIV-1–seropositive women in resource-poor areas be encouraged to
make an informed choice about infant feeding, ie, that consideration of risks
and benefits of feeding practices be individualized for each woman.10 To make this informed choice, a reasonably accurate
estimate of risk and timing of breast milk HIV-1 transmission is required.
In 1992, we initiated a randomized clinical trial of breastfed and formula-fed
infants of HIV-1–infected women to determine frequency of breast milk
HIV-1 transmission and to compare mortality rates in the 2 arms.
Pregnant women attending 4 Nairobi City Council antenatal clinics were
offered counseling and serologic testing for HIV-1 by the research team. Seropositive
women were invited to attend the research clinic at Kenyatta National Hospital.
Women were eligible if they resided in Nairobi and had access to municipal-treated
water. Of Nairobi residents, 92% had access to municipal water during the
All eligible women received extensive counseling by study physicians
(R.N., G.J., and D.M.) on mother-to-child HIV-1 transmission, risks and benefits
of breastfeeding and formula feeding, and the nature of randomized clinical
trials. Policy recommendations for breastfeeding by HIV-1–infected women
issued by the WHO or UNAIDS were discussed.8- 10
Women agreeing to adhere to the mode of infant feeding determined by the randomization
process were enrolled.
At enrollment, the women had a standardized interview and a physical
examination. Interim history and physical examination were obtained at each
prenatal visit. A pelvic examination, which included screening for genital
tract infections and collection of cervical and vaginal secretions for HIV-1
DNA–polymerase chain reaction (PCR) analysis was conducted at about
32 weeks' gestational age.12 To determine CD4
and CD8 cell counts, HIV-1 RNA viral loads, and vitamin A levels, 15 mL of
blood was collected. Antiretroviral therapy was not used by participants.
Women were randomized to breastfeed or formula feed at about 32 weeks
using computer-generated block randomization. The formula group was given
free dried milk formula and safe preparation was demonstrated. Women were
told to boil water for mixing formula and to feed the infant with a cup instead
of a bottle to minimize bacterial contamination. At the next visit, women
were asked to demonstrate formula preparation. We purchased formula made in
Kenya and packaged in 500-g tins with a standardized measuring scoop, costing
400 Kenya shillings (US $7) per tin. Six months of formula costs about US
At delivery, 15 ml of cord blood was collected for lymphocyte separation.
Mother-infant pairs were followed up monthly in the first year and quarterly
in the second year of an infant's life. At each follow-up visit, an interim
history was obtained, including feeding history, and a physical examination
of infant and mother was performed. At 3-month intervals, 25 mL of breast
milk was collected. At birth, 6 weeks, 14 weeks, and every 3 months until
24 months of age, 5 mL of anticoagulated infant blood was collected in EDTA
tubes, along with 5 drops of blood on filter paper (Schleicher & Schuell,
Keene, NH) for HIV-1 DNA PCR testing. Study infants received standard childhood
immunizations and general medical care in the research clinic.
After delivery, staff again observed formula preparation and cup feeding.
A nurse visited women in their homes within 2 weeks of delivery to counsel
them about infant feeding, with repeat visits on an as-needed basis or following
a failed clinic appointment. Women who had left Nairobi were traced to their
The study was approved by the universities of Nairobi's and Washington's
institutional review boards and all women provided informed consent. Women
were encouraged to discuss study participation with husbands and key persons,
and many had several discussions with study physicians before deciding. The
Kenyan Ministry of Health gave permission to conduct the study.
For HIV-1 serologic testing an HIV enzyme-linked immunosorbent assay
(ELISA) (Behring, Ausgabe, Germany) was used for screening and a second ELISA
(Cambridge Biotech, Rockville, Md) for confirmation. The CD4 and CD8 cell
counts were determined using monoclonal antibodies (Becton Dickinson, Erembodegem-Aalst,
Belgium) and flow cytometry. Vitamin A levels were measured using high-performance
liquid chromatography on maternal serum or plasma samples.
Processing of peripheral blood mononuclear cell (PBMC), filter paper,
breast milk, cervical, and vaginal specimens has been described.12- 14
Nested PCR that detects a single HIV-1 provirus copy was used to detect HIV-1
in all specimens. Primers that recognized highly conserved gag gene sequences were used.12- 14
All PBMC samples from all children at all time points were tested using
HIV-1 PCR, allowing us to evaluate consistency of PCR results for each infant
and frequency of false-positive and false-negative test results. Of infants
classified as HIV-1 infected, 157 (95%) of 166 PBMC PCR test results, taken
after infant diagnosis of HIV-1 infection, were positive. Of infants classified
as HIV-1 uninfected, 1293 (98%) of 1318 noncord blood PBMC PCR results were
Maternal HIV-1 env subtype was determined using
heteroduplex mobility assays and/or sequence analysis.15
Maternal plasma viral load was measured using Gen-Probe HIV-1 RNA assay (Gen-Probe,
La Jolla, Calif).15 The lower limit of detection
is 50 copies/mL.
A child was determined to be HIV-1 infected if PBMC or filter paper
blood samples from 2 consecutive dates had positive test results for HIV-1
DNA by PCR, if a single blood sample had a positive test result for HIV-1
DNA if the sample was obtained at last visit seen, or if a serum sample had
a positive HIV-1 ELISA test result if the sample was obtained at the last
visit of a child 15 months or older with no sample from that date available
for PCR testing. A child was determined to be HIV-1 uninfected if no HIV-1
infection criteria were met, and if a blood sample obtained at the child's
last visit had a negative HIV-1 DNA test result, or if a serum sample obtained
at the last visit had a negative ELISA test result from a child 15 months
or older with no sample from that date available for PCR testing. For a child
determined to be HIV-1 infected because of 2 consecutive positive PCR test
results, time of infection was defined by the first test result.
The study was designed to have a sample size of 400 for 90% power to
detect a 1.6-fold difference in HIV-1 infection rates between breastfed and
formula-fed infants using a 2-sided test with α = .05, and allowing
for 25% loss to follow-up, based on the 48% transmission rate seen in a prior
Kenyan observational study.16
All analyses were intent-to-treat. For routine analyses, SPSS Version
8.0 (SPSS Inc, Chicago, Ill) was used. Differences between the 2 groups were
tested using the Mann-Whitney U test for continuous variables and Pearson χ2 test or Fisher exact test for binary variables. All tests were 2-tailed.
Only live-born singletons and first-born (more similar to singleton
delivery) twins were analyzed. In follow-up analyses of the HIV-1 infection
end point, an infant was defined as lost to follow-up at birth if not tested
for HIV-1. An infant was defined as lost to follow-up at time of the infant's
last HIV-1 test if the test preceded the end of the study or the infant's
death by more than 3 months. Follow-up duration was defined as age at last
HIV-1 test, or 24 months, whichever was less.
Mortality rates in the 2 arms were compared using Kaplan-Meier survival
analysis. However, we chose not to use Kaplan-Meier techniques for analysis
of the HIV-1 infection end point comparisons because we were concerned that
our data violated 2 key assumptions. One necessary assumption in Kaplan-Meier
analysis is that censored subjects are at the same risk as those remaining
in the analysis, ie, censoring is noninformative. Infants testing HIV-1 negative
several months prior to death would be censored at the time of last negative
HIV-1 test result in a standard Kaplan-Meier analysis. Since death and HIV-1
infection are highly correlated, death status provides information about infection
status. Thus, in these data, we had informative censoring. Another assumption
in Kaplan-Meier analysis is that event times are known exactly. In perinatal
HIV-1 studies, it is only known that infant infection occurred between the
last negative and the first positive HIV-1 test result; ie, the data are interval
censored. Due to informative censoring (death) and interval censoring, standard
survival analysis methods were inappropriate for use in estimating timing
of HIV-1 transmission and HIV-1–free survival. Also, as seen in other
perinatal HIV-1 studies, use of cord blood to assess HIV-1 infection at birth
was less than 100% specific, due to possible contamination by maternal blood.17 In our study, the HIV-1 PCR assay had a 90% (124/138)
specificity when applied to cord blood samples vs 100% for infant venous birth
samples, and 98% for all infant venous samples. Of the 233 available birth
blood samples, 181 were cord blood and 52 were infant venous blood draws.
Thus, a method for estimating joint distribution of death and HIV-1 infection,
which accounts for informative censoring, interval censoring, and imperfect
diagnostic test specificity at birth, was developed to estimate timing of
transmission and HIV-1–free survival.18
For the following equation, let s denote the time
of HIV-1 infection and t denote time of death. Then ws,t = ftgs|t where w is the
joint density of death and HIV-1 infection time, f
is the marginal density of death time, and g is the
conditional density of HIV-1 infection time given the death time. Since all
death times were known or right censored (we assume noninformatively), ft was modeled nonparametrically. Conditional
on time of death, t, the density g was assumed to have the form of a Weibull distribution with point
mass at time 0 (representing proportion of infants infected at birth), and
point mass for infants uninfected at 24 months or death (whichever came first).
in the equation shown above, the first line is the value of gs|t when s = 0, the second line is the value of gs|t when 0≤s≤t, and the third line is the value of gs|t
when s = NI, where NI equals not infected. The probability of escaping in
utero infection, pt, and the Weibull parameters, bt, and ct
were assumed to vary slowly in t using natural splines
with 0 or 1 knot to accomplish this. The overall model was fit by alternately
maximizing the likelihood of ft conditional
on gs|t and then maximizing the likelihood
of gs|t conditional on ft until convergence. The marginal distribution of time
of HIV-1 infection and estimates of HIV-1–free survival were derived
by appropriate summations or integration of the joint distribution ws,t. Tests for differences at fixed ages between the 2
groups were based on standard z tests using jackknife
SEs.19 A permutation test was used to test
for a difference in the distribution of HIV-1 infection time.19
More details are included in a technical report.18
All conclusions about timing of HIV-1 transmission and HIV-1–free survival
were robust to different assumptions and analytic approaches, including Kaplan-Meier
The data and safety monitoring board (DSMB) reviewed study progress
and interim analyses of primary end point data every 6 months; it made recommendations
for study continuation or cessation based on O'Brien-Fleming criteria for
group sequential testing.20 No outcome data
analyses were available to physician investigators during the study to ensure
masking to interim results.
The trial was originally designed to continue until 24 months following
the last birth. In July 1997, the DSMB recommended the study continue only
until 6 months after the last birth, by which time 95% of the primary infant
outcome results would be available. In April 1998, it recommended that breastfeeding
women be advised to stop breastfeeding and be given formula, and that the
study continue until July 31, 1998 (6 months after the last delivery) to complete
data collection. In April 1998, 13 women still being followed up had reported
breastfeeding at their last visit (including 12 randomized to the breastfeeding
arm). These women were advised to stop breastfeeding.
From November 6, 1992, to October 7, 1997, 16,529 women attending 4
antenatal clinics were screened for HIV-1 antibodies. Of these, 2315 (14%)
were HIV-1 seropositive. Of the HIV-1–seropositive women, 1708 (74%)
returned for results. Of those, 425 (25%) were enrolled. Thus, 18% of all
seropositive pregnant women identified were enrolled in the trial. This was
a highly selected subgroup, including women willing to have the feeding modality
for their infant be randomly assigned and meeting eligibility criteria that
would limit morbidity due to formula use and maximize follow-up and compliance
likelihood. The most common reasons for nonparticipation were participants'
unwillingness to be randomized to formula feeding and their plans to leave
Nairobi after delivery.
Median age of enrolled women was 23 years. Subjects were largely of
lower socioeconomic status, with 61% of women living in a 1-room home, 74%
sharing a toilet with other households, and 5% owning a refrigerator. All
women had access to clean water, and 76% had access to flush sanitation.
The HIV-1–related immunosuppression at about 32 weeks gestation
was moderate in the group overall, with only 47 (12%) of 381 women tested
having absolute CD4 cell counts of less than 200 × 106/L.
The median plasma viral load at this same visit was 42,360 (range, 112-2,483,750)
Of the 425 women enrolled, 212 were randomly assigned to breastfeed
and 213 to use formula (Figure 1).
The 2 groups had similar enrollment characteristics (Table 1).
At the time of delivery, 408 women remained in the study (Figure 1). After excluding stillbirths and second-born twins, 401
infants remained. Women randomized to the breastfeeding and formula groups
had similar pregnancy, labor, delivery, and neonatal characteristics (Table 2).
Of the 401 mother-infant pairs included in the analysis data set for
trial end points, 197 were in the breastfeeding arm and 204 in the formula
arm. The median follow-up time was 24 months for both groups (P = .88). Of the 401 infants, 68 (17%) were lost to follow-up before
determining their HIV-1 status at age 2 years, death, or study completion.
Women with infants lost to follow-up were not significantly different from
women with followed up infants in age, years of education, absolute CD4 cell
count, plasma RNA viral load, and infant birth weight.
The HIV-1 status outcome at study end was available for 333 infants
(83%), including 171 (87%) in the breastfeeding arm and 162 (79%) in the formula
arm (Figure 1). Mortality data at
study end were available for 371 infants (93%), and HIV-1 infection status
and/or mortality data at study end for 376 infants (94%), including 189 (96%)
in the breastfeeding arm and 187 (92%) in the formula arm. Children at study
end ranged in age from 6 to 24 months due to early trial termination. At study
end, 66% (263) of children had been enrolled at least 24 months previously,
82% (330) 12 months or more, and 100% (401) 6 months or more.
Compliance with the formula-feeding intervention was defined by complete
avoidance of breast milk. Compliance with the breastfeeding intervention was
defined by any use of breast milk. Compliance determinations were based on
self-reported feeding practices. Overall, 331 (83%) of the 401 participants
reported that they had complied with the assigned feeding modality, but the
percentages differed significantly by group. Of the 197 in the breastfeeding
arm 189 (96%) complied, but only 142 (70%) of the 204 women in the formula
arm (P<.001) complied.
Among compliant women in the breastfeeding arm, 95% were breastfeeding
at 3 months, 90% at 6 months, 80% at 12 months, 47% at 18 months, and 23%
at 24 months. Median breastfeeding duration was 17 months (range, <1 wk
to >24 mo). Median time to introduction of weaning foods was 3.8 months. In
the breastfeeding arm, 83% of women were exclusively breastfeeding at 6 weeks,
62% at 3 months, and 9% at 6 months after delivery (exclusive breastfeeding
defined as no intake other than breast milk).
Of the 401 infants in the study, 92 were HIV-1 infected, including 61
in the breastfeeding group and 31 in the formula group. Cumulative probability
of HIV-1 infection was significantly higher for infants randomized to breastfeeding
than for those randomized to formula (P<.001).
At 24 months, the cumulative probability of HIV-1 infection was 36.7% (95%
CI, 29.4%-44.0%) in the breastfeeding arm and 20.5% (95% CI, 14.0%-27.0%)
in the formula arm (P = .001) (Table 3). Thus, the excess transmission occurring in the breastfeeding
arm of the trial was 16.2% (95% CI, 6.5%-25.9%). In this arm, 44.1% of all
transmission was attributable to breastfeeding.
To assess timing of HIV-1 infection through breastfeeding, we compared
cumulative infection probabilities in the 2 groups at 6 specific ages at which
blood sampling was scheduled (Table 3).
There was a significant difference between the 2 groups at all ages after
birth, with most difference occurring early. Even by the 6-week point, the
risk difference was already 10.2% (95% CI, 3.1%-17.3%). Thus, 63% of overall
risk difference had occurred by 6 weeks, 75% by 6 months, and 87% by 12 months
of age. These data suggest that most breast milk HIV-1 transmission occurs
early during breastfeeding. However, the transmission risk difference between
the 2 arms continued to increase throughout the 24 months of the study, consistent
with ongoing breast milk HIV-1 transmission throughout the duration of exposure.
It should be noted that there was a nonstatistically significant 3.9% risk
difference between the 2 arms at birth. If this difference was subtracted
from the 24-month risk difference, excess transmission in the breastfeeding
arm at 2 years was still statistically significant (P
Eighty-four children died during the study, 45 in the breastfeeding
arm and 39 in the formula arm. The 24-month mortality rate was 24.4% (95%
CI, 18.2%-30.7%) in the breastfeeding arm and 20.0% (95% CI, 14.4%-25.6%)
in the formula feeding arm (P = .30) (Table 4). There was no significant difference in mortality curves
overall (P = .41) nor at 5 specific time points (Table 4), although there was a trend for
formula-fed infants regarding increased mortality during the first 6 weeks
of life (1.0% breastfed vs 3.9% formula-fed, P =
.06). An ongoing analysis of morbidity and mortality will be published separately.
Eighty infants in the breastfeeding arm and 58 in the formula arm were
either dead or HIV-1 infected by 24 months of age. The percentage of those
who were dead or infected at 24 months was significantly higher in the breastfeeding
arm than in the formula arm (42.0% vs 30.0%, P =
.02). The risk difference at 24 months was 12.0% (95% CI, 2.4%-21.6%). Expressed
conversely, HIV-1–free survival rates in the 2 arms were 58.0% and 70.0%,
In this trial, the estimated rate of breast milk HIV-1 transmission
was 16.2% during the first 2 years of life. Given an HIV-1 infection rate
of 36.7% in the breastfeeding arm, breast milk transmission accounted for
44% of all infant infections among those exposed to breast milk. Because more
than one quarter of women in the formula arm admitted to noncompliance with
feeding modality, our estimated breast milk transmission rate is an underestimate.
If we assumed that all transmissions in the formula arm that occurred after
14 weeks were due to noncompliance, our estimated breast milk transmission
rate would be 23.5% (36.7% − 13.2%, Table 3).
The second important finding of our trial concerns the timing of breast
milk HIV-1 transmission. Because cumulative HIV-1 infection rates in the 2
arms were significantly different as early as 6 weeks of life, our data suggest
that substantial transmission occurs early during breastfeeding. By 6 months,
an estimated 75% of all breast milk transmission had occurred, despite ongoing
exposure for an average of 1 additional year. Thus, transmission risk is nonlinear
during breast milk exposure duration. This could be due to variation in breast
milk infectivity over time. In a prior study of breast milk samples from birth
to older than 9 months, we found the highest prevalence of HIV-1 DNA in breast
milk cells in samples collected between 1 week and 3 months.13
Also, exposure diminishes as weaning foods are introduced and milk intake
declines. Infant susceptibility may vary over time and may be affected by
the developing immune system or gastrointestinal tract maturity. Finally,
within a cohort, as infections occur, the remaining pool of children may be
relatively resistant to infection and/or the pool of mothers less likely to
The third major finding was that infants assigned to the breastfeeding
and formula arms had comparable mortality rates through 24 months. There was
a nonstatistically significant increased mortality in the formula arm during
the first 6 weeks, when newborns may be at particular risk of serious infectious
disease morbidity. The mortality rates we observed were much higher than those
for the Nairobi population as a whole; the infant mortality rate was reported
to be 4.1% in 1998.11 However, mortality rates
in our trial were comparable to those seen in other cohorts of children of
HIV-1–infected women in Africa.21
The goal of any intervention to prevent mother-to-child HIV-1 transmission
is to have an uninfected infant who survives. The HIV-1–free survival
at age 2 years best captures the cumulative hazards of breast milk and formula
since most breastfed infants are completely weaned by this age (no longer
exposed to HIV-1) and most formula-fed infants should no longer be at risk
of diarrheal disease mortality. We found that HIV-1–free survival rates
at 2 years were significantly lower in the breastfeeding arm than in the formula
arm. Only 58% of women in the breastfeeding arm had an infant at 2 years who
was alive and HIV-1–infection free.
The major strength of this study was its randomized clinical trial design.
This approach avoided the limitations of observational cohort data as outlined
above. Because of randomization, women in both arms were comparable in all
measured baseline variables. Our results should thus give an unbiased estimate
of breast milk-transmission risk, since any differences in infant infection
rates in the 2 arms should be attributable to breastfeeding. Also, the clinical
trial design sidesteps difficulties in determining route of infection for
an individual child by comparing overall transmission rates in the 2 arms.
Although the randomized clinical trial design was the major strength
of our study, the unique nature of the intervention contributed to its main
weakness, compliance. Breastfeeding is the norm in Kenya, and women assigned
to the formula arm often experienced community, family, or spousal pressure
to breastfeed and were sometimes concerned about maintaining confidentiality
of their HIV-1 status. Also, formula-feeding logistics are more difficult
than breastfeeding, particularly in resource-poor areas. Despite knowledge
about the breast milk HIV-1 transmission risk, more than one quarter of women
randomized to use formula admitted to noncompliance. The true rate may have
been higher. Thus, our results are biased toward the null hypothesis, and
the breast milk transmission rate is an underestimate.
We conducted a randomized clinical trial, and we used the standard intent-to-treat
approach for all analyses, as is recommended for this study design.22 We included data on compliance rates, time of introduction
of weaning foods, and breastfeeding duration to aid in interpretation of results
or in considering generalizability to other populations. We did not present
secondary analyses of self-reported feeding behavior and HIV-1 transmission
or mortality, because feeding practices may be associated with confounding
variables that affect primary study outcomes. For example, compliance with
formula feeding was associated with significantly higher maternal plasma viral
load, ie, the decision to breastfeed despite randomization to formula was
related to maternal disease status.
Similarly, our trial was not designed to assess the impact of weaning
practices or duration of breastfeeding on HIV-1 transmission risk, and a secondary
analysis may well be misleading. The most common reasons for early introduction
of weaning foods in our trial were maternal illness, insufficient milk production
(often due to maternal illness), or poor infant feeding, all of which may
be linked to infant HIV-1 infection. If an association between weaning practices
and HIV-1 transmission were observed (as reported from an observational study),23 it would be difficult to adjust for all confounders
and to establish direction of causality.23
The results of this trial have significant public health implications.
Breastmilk avoidance could potentially decrease overall mother-to-child transmission
by 44%, a similar magnitude of reduction as that found at 3 to 6 months with
the short-course zidovudine regimens assessed for perinatal transmission prevention
in Côte d'Ivoire and Burkina Faso.24,25
Risks of HIV-1 transmission via breast milk may be fairly comparable across
populations, given similar exposure, but risks associated with formula are
community specific. In our trial, mortality rates in the formula and breastfeeding
arms were similar, but participants had access to clean water and extensive
instruction in safe use of formula. In developing country communities in which
clean water and formula-feeding knowledge are limited, the balance of risks
and benefits could be shifted. Finally, our results suggest that children
continue to acquire HIV-1 infection throughout their exposure to breast milk
but most transmission occurs during the first few months. Early cessation
of breastfeeding would prevent some infections but complete avoidance would
be necessary to markedly reduce transmission.
Our trial demonstrated that formula feeding results in a substantial
decrease in HIV-1 transmission risk, but formula is unaffordable for most
HIV-1–infected women in sub-Saharan Africa. In addition, this intervention
requires antenatal HIV-1 testing and a health care infrastructure to provide
education on formula feeding. Given the high HIV-1 seroprevalence in pregnant
women in sub-Saharan Africa, the current priority is to find ways to make
interventions to prevent infant HIV-1 infection widely available.