Breast-Feeding and HIV-1 Transmission—How Risky for How Long?

[Guest guest]

Breast-Feeding and HIV-1 Transmission—How Risky for How Long?

Grace C. -, University of Washington School of Medicine,

Seattle

EDITORIAL COMMENTARY. The Journal of Infectious Diseases

2007;196:1-3

Reprints or correspondence: Dr. Grace C. -, University of

Washington School of Medicine, Seattle, WA, 98195.

(http://gjohn@u.washington.edu).

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Breast milk transmission of HIV-1 continues to present enormous

challenges for prevention of infant HIV-1 infection. Breast milk

confers a variety of benefits to infants but can also be a vehicle

for HIV-1 transmission. Determining the amount of risk due to breast-

feeding, duration of risk, and cofactors for risk is useful for

designing efficient interventions to decrease the incidence of infant

HIV-1 infection.

In this issue of the Journal, Taha et al. [1] evaluated late

postnatal transmission in cohorts of Malawian mother-infant pairs who

participated in 2 previously published clinical trials of

antiretrovirals to prevent mother-to-child transmission (the

nevirapine-zidovudine studies) [2, 3]. Overall, 1256 infants without

HIV-1 infection at 1.5 months were monitored for 24 months to

determine the risk of late postnatal transmission. The risk of HIV-1

acquisition in this group was 9.7%, and the vast majority (87.4%) of

late infections occurred after 6 months of age. The study was large,

yielded a fairly precise risk estimate, and included a 2-year follow-

up, which enabled comparison of risk estimates for serial intervals

of 6 months. Interestingly, the 1.5–6-month age interval was the one

with the lowest risk of HIV-1 transmission (1.22%). Finally,

utilizing the cohort's size and long follow-up period, the authors

were also able to identify several significant correlates of late

postnatal transmission.

How do these late postnatal transmission risk estimates fit into what

is currently known about breast milk HIV-1 transmission, and what are

the implications? As pointed out by the authors, these data confirm

previous studies and add to the growing evidence that late postnatal

transmission of HIV-1 can be substantial.

The transmission risk was 9.7%, which is similar to an estimate from

a large multisite meta-analysis (9.3%) and slightly lower than what

was seen in a Zimbabwean cohort (12.1%) [4, 5]. The data support

current guidelines from World Health Organization/Joint United

Nations Programme on HIV/AIDS that HIV-1–infected women should stop

breast-feeding when infants are 6 months of age [6].

At the same time, there is worrisome evidence from ongoing studies

suggesting that cessation of breast-feeding at 6 months may be

associated with increased morbidity and nutritional compromise.

Together, these observations point to an urgent need for realistic

strategies to support nutrition and prevent diarrhea in infants or

HIV-1–infected mothers who stop breast-feeding at 6 months.

A few caveats regarding denominators are important to consider

regarding risk of breast milk HIV-1 transmission.

First, the term " late postnatal transmission " only includes infants

who survived to 1.5 months without becoming infected. Although this

cut-off clearly excludes in utero or intrapartum infection, it also

excludes infants infected by breast milk HIV-1 transmission before

1.5 months of age. This leads to inconsistencies in statements

regarding the proportion of breast milk HIV-1 infection

occurring " early " or " late. " Because infant HIV-1 infections detected

during the first 6 weeks of life may be due to in utero, intrapartum,

or early breast milk transmission, the only way to determine early

breast-feeding transmission risk would be in a randomized comparison

with a non–breast-feeding cohort. Although both groups in such a

trial would have in utero and intrapartum infections, with

randomization, transmission risk difference between the groups at 1.5

months could be ascribed to breast-feeding HIV-1 transmission. In a

randomized trial comparing breast- and formula-feeding infants,

overall risk of breast-feeding HIV-1 transmission was 16.2% between

birth and 24 months, with 75% of the risk difference occurring by 6

months of age [7]. If late postnatal transmission cut-offs were

applied to this randomized trial, breast-feeding transmission risk

was 10.2% before 1.5 months, 6.0% between 1.5 and 24 months, and 4%

between 6 months and 24 months; hence, among the infants uninfected

at 1.5 months, 67% of risk occurred after 6 months.

Two conclusions thus remain true and noncontradictory: early breast

milk transmission of HIV-1 infection is substantial (before 1.5

months), particularly if mother-infant pairs do not receive

nevirapine, and " later late " (after 6 months) breast milk

transmission of HIV-1 infection is substantial (among infants who are

uninfected at 1.5 months).

A second caveat is that peripartum maternal nevirapine not only

affects early breast milk HIV-1 transmission but may also affect

estimation of late postnatal transmission risk.

For example, Taha et al. noted evidence of persistent effects of

maternal nevirapine on late transmission risk during the 1.5–6-month

interval.

Thus, the baseline peripartum antiretroviral intervention should be

kept in mind when comparing late transmission risk estimates.

Finally, the risk estimates between studies for late transmission

would be expected to be lower in some settings because

immunocompromised women, who have the greatest risk of late postnatal

transmission, may receive highly active antiretrovial therapy

(HAART). Thus, in countries such as Botswana with a longer history of

HAART provision, late postnatal transmission rates would be expected

to be lower than in Zimbabwe or Malawi, where HAART provision may not

yet be as widespread.

Taha et al. noted interesting differences in transmission risk

between intervals over the 2-year postpartum period—particularly, a

relatively low risk between 1.5 and 6 months, followed by a much

higher risk.

The authors also observed that mothers who received nevirapine had

significantly lower likelihood of having detectable breast milk HIV-1

between 1.5 and 3 months than women who did not receive nevirapine.

Persistent nevirapine effect may explain some residual decreased risk

between 1.5 and 6 months, despite the observation in this cohort that

nevirapine levels were almost never detectable in breast milk or

plasma after 1.5 months. Little is known regarding the origin of

breast milk HIV-1—the source could be locally HIV-infected

replicating cells or HIV-1–infected cells and free virus that migrate

from the systemic circulation.

The persistent suppression of breast milk HIV-1 despite drug absence

in this study is consistent with findings of other studies and

suggests compartmentalization of breast milk HIV-1 [8, 9]. The

authors also speculate that if the viral population in breast milk

takes months to revert from nevirapine resistance to the preexisting

wild type, the drug's residual effects on transmission may be

enhanced if resistant virus is less transmissible. Population studies

such as this one complement in vitro studies on infectiousness and

could be extended to discern effects of antivirals on infectivity

that may persist after intervention.

Three factors in this study predicted increased risk of late

postpartum transmission: maternal plasma viral load, primaparity, and

clinical mastitis. Transmitters were also noted to have significantly

higher likelihood of detectable breast milk HIV-1 than

nontransmitters. Although associations of plasma HIV-1, breast milk

HIV-1, and mastitis with breast milk HIV-1 transmission have been

reported previously, this study was larger than previous studies [10,

11]. Primaparity may have been a surrogate for inappropriate

lactation techniques or likelihood of subclinical mastitis.

Several interventions may address these correlations. Improved

lactational counseling would be expected to decrease mastitis.

Maternal viral levels of HIV-1 in breast milk can be decreased with

HAART; this is an ideal strategy for women who meet criteria for

HAART initiation, but it is less appealing for women who would not

otherwise start HAART.

Interventions to " sterilize " breast milk without systemic

administration may also be useful, but the process of expressing and

sterilizing breast milk before feeding may be cumbersome.

Infant antiretroviral prophylaxis is a particularly appealing

strategy to allow prolonged breast-feeding in settings where breast

milk substitutes are clearly suboptimal for safety and growth of

infants, and studies are under way to evaluate this approach.

In summary, Taha et al. have demonstrated in a large study that

breast milk transmission of HIV-1 persists into the very late

postnatal period and that the risk after 6 months postpartum

contributes the majority of risk between 1.5 and 24 months.

To put this in context, the risk of mother-to-child HIV-1

transmission is 30%–40% without any interventions; with peripartum

antiretrovirals, this risk declines to 10%–20% when breast-feeding is

limited to 6 months, which could increase by 8% if breast-feeding

continued to 24 months. Thus, with peripartum interventions to

prevent mother-to-child transmission, breast-feeding would contribute

to 30%–50% of infant HIV-1 infections if the breast-feeding period

were extended to 2 years.

Ultimately, new strategies such as vaccines that enable prolonged

risk-free breast-feeding by HIV-1–infected mothers would offer an

ideal solution. In the meantime, better ways to implement peripartum

interventions and either safely stop breast-feeding at 6 months or

reduce breast-feeding transmission risk after 6 months are critical

to decreasing infant HIV-1 infection.

References

1. Taha TE, Hoover DR, Kumwenda NI, et al. Late postnatal

transmission of HIV-1 and associated factors. J Infect Dis 2007;

196:10–4 (in this issue). First citation in article

2. Taha TE, Kumwenda NI, Gibbons A, et al. Short postexposure

prophylaxis in newborn babies to reduce mother-to-child transmission

of HIV-1: NVAZ randomised clinical trial. Lancet 2003; 362:1171–7.

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at birth to reduce perinatal transmission of HIV in an African

setting: a randomized controlled trial. JAMA 2004; 292:202–9. First

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