Nevirapine in breast-fed babies prevents HIV infection, leads to drug resistance

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Prolonged nevirapine in breast-fed babies prevents HIV infection but

leads to drug-resistant HIV

Babies born to HIV-positive mothers and given the antiretroviral drug

nevirapine through the first six weeks of life to prevent infection

via breast-feeding are at high risk for developing drug-resistant HIV

if they get infected anyway, a team of researchers report. But the

investigators highlight the proven superiority of the six-week

regimen in preventing mother-to-child HIV transmission in breast-fed

infants.

In a study led by researchers at s Hopkins Children's Center,

risks of drug resistance in the first year of life were compared in

Indian infants getting a standard single dose of nevirapine at birth

and those on the six-week regimen.

" While extended nevirpaine prophylaxis dramatically reduces HIV

transmission during the first six weeks of life, our data show that

if infection does occur, it will most likely be with strains

resistant to nevirapine, making HIV much harder to treat early with

nevirapine, " says senior investigator Deborah Persaud, M.D., a

pediatric HIV expert at Hopkins Children's. " But until other

interventions become available, the extended nevirapine regimen

remains a reasonable way to prevent infections through breast-

feeding. "

Published in the Jan.1 issue of Public Library of Science One

(PLoSOne), the research report emphasized that in the developing

world especially, where bottle feeding is not safe, too expensive or

simply unavailable, the extended nevirapine therapy remains one of

the best ways to reduce mother-to-child transmission of HIV through

breast milk.

Given the high risk of death from HIV in infancy, the benefits of

fewer infections still outweigh the risk of increased resistance, the

researchers conclude.

The findings also suggest that because of their higher risk for

acquiring resistant HIV strains, infants given extended courses of

nevirapine¡ªshould they get infected¡ªshould receive treatment with

protease inhibitors (PIs), which are effective against nevirapine-

resistant strains.

" In the developing world testing for resistance is not available or

too expensive, " Persaud says, " so if extended nevirapine regimens

become widespread, PIs should be made available as a first line of

treatment early on for all infants who get infected despite

prophylaxis. "

The new report comes on the heels of two separate multi-center

studies from s Hopkins and other institutions, published in 2008,

showing that a six-week regimen with nevirapine or a 14-week regimen

with nevirapine slashed the risk of HIV infection from breast-feeding

by 46 percent and 66 percent, respectively.

For the current study, investigators analyzed samples from 74 Indian

babies infected with HIV before, during or after birth. Of the 74

infants, 22 were infected before birth, 19 were infected during birth

or during early breastfeeding (three to six weeks after birth) and 33

were infected during late breast-feeding (around six months after

birth). Of the 19 infants infected through breastfeeding in the first

six weeks of life, four were given daily nevirapine for six weeks,

and 15 received a single dose at birth. All four babies on extended

nevirapine developed resistant strains of the virus, while only four

of the 15 given a single dose tested positive for resistant strains

after infection.

It is important to keep in mind that while the risk of resistance is

higher with extended nevirapine regimens once infection occurs, the

risk of acquiring HIV with extended regimens is dramatically reduced,

the investigators say. Thus, in the long run, extended nevirapine

regimens do not lead to more resistant cases than the single-dose

regimens because single-dose regimens also carry some risk of

resistance and are also less effective in preventing new infections.

Indeed, when researchers compared resistance among infants infected

during late breast-feeding, the gap in resistance risk virtually

disappeared. Fifteen percent of the 13 infants given extended

nevirapine developed resistance, and so did 15 percent of the 20

infants who received a single dose of the drug.

When investigators used more sensitive assays to detect nevirapine-

resistant mutations that are normally not detected by standard tests,

the proportion of infants with resistant strains who had received

single-dose nevirapine went up from 38 percent to 59 percent among

the 29 infants who got the single dose, but remained unchanged in the

group receiving the six-week regimen, 92 percent of 12.

Likewise, the proportion of infants testing positive for resistance

went up in the group infected after six weeks of age. In that group,

31 percent of 13 infants on the extended regimen tested positive for

resistant strains, and 40 percent of 20 infants who got the single

dose had resistant strains. However, researchers say, the clinical

significance of mutations that are not detected by standard testing

remains unclear.

The infants in this trial were infected with HIV subtype C, but

previous studies have shown that the six-week regimen increases

resistance in infants who get infected with other HIV subtypes as

well.

Despite the risk of HIV transmission, breast-feeding for at least six

months is widely encouraged by the World Health Organization (WHO)

and other organizations as a proven factor in better infant survival.

In 2007 alone, 420,000 infants acquired HIV in utero, during birth or

during breast-feeding, according to WHO estimates. HIV infection is

estimated to occur in 1 out of 10 breast-fed infants, with many of

the infections occurring in the first six to 14 weeks of life.

###

The research was funded by the Glaser Pediatric AIDS

Foundation and by the National Institutes of Health.

Anita Moorthy of s Hopkins is the first author on the study.

Other s Hopkins investigators in the study: Bollinger,

Amita Gupta and Ziemniak. Investigators from the Indian arm of

the trial include: Ramesh Bhosale, Renu Bharadwaj, Anju Kagal, Arvind

Bhore and Varadharajan Venkataramani of Byramjee Jeejeebhoy Medical

College; Skrikanth Tripathy, Smita Kulkarni and Madhuri Thakar of the

National AIDS Research Institute; and Jayagowri Sastry, Sandesh

Patil, Vandana Kulkarni, Usha Balasubramaniam, Nishi Suryavanshi, and

Nikhil Gupte of the India SWEN Study Team.

ABSTRACT

Nevirapine Resistance and Breast-Milk HIV Transmission: Effects of

Single and Extended-Dose Nevirapine Prophylaxis in Subtype C HIV-

Infected Infants

Anitha Moorthy1, Amita Gupta2, Ramesh Bhosale3, Srikanth Tripathy4,

Jayagowri Sastry5, Smita Kulkarni4, Madhuri Thakar4, Renu Bharadwaj3,

Anju Kagal3, Arvind V. Bhore3, Sandesh Patil5, Vandana Kulkarni5,

Varadharajan Venkataramani3, Usha Balasubramaniam5, Nishi

Suryavanshi5, Ziemniak6, Nikhil Gupte5, Bollinger2,

Deborah Persaud6*, for the India SWEN Study Team

1 Department of Molecular Microbiology and Immunology, s Hopkins

Bloomberg School of Public Health, Baltimore, land, United States

of America, 2 Department of Adult Infectious Disease, s Hopkins

University School of Medicine, Baltimore, land, United States of

America, 3 Byramjee Jeejeebhoy Medical College, Pune, India, 4

National AIDS Research Institute, Pune, Maharashtra, India, 5 India

SWEN Study Team, Pune, Maharashtra, India, 6 Department of

Pediatrics, s Hopkins University School of Medicine, Baltimore,

land, United States of America

Abstract

Background

Daily nevirapine (NVP) prophylaxis to HIV-exposed infants

significantly reduces breast-milk HIV transmission. We assessed NVP-

resistance in Indian infants enrolled in the ¡°six-week extended-dose

nevirapine¡± (SWEN) trial who received single-dose NVP (SD-NVP) or

SWEN for prevention of breast-milk HIV transmission but who also

acquired subtype C HIV infection during the first year of life.

Methods/Findings

Standard population sequencing and cloning for viral subpopulations

present at ¡Ý5% frequency were used to determine HIV genotypes from

94% of the 79 infected Indian infants studied. Timing of infection

was defined based on when an infant's blood sample first tested

positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six

weeks of age had a significantly higher prevalence of NVP-resistance

than those who received SD-NVP, by both standard population

sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency

clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of

infection with NVP-resistant HIV through breast-milk among infants

infected after age six weeks was substantial, but prevalence of NVP-

resistance did not differ among SWEN or SD-NVP exposed infants by

standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00)

and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-

resistance mutations and patterns of persistence at one year of age

were similar between the two groups. NVP-resistance mutations did

differ by timing of HIV infection; the Y181C variant was predominant

among infants diagnosed in the first six weeks of life, compared to

Y188C/H during late breast-milk transmission.

Conclusions/Significance

Use of SWEN to prevent breast-milk HIV transmission carries a high

likelihood of resistance if infection occurs in the first six weeks

of life. Moreover, there was a continued risk of transmission of NVP-

resistant HIV through breastfeeding during the first year of life,

but did not differ between SD-NVP and SWEN groups. As with SD-NVP,

the value of preventing HIV infection in a large number of infants

should be considered alongside the high risk of resistance associated

with extended NVP prophylaxis.

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