Thai Study Shows That Inexpensive Treatment Reduces Risk Of Mother To Child HIV Transmission|
Second Study Shows Treatment May Increase Drug Resistance
A single dose of the drug nevirapine given at the beginning of
labor, when combined with a short course of the anti-HIV drug AZT
(zidovudine), dramatically reduces a woman's chances of passing
HIV on to her child, according to a study of Thai women funded in
part by the National Institute of Child Health and Human Development
of the National Institutes of Health.
The study authors, publishing in the July 15 New England Journal
of Medicine, found that the two drug combination reduces transmission
of the virus to below 2 percent, similar to what is achieved with
more expensive three-drug regimens routinely prescribed in developed
However, in a second NIH-funded study in the same issue of the journal,
the same researchers followed the progress of women from the first
study who developed low levels of CD4+ cells after they had given
birth. CD4+ cells are a type of immune cell and low CD4+ levels
indicate that the HIV infection is growing worse and advancing toward
AIDS. The researchers found that some women who, after they had
given birth, developed low CD4 levels and who had received single-dose
nevirapine, harbored a strain of the virus that had grown resistant
to nevirapine. Women with resistant virus were less likely to show
a decrease in HIV levels when receiving anti-HIV therapy that contained
the drug nevirapine than women without such resistance. This second
study also received funding from NICHD, as well as from NIH's National
Institute of Allergy and Infectious Diseases.
In Thailand at the time of the study, the standard treatment to
reduce the risk of pregnant women passing HIV on to their infants
was a regimen of AZT, given during labor and delivery, and to newborns
for 1 week. The standard treatment also called for infants to formula
feed, rather than breast feed, to reduce the risk of transmitting
the virus through breast milk.
The lead author of the first study was Marc Lallemant, M.D., Institut
de Recherche pour le Développement, in Paris, France. In
2001, Dr. Lallemant and his coworkers began a study to determine
whether adding nevirapine to the standard therapy would further
reduce transmission of HIV from mother to child. Specifically, the
researchers sought to determine if adding a single dose of nevirapine
to the mothers during labor and to their infants after birth to
the standard AZT regimen would reduce transmission of the virus.
Enrollment in the trial was offered to 1844 pregnant Thai women
infected with HIV who were receiving care at 37 hospitals throughout
All women in the study received AZT starting at the beginning
of the last trimester, and infants were given the standard AZT treatment.
The women were then assigned at random to one of three groups. In
the first group, the women received a single dose of nevirapine
at the beginning of labor and their infants were given a single
dose of nevirapine at 48 to 72 hours of age. In the second group,
the women received nevirapine and their infants received a placebo
instead of nevirapine, while in the third group, both the women
and their infants received placebos instead of nevirapine.
In May of 2002, the AZT-alone arm of the study was discontinued
after the study's Data and Safety Monitoring Board conducted an
interim analysis and found that women receiving nevirapine were
much less likely to pass HIV on to their infants. Data and Safety
Monitoring Boards are independent panels that periodically monitor
the study's data to see whether any treatments need to be changed.
The researchers resumed the study, however, to determine if giving
a dose of nevirapine to the infants in addition to giving one dose
of the mothers would further reduce transmission of the virus.
Among the women who gave birth before the interim analysis, HIV
was transmitted from mother to child at a rate of 1.1 percent in
the group in which both mothers and infants received nevirapine.
The transmission rate was 6.3 percent for the group in which both
mothers and infants received AZT only. After the study's completion,
the final analysis also showed the rate of mother-to-infant HIV
transmission was 2.0 percent in the group in which both mother and
infant received nevirapine, compared to 2.8 percent for the group
in which only the mother received nevirapine. Overall, these two
rates were not statistically different. However, in women with low
CD4+ levels or higher HIV levels, giving nevirapine to both mothers
and infants seemed to reduce transmission of the virus slightly
more than did giving nevirapine to mothers alone.
By comparison, in the U.S., where pregnant women with HIV infection
usually receive three anti-HIV drugs starting in the second trimester,
the mother-to-child transmission rate is under 2 percent, said the
NICHD project officer for the study, Lynne Mofenson, M.D., Chief
of the Pediatric, Adolescent and Maternal AIDS Branch.
"The study shows that a short, inexpensive two-drug regimen
can be applied in developing countries and achieve success rates
near those seen with the current, more complex and expensive treatments
used in the U.S.," Dr. Mofenson said.
However, previous studies have shown that a few weeks after delivery,
some women who receive a single dose of nevirapine may harbor HIV
that is resistant to nevirapine, Dr. Mofenson said. She explained
that after treatment with nevirapine, low levels of the drug may
remain in the blood for up to 3 weeks. Under these conditions, HIV
strains that are susceptible to nevirapine quickly die off, while
the few viruses from a strain that is naturally resistant to the
When nevirapine is no longer present in the blood, the HIV strains
that are resistant to the drug fade and strains that are sensitive
to the drug return, Dr. Mofenson added. However, the resistant strains
may be present at low levels, and researchers do not know if the
presence of this resistant strain might alter the effectiveness
of nevirapine in women who later become sick and require treatment.
In a second study, Gonzague Jourdain, MD, of the Harvard School
of Public Health, and his colleagues, followed the progress of 269
women from the first study. These women later required anti-HIV
therapy because they developed low CD4+ counts at some time often
many months after they had given birth. In Thailand, the standard
treatment for HIV-infected persons with low CD4+ cell counts is
a regimen of three anti-HIV drugs, which includes nevirapine. The
researchers compared the women's responses after 6 months of three
anti-HIV drug therapy, which included nevirapine. Of the 269 women,
221 had received a single dose of nevirapine and 48 had not.
Compared to women who had not received nevirapine during labor,
those who had received the drug during labor were less likely to
achieve maximum HIV suppression. Maximal viral suppression is a
measure the researchers took to determine if the treatment had succeeded
in reducing the levels of HIV in the blood. Specifically, the researchers
considered maximal viral suppression to be less than 50 copies of
HIV per 1 milliliter of plasma.
After 6 months of therapy, the researchers were able to determine
the plasma levels of HIV for 229 women. Of these, 49 percent of
188 women who had received a single dose of nevirapine during labor
experienced maximal viral suppression. In comparison, 68 percent
of 41 women who had not received nevirapine experienced maximal
viral suppression. High levels of HIV in the blood before therapy
was begun were also associated with decreased likelihood of maximal
viral suppression, regardless of whether or not the women had received
a single dose of nevirapine during labor.
However, the women did not differ in some other indicators of response
to therapy. After 6 months of treatment, the women showed no difference
in the amount of increase in CD4+ levels or in the amount of weight
they had regained. Regaining lost weight is an indication that HIV
patients are responding to drugs that suppress the virus.
The researchers also looked for HIV strains that were resistant
to nevirapine in stored blood samples taken 10 days after the women
had given birth. In those women for whom blood samples were available,
32 percent of 209 women who had received a single dose of nevirapine
during labor had nevirapine-resistant HIV. By comparison, none of
the 47 women who had not received a single dose of nevirapine during
labor had nevirapine resistant HIV. Women who developed resistance
were more likely to have had lower CD4+ levels and higher HIV levels
before the second study began than women who did not develop resistance.
In the women who had received a single dose of nevirapine during
labor, those who had viral strains resistant to nevirapine 10 days
after they gave birth were least likely to experience maximal viral
suppression after 6 months of treatment 38 percent of 61 women.
In comparison, 52 percent of 119 women who had received a single
dose of nevirapine but did not have a resistant strain of the virus
achieved maximal viral suppression.
Dr. Mofenson noted that women with higher CD4+ levels and lower
levels of HIV are at less risk for developing nevirapine resistance
than those with low CD4+ counts and higher viral levels.
Given these facts, the study authors wrote that single dose nevirapine
therapy combined with the standard AZT treatment would be an important
tool for preventing the spread of HIV in developing countries and
were optimistic that methods could be found for preventing or treating
Dr. Mofenson noted that the researchers and the Thai Ministry of
Public Health have studies under way to find ways to reduce the
risk of nevirapine resistance and to determine the most effective
therapy for women who have received a single dose of nevirapine.
The Thai government now considers the combination of short course
AZT with single dose nevirapine as the standard for preventing mother
to child transmission of HIV.
In addition to support from NIH, this research was also supported
by the Agence Nationale de Recherches sur le Sida; the Ministry
of Public Health, Thailand; the Institut de Recherche pour le Développement,
France; the Institut National d'Etudes Démographiques, France;
and the Department of Technical and Economic Cooperation, Thailand.
The NICHD is part of the National Institutes of Health (NIH),
the biomedical research arm of the federal government. NIH is an
agency of the U.S. Department of Health and Human Services. The
NICHD sponsors research on development, before and after birth;
maternal, child, and family health; reproductive biology and population
issues; and medical rehabilitation. NICHD publications, as well
as information about the Institute, are available from the NICHD
Web site, http://www.nichd.nih.gov,
or from the NICHD Information Resource Center, 1-800-370-2943; e-mail