NIH Trial Tests Very Early Anti-HIV Therapy in HIV-Infected Newborns

November 3, 2014

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​A new clinical trial is exploring whether giving anti-HIV therapy soon after birth to infants who became infected with HIV in the womb leads to remission of the virus, enabling the children eventually to stop treatment for an extended time period. The study is sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both part of the National Institutes of Health.

“HIV typically takes just a few days to gain a permanent foothold in a newly infected person,” explained NIAID Director Anthony S. Fauci, M.D. “The theory behind this study is that starting antiretroviral therapy within hours of birth in newborns who became HIV-infected in the womb may limit how entrenched the virus becomes.”

“If this theory is correct, then very early therapy may create conditions that enable the developing immune systems of HIV-infected infants to suppress the virus long term,” said Rohan Hazra, M.D., a medical officer at NICHD.

Adding perspective, Dr. Fauci said, “It is much better to prevent a baby from being born with HIV than to treat a baby who is born infected. The global health community has proven strategies for preventing mother-to-child HIV transmission, but unfortunately, they have not yet been implemented or adopted universally. That is why we must conduct this trial while also striving toward 100-percent prevention of mother-to-child HIV transmission.”

Leading the Phase I/II proof-of-concept study are Yvonne Bryson, M.D., distinguished professor and chief of global pediatric infectious diseases in the David Geffen School of Medicine at the University of California, Los Angeles and Mattel Children’s Hospital UCLA; and Ellen Chadwick, M.D., professor of pediatrics at the Northwestern University Feinberg School of Medicine and the Ann and Robert H. Lurie Children’s Hospital of Chicago.

The trial aims to build on the results of the Mississippi Baby case of an infant born with HIV infection in July 2010 who received triple-drug anti-HIV therapy starting at 30 hours of age—more drugs at higher doses than the norm at that age in the United States. The child fell out of medical care and stopped taking the drugs around 18 months of age, but returned to care 5 months later with no detectable virus in the blood. HIV remained in remission for another 22 months (for a total of 27 months) before it reappeared and the child restarted treatment.

“This case, in which the virus was in remission for an unprecedented length of time for a child who acquired HIV perinatally, represents the first step on a path toward the goal of a lifetime free of therapy for HIV-infected children,” said Dr. Chadwick.

 

“The intermediate goal that we hope to achieve in the current study is sustained HIV remission in young children to substantially delay the time when they must resume treatment,” added Dr. Bryson.

The study is being conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), a network jointly funded by NIAID, NICHD and the National Institute of Mental Health at NIH. AbbVie Inc., of North Chicago, Illinois, is donating one of the study medications.

The trial, called IMPAACT P1115, will involve up to 472 babies and their HIV-infected mothers in at least nine countries in Africa and North and South America. With their mothers’ consent, two groups of infants will participate. One group will involve approximately 440 babies at high risk for HIV infection because they were born to HIV-infected women who did not receive any anti-HIV drugs during pregnancy. Within 48 hours of birth, these infants will be enrolled in the study, tested for HIV and started on triple-drug antiretroviral therapy. If it is confirmed that an infant became infected in the womb, he or she will remain in the study; otherwise, the baby will

transition to a routine preventive HIV drug regimen and will leave the trial by 4 weeks of age. The study team expects to identify 22 infants in this group who became infected with HIV in the womb.

The second group will comprise up to 32 babies born with HIV infection even though their infected mothers may have taken antiretrovirals during pregnancy. Unlike the first group, these infants will have received their first HIV test and begun receiving antiretroviral therapy outside the trial within 48 hours of birth. They will be enrolled in the study within 10 days of birth if it is documented that they became infected in the womb, and they will continue receiving antiretroviral therapy within the trial.

Study investigators will monitor the health and amount of virus in the blood of all HIV-infected infants.

To learn if giving HIV-infected newborns very early antiretroviral therapy leads to HIV remission, the investigators will, after consultation with the children’s families or legal guardians, stop treatment in those children who are at least 2 years old and in whom the virus has been undetectable for at least 72 weeks. These children will stay off therapy as long as HIV remains undetectable in their blood, and they will be carefully monitored through at least age 5 years and as long as the virus is in remission. The investigators will consider a child’s HIV to be in remission if his or her virus is undetectable for 48 consecutive weeks while off treatment. If the virus reappears in a child’s blood, he or she will restart antiretroviral therapy.

An expert panel will periodically review the state of the science in HIV remission research to determine whether the study’s eligibility criteria for halting treatment are aligned with the latest available data. If necessary, the panel will advise the protocol team to change the criteria. In addition, when a child becomes eligible to stop treatment, study staff will meet with the child’s family or legal guardian to discuss the latest relevant research and work with them to decide whether it is in the child’s best interest to halt treatment.

The study team will separately track babies who are breastfed and those who are formula-fed, as there is a small risk that breastfed babies could acquire a second HIV infection through their mothers’ breast milk, which would complicate interpreting the impact of very early treatment.

The HIV-infected mothers will be cared for by health professionals in the hospitals where they give birth, counseled to start or resume antiretroviral therapy, and linked to physicians in their communities for ongoing medical care for HIV infection.

For more information about the IMPAACT P1115 clinical trial, please see Questions and Answers: The IMPAACT P1115 HIV Clinical Trial or ClinicalTrials.gov under study identifier NCT02140255.

 

This study is funded by NIH grant numbers UM1-AI-068632, UM1-AI-068616, UM1-AI-106716, UM1-AI-069469, UM1-AI-069436, UM1-AI-069521, UM1-AI-069423, UM1-AI-069477, UM1-AI-069465, UM1-AI-069530, UM1-AI-069421, UM1-AI-069463, UM1-AI-069536, UM1-AI-069518 and UM1-AI-069415, and by contract number HHSN275201300003C.

Question & Answer: 

The IMPAACT P1115 HIV Clinical Trial

What is the IMPAACT P1115 clinical trial?

The IMPAACT P1115 clinical trial is a Phase I/II proof-of-concept study exploring whether giving anti-HIV therapy soon after birth to infants who became infected with HIV in the womb leads to remission of the virus, enabling the children eventually to stop treatment for an extended time period.

What is the hypothesis underlying this trial?

This study is testing the hypothesis that starting antiretroviral therapy within hours of birth in newborns who became HIV-infected in the womb may limit how entrenched the virus becomes. If this hypothesis is correct, then very early therapy may create conditions that enable the developing immune systems of HIV-infected infants to suppress the virus long term.

Who will participate in IMPAACT P1115?

The trial will enroll up to 472 babies and their mothers. Ultimately, up to 54 HIV-infected mother-infant pairs are expected to remain in the study. For a detailed explanation of the number of study participants, please see the answer to question 7 below.

When and where will the trial take place?

The first clinical trial sites opened for enrollment this month, and the study is expected to last at least 5 to 7 years.

The trial will take place in at least nine countries, including Argentina, Brazil, Haiti, Malawi, South Africa, Uganda, the United States, Zambia and Zimbabwe.

Who is sponsoring and funding the trial?

The study is sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both part of the National Institutes of Health. AbbVie Inc. of North Chicago, Ill., is donating one of the study medications (ritonavir-boosted lopinavir).

Who is leading and conducting the trial?

Leading the trial are Yvonne Bryson, M.D., distinguished professor and chief of global pediatric infectious diseases in the David Geffen School of Medicine at the University of California, Los Angeles and Mattel Children’s Hospital UCLA; and Ellen Chadwick, M.D., professor of pediatrics at the Northwestern University Feinberg School of Medicine and the Ann & Robert H. Lurie Children’s Hospital of Chicago; along with Mark Cotton, M.Med, FCPaed (SA), Ph.D., professor and head of the division of pediatric infectious diseases at Tygerberg Children's Hospital in the Faculty of Medicine and Health Sciences at Stellenbosch University in Parow, South Africa.

The study is being conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), a network jointly funded by NIAID, NICHD and the National Institute of Mental Health at NIH.

How is the IMPAACT P1115 trial designed?

The study team will enroll two groups of infants and their mothers. The first group will involve around 440 babies born to HIV-infected women who did not receive any antiretroviral drugs during pregnancy. Within 48 hours of birth, these infants will be enrolled in the study, tested for HIV and started on triple-drug antiretroviral therapy. If it is confirmed that an infant became infected in the womb, he or she will remain in the study; otherwise, the baby will transition to a routine HIV preventative drug regimen by age 2 weeks and then leave the trial by age 4 weeks. The study team expects to identify 22 infants in this group who became infected with HIV in the womb.

The second group will comprise up to 32 babies born with HIV infection because, during pregnancy, their infected mothers either did not receive any antiretrovirals or did not receive a sufficiently protective course of antiretrovirals. Unlike the first group, these infants will have received their first HIV test and begun receiving antiretroviral therapy outside the trial within 48 hours of birth. They will be enrolled in the study within 10 days of birth if it is documented that they became HIV-infected in the womb, and they will continue receiving antiretroviral therapy within the trial.
 
Mother-infant pairs will be enrolled in the trial such that some of the babies are formula-fed and some are breastfed, depending on the infant feeding guidelines for HIV-infected mothers in their country.
 
Study investigators will monitor the health and amount of virus in the blood of all HIV-infected babies. For the monitoring schedule, please see question 10.
 
To learn if giving HIV-infected newborns antiretroviral therapy very early leads to HIV remission, the investigators will, after consultation with the children’s families or legal guardians, stop treatment in those children who are at least 2 years old and in whom the virus has been undetectable for at least 72 weeks. These children will stay off therapy as long as HIV remains undetectable in their blood, and they will be carefully monitored through at least age 5 years and as long as the virus is in remission. The investigators will consider a child’s HIV to be in remission if it is undetectable for 48 consecutive weeks after stopping therapy. If the virus reappears in a child’s blood, he or she will restart antiretroviral therapy.
 
Those children who never meet the criteria for stopping antiretroviral therapy will be carefully monitored until they are roughly 4 years old and then will leave the trial.

How will each child’s family be involved in the decision to stop treatment?

When a child becomes eligible to stop treatment, clinical staff will meet with the child’s family or legal guardian to discuss the latest relevant research and the study’s eligibility criteria for halting treatment and will work with the family or legal guardian to decide whether taking the child off antiretroviral therapy is in his or her best interest.

How will scientific developments impact the timing of treatment cessation?

When the first child whose virus is suppressed by antiretroviral therapy reaches age 1 year, an independent panel of experts will review the state of the science in HIV remission research to determine whether the study’s eligibility criteria for halting treatment are aligned with the latest available data. If necessary, the panel will advise the protocol team to amend the criteria. This process will be repeated before the first child stops treatment and periodically throughout the study.

How frequently will the study team monitor the HIV-infected children in the trial?

Children on therapy will be monitored weekly for their first two weeks in the study, biweekly through week 8, every 4 weeks through week 72, and every 12 weeks through roughly age 4 years. When a child is taken off antiretroviral therapy, he or she will be monitored weekly for the first 4 weeks after halting treatment, biweekly through week 8, every 4 weeks through week 16, every 8 weeks through week 48, and every 12 weeks through at least age 5 years and as long as the virus is in remission.

What drug regimens will the infants receive?

The infants in the first group (those enrolled within 48 hours of birth) will initially receive nevirapine and two nucleoside reverse transcriptase inhibitors (NRTIs) selected by their primary health care provider. The dosing will be as follows:
nevirapine: 6 milligrams per kilogram (mg/kg) orally twice daily (this dose may be changed based on pharmacokinetic analysis of the first 30 babies to receive it)
NRTIs: Dosing according to national or World Health Organization (WHO) guidelines
Beginning at 14 days of age and 42 weeks postmenstrual age, all HIV-infected babies in both groups will continue this regimen with the addition of ritonavir-boosted lopinavir. The dosing will be as follows:
nevirapine: 6 mg/kg orally twice daily (this dose may be changed based on pharmacokinetic analysis of the first 30 babies to receive it) until the child’s week 4 visit to the study site, then 200 mg per square meter (mg/m2) twice daily or WHO weight band dosing (which assigns a fixed dose of medication for each pediatric weight range)
ritonavir-boosted lopinavir: 300 mg/m2 lopinavir and 75 mg/m2 ritonavir orally twice daily
NRTIs: Dosing according to national or WHO guidelines
If the viral load of an infant becomes undetectable for 12 consecutive weeks, nevirapine will be removed from the drug regimen and the infants will remain on ritonavir-boosted lopinavir and two NRTIs.

 

What drug regimen do newborns in the United States usually receive if a physician believes the child may have acquired HIV infection from his or her HIV-infected mother during pregnancy, labor or delivery?

If a physician in the United States suspects that a newborn is at high risk for acquiring HIV infection from his or her HIV-infected mother during pregnancy, labor or delivery, the HIV-exposed infant usually receives one primary drug (zidovudine) twice daily for the first 6 weeks of life and three doses of a second drug (nevirapine) during the first week of life. If HIV infection is determined by viral diagnostic testing, the infant then starts triple-drug therapy, usually with ritonavir-boosted lopinavir and two NRTIs at around age 2 weeks.

How will the safety of the participating infants be ensured?

The IMPAACT P1115 Clinical Management Committee, which consists of scientists who designed the trial, will regularly monitor the safety of the enrolled children through reports on any side effects they may experience by participating in the study. In addition, an independent Study Monitoring Committee (SMC) composed of pediatric HIV researchers and scientists, statisticians, and representatives from NIAID and NICHD will review the safety of the enrolled children every 6 months. The SMC will alert the study team if anything appears to compromise the children’s health and well-being or if it becomes clear that the study cannot answer a question it was designed to address.

What care will the mothers receive for their HIV infection?

The HIV-infected mothers will be cared for by health professionals in the hospitals where they give birth, counseled to start or resume antiretroviral therapy, and linked to physicians in their communities for ongoing medical care for HIV infection.

How does this study relate to the Mississippi Baby?

The IMPAACT P1115 trial aims to build on the results of the Mississippi Baby case of an infant born with HIV infection in July 2010 who received triple-drug anti-HIV therapy starting at 30 hours of age, stopped taking the drugs around 18 months of age when she fell out of medical care, and returned to care five months later with no detectable virus in the blood. HIV remained in remission for another 22 months (for a total of 27 months) before it reappeared and the child restarted treatment.
(The baby became infected because the HIV-infected mother did not receive antiretroviral therapy during pregnancy to prevent transmission of the virus to her child.)

What changes were made to the study after the Mississippi Baby’s virus rebounded?

Once NIAID learned that the Mississippi Baby’s virus had rebounded after a 27-month period of remission, the study underwent an intensive review to determine whether it would still be ethical to conduct the trial, and if so, what changes, if any, should be made to the study protocol. It was determined that the following changes would ensure the safe and ethical treatment of study participants:

  • The informed consent forms now explicitly state that participation in this study is not expected to cure a child of HIV infection and that the Mississippi Baby was not cured of HIV infection. The forms also note that the Mississippi Baby’s HIV was in remission for more than 2 years in the absence of treatment.
  • Beginning when the first child whose virus is suppressed by antiretroviral therapy reaches age 1 year, an independent panel of experts will review the state of the science in HIV remission research to determine whether the study’s eligibility criteria for halting treatment are aligned with the latest available data. If necessary, the panel will advise the protocol team to amend the criteria. This process will be repeated before the first child stops treatment and periodically throughout the study.
  • When a child becomes eligible to stop treatment, clinical staff will meet with the child’s family or legal guardian to discuss the latest relevant research and the study’s criteria for halting treatment and will work with the family or legal guardian to decide whether taking the child off antiretroviral therapy is in his or her best interest.
  • It was originally planned that those children who are taken off antiretroviral therapy would be carefully monitored through age 5 years. Now those children will be carefully monitored through at least age 5 years and as long as the virus is in remission.

Do methods exist to prevent HIV transmission from an HIV-infected pregnant woman to her child? If so, why are babies born infected?

Yes, there are proven methods to prevent HIV transmission from HIV-infected pregnant (and breastfeeding) women to their children. But some women are not diagnosed with HIV infection until late pregnancy, labor or after delivery, so they either do not receive any antiretroviral drugs during pregnancy or do not receive a course of antiretroviral drugs during pregnancy that is sufficient to prevent HIV transmission to their babies. That is why the Mississippi Baby was born with HIV infection.
 
Worldwide in 2013, only 46 percent of pregnant women were tested for HIV according to UNAIDS estimates, and of those pregnant women with known HIV infection, only 68 percent received antiretrovirals to treat their own infection and prevent transmission to their babies. As a result, an estimated 240,000 infants became infected with HIV during pregnancy, birth or breastfeeding in 2013. It is notable, however, that the dramatic increase in antiretroviral use by pregnant women globally between 2001 and 2013 led to a 60 percent decline in mother-to-child HIV transmission during that period. In the United States, fewer than 200 babies are born with HIV infection each year.

Why is this study focused on infants who became infected in the womb and not during labor or delivery?

This study is focused on babies who became HIV-infected in the womb, and not during labor or delivery, for two reasons: one, to determine if it is possible to reproduce the experience of the Mississippi Baby, who also became HIV-infected in the womb; and two, because, of all babies born with HIV, those infected in the womb may be the most vulnerable to HIV disease progression and death.

Why is the study designed so that some of the enrolled babies will be breastfed and others formula-fed?

Most babies born to HIV-infected mothers in developed nations are formula fed, as was the Mississippi Baby. By contrast, in resource-constrained countries, where infants born with HIV infection are most prevalent, HIV-infected mothers are encouraged to breastfeed their babies while taking an HIV preventive drug regimen because this is in the best interest of the overall health and survival of the infants. Therefore, it is important to study the effects of very early treatment on both breastfed and formula-fed babies, so both are included in this trial.

Although the HIV-infected breastfeeding women in the study will receive antiretroviral therapy, there remains a small risk that HIV-infected breastfed babies in the study who have achieved viral suppression on treatment could acquire a second HIV infection through their mothers’ breast milk. This would complicate interpreting the results of very early treatment. Consequently, investigators will track the study outcomes for breastfed and formula-fed babies separately. In addition, the trial is designed to limit the possibility of HIV infection through breast milk by ensuring that all HIV-infected breastfeeding mothers are receiving antiretroviral therapy and that HIV-infected infants have stopped breastfeeding for at least 6 weeks before their antiretroviral therapy is halted.

For more information about the IMPAACT P1115 clinical trial, please see the related press release, NIH Trial Tests Very Early Anti-HIV Therapy in HIV-Infected Newborns, and visit ClinicalTrials.gov under study identifier NCT02140255.  

Content last reviewed on November 3, 2014