News Release 

Does timing matter for initiating HIV therapy in infants?

Study shows similar results for starting at 2 days or 2 weeks; ART alone unlikely to lead to remission

Columbia University's Mailman School of Public Health

Starting HIV antiretroviral therapy (ART) within hours of birth has been hypothesized to have positive effects raising the possibility of remission in some children with HIV. To test the hypothesis, researchers at Columbia Mailman School of Public Health and Columbia University Irving Medical Center designed a trial in a group of newborns with HIV who started ART within 14 days of birth. The results showed that about 75 percent of infants attained viral suppression on ART; but only 52 percent attained and sustained viral suppression on ART. The success of attaining and sustaining viral suppression was similar in the 46 infants starting ART less than two days old (51 percent) and the 27 infants starting therapy between 2 and 14 days after birth (54 percent). The findings are published online in E-Clinical Medicine.

"The results of our trial suggest that very early treatment in newborns may not have to mean within hours of birth," said Louise Kuhn, PhD, Columbia Mailman School professor of epidemiology (in the Sergievsky Center). "We learned that we must be more attune to basing decisions about how quickly to start ART on optimizing maternal adherence with treatment rather than with just focusing on speed. While we certainly do not want to introduce undue delay, starting ART within the first two weeks of life led to similar outcomes to starting within the first two days of life."

The study was designed shortly after the report of the infant in Mississippi who started antiretroviral treatment within 30 hours of birth and who was able to maintain viral suppression off treatment for over two years. This case report led to optimism that ART started within hours of birth may lead to protection of critical immune processes and smaller viral amounts, making possible remission in a sizable minority of infants treated in this way. "The outcome in Mississippi raised the tantalizing possibility that we may be able to facilitate remission in infants if we start ART very early in life," noted Kuhn.

To yield the target population for the trial, clinical protocols were established at Rahima Moosa Mother and Child Hospital (RMMCH), Johannesburg, South Africa. The analysis included 73 children who were born between March 1, 2015 and September 30, 2017 with confirmed HIV infection and ART initiated within 14 days. The initial ART regimen consisted of nevirapine, lamivudine and zidovudine; nevirapine was replaced with lopinavir-ritonavir once the child reached 42 weeks post-menstrual age, usually about 4 weeks of age in calendar time. ART was initiated based on results of the first round of diagnostic testing and was continued throughout the study.

Of those surviving during the study, 75 percent attained viral load <50 copies/ml on ART but not all of these sustained this low level of virus. Dividing the group into the 46 infants who started ART less than two days old and the 27 infants starting ART between 2 and 14 days old, showed a similar percent achieving and sustaining viral load <50 copies/ml on ART. In the very early treated infants (less than 2 days old), 51 percent achieved and sustained viral suppression; in the early treated infants (2 to 14 days old), 53 percent achieved and sustained viral suppression.

"Viral suppression rates, especially to more stringent cut-offs than required by our protocol were lower than expected, and we concluded that very early ART on its own, with routinely-available regimens, is unlikely to lead to remission in a sizable minority of early-treated infants," said Kuhn. This is most likely explained by the significant challenges of adequate maternal adherence with ART for neonates and infants including major practical difficulties of sustaining adherence with twice-daily, poorly-palatable liquids for infants. Moreover, most of the study participants' caregivers live in impoverished economic circumstances with complex social problems and experience a high degree of HIV-related stigma.

"We need to find interventions to treating newborns that are reasonable for mothers to fully adhere to," said Kuhn. Long-acting formulations and/or alternative interventions may be more adherence-friendly and need to be investigated. These may enable more rapid and sustained viral control and immune recovery in a larger proportion of early treated infants as a stepping stone to achieve remission.

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Co-authors are Stephanie Shiau, Elaine Abrams, and Wei-Yann Tsai, Columbia Mailman School; Yanhan Shen, Columbia Sergievsky Center; Renate Strehlau, Faeezah Patel, Karl-Günter Technau, Megan Burke, Gayle Sherman, Ashraf Coovadia, Rahima Moosa Mother and Child Hospital and University of the Witwatersrand, Johannesburg; Grace M. Aldrovandi, UCLA; Rohan Hazra, Eunice Kennedy Shriver National Institute of Child Health and Human Development; and Caroline Tiemessen, National Institute for Communicable Diseases, National Health Laboratory Services, and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

The study was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institute of Allergy and Infectious Disease, National Institutes of Health (U01HD080441), USAID/PEPfAR, the South African National HIV Programme, and South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa..

Columbia University Mailman School of Public Health

Founded in 1922, the Columbia University Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Columbia Mailman School is the seventh largest recipient of NIH grants among schools of public health. Its nearly 300 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change and health, and public health preparedness. It is a leader in public health education with more than 1,300 graduate students from 55 nations pursuing a variety of master's and doctoral degree programs. The Columbia Mailman School is also home to numerous world-renowned research centers, including ICAP and the Center for Infection and Immunity. For more information, please visit http://www.mailman.columbia.edu.

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