On Monday, March 4, 2013, at the Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta, Dr. Deborah Persaud of the Johns Hopkins University presented an intriguing case study of a child who by all measures seems to be cured of HIV infection. This single case has sparked significant conversation, debate, and optimism. This blog highlights the important questions that have naturally arisen from this case and examines aspects of the research agenda that now need to be pursued.
Certain of the facts are clear. An infant was born at a hospital in Mississippi to a woman unaware she was infected with HIV until she was already in labor. Having been born somewhat prematurely, the child was transferred to the University of Mississippi Medical Center, where the baby came under the experienced and skilled care of pediatrician Dr. Hannah Gay. Knowing that the mother was not previously treated for HIV infection (which put the infant at a high risk of becoming infected), Dr. Gay proceeded under the assumption that the infant had become infected. She started the infant on a three-drug cocktail of antiretroviral medications for HIV treatment, as opposed to the standard two-drug regimen for prophylaxis (prevention) of infection. Blood samples from the infant were repeatedly drawn, and lab results confirmed that the baby indeed had a detectable level of virus. Over the course of several weeks of treatment with antiretroviral drugs, the amount of virus in the child’s blood declined to undetectable levels. The child was discharged from the hospital on antiretroviral therapy that continued for up to 18 months, at which point the mother and child interrupted their medical care. Fast forward several months: the child reappeared in care after a significant lapse in antiretroviral therapy. Surprisingly, the child had no detectable circulating virus, no detectable anti-HIV antibodies, and was clinically healthy. Dr. Gay then reached out to Dr. Persaud and Dr. Katherine Luzuriaga of the University of Massachusetts to perform laboratory studies to help understand what had happened with this toddler.
This case is an excellent example of modern medicine and science at its finest. First, the potential importance of this case was recognized immediately and some of the best laboratories in the world were brought in to help validate the laboratory data. Investigators with long-standing working relationships, some established a decade or more ago, collaborated on state-of-the-art analyses of specimens. The results from all the laboratory studies confirmed that there was no ongoing HIV replication in this child; all that apparently remained was miniscule snippets of viral material.
This case study has touched off vigorous discussions, with both agreements and disagreements about key questions — a healthy and important part of the scientific process. For example, questions have arisen whether the child was ever truly infected in the first place, or was the virus detected in the blood stream of the infant soon after birth actually virus that was passed from the mother during pregnancy or during birth? Was the observed result due to the early treatment within 30 hours of birth, or was there something important about the intensity of the antiretroviral treatment or even some characteristic of the infant’s immature immune system?
It is essential that critically important questions are raised and ultimately addressed. This is a report of a single case, and as scientists, our goal is to confirm or refute research findings, and through this process, we also seek to fill in the missing details. There are several immediately obvious lines of research that will be pursued. First, we will work to better understand the relationship and/or difference between the virus passed to an infant from the mother and the virus produced by an infant’s infected cells during the early hours and days following exposure. Second, assuming that the immediate treatment of infants at high risk for infection could result in a possible “cure” of a truly infected infant, the risk-to-benefit ratio of starting very early 3-drug treatment (rather than 2-drug prophylaxis) for babies born under such conditions is now altered and must be discussed and possibly reconsidered. In addition, studies need to be designed and implemented to investigate the questions of timing and duration of pediatric antiretroviral treatment. In this regard, we need to examine existing cohorts of children who years ago were truly infected (or were assumed to be infected) and were treated not within hours of detection of virus but within weeks to months to determine if such cases had similar outcomes to the Mississippi child and can shed light on the timing and intensity of starting therapy. To this end, the team led by Drs. Persaud and Luzuriaga presented information at CROI on five additional children who had been perinatally infected and started antiretroviral therapy at a median of 2 months after birth. Encouragingly, in these children long-term control of HIV replication following early antiretroviral treatment has resulted in extremely low levels of virus and diminished anti-HIV immune responses.
Of course, as we move forward with our research agenda we must engage in serious discussions on the criteria, risks and ethics involved in all our studies, including the idea of stopping antiretroviral therapy in individuals who may be “cured.” As physicians and scientists, we must first do no harm as we seek ways to improve the health of the nation and world through biomedical research.