Deborah Persaud, MD, Director of Pediatric Infectious Diseases at Johns Hopkins University School of Medicine, talks about babies born with HIV in remission.
Interview conducted by Ivanhoe Broadcast News in 2024.
Tell me about a baby being born HIV. What is her or his life like?
Persaud: Without antal treatment, which is treatment with three drugs, a child living with HIV or born with HIV is likely to die in the first two years of life. A very high mortality rate without treatment. But with treatment, kids living with HIV can live, we know now, 30 to 40 years of age. With even better therapies, this could perhaps be the age of 50 or 60. The problem is that treatment is lifelong. Think about a baby being born diagnosed with HIV and having to receive treatment for four or five decades of life.
What other challenges would that baby have from the beginning, the first six months, and so forth?
Persaud: We could start with challenges with the treatment and then challenges with life itself. Challenges with the treatment, include taking several liquid medications to taste very poorly every day for years for that child to be able to stay healthy and live. The challenge is, that children are dependent on a caregiver to give them their medicines. Most of the infections occurring now in children are actually in Sub-Saharan Africa, where resources are limited. Access to drugs is limited. A child at any point can have that therapy interrupted, which puts them at risk of actually reversing any benefits he would have gotten from starting treatment early. Kids living with HIV we know, taking anti-trial drugs have a lot of issues and toxicities from the drugs, including problems with their kidneys, bone loss, mental health issues, depression, and anxiety. It’s an infection that encompasses all of one’s life. A major distinction for children is neurodevelopmental abnormalities because the infection is established in the context of a developing brain. There are many obstacles to well-being for a child being born with HIV. However we know that treatment is lifesaving and can reverse or delay the onset of many of these signs and symptoms of untreated disease.
How are they treated with anti-therapy ART? What is ART?
Persaud: ART, as you said is entra-drug therapy. It’s a cocktail of drugs. To treat HIV infection, you need three different drugs to keep the virus in check from replicating within your immune cells. What it means it’s a combination of antiviral drugs that blocks HIV from replicating within an individual.
Tell me about this research and how it has worked.
Persaud: The first thing to recognize is that any child or adult starting on ART or anti-drug treatment. That treatment needs to be for the life of that individual. Why is that? Because HIV establishes or forms a latent reservoir. It infects a group of cells that allows the virus to stay in a very sleepy, quiet, dormant state so that your immune system is not able to clear those cells. Those cells are special. They’re called immune cells. They’re cells that remind your body that you’ve received the vaccine so that you can respond quickly if you get exposed to that infection, or if you had an infection and developed immunity, those cells are formed to be able to give you that lifelong immunity. By HIV establishing its livelihood in those lifelong cells, it lingers around and stays in those cells for your lifetime. If someone stops revile treatment, the virus starts replicating again in the bloodstream and you can detect it within two to four weeks in most people. That’s why there’s this terminology now called ART-free remission. What does ART-free remission mean for the field of HIV treatment? It means that a person got some special treatment or intervention that allowed them to get to a state where those cells that carry HIV in its dormant or latent state are kept at such a low level. When they go off the treatment, the virus doesn’t come back in two to four weeks. It actually can stay suppressed, not replicating for weeks to months to years. We’re still in the discovery phase of thinking about art-free remission for HIV. In the field of cancer, this is a well-known terminology. You get treated for your cancer. If you go five years without your cancer coming back, you’re considered in remission for those five years, and then if it doesn’t come back, you’re considered cured of HIV. We don’t have that timeline for HIV treatment. When does someone go from remission to cure? I know you were going to ask that. There are special cases of cure for HIV in adults using stem cell transplantation. Transplanting that person with specialized immune cells and they’ve been off therapy for years. We can’t transplant everyone living with HIV in the world? It’s 38 million people living with HIV worldwide requiring enter-trial treatment. For our clinical trials, we defined remission as 48 weeks, so close to a year or more. If we treat in this trial and we can go into the details of the trial, the intervention we used was very early treatment, very early art with a three-drug regimen originally with the addition of a fourth drug a few weeks later, and the children stayed on that drug cocktail.
Why is it so important 48 hours after birth?
Persaud: Yes, it’s very important. That’s our definition of very early treatment. This whole clinical trial, I must step back and say, was based on a single case of art-free remission, we reported on a child in 2013, the infamous Mississippi baby whom we identified that child was born with HIV and was treated within 30 hours of life. We identified that’s what was unique about that case that led to that 27 months of remission that we’ve never seen before in the field prior to 2013. So that was a discovery. It was a single case, but we weren’t sure if there was something unique other features of that case besides the very early treatment that led to the 27 months of remission, really unprecedented for the field.
Is it important to do it early?
Persaud: It’s important to do it very early because we think it prevents the virus from really establishing a very large foothold in these reservoirs that could prevent us from actually getting to remission and cure. This trial was developed between 2013 and 2015 to test its very hypothesis. If we treated babies born with HIV within the first 48 hours of life perhaps we would figure out a window of opportunity that could be a week. That’s something we need to think about how to move it forward. But because it was a proof of concept, because we wanted to be sure, could this very early treatment result in remission? We were very cautious in being strict about the time frame and who could stay on the study to test for remission for now, we say within 48 hours is likely the critical time frame.
Back to these children who are treated within 48 hours, will these children need stem medication or do anything differently now that they are in remission? What happens to these children?
Persaud: I want to come back to the numbers to emphasize to the field and your audience that this is still a proof of concept. Is it not something pediatricians should do to take their kids off their drugs to see if they’re in remission? This was a study that was carried out from 2015 to 2017 in this first version of it, we have better versions that are enrolling. What it took is the first thing is not every child born to a mother with HIV is infected. We have great ways to prevent what we call perinatal transmission to the infant. That can occur at three different time points. It can occur during the pregnancy itself, which is what we call in utero infection, or being born with HIV. It can occur during the time of the actual labor and delivery process with exposure to blood. Then 50 percent of our new infections occur through breastfeeding. Even if a child escapes HIV infection during the pregnancy and fetal life or the labor and delivery process, breastfeeding is lifesaving in Sub-Saharan Africa, where the burden of infection lies. Women living with HIV breastfeed their infants, and so there’s this ongoing risk of transmission if the mothers are not on antiretroviral treatment or if they acquire HIV during the breastfeeding period, which can happen. For this study, we enrolled 460 mother-infant pairs to get to the 54 infants diagnosed with an infection that was acquired in utero or being born with HIV to get to our number of four at the end in remission. For that trial, to get to the point of testing for remission, that child had to stay on therapy every day, keep the virus in check from a year onwards, and stay completely suppressed. Now, as part of this trial, we planned to stop the antiretroviral drugs at around age two, which is when the Mississippi baby was found to be in remission. Because of COVID, it got delayed. The children were five years old when they stopped their treatment. So to bring the numbers around and get back to your question, a long answer is that 54 kids had infection all through COVID being suppressed, six suppression criteria. Then they had to have special testing done, which was done in this laboratory, right in this space behind me, to measure how many infected cells were still present in their bloodstream. They had to have no infected cells present in their bloodstream and no antibody to the virus to then qualify to stop the treatment to see if they had remission. I want to say, we don’t know- we don’t have a blood test that can say this child is treated very early and is at a point that they’re in remission, so you can stop treatment. The only way we can detect remission is we have to stop the antiretroviral drugs, which is unfortunate because we spend so much time telling families, that you have to be adherent, you have to take your drugs. But this is part of the clinical trials. The parents and guardians consent to the second step of stopping, and then we follow the children very closely with viral load monitoring. You asked how long should they be off treatment. We monitored for the virus to come back, and as I said, our benchmark for remission was 48 weeks or more, so close to a year or more. Two of the six had the virus come back very quickly at three weeks and eight weeks, leaving us with four children in remission. Right now, we have three still being followed. One child rebounded at 20 months of that antiretroviral treatment.
With those four children, what is their case difference from the other newborns?
Persaud: The burning question for us to figure out what’s different about these four children. I think the first way to look at this is we had an n(1) in 2013. Through the clinical trials, really systematically with the treatment and follow-up, we end up with an n(4), so four times more than we started with. It gives the proof of concept and guidance on how we can improve our therapies going forward. We haven’t identified anything different about those four kids than the other starting, but just to say, they were the ones who had the best suppression of their virus throughout the clinical trial for 5 1/2 years to reach that benchmark. So what do we need to do better as a field? A lot of those kids did not get to the viral suppression that they needed. We need to figure out how to get more kids suppressed like those six who made it to the endpoint, to then better understand what is driving that remission outcome.
What’s next?
Persaud: A lot is next. I’ll tell you we have to start where we started, and that is we never treated newborns for HIV infection. We never tested them systematically to see if they were born with HIV infection. Most testing for children is done at six weeks of age in the countries where this pandemic is happening in children and just to put the numbers out there, still, 130,000 children or infants are being infected every year with HIV. With this, I’m going to say what this remission and new goal for therapeutics for HIV. It’s not keeping someone in therapy for life, for children, think of every day having to wake up, take medications, reminding you what our parents say and what the children say as they age up. Every day I take my meds, this reminds me I’m infected with HIV. This reminds me I’m different. I can’t go to sleepovers. I can’t go to camp. I can’t go to boarding schools. In a lot of these countries, boarding schools are part of life. It impacts their lives.
Could this change how babies born with HIV are treated?
Persaud: We don’t do implementation science, but we inform implementation science, so larger groups and leaders of the PEPFAR program were at the meeting, and I think this is going to be considered. First, we have to diagnose the infection. I think it will change the lens of the timing of diagnosis. If you diagnose an infant, you have to treat that infant because it is lifesaving. I do think this first proof of concept study will influence how we think about infants. These are really newborns with HIV infection, how to treat them, and we will have studied the safety and how to rightly dose these medications in babies.
Are there any risks?
Persaud: Yes. The risk before we started this trial, as I said to you, not every infant who’s born to a mother with HIV acquires infection. In utero, it’s about six to eight percent of babies. Then if a mom’s not treated around the time of birth, it’s about 30 to 40 percent risk of transmission. We had to have ethical considerations around giving the 400 plus inference that weren’t infected; these three-drug regimens. drugs have toxicities. We monitor these toxicities. A major toxicity of the regimens we’re using. It’s lowering the white cell count, so the inference needs to be followed to have drugs switched off. What we identified that we didn’t expect during the treatment interruption phase to detect the remission is two of the three children who rebounded, developed what’s called acute retroviral syndrome. And this is- it’s like infectious mononucleosis. It seems very common in adults presenting with primary HIV infection. It’s probably an immune-mediated response to the virus that children don’t have early on in life. Two of the three children who rebounded developed this acute retroviral syndrome that’s made plans for following these kids in the clinical trials a little differently. Even if they have a little bit of sore throat, we’re going to do a viral load test on them.
Is there anything that might be missing that you want to add?
Persaud: I think what I would like to add it’s a small number of cases, it’s four, but it’s transformative for our field because what we want to do is treat HIV differently where all individuals, children, and adults don’t have to take these medications every day that comes with stigma, anxieties and this lifelong reminder that you’re living with HIV. But at the same time, these are lifesaving drugs, and we’re tremendously grateful for the investments. This is a large investment from the National Institutes of Health from the countries. This is not my study. This is our study. This is a global village of clinicians, researchers, and investments by pharmaceutical companies in trying to establish safety and pharmacokinetics for new drugs in babies, not an easy field to be in. This is a triumph for the field of HIV in general because I will say that outcomes in children and the perinatal setting have influenced treatment in adults and prevention in adults because prevention of HIV infection started in the mother-infant model when this epidemic first started. I’m a pediatrician. I lived through that epidemic. I’ve seen kids die, and so for me, this is very rewarding, and I’ll use the word triumphant or comfort or field. That’s a reflection of many individuals and bodies supporting this charge.
END OF INTERVIEW
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