Dr. Deborah Persaud explains how a clinical trial may open new treatment options for newborns

A milestone in treating children with HIV was announced at CROI when Deborah Persaud, MD, a professor of pediatrics, shared the results of four infants who had achieved remission with antiretroviral drugs. An NIH-funded clinical trial, IMPAACT P1115 (International Maternal Pediatric Adolescent AIDS Clinical Trials Network) enrolled 440 infants who had been born to women living with HIV in Brazil, Haiti, Thailand, the United States and throughout sub-Saharan Africa. The 54 babies who were born with HIV were given antiretroviral medication within days of birth, initially starting on an older HIV regimen, including AZT (Retrovir) or abacavir, lamivudine and nevirapine. Lopinavir/ritonavir (Kaletra) was added later. Of the 54, six met the criteria for an analytical treatment interruption, halting their HIV treatment to observe what would happen. Four have remained HIV-free so far, more than 48 weeks later.

For clinical trials purposes, we define remission as being off [ART] for 48 weeks or more without having the virus come back.

Dr. Persaud, IMPAACT’s scientific chair of the HIV CURE Scientific Committee, is also a pediatric infectious disease specialist at the Johns Hopkins Children’s Center, where she heads the fellowship program in pediatric infectious diseases. Dr. Persaud shared the trial’s results and her observations with POSITIVELY AWARE.

(This interview has been shortened and edited for clarity.)

Could you describe the results that you presented this year at CROI?

What we found in this study is four of six children [who were eligible for an analytic treatment interruption] were able to stay off of their antiretroviral drugs for 48 weeks or more. So almost a year. This is an unprecedented finding because we know that almost every person living with HIV, adults and children, when they begin antiretroviral therapy (ART), it’s a lifelong course of treatment. This is because of viral reservoirs that allow HIV to stay in a person’s T cells for their lifetime. [Our results show] for infants with HIV, not those that have HIV that's already been established for years, there's a window of opportunity to treat them and potentially get more kids into a state of remission, where they can stay off therapy for an extended period of time.

How is remission defined?

For clinical trials purposes, we define remission as being off [ART] for 48 weeks or more without having the virus come back. These kids are followed very closely and regularly during clinical trials with frequent viral load testing to really identify whether the virus would come back or not. It’s still in the phase of experimental medicine. But we’re very hopeful that at least we can identify one strategy for newborns that could potentially get us to this phase of ART-free remission for children.

The concept around getting to remission through this strategy started in 2013, when we reported on the case of the Mississippi baby, an infant who had an unprecedented 27 months off of antiretroviral treatment with no sign of HIV present. In that case, what we discovered that was different about that baby was starting a three-drug regimen 30 hours after birth. Infant prophylaxis did not consist of a three-drug regimen. And so we thought that perhaps this three-drug regimen that was meant for prophylaxis gave this remission outcome.

At that time the word “remission” was not used. You were considered “cured” of HIV as was the Berlin patient [Timothy Ray Brown, the first person living with HIV to be cured] in 2009. And then the field came up with this terminology of “functional cure.” So when we first reported the Mississippi baby, we used the term functional cure. But we’ve learned that because the virus rebounded, it was a period of remission. So with that case being reported, in the U.S. and in resource-rich settings, some places had incorporated a now-standard of care, testing in the first 48 hours of life.

Testing and getting newborns on ART is not standard of care for infants who are born with HIV in sub-Saharan Africa, right?

In sub-Saharan Africa, testing in the first 48 hours is not done. In fact, testing is not done until six weeks of age. So most infants don’t get identified and treated until two to three months or even later, because the turnaround time [for results] differs in different countries.

There has been significant progress in preventing vertical transmission, that is, in infants acquiring HIV through their mothers. Identification of HIV in mothers is key, and treatment of the mother to suppress viremia to prevent transmission is our goal. But standard of care is not treatment. It is not testing [for HIV] in infants and newborns. So even though we’ve made significant progress in knowing how to prevent vertical transmission of HIV, we still have about 135,000 cases per year and most of those occur in sub-Saharan Africa. In the U.S., we still have about 50 to 60 new cases of [newborns with HIV]. I believe our study will influence thinking around testing.

How might your findings impact the standard of care for newborns with HIV?

I think with the report of the Mississippi baby [as a] guide— [U.S. Department of Health and Human Services] guidelines to public health recommend testing an infant born from a mother who is believed to have HIV within the first 48 hours after birth. There is guidance in the U.S. and in Europe for infants who are considered highly vulnerable to HIV—meaning their moms are not on antiretroviral treatment, or on therapy but not suppressed—to consider starting this three-drug regimen and testing awaiting confirmation of HIV diagnosis.

In sub-Saharan Africa, that has not been recommended; there’s no infrastructure in place to test [newborns]. And so we believe that this finding of potential to achieve remission could provide some evidence and guidance around consideration for incorporating testing in the first 48 hours after birth.

What is a potential longer-term goal for children who achieve HIV remission?

I think ARV-free remission is the better terminology because there’s no way these treatment strategies are going to completely clear reservoir cells from a person. ARV-free remission is being off ARVs for a meaningful period of time, to spare that person from taking daily [pills]. And for our clinical trials, we picked 48 weeks as a substantial amount of time to spare a child and family from taking medications every day. Obviously, we want to move the needle beyond a year; we want to make it five years. But can we figure out a way to give a child a therapeutic vaccine that can generate HIV-specific immune responses to help control any virus that would pop back? The way we think about this is someone living with persistent herpes simplex where you get cold sores, but your immune system eventually controls it and it goes back into its sleepy state until it comes back again. The same for chickenpox and zoster—you get an outbreak of zoster shingles, but your immune system keeps it in check. Can we get to that point in HIV, where if the virus reawakens, your immune system can keep it in check? Obviously, that’s a very long-term goal, maybe a five- to 10-year goal here. But for us getting to 48 weeks, close to a year, is substantial progress.

When the virus did rebound in children, what was the result?

Two to four weeks is the usual time when any person, a child or adult, who goes off treatment can expect the virus to come back. We had one child rebound at three weeks, and the second child rebounded at eight weeks. I’ll tell you, for the adult trials, if they see eight weeks, they’re excited. But we will consider those two-, three- and eight-week rebounders as early rebounders. One of the early rebounders developed acute retroviral syndrome similar to adults presenting with acute HIV infection, where it feels like a cold and sore throat, mild symptoms that evolved into an acute syndrome with fever and a rash. That led us to modify our protocol to really jump on any signs or symptoms to get a viral load test. And this is why they should still only be done in a clinical trial setting. [The test] has a turnaround time of 90 minutes, so the child stays in the clinic while we do the viral loads.

To the early rebounders, we suppress their virus with the regimen that they were on before they went off treatment. And they were [re-suppressed] very quickly, within eight weeks. There was one child who took 20 weeks, because of problems with adherence, but all became virally suppressed. And re-suppression on the same regimen suggests no resistance developed.

How can addressing treatment and testing gaps, especially in sub-Saharan Africa, make it possible to achieve the remission results you found in the trial?

Many pregnant women living with HIV [in sub-Saharan Africa] don’t know their status. It’s very complex in terms of—even if you know your status—staying compliant and staying suppressed.

Access to drugs could be problematic. We’ve learned from our clinical trials experience, the women travel very far to participate. People who live in rural areas don’t have access to care or regular access to drugs, even though the PEPFAR program has done well in focusing on coverage of pregnant people.

The bottom line is that women are susceptible to acquire HIV at any point during pregnancy, and even when the pregnancy is over. And even in women who have escaped acquiring HIV, they can get HIV during the breastfeeding period, which puts infants at continuous risk for HIV [acquisition]. So we need close attention to testing people in general. We need more near point-of-care tests to make it easier for people to get results on the spot. For adults, it’s easier because antibody tests can identify infection in most cases. But for infants, it’s more complex. You need to do special PCR tests to detect the virus’ nucleic acid in the bloodstream of the baby to detect and identify infection, because the antibody crosses the placenta. And so a positive antibody test in a baby tells you the baby has been exposed but it doesn’t tell you that the baby has HIV.

But I think there has been such progress made in these near point-of-care tests to get results in 90 minutes, they’re not so hard to do. Efforts should be made to test and treat very early. If we can identify [HIV] in infants within the first six weeks and implement early testing and treatment programs in the first six weeks of life, I think we can make a difference in treatment outcomes and survival in children, because we’ve clearly demonstrated that early treatment is lifesaving for children. Getting treatment early is critical to child survival and retention in care.

What are the next steps of your clinical trial?

We’re very excited because before this [trial] there was really no focus on infant treatment and better drugs for children. It’s why we still had a regimen of AZT and lamivudine and nevirapine to start with, and had great success. But these are older drugs and the treatment landscape has changed towards integrase inhibitors. If you can block the virus from integrating into your host cell, that’s your best shot at preventing establishment of reservoirs in children through very early testing and treatment.

The trial has moved on from a first version with archaic regimens that still worked, to integrase inhibitors and broadly neutralizing antibodies. We are including immunotherapy into this very early treatment approach to see if we can do better with virologic suppression.

We’re still in the phase of experimental medicine in terms of trying to understand the outcome in these four children and not more children. But a 7% outcome in a first proof of concept clinical trial should give the field enough information to think to what extent we should try this on a larger scale. And especially since this outcome occurred with not the best drugs to treat HIV in infants. But these are clinical trials, and we don’t do implementation where we could inform policy through our findings. I think the key messages are that very early testing of newborns to identify those who [acquired HIV] in utero has a potential for very early treatment with promising outcomes, and the hope of getting to ARV-free remission for more individuals with different strategies could be expedited for children.

[The trial] opened up the treatment landscape for infants and children with this lens on ARV-free remission, rather than just virologic suppression, which I must emphasize that nearly 45% of our kids on treatment are not suppressed. It’s very hard for kids to take medications daily. Taking medicine at the start of life, that’s lifelong therapy for decades. We need to do better, and that’s what this treatment approach and clinical trials testing approach is doing; it’s changing how we think about lifelong treatment for our children.