A recent clinical trial of early ARV treatment of babies with HIV has added substantially to existing evidence that giving antiretroviral therapy (ART) to newborns with HIV within the first days of life, rather than within weeks or months, can safely suppress amounts of HIV in the blood to undetectable levels, said the scientists.
Findings of the study – designed to replicate the case of the Mississippi Baby reported in 2013, who experienced a more than two-year remission of HIV – of more than 50 babies aged up to two-years-old, in Africa, Asia, North America and South America were published in The Lancet HIV.
It was co-led by Johns Hopkins Children’s Centre physician-scientist and researcher Deborah Persaud, MD, sponsored by the National Institutes of Health (NIH) and the International Maternal Paediatric Adolescent Aids Clinical Trials Network.
While there is no cure for HIV, ART can help control the virus and prevent it from progressing to Aids: the WHO says a pregnant woman with HIV who is not receiving ART has a 15% to 45% chance of transmitting the infection during pregnancy, childbirth or breast-feeding.
This chance decreases to less than 1% if she receives ART.
In 2013, Persaud, now the director of the Eudowood Division of Paediatric Infectious Diseases at the Children’s Centre, was part of a research team studying the child known as the Mississippi baby, believed to be the first documented case of HIV remission in an infant born with the virus. The baby, given ART within 30 hours of birth, remained free of active HIV for 27 months after stopping ART.
Persaud, a professor of paediatrics at the Johns Hopkins University School of Medicine, said standard treatment of babies with HIV typically starts when they are two to three-months-old, often due to delays in testing and getting results, particularly in countries where the burden of HIV is highest and ART drugs less available.
ART side effects are also a concern and include anaemia, nausea, vomiting and diarrhoea.
With the latest study, Persaud and the clinical trials team sought to replicate the case of the Mississippi baby by starting infants on what they call “very early treatment,” defined as in the first 48 hours after birth, which they believe halted the formation of hard-to-treat viral reservoirs – cells carrying genetic material of latent viruses and unreachable for antiviral drugs, typically allowing HIV to survive in the body for life.
“We are looking for proof of the concept that if you can safely treat babies with a three-drug regimen within 48 hours of life, you can limit the build-up of these reservoirs and get them to very low levels that may lead to ART-free remission, where the virus doesn’t come back quickly if the ART is stopped in later phases of the trial,” Persaud said.
The team enrolled 54 newborns into two groups at 30 sites in 11 countries, mostly in sub-Saharan Africa but also in Brazil, Thailand, the US and other countries, between January 2015 and December 2017.
One group of 34 infants (whose mothers had HIV and were not on ART during pregnancy) were started on a three-drug oral ART regimen of azidothymidine (AZT) or abacavir, lamivudine (3TC) and nevirapine within two days of life. All of the drugs had previously been shown to help prevent HIV transfer to newborns.
In the second group of 20 infants (whose mothers had HIV and were on ART during pregnancy) were started on the same three-drug regimen, but with a lower dose of nevirapine shortly after birth.
They then were switched to the same study regimen as the first group by 10 days of age, once enrolled in the study.
A fourth medicine, lopinavir-ritonavir, was also added to the regimen for all babies who were HIV positive after about 14 days, an age considered safe for use of the medicine based on previous research. Both groups were on ART through the infants’ first two years of life during this phase of the study.
“Overall, these four drugs are not the most potent ART regimen, but were the only drugs approved for the prevention of HIV in newborns and treatment of infants, at the time of the study,” Persaud said.
Researchers estimated that infants had a 33% chance (group 1) or 57% chance (group 2) of reaching and maintaining undetectable plasma levels of HIV in the blood beyond the age of two years.
At the end of the study period until they were two-years-old, among the participants who remained with virologic suppression, 83% in group one and 100% in group two tested negative for HIV antibodies, and 64% in group one and 71% in group two had no detectable HIV DNA.
Among the 54 infants who received very early ART, 19% met all of the study’s criteria for becoming eligible to stop treatment in later phases of the ongoing trial.
“If you treat at two to three months of age, when most children start a regimen, very few kids would actually get to this undetectable stage by two years of age,” Persaud said. “It would actually take them until five or older to get to a low HIV DNA level, and it’s never to this undetectable level.”
The researchers said most participants in both groups could not be followed to the end of the study period, mostly because their virus was not suppressed to undetectable levels, possibly due to lack of daily adherence to the therapy.
For infants to be considered as trial participants, researchers were able to diagnose HIV in the infants within a strict timeline and monitor them at frequent intervals.
The team acknowledged that these same practices can be feasible in future clinical research related to early infant diagnosis and treatment, but they remain challenging in clinical care settings because of lack of testing availability and other limitations.
Therefore, the researchers said these practices should be prioritised for global HIV testing and treatment programmes.
They said their study suggests that very early ART is safe and is key to suppressing HIV to undetectable levels during early childhood periods of rapid growth.
Persaud added that a very early treatment strategy was a first step toward getting more infants in a good place for remission so they can be kept off ARVs for longer, and need not face the stigma still in place in many settings regarding taking daily HIV medicine.
As the trial continues, the team will evaluate newer and more effective treatment regimens, and share results of its research on ART-free remission among infants.
Study details
HIV-1 reservoir size after neonatal antiretroviral therapy and the potential to evaluate antiretroviral-therapy-free remission (IMPAACT P1115): a phase 1/2 proof-of-concept study
Deborah Persaud, Yvonne Bryson, Bryan Nelson, Camlin Tierney, Mark Cotton,
Anne Coletti, et al.
Published in The Lancet HIV on 4 December 2023
Summary
Background
Infants born with HIV-1 require lifelong antiretroviral therapy (ART). We aimed to assess whether very early ART in neonates might restrict HIV-1 reservoirs, an important step towards ART-free remission.
Methods
IMPAACT P1115 is an ongoing, phase 1/2, proof-of-concept study in which infants were enrolled at 30 research clinics in 11 countries (Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, the USA, Zambia, and Zimbabwe) into two cohorts. Infants at least 34 weeks’ gestational age at high risk for in-utero HIV-1 with either untreated maternal HIV-1 (cohort 1) or who were receiving pre-emptive triple antiretroviral prophylaxis outside of the study (maternal ART permissible; cohort 2) were included. All infants initiated treatment within 48 h of life. Cohort 1 initiated three-drug nevirapine-based ART, and cohort 2 initiated three-drug nevirapine-based prophylaxis then three-drug nevirapine-based ART following HIV diagnosis by age 10 days. We added twice-daily coformulated oral ritonavir 75 mg/m2 and lopinavir 300 mg/m2 from 14 days of life and 42 weeks’ postmenstrual age. We discontinued nevirapine 12 weeks after two consecutive plasma HIV-1 RNA levels below limit of detection. We tracked virological suppression, safety outcomes, and meeting a predetermined biomarker profile at age 2 years (undetectable RNA since week 48, HIV-1 antibody-negative, HIV-1 DNA not detected, and normal CD4 count and CD4 percentage) to assess qualification for analytical treatment interruption.
Findings
Between Jan 23, 2015, and Dec 14, 2017, 440 infants were included in cohort 1 and 20 were included in cohort 2. 54 of these infants (34 from cohort 1 and 20 from cohort 2) had confirmed in-utero HIV-1 and were enrolled to receive study ART. 33 (61%) of 54 infants were female and 21 (39%) were male. The estimated probability of maintaining undetectable plasma RNA through to 2 years was 33% (95% CI 17–49) in cohort 1 and 57% (28–78) in cohort 2. Among infants maintaining protocol-defined virological control criteria through to study week 108, seven of 11 (64%, 95% CI 31–89) in cohort 1 and five of seven (71%, 29–96) in cohort 2 had no detected HIV-1 DNA. Ten of 12 (83%, 52–100) in cohort 1 and all seven (100%, 59–100) in cohort 2 tested HIV-1 antibody-negative at week 108. Among 54 infants initiated on very early ART, ten (19%; six in cohort 1 and four in cohort 2) met all criteria for possible analytical treatment interruption. Reversible grade 3 or 4 adverse events occurred in 15 (44%) of 34 infants in cohort 1 and seven (35%) of 20 infants in cohort 2.
Interpretation
Very early ART for in-utero HIV-1 can achieve sustained virological suppression in association with biomarkers indicating restricted HIV-1 reservoirs by age 2 years, which might enable potential ART-free remission.
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