Early Antiretrovirals Shrink HIV Reservoir in Newborns

Pam Harrison

July 28, 2014

MELBOURNE, Australia — Babies at high risk for HIV should be started on antiretrovirals to reduce the disease to undetectable levels and potentially induce long-term viral remission, new Canadian research suggests.

"Treat as soon as possible — that's our motto," said Jason Brophy, MD, assistant professor of pediatrics at the University of Ottawa in Ontario, Canada.

"Our approach is to recommend initiation of treatment within 48 to 72 hours of birth, although really, the sooner the better," he told Medscape Medical News. "If we could get to a point where we could say, 'this approach will give you a 50% chance or even a 90% chance of viral remission,' that would be a major step forward in terms of helping children live better lives."

The study was conducted in 3 pediatric hospitals in Canada: the Hospital for Sick Children in Toronto, the Children's Hospital of Eastern Ontario in Ottawa, and Sainte-Justine University Hospital in Montreal. All 3 centers routinely offer postexposure prophylaxis for high-risk neonates.

In a retrospective review of 136 infants who received triple therapy essentially at birth, the team found that 12 (8.8%) seroconverted despite early intervention. "In utero infection probably occurred in at least 50% of them," Dr. Brophy noted, because "6 of them had a positive DNA PCR in the first 48 hours after birth."

 
Stopping treatment is a real dilemma, especially now that we know that the Mississippi baby did virally rebound.
 

The timing for the other 6 HIV-positive infants remains unclear, he added.

Four infants went on to sustained viral suppression, defined as an absence of detectable virus with standard assay subsequent to having achieved an undetectable viral load. The remaining infants never achieved sustained viral suppression because of poor adherence to therapy.

All 4 infants — 2 of them twins — continue to have sustained viral suppression and "remain on the original regimen of zidovudine, lamivudine, and nevirapine," Dr. Brophy reported.

The 3 mothers had advanced HIV disease at the time of delivery, with low CD4 cell counts, and all 4 infants were premature.

"All infants had birth PCRs within the first 48 hours of life that were positive," Dr. Brophy noted.

They also had subsequent viral loads that were positive, and some of them had confirmatory PCRs that were also positive. "We have no doubt that they were infected," Dr. Brophy said.

After the introduction of early antiretrovirals, HIV-specific cell-mediated immune responses could not be detected in any of the 4 infants. Even with ultrasensitive viral load assays, the team saw no evidence of HIV in the blood.

Nor could HIV DNA be detected in a large sample of CD4 cells.

After the stimulation of CD4 cells in the infants, HIV RNA could not be detected in any of the 4 infants. However, when a larger number of CD4 cells was examined, the researchers were able to measure replication-competent HIV in 1 child. Genetic characterization showed that 3 of the 4 infants harbored genotypes considered to be associated with better HIV control.

"Interestingly, the child in whom replication-competent virus was detected was the one who did not have any protective genotype," Dr. Brophy observed.

Table. Status of the 4 Children

Case Age (Years) Serology HIV-specific T-cell response Plasma viremia (copies/mL)
1 7 negative undetectable <1.5
2 7 negative undetectable <1.5
3 2.5 negative undetectable <1.5
4 2.5 negative undetectable <1.5

 

"The only tests that were positive were cell-associated RNA, but we really don't know what the significance of this might be, and it was a very small amount of infectious virus," Dr. Brophy told Medscape Medical News.

A fifth child with a protective genotype achieved similar levels of HIV suppression up to the age of 3.

However, in that case, the maternal genotype returned, along with resistance to the non-nucleosides, and the infant's treatment was changed to zidovudine, lamivudine, and the coformulation of lopinavir plus ritonavir (Kaletra).

That child was also having significant difficulty with medication adherence. Rather than having the child on a regimen that resulted in only half of the medications being received, "a medication interruption was done and the child quickly developed viral rebound," Dr. Brophy explained. As researcher Fatima Kakkar, MD, from Sainte-Justine University Hospital, pointed out, it is very difficult to give children some of these HIV medications.

"They don't taste good," she told Medscape Medical News; Kaletra apparently tastes like kerosene.

In addition, "at least half of our children will stop treatment at some point in their follow-up. What we are trying to figure out is whether there is a safe point at which we could offer a treatment interruption, as most children will be stopping treatment on their own accord anyway," Dr. Kakkar said.

The fact that viremia rebounded so rapidly after treatment discontinuation in the fifth child — despite a very limited HIV reservoir at the time — demonstrates that early therapy will not be effective in all patients, Dr. Brophy cautioned.

Stopping treatment is "a real dilemma, especially now that we know that the Mississippi baby did virally rebound," explained researcher Stanley Read, MD, from the University of Toronto and consultant at the Hospital for Sick Children.

After 27 months off antiretrovirals, the Mississippi baby in whom therapy had been discontinued at 18 months tested positive on routine assessment, and treatment was reintroduced, as reported by Medscape Medical News.

"We must do further investigations on these 4 children before we even consider any kind of treatment interruption," Dr. Read said.

"There is no clear right or wrong answer," he added. "We are just going to have to put our heads together and come up with a strategic plan that makes sense."

Catalyst to Move Forward

"I'm very optimistic for remission in pediatric HIV patients," Deborah Persaud, MD, from the John Hopkins Children's Center in Baltimore, Maryland, said during a news conference here. Dr. Persaud is one of the pediatric HIV experts involved in the ongoing analysis of the Mississippi baby. Hannah Gay, MD, from the University of Mississippi Medical Center in Jackson, who has been involved in the child's care since birth, was also present at the briefing.

Having the child off treatment for 27 months with absolutely no indication that the virus was present until it made a sudden reappearance is "spectacular in my mind, and really the catalyst for us to move forward," Dr. Persaud said.

Even for a child infected in utero, as the Mississippi baby was, with "very early treatment — and here early was at 30 hours of age — we still have a wide window of opportunity because we can intervene as early as a half an hour after birth," she explained.

"While we are disappointed that this child now requires treatment to control the virus, this is really unprecedented for the field, and a major step forward."

The Canadian team is now planning the EPIC4 study to compare reservoir size and immune factors in children who start treatment early in life and those who start later.

The authors have disclosed no relevant financial relationships.

20th International AIDS Conference: Abstract TUAB0206LB. Presented July 22, 2014.

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