A Canadian preschooler who doctors hoped was essentially cured of HIV experienced a swift resurgence of the virus after being taken off medication, an outcome researchers are calling a “cautionary tale” for scientists trying to wipe out the disease in its youngest sufferers.
The 3-year-old was one of five Canadian children that a team of pediatric HIV-AIDS researchers in this country identified after hearing the astonishing story of the Mississippi baby, an American girl, now 3, who appears to have been "functionally cured" of the virus that causes AIDS.
The Canadian group, which presented its preliminary results at the Canadian Conference on HIV-AIDS research in St. John’s on Saturday, found no evidence of the virus lurking in four other HIV-positive children who received high doses of three drugs shortly after birth, just like the Mississippi child.
However, unlike in the cases of the Mississippi and the Canadian preschooler whose viral load rebounded, the other four Canadian children are still taking the antiretrovirals that keep the virus a bay.
The only way to say for certain that the Canadian children have been "functionally cured" is to halt their medications, an ethical dilemma for doctors who do not want to put their small patients' immune systems at risk.
“Talking about an HIV cure is, in my view and I think [the view of] our team as a whole, premature,” said Ari Bitnun, a physician in the department of infectious diseases at the Hospital for Sick Children in Toronto. “Whether or not the outcome of the Mississippi baby can be replicated, I don’t think there is an answer to that question yet.”
The Canadian researchers’ quest began when Deborah Persaud, a pediatric infectious disease physician at the Johns Hopkins Children’s Center in Baltimore, revealed the story of the Mississippi baby at the March 2013 Conference on Retroviruses and Opportunistic Infections in Atlanta.
The case involved a pregnant woman who was unaware she was HIV-positive and therefore did not take drugs to prevent transmission of the virus to her infant daughter.
Doctors started the baby on high doses of three drugs – AZT, 3CT and nevirapine – 31 hours after birth, a protocol more aggressive than the standard treatment in the United States. Those higher treatment doses are not usually administered to babies until an HIV infection is confirmed. Researchers working on the case say the Mississippi baby tested positive for HIV.
The baby took anti-retroviral medication until she was 18 months old, at which point her mother stopped attending medical appointments and halted the medication. Five months later, doctors were shocked to discover the child was virus-free.
“That was really a clap of thunder in the field,” said Hugo Soudeyns, a microbiologist at Ste. Justine hospital in Montreal and part of the Canadian research group, which has received $2-million in funding from the Canadian Institutes of Health Research, the International AIDS Society and the Canadian Foundation for AIDS Research to study more than 200 HIV-positive children across the country.
Dr. Soudeyns said some of his colleagues quickly realized that the protocol used in the Mississippi case was already standard practice in Canada in the rare instances where a mother passes the virus to her newborn. (Properly treated HIV-positive mothers run virtually no risk of giving their babies HIV; mother-to-child transmission is considered a major public health failure. )
“So the question we immediately asked was, ‘Are there any Mississippi babies in Canada?’” Dr. Soudeyns said.
The team, made up of doctors from SickKids, Ste-Justine and the Children’s Hospital of Eastern Ontario in Ottawa, found 136 children who received treatment doses of the three-drug combination within 72 hours of their birth.
Of those, 12 wound up infected with HIV and seven had clear signs of ongoing infection, Dr. Bitnun said.
That left five children who range in age from 2 1/2 to nearly 8, all of whom showed no detectable signs of the virus, even in ultra sensitive tests.
Then chance intervened. One of the children, a now 3-year-old being treated at CHEO, was having difficulty sticking with the medication. Swallowing several tablespoons of unpleasant-tasting medicine twice a day is a common challenge for HIV-positive children.
“Sometimes it’s just not possible to keep going with the medication and because we would rather them not take it at all than take it intermittently, we sometimes, together with the family, make a decision to stop for a while,” said Lindy Samson, an infectious disease physician at CHEO.
This child's family and doctors opted to take the child off therapy briefly and monitor him or her closely. (So few Canadian children are infected with HIV at birth that the researchers declined to reveal any of the children's genders or hometowns for fear of violating their privacy.)
Unfortunately, the virus started replicating quickly, proving the child had not been functionally cured at all. The virus had simply been well suppressed. The child's viral load skyrocketed from fewer than 40 copies of the virus per millilitre of blood to 7,797 copies in two weeks and 11,358 copies in four.
The Canadian team has some theories about what might differentiate this child from the other four. The child developed resistance to one of the drugs in the treatment cocktail early on and it took nearly six months to suppress the virus. The child also had a barely detectable viral load in one test, suggesting some of the virus remained hidden in "reservoirs" in the child's body.
The child is now back on medication and doing well, Dr. Samson said.
The outcome, though disappointing, wasn't a surprise, said Dr. Jason Brophy, another infectious disease doctor at CHEO. “Realistically, the majority of people who have HIV have it for life, permanently. The Mississippi baby got a lot of attention because it was so atypical, it was so unusual. We weren’t expecting miracles.”
Dr. Persaud, the pediatric HIV-AIDS expert who presented the Mississippi baby case and is not involved in the Canadian study, said there was an important difference between all five Canadian children and the Mississippi girl: The time it took to suppress the virus in the first place. The Mississippi baby's viral load was suppressed to undetectable levels 19 days after she started taking the medication, whereas in the Canadian children the initial suppression took three to six months.
Another baby from Long Beach, Calif. who received the high-dose three-drug combo four hours after birth achieved suppression after just six days, Dr. Persaud said. That child is still on antiretrovirals.
"This [the Canadian cases] doesn’t appear to be different than what we see with [antiretrovirals started] around two to three months of age, which may mean that the outcome in the Mississippi child may not be the most common outcome for this very early treatment strategy," Dr. Persaud said. "But we need clinical trials and additional cases to be able to answer that question and address whether a functional cure can be achieved.”
Does the hour at which the high-dose drugs are administered to a newborn matter? Is there some other, unknown, reason the Mississippi baby apparently managed to throw off the virus? What implications do these cases have for children living with HIV, and the hopes they might one day be able to stop taking antiretrovirals?
Those are some of the questions the Canadian team is hoping to answer as it continues its work.