March 6, 2013 -- Dr. Hannah Gay and her colleagues became the rock stars of the medical community this week after they announced at a conference last Sunday that they'd cured a 2-year-old of HIV by using an aggressive three-drug treatment that started when the little girl was only 30 hours old.
But with excitement comes confusion as experts question whether this so-called cure is real, and whether high doses of potentially toxic drugs should be administered before an HIV diagnosis can be confirmed.
"In trying new things on kids, you want to make sure every 'i' is dotted and every 't' is crossed, because they can't make choices themselves," said New York University bioethicist Arthur Caplan.
Did the Baby Really Have HIV?
The story started more than two years ago in rural Mississippi, where a mother learned she was HIV positive during labor. (Her identity has been kept under wraps for privacy reasons.)
Once the baby was born, doctors wanted to administer the standard dose of antiretroviral medications to prevent the virus from taking hold, but they did not have the liquid version of the drug intended for infants, according to The Associated Press. The baby was transferred to the University of Mississippi Medical Center, where Gay is a pediatric HIV specialist.
The baby girl had a higher risk of being infected with the virus because her mother, not knowing her HIV status, had not taken transmission-reducing drugs during pregnancy, which have been found to reduce the rate of HIV transmission to 1 percent, said Dr. Mark Kline, a pediatric HIV and AIDS specialist at Baylor College of Medicine in Houston. Without these prenatal preventive measures, babies have a 20 to 25 percent chance of becoming infected with their mother's HIV, Kline said.
In other words, babies born to HIV-positive mothers who do not receive prenatal transmission-reducing drugs have, on average, a 75 percent to 80 percent chance of being born free of HIV.
"That's a rather surprising statistic, I think, because you think to yourself: If the mother has HIV, won't the newborn almost certainly also have HIV?" Kline said. "In fact, even in an era in which we did nothing at all, only minor numbers of infants actually acquired HIV infection."
According to the Centers for Disease Control and Prevention, the number of children born with HIV decreased dramatically in the 1990s from nearly 1,700 babies per year to fewer than 150 babies per year. Worldwide, however, 330,000 HIV-positive babies were born in 2011, according to the United Nations.
Gay ran virologic tests just before she started the baby on HIV treatment, but she did not wait the several days it would take for the test results to confirm whether the baby was actually infected.
What Was the Treatment?
Doctors usually give newborns of HIV-positive mothers one antiretroviral -- nevirapine -- for the first six weeks of life, at which point they can confirm the HIV antibodies or HIV DNA and RNA fragments in tests actually belong to the baby, and weren't just passively passed from the mother during birth. By the time the baby is six weeks old, the mother's antibodies and viruses are expected to be gone from the baby's body, eliminating a chance for a false positive HIV test result. (Kline said false negatives were far more likely.)
But Gay decided that this child's risk was too great for standard care.
"When we consider starting any medication in any patient, we always consider the risk-benefit ratio," Gay said during Monday's press conference. "When the risk is something as serious as HIV disease, then it's worth the benefit that you may get from preventing that disease. Even though you never want to start drugs that may cause toxicities, if the benefit outweighs the risk, you do it."
So instead of a standard dose of nevirapine, Gay administered three antiretroviral drugs -- AZT, 3TC and a double dose of nevirapine – when the baby was 30 hours old, according to Dr. Deborah Persaud, who works at Johns Hopkins Children's Center and would become Gay's research colleague 18 months later, and has studied the case.
Nevirapine was given twice daily, which is the higher dose needed to treat HIV infection rather than prevent it, Persaud said.
Gay said the baby's treatment was "in no way experimental," because the drugs have been used before and are approved by the U.S. Food and Drug Administration. But Persaud said she did not know of any other cases in which a child had been treated this early with this combination of powerful drugs.
Although Gay began administering treatment-size doses, a diagnosis was not yet clear. It wasn't until several days into the therapy that Gay confirmed the baby was HIV-positive with the virologic testing initiated before treatment.
Gay learned -- and outside researchers later confirmed -- that the baby had such high viral loads that it would be "virtually impossible" for it to have had anything other than an HIV infection.
What Are the Risks of These Drugs?
In the short term, these drugs carry the risk of liver inflammation, allergic reactions, and bone marrow suppression, which can predispose the patient to other infections, Kline said.
They also may have long-term toxicities, but there is little data on the long-term effects of taking these drugs early in life, which is another reason why it worries doctors to prescribe them unnecessarily, he said.
"What if we found out one of these medicines increased the risk of developing cancer in 20 years?" Kline said. "It's one of the reasons we reserve this therapy only for infants who have confirmed infection. Then, you say to yourself, even if there are long-term effects of medication, that's unlikely to be worse than having HIV."
Gay and her colleagues operated under the assumption that the baby was infected, and it's fortunate that they made the right call, said immunologist Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases.
"You don't want to be inappropriately treating babies if they're not infected," said Fauci, a pioneer in HIV and AIDS research. "You don't want to put them at risk."
Did the Mother Give Informed Consent?
Gay said in an email that the baby's mother told her to "please do whatever you need to do to keep my baby healthy."
Because the baby wasn't part of a study, there was no need to require the mother to sign a consent form for her child's treatment involving nonstandard medication use, Gay said.
Indeed, the 2013 HIV guidelines from the National Institutes of Health indicate that added drugs beyond standard of care can be used in "other scenarios" but should "be accompanied by counseling of the mother on the potential risks and benefits of this approach."
"It certainly was not the complete education that I like to give to moms before initiating therapy, but considering that she had only learned that day of her own diagnosis, I knew that it would be impossible for her to understand all of the pathogenesis of HIV within the time limitations that we had," Gay said.
This was complicated by the fact that the baby's mother did not accompany the baby to the University of Mississippi Medical Center. Instead, she stayed behind at the hospital where she'd given birth.
"Physical location doesn't make it any the less important to secure her express permission to an off-label use in a circumstance where they're not certain the baby really has the disease," Caplan said. "In general, you don't want to do anything and everything you think of on the basis of an open-ended or vague consent."
Still, Caplan and Kline said they believe Gay had the patient's interests at heart, and that she had the right to deviate from standard of care.
When Did They Find the 'Cure'?
The baby continued the three-drug regimen for the next 18 months, until the baby's mother stopped taking her to clinic appointments, bringing treatment to a halt, Gay has said. It is not clear why they stopped coming to appointments or why they resumed.
The 2-year-old spent five months off treatment before returning to Gay, at which point the doctor expected to see test results showing high viral loads. Instead, the child's HIV appeared to have remained at almost undetectable levels.
"I did not expect that this baby would turn out to be a cure," Gay said in a press conference Monday. "That was a surprise to me."
Gay teamed with doctors at the University of Massachusetts Medical School and John's Hopkins Children's Center to perform more sensitive tests, and they still found almost no trace of HIV. The child has now been off treatment for 10 months with no sign of symptoms, although trace amounts of HIV DNA and RNA remain in the peripheral blood cells.
When the team of doctors announced the world's first "functional cure" of HIV at the Conference on Retroviruses and Opportunistic Infections in Atlanta, news articles appeared that night in The New York Times and the Wall Street Journal. Soon, word of a "cure" spread around the globe.
But even the researchers acknowledge that it's possible the treatment wasn't responsible for the baby's outcome.
"I'll say the early treatment most likely contributed to the outcome in this child," Persaud said during a news conference on Monday. "But whether it's the only intervention that allowed this outcome is unclear and requires further study."
Gay said in an email that "it may or may not have happened due to starting aggressive therapy very early but that is our best guess as to the cause at this point."
How Do We Know It May Be a Cure?
Fauci said the medical community has long believed that the only way to cure someone of HIV is to start treatment as early as possible, before the virus forms reservoirs or damages the immune system, which is what makes it incurable in older children and adults. But Fauci is not celebrating just yet.
"Is it the breakthrough case of the year? Not necessarily," Fauci said. "First of all, you always need to replicate something multiple times. With a single case, you always have to take it with a grain of salt.
"The fact remains that it's important proof of a concept that deserves further study," he said.
Although the child is not on HIV medication now, that doesn't mean symptoms won't return, said Dr. Myron Cohen, director of the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill, who was present at the conference where the "cure" was announced.
"We desperately want to cure the infection," Cohen said. "There's no doubt about our commitment. The big hole is, of course, only massive amounts of time will say whether this child is not infected."
Kline, who has treated children with HIV and AIDS since the 1980s, said calling this a cure, even a functional cure, sends the wrong message to the rest of the world by giving people false hope. It's possible that the child was one of a handful of patients who were born with HIV and were somehow able to control the virus on their own, Kline said.
One of Kline's patients, who is now 22 years old, initially tested positive for HIV and then tested negative just before he started treatment. The patient's test results waffled from positive to negative, and Kline found that he was infected with HIV, but the virus remained dormant most of the time. As such, the patient doesn't need treatment.
"These are unusual cases, and I do think we have something to learn from them, but to say this baby was 'cured' because we gave him powerful medications in the first 30 hours of life, I think that's a real stretch," Kline said.
Since Sunday's announcement, Kline said he's been bombarded with calls and emails from around the world from people who want to know whether the standard of care for HIV patients should change or whether they should explore stopping therapies for some patients.
"I think we've done a real disservice," Kline said. "We might cause some practitioners to erroneously think that now they should be treating every single baby born to a mother with HIV with potentially toxic medication. We're experimenting on babies who, in many cases, are not even infected with HIV."