A Functionally Cured CROI Baby?
March meeting showcases new data on PrEP, hormonal contraception and vaccines—but a toddler steals the show
By Regina McEnery
The 20th Conference on Retroviruses and Opportunistic Infections (CROI) opened in Atlanta with a blockbuster about a Mississippi toddler who appears to be the first child—and only the second person—to have been functionally cured of HIV. The toddler was abruptly taken off treatment after receiving antiviral drugs during the first 18 months of life. Several months later, doctors could find no detectable replication-competent virus in the toddler’s blood or any evidence of disease.
Unveiled at an early press conference and rounded out a day later in an oral abstract session, the case report sparked a rare media firestorm for the organizers of this otherwise low-key, science-heavy meeting. Within 72 hours, a news story by The Associated Press had generated close to 5,000 comments on The Huffington Post website. Deborah Persaud, the Johns Hopkins researcher who presented the findings, seemed ubiquitous on television screens, and Hannah Gay, the treating pediatrician from the University of Mississippi Medical Center who referred the case to Persaud, became an instant celebrity. The story captivated the blogosphere for days.
Even before this remarkable case landed in CROI’s late-breaker pile—reserved for abstracts that are considered after the deadline for submissions—it was clear that HIV cure research was going to be a hot topic at this year’s conference, given how much researchers have lately learned about the cellular reservoirs in which HIV persists despite highly active antiretroviral therapy (HAART). The hope is that this expanding knowledge will one day inform new therapies to better control HIV or even snuff it out entirely (see Primer on Understanding Therapeutic Vaccination, this issue).
Still, despite recent advances, and even a scientific roadmap (see IAVI Report blog, Cure Research: An Update and a Roadmap, July 27, 2012) for the burgeoning field, HIV cure researchers are probably years from achieving their ultimate goal.
One of those challenges will be confirming the toddler’s apparent functional cure. But it’s worth the effort. “With this case, we may have not only a positive outcome for the particular child, but also a promising lead for additional research toward curing other children,” said Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, in an agency release.
So far, not a great deal of personal detail has been disclosed about the toddler, primarily to protect patient confidentiality. We are informed that the child, from rural Mississippi, was born prematurely at 35 weeks to a mother who received no antiretroviral treatment (ART) or prenatal care. Doctors affiliated with the University of Mississippi Medical Center have been treating the child, who is now 2 ½, since birth and the child is reportedly thriving. But Persaud has declined to divulge the child’s gender, the mother’s age, why the mother didn’t receive ARVs during her pregnancy and, perhaps most importantly, why the child was taken off ART after 18 months.
What we do know is that when the baby was 30 hours old, doctors began administering a liquid cocktail of three ARVs—zidovudine, lamivudine, and nevirapine, which was given at a therapeutic dose, which is higher than a preventive dose, according to Persaud. Blood samples obtained the same day confirmed HIV infection. The RNA test showed a viral load of 19,812 copies per milliliter of blood. Subsequent tests, conducted when the child was 7, 12 and 20 days old, showed steadily declining levels of virus in the blood before it became undetectable at 29 days.
The baby was discharged from the hospital at one week of age and switched to an ARV cocktail of zidovudine and lamivudine co-formulated with lopinavir-ritonavir. The liquid regimen continued for 18 months. Then, for reasons that are not clear, treatment was stopped and the child was apparently lost to follow up. When Gay, the Mississippi pediatrician, finally saw the child about six months later, she discovered there were still no detectable levels of HIV in the child’s blood, even though the baby had been off ART for about as long. This surprised Gay because previous studies have found that the virus resurges swiftly following treatment interruption.
Gay consulted both Persaud, a researcher at Johns Hopkins Children’s Center, and Katherine Luzuriaga at the University of Massachusetts Medical School, who recommended ultrasensitive RNA and DNA tests that can detect extremely low levels of virus in the blood. Those tests, done at 26 months of age, detected a single copy of HIV RNA in the child’s plasma and extremely low levels of HIV DNA. But plasma viral load, HIV DNA, and HIV-specific antibodies remained undetectable in standard tests, leading Persaud and colleagues to conclude that the child had been functionally cured. This contrasts with the sterilizing cure—complete eradication of all viral traces from the body—initially documented in Timothy Brown, an HIV-infected man known as the “Berlin patient” who received a stem cell transplant from a donor naturally resistant to HIV. However, after some bits and pieces of viral DNA and RNA were discovered last year in Brown’s blood and tissue, scientists now question whether the Brown case really is an example of such a cure. Scientists aren’t sure if the traces are the result of false laboratory readings or indeed evidence that transient virus still exists in Brown’s body.
There have been other reported cases of transient HIV infection in infants, but Persaud said the details of those cases were murky. Indeed, a study published 15 years ago in the journal Science by University of Rochester researchers analyzed 42 cases of suspected transient HIV viremia. It found that most of the results had been misinterpreted.
Persaud said the Mississippi case suggests that delivering ARVs within days of exposure could potentially induce long-term remission without the need for daily ARVs. But whether this alone accounts for the outcome in the Mississippi case remains unclear, she said.
The next step will be to replicate the result in other high-risk newborns. Persaud, who is the scientific chair of the HIV Cure Committee of the International Maternal, Pediatric Adolescent AIDS Clinical network, said clinical trials are already being planned. “This is a single case,” said Persaud. “But, certainly, if it is replicated, we do think this will transform management of children” born to HIV-infected mothers.
But Persaud’s wasn’t the only notable talk on viral clearance. Louis Picker detailed in one of the last presentations at the conference how a novel viral vector vaccine candidate bearing antigens against the simian immunodeficiency virus (SIV), the monkey form of HIV, appeared to have cleared residual virus in rhesus macaques who had been challenged with a pathogenic form of SIV. A professor of pathology at Oregon Health & Science University, Picker has been working for nearly a decade on an HIV vaccine candidate built on a replicating rhesus cytomegalovirus (rhCMV) viral vector. His research has potentially broad implications for the development of both preventive and therapeutic HIV vaccine candidates, though CMV viral vectors have not yet progressed to human HIV trials.
Persistent replicating vectors are attractive to vaccinologists because such vectors are capable of continuously expressing target antigens after delivery. Their persistence is also likely to elicit broader, long-lasting, and more potent immune responses. Further, CMV vectors—which elicit distinct populations of SIV-specific CD4+ and CD8+ T cells—maintain effector memory cell responses at mucosal sites. These cells are retained in tissues where HIV gains a foothold in the early stages of infection and can kill infected cells before HIV establishes a life-long infection. Picker and colleagues reported in 2011 that the rhCMV vaccine, when given alone or in combination with another SIV vaccine vector, stringently suppressed SIV indefinitely in 13 of 24 macaques who had been challenged rectally with a highly pathogenic strain known as SIVmac239.
At CROI, Picker offered proof that the rhCMV-vaccine elicited response hadn’t just suppressed the SIV in protected animals, but cleared it. He and his colleagues took 60 million cells from five SIV-infected animals that had controlled the SIV infection for at least 17 months and injected them into SIV-uninfected animals. When the cells from SIV-infected monkeys on fully suppressive HAART or from monkeys able to control SIV without ARVs were injected into SIV-uninfected animals, their transfer led to rapidly detectable infection. But in the case of the rhCMV vaccine-protected animals, no infection occurred following transfer.
“The implication is that there is no residual SIV in the rhCMV/SIV vector-vaccinated, long-term protected animals,” said Picker. “The SIV infection, which was demonstrable there early on, after challenge, is now gone, cleared, nada.”
So did the CMV vector eradicate the virus? “My partner suggested I not use the ‘E’ word,” he said. “But certainly, the implication is that these animals are virus-free at this point.”
Still, CMV is not entirely benign. Though it is widespread—90% of people in sub-Saharan Africa have been infected with it—and is generally harmless in healthy people, the virus does pose a risk to fetuses and immune-compromised individuals, including those with HIV. Picker has therefore been trying to develop an attenuated CMV vector that does not cause disease but remains effective. He did not report any new results from that effort at CROI.
For women, some mixed signals
Advocates of pre-exposure prophylaxis (PrEP) were recently dealt a blow when an international study of 5,029 women found that a prescribed regimen of ARVs did not prevent HIV acquisition. A University of Washington researcher who presented the findings at CROI said this appeared to be because women in the trial didn’t use the oral and topical PrEP regimens consistently (see IAVI Report blog, The VOICE results, loud and clear: Adherence Matters, Mar. 4, 2013).
Two studies also delivered conflicting verdicts on whether hormonal contraception increases a woman’s risk of HIV acquisition and of transmitting the virus to men. In a study of 99 HIV-infected women from Kenya who adhered to a three-drug ARV regimen for an average of 34 months, HIV viral loads in blood and genital secretions remained suppressed most of the time. University of Washington researcher Summer Day said viral load levels did not differ between women who took the injectable hormonal contraceptive depot medroxyprogesterone acetate (Depo-Provera) and those who did not. Previous studies had suggested Depo-Provera may increase the risk of HIV transmission.
Data from the current study suggest that consistent use of triple-combination therapy seems to counter any increase in viral load induced by the contraceptive, which is popular in developing countries. Day said ARVs should be considered along with condom use as a strategy for decreasing the risk of heterosexual transmission of HIV by infected women who use this form of birth control.
A British study was less encouraging. A secondary analysis of the Microbicides Development Programme (MDP301) trial found an increased HIV incidence in women using two different injectable hormonal contraceptives—Depo-Provera and norethisterone oenanthate (NET-EN). MDP301 evaluated the microbicide PRO 2000, which was found to be ineffective (see VAX Feb. 2009 Spotlight article, Canvassing CROI).
The sub-analysis included 8,663 women under age 50 from four African countries, who were tested every three months. Researchers identified 417 HIV infections after a year of follow up. Angela Crook, a researcher from the UK Medical Research Council, said initial results showed an increase in HIV incidence among women using the two injectable contraceptives and no increase in HIV among users of oral contraceptives. But after adjusting for various factors, including age, condom use, frequency of sex, study recruitment site, and occurrence of the sexually transmitted diseases chlamydia and herpes simplex virus-2, there was no increased risk of HIV between users of NET-EN or oral contraceptives. Still, researchers found a higher risk of HIV associated with Depo-Provera, though it was less than what the original analysis suggested.
The conclusion: More research required.