- Category: Search for a Cure
- Published on Friday, 11 July 2014 00:00
- Written by Liz Highleyman
A child in Mississippi who had undetectable HIV viral load for more than 2 years off antiretroviral treatment and was heralded as a rare case of "functional cure" has been found to still be infected with the virus, researchers announced this week, tempering optimism about one cure research approach.
The Mississippi baby topped the headlines at the 2013 Retrovirus Conference, where researcher Deborah Persaud of Johns Hopkins first described the case. Further details were published in the November 7, 2013 New England Journal of Medicine.
The girl -- now almost 4 years old -- was born in 2010 to a woman with HIV in Mississippi who was not diagnosed until the time of delivery, was not on antiretroviral therapy (ART), and had a low but detectable viral load. The baby was delivered prematurely before the mother could be given antiretroviral drugs to prevent mother-to-child transmission.
At approximately 30 hours after birth, the baby was started on a 3-drug combination ART regimen using nevirapine (Viramune), zidovudine (AZT or Retrovir), and lamivudine (3TC or Epivir). Repeat testing revealed HIV RNA in the infant's blood plasma and HIV DNA in peripheral blood cells, indicating that the baby had in fact been infected, not just carrying the mother's HIV antibodies.
The baby continued on ART, with lopinavir/ritonavir (Kaletra) substituted for nevirapine. The child achieved viral load suppression within a month -- a pattern of viral decline similar to that seen in treated adults. After remaining on ART for a year and a half, however, the child began missing clinic visits and was later reported to have stopped treatment.
But when the girl was brought back for care at about 2 years old, her viral load was undetectable (<20 copies/mL) despite being off treatment for several months. Normally HIV would be expected to rebound rapidly after stopping therapy. Extensive testing over the ensuing year, including HIV DNA testing of peripheral blood cells, failed to detect replication-competent virus. At this year's Retrovirus Conference in March, Persaud reported that the child still had undetectable HIV 2 years after interrupting ART.
An update was expected at the 20th International AIDS Conference later this month in Melbourne, but researchers broke the news with a National Institute of Allergy and Infectious Diseases press release and media briefing on July 10.
During a routine clinical visit earlier this month, the child was found to have detectable HIV in her blood, with a viral load of 16,750 copies/mL. Repeat testing 72 hours later confirmed this finding, with a reading of 10,564 copies/mL. The child also had a decreased CD4 T-cell count, indicating that the replicating virus was starting to kill off immune cells. She was put back on antiretroviral therapy, and to date is tolerating treatment well and shows a declining viral load as the drugs start to work.
"Certainly, this is a disappointing turn of events for this young child, the medical staff involved in the child’s care, and the HIV/AIDS research community," said NIAID director Anthony Fauci. "Scientifically, this development reminds us that we still have much more to learn about the intricacies of HIV infection and where the virus hides in the body."
Setback in the Search for a Cure
HIV establishes reservoirs of latent virus in resting T-cells soon after infection -- where it is not susceptible to immune responses or antiretroviral drugs -- which makes it very difficult to cure. While ART effectively suppresses replicating virus, it cannot reach this hidden viral genetic material. When these resting cells are later activated, the viral genetic blueprint can "wake up" and start producing new virus.
In the Mississippi case, researchers hoped that starting a combination of antiretrovirals very early might have prevented establishment of long-term infection. This is similar to the principle of post-exposure prophylaxis (PEP), where drugs are started within 72 hours after exposure. In this case, while treatment was started about 30 hours after birth, the baby could have been infected substantially earlier, during gestation.
"The fact that this child was able to remain off antiretroviral treatment for 2 years and maintain quiescent virus for that length of time is unprecedented," Persaud said. "Typically, when treatment is stopped, HIV levels rebound within weeks, not years."
"The prolonged lack of viral rebound, in the absence of HIV-specific immune responses, suggests that the very early therapy not only kept this child clinically well, but also restricted the number of cells harboring HIV infection," added Katherine Luzuriaga from the University of Massachusetts Medical School, senior author of the 2013 New England Journal of Medicine report.
The latest news casts new light on a handful of other cases of babies who started ART soon after birth. At this year's Retrovirus Conference, Persaud also described a baby in Los Angeles County who started treatment very early and appears not to have detectable HIV using the most sensitive tests.
In the June 9, 2014, advance edition of Clinical Infectious Diseases, Canadian researchers described 4 children who had started combination ART within 72 hours after birth due to risk of mother-to-child transmission (for example, the mother had detectable viral load at the time of delivery). They had confirmed infection and achieved sustained viral suppression with an ART regimen of nevirapine, zidovudine, and lamivudine. After 2 to 7 years of follow-up testing, all 4 children continued to have undetectable plasma viral load and undetectable HIV DNA in peripheral blood cells. However, all 4 had detectable bits of viral genetic material, like the Mississippi baby, and 1 had a very low level of replication-competent virus (0.1 per 1,000,000 CD4 cells).
Importantly, the Los Angeles baby and the 4 Canadian children were never taken off antiretroviral treatment to see if they would maintain undetectable virus in the absence of therapy.
However, at the Canadian Association for HIV Research meeting in May, The Canadian team reported a single case of an infant who started very early combination ART and was taken off treatment. As described by MedPage Today, this child (now age 3) had sustained undetectable plasma viral load and peripheral blood HIV DNA before stopping treatment temporarily due to difficulties with adherence. In contrast to the Mississippi baby, this child's plasma viral load rebounded rapidly, reaching 11,358 copies/mL in 4 weeks
"Given that it is not possible to examine every cell in each infant, a structured treatment interruption may be the only practical way to determine if HIV-1 eradication or functional cure can be achieved in such treatment," the Canadian study authors concluded.
"If virologic rebound were to occur following combination ART discontinuation it would likely be accompanied by expansion of the HIV-1 reservoir, potentially making future HIV-1 reservoir eradication more difficult," they cautioned. "Therefore, a thorough discussion of the risks and benefits of stopping combination ART with patients and caregivers is imperative and, if undertaken, will require long-term follow-up."
With the recent Mississippi revelation, this potentially risky strategy seems even more ethically fraught.
Investigators with the NIH-funded International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) had been planning a proof-of-concept trial (IMPAACT P115) in which at-risk infants born to mothers with HIV would be started on intensive combination antiretroviral treatment immediately after birth. They would be monitored closely for 2 or more years, and if no HIV were detected and they appeared to have no other risk factors, they would undergo analytic treatment interruption to see if the virus returned.
After the new findings, however, experts will re-evaluate this approach. In particular, researchers want to learn what enabled the Mississippi child to remain off ART so long without viral rebound or any apparent negative effects on her health.
"The case of the Mississippi child indicates that early antiretroviral treatment in this HIV-infected infant did not completely eliminate the reservoir of HIV-infected cells that was established upon infection but may have considerably limited its development and averted the need for antiretroviral medication over a considerable period," said Fauci. "Now we must direct our attention to understanding why that is and determining whether the period of sustained remission in the absence of therapy can be prolonged even further."
National Institute of Allergy and Infectious Diseases. "Mississippi Baby" Now Has Detctable HIV, Researchers Find. Press release. July 10, 2014.
Interview with Anthony Fauci on "Mississippi Baby." Blog.AIDS.gov. July 11, 2014.
D Persaud, H Gay, C Ziemniak, et al. Functional HIV Cure after Very Early ART of an Infected Infant. 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013). Atlanta, GA, March 3-6, 2013. Abstract 48LB.
D Persaud, A Deveikis, H Gay, et al. Very Early Combination Antiretroviral Therapy in Perinatal HIV. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 75LB.
A Bitnun, L Samson, TW Chun, et al. Early Initiation of Combination Antiretroviral Therapy in HIV-1-Infected Newborn Infants Can Achieve Sustained Virologic Suppression with Low Frequency of CD4+ T-cells Carrying HIV in Peripheral Blood. Clinical Infectious Diseases. June 9, 2014 (Epub ahead of print).
M Smith. Culture Shock: No 'Mississippi Baby' in Canada. MedPage Today. May 11, 2014.
DF Maron. HIV on Trial: An Attempt to Cure the World’s Smallest Patients. Scientific American. June 16, 2014.
SK Shah, D Persaud, DS Wendler, et al. Research into a functional cure for HIV in neonates: the need for ethical foresight. Lancet Infectious Diseases. June 4, 2014 (Epub ahead of print).