Initial results from the Canadian pediatric HIV research mentioned in a recent blog post were published in Clinical Infectious Diseases on June 9th. The paper notes that Canada’s three pediatric HIV care institutions have a longstanding policy of administering triple drug antiretroviral therapy (ART) regimens to newborns considered at a high risk of HIV infection (either because the mother has detectable viral load at delivery or, in the absence of viral load results, if there is evidence of non-adherence to ART). Treatment is continued if HIV infection is subsequently confirmed. The researchers, inspired in part by the Mississippi baby case report (before the news of viral rebound emerged), searched their records for examples of children who had been started on ART within 72 hours of birth. A total of 136 were identified and, of those, 12 were confirmed to have acquired HIV infection. Four have since been maintained on ART with continuous viral load suppression; ages range from 2.5-7.5 years.
Consistent with other studies of early ART in infants, all four were found to lack detectable HIV-specific antibody and cellular immune responses, and displayed undetectable or extremely low levels of HIV DNA and RNA. In two of the children, tests for replication-competent virus were performed; in one case the result was negative and in the other 0.1 infectious units per million CD4 T cells were detected (the lowest level of detection possible with the assay). The researchers are scheduled to present an update on the cohort next week at the International AIDS Conference in Melbourne, during the “Challenges in Paediatrics” session on Tuesday July 22nd (abstract TUAB0206LB).
Regrettably, the notoriously unreliable media outlet The Daily Mail (often colloquially referred to as The Daily Fail) has already offered wildly misleading coverage of this research, with a headline on July 1st that read: “Three babies 'CURED' of HIV after being given revolutionary new vaccine.” As is typical, the exciting-sounding but mistaken article rapidly proliferated on the web, being copied on multiple other sites and social media. After complaints, the Mail made a small and completely inadequate correction to the headline, removing the imaginary vaccine and instead offering: “Three babies 'CURED' of HIV after being given revolutionary new medical treatment in the first hours of their lives” (the reference to a vaccine persists in the URL and page header). A few paragraphs down, the article flatly contradicts its own headline with an eminently sensible quote from Dr. Sharon Lewin: “At the moment, the doctors do not know whether they are in fact cured. The only way they can tell is if they stop the anti-HIV drugs and see if it comes back.” The importance of Lewin’s point has, sadly, since been further emphasized by the news about the viral load rebound in the child in Mississippi.
The Canadian researchers themselves, in a separate presentation at the 23rd Annual Canadian Conference on HIV/AIDS Research in May, documented an example of viral load rebound after ART interruption in another of the 12 children identified in their analysis (abstract appended below).
Although hopes of achieving a cure with early ART alone have now been diminished, studies like these remain essential for understanding the extent to which the HIV reservoir can potentially be reduced by early treatment, and for setting the stage for studies of interventions that might be able to target the residual amounts of virus for elimination.
Clin Infect Dis. 2014 Jun 9. pii: ciu432. [Epub ahead of print]
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.
Bitnun A, Samson L, Chun TW, Kakkar F, Brophy J, Murray D, Justement S, Soudeyns H, Ostrowski M, Mujib S, Harrigan R, Kim J, Sandstrom P, Read SE.
BACKGROUND: An HIV-1 infected infant started on combination antiretroviral therapy (cART) at 30 hours of life was recently reported to have no detectable plasma viremia after discontinuing cART. The current study investigated the impact of early cART initiation on measures of HIV-1 reservoir size in HIV-1-infected children with sustained virologic suppression.
METHODS: Children born to HIV-1-infected mothers started on cART within 72 hours of birth at three Canadian centers were assessed. HIV serology, HIV-1-specific cell-mediated immune responses, plasma viremia, cell-associated HIV-1 DNA and RNA, presence of replication-competent HIV-1 and HLA genotype were determined for HIV-1-infected children with sustained virologic suppression.
RESULTS: Of 136 cART treated children, 12 were vertically infected (8.8%). In the four who achieved sustained virologic suppression HIV serology, HIV-1-specific cell-mediated immune responses (Gag, Nef) and ultrasensitive viral load were negative. HIV-1 DNA was not detected in enriched CD4+ T-cells of the four children (<2.6 copies/106 CD4+ T-cells), whereas HIV-1 RNA was detected (19.5-130 copies/1.5 µg RNA). No virion-associated HIV-1 RNA was detected following mitogenic stimulation of peripheral blood CD4+ T-cells (5.4-8.0 million CD4+ T-cells) in these four children, but replication competent virus was detected by quantitative co-culture involving a higher number of cells in one of two children tested (0.1 infectious units/106 CD4+ T-cells).
CONCLUSIONS: In perinatally HIV-1-infected newborns, initiation of cART within 72 hours of birth may significantly reduce the size of the HIV-1 reservoirs. Cessation of cART may be necessary to determine whether functional HIV cure can be achieved in such children.
CAHR 2014 23rd Annual Canadian Conference on HIV/AIDS Research (abstract book)
IS FUNCTIONAL HIV CURE POSSIBLE FOLLOWING PERINATAL INFECTION? A CAUTIONARY TALE
Samson, Lindy M; Brophy, Jason; Bitnun, Ari; Kakkar, Fatima; Soudeyns, Hugo; Ostrowski, Mario; Kim, John; Sandstrom, Paul; Chun, Tae-wook; Read, Stanley E.
BACKGROUND: The possibility of eradicating HIV following early initiation of combination antiretroviral therapy (cART) and sustained viral suppression (SVS) is of current interest. We report one such child who discontinued therapy and had rapid viral rebound.
METHODS: History and laboratory testing are summarized. HIV-specific T-cell responses were measured by ELISPOT assay. Plasma viremia and cell-associated HIV-1 RNA were determined by Cobas Ampliprep/Cobas Taqman HIV-1 Test, cell-associated HIV-1 DNA by real-time PCR and presence of replication competent virus by culture of stimulated CD4+ T-cells.
RESULTS: An infant whose mother had inadequately controlled HIV infection at delivery, commenced nevirapine-based cART on the day of birth. HIV DNA PCR was positive on day 6 and initial viral load (VL) on day 28 was 808 c/mL. Maternal genotyping demonstrated NNRTI resistance, and cART was changed on day 25 to a lopinavir/ritonavir-based regimen. SVS was achieved at 175 days, and remained so for 2.5 years except for a single measurement of 40 c/mL. At age 3, HIV serology and ultrasensitive VL were negative. Cell-associated proviral DNA (detection limit 2.6 copies/μg DNA) was undetectable, whereas cell-associated RNA was 149 copies/1.5 μg RNA. Replication competent virus was not demonstrated in stimulated CD4+ T-cell co-culture (6.7 million cells). At age 3.25 years, cART was interrupted following adherence difficulties. Two and four weeks later, VL was 7797 c/mL and 11358 c/mL respectively. HIV-1 specific T-cell responses to gag and nef were also positive. Repeat serology is pending.
CONCLUSIONS: Viral resistance to the initial cART regimen, prolonged time to SVS and residual HIV replication (as evidenced by history of a single detectable VL) may have contributed to the development and persistence of viral reservoirs in this child. Caution should be exercised prior to attempting treatment interruption to evaluate for potential cure in this setting.