An open access paper published in the Journal of Infectious Diseases reports that earlier HIV suppression by ART is associated with significantly smaller HIV reservoirs in perinatally infected youths. The study, by Katherine Luzuriaga and colleagues, was initially presented at CROI last year and compared two groups of four individuals: one group started ART at 0.5–2.6 months of age and the other at 6-14.7 years of age. HIV DNA levels were significantly lower in the early-treated group, and replication-competent virus could only be detected in one out of the four, at a very low level, but was found in all of the late-treated study participants. Additionally, there was evidence of a decrease in HIV DNA levels over time in the early-treated group. At this year’s CROI, Deborah Persaud described a similar but much larger analysis that echoed these findings, and also identified negative or indeterminate HIV antibody tests as a marker for smaller reservoirs (the presentation can be viewed via webcast).
Both the Journal of Infectious Diseases paper and an accompanying commentary by Jonathan Li and Rajesh Gandhi note that the results are consistent with prior studies in adults demonstrating that early initiation of ART is associated with a significantly lower HIV reservoir (see abstracts and links to free full text for two examples below). One implication is that some early-treated individuals may ultimately be able to safely interrupt ART, but the authors emphasize that this needs to be tested in carefully conducted clinical trials. Several cautionary examples of HIV rebound despite undetectable or extremely low reservoirs prior to ART interruption are cited, including the Boston patients and a case report from the laboratory of Tae-Wook Chun.
An additional example involving a 3-year-old child started on ART within 72 hours after birth was reported recently at the Canadian Association for HIV Research conference. According to an article in the Globe & Mail, an ART interruption was prompted by adherence difficulties and viral load rebounded from undetectable levels to 7,797 copies in two weeks and 11,358 copies in four (although the article uses the word “skyrocketed,” these viral load levels are actually low for untreated pediatric HIV infection and the apparent increase from the second to fourth week is small and within the variability of the assay). ART has since been restarted and viral load once again suppressed. The researchers presenting this case noted some differences with the Mississippi baby, including a longer time to viral load suppression (six months versus 19 days) and an instance of a borderline detectable viral load prior to the ART interruption.
A clinical trial investigating immediate ART in babies born to HIV-positive mothers who did not receive prevention of mother-to-child transmission (PMTCT) is about to be launched by the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network. An entry for the trial is now posted in the clinicaltrials.gov database and additional information, including the protocol, is available on the IMPAACT website. The primary aim is to assess whether the apparent remission of HIV infection that has been achieved in the Mississippi baby can be duplicated in other infants.
Update 6/9/14: The IMPAACT trial investigators have published a "personal view" article in Lancet Infectious Diseases that discusses some of the ethical issues raised by their research. The article is accessible free of charge but requires registration for the website.
J Infect Dis. (2014) doi: 10.1093/infdis/jiu297
First published online: May 21, 2014
Katherine Luzuriaga1,2,4, Barbara Tabak1,3, Manuel Garber1,3, Ya Hui Chen5, Carrie Ziemniak5, Margaret M. McManus1,2, Danielle Murray6, Matthew C. Strain7, Douglas D. Richman7, Tae-Wook Chun6, Coleen K. Cunningham8 and Deborah Persaud5
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, 01605, US
2Department of Pediatrics, University of Massachusetts Medical School, Worcester, 01605, US
3Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, 01605, US
4Center for Clinical and Translational Science; University of Massachusetts Medical School, Worcester, 01605, US
5Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, 21205, US
6Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, US
7University of California San Diego, La Jolla, CA, 92093 and Veterans Affairs San Diego Healthcare System, San Diego, 92161, US
8Department of Pediatrics, Duke University Medical Center, Durham, 27710, US
Abstract
Background. Early combination antiretroviral therapy (cART) of HIV-1 infected infants controls HIV-1 replication and reduces mortality.
Methods. Plasma viremia (LOD<2 copies/ml), T cell activation, HIV-1 specific immune responses, and the persistence of cells carrying replication-competent virus were quantified under long-term effective cART in four early-treated (ET) and four late-treated (LT) perinatally HIV-1 infected youth. Decay in peripheral blood mononuclear cell (PBMC) proviral DNA levels was also measured over time in the ET youth.
Results. Plasma viremia was not detected in any ET youth but was detected in all LT youth (median 8 copies/ml; p=0.03). PBMC proviral load was significantly lower in ET youth (median 7 copies per million peripheral blood mononuclear cells) than in LT youth (median 181 copies; p=0.03). Replication competent virus was recovered from all LT youth but only one ET youth. Decay in proviral DNA was noted in all four ET youth in association with limited T cell activation and absent to minimal HIV-1 specific immune responses.
Conclusions. Early effective cART from infancy significantly limits circulating levels of proviral and replication-competent HIV-1 and promotes continuous decay of viral reservoirs. Continued cART with reduction in HIV-1 reservoirs over time may facilitate HIV-1 eradication strategies.
J Infect Dis. (2014) doi: 10.1093/infdis/jiu298
First published online: May 21, 2014
Jonathan Z. Li1,2, and Rajesh T. Gandhi2,3
1Division of Infectious Diseases, Brigham and Women’s Hospital
2Harvard Medical School
3Division of Infectious Diseases, Massachusetts General Hospital, Ragon Institute of MGH, MIT, Harvard
J Infect Dis. 2013 Oct 15;208(8):1202-11. doi: 10.1093/infdis/jit311. Epub 2013 Jul 12.
Jain V, Hartogensis W, Bacchetti P, Hunt PW, Hatano H, Sinclair E, Epling L, Lee TH, Busch MP, McCune JM, Pilcher CD, Hecht FM, Deeks SG.
Abstract
Background. CD4(+)/CD8(+) T-cell activation levels often remain elevated in chronic human immunodeficiency virus (HIV) infection despite initiation of antiretroviral therapy (ART). T-cell activation predicts early death and blunted CD4+ T-cell recovery during ART and may affect persistent HIV reservoir size. We investigated whether very early ART initiation is associated with lower on-therapy immune activation and HIV persistence.
Methods. From a cohort of patients with early HIV infection (<6 months duration since infection) we identified persons who started ART early (<6 months after infection) or later (≥2 years after infection) and maintained ≥2 years of virologic suppression; at-risk HIV-negative persons were controls. We measured CD4(+)/CD8(+) T-cell activation (percent CD38(+)/HLA-DR(+)) and HIV reservoir size (based on HIV DNA and cell-associated RNA levels).
Results. In unadjusted analyses, early ART predicted lower on-therapy CD8(+) T-cell activation (n = 34; mean, 22.1%) than achieved with later ART (n = 32; mean, 28.8%; P = .009), although levels in early ART remained elevated relative to HIV-negative controls (P = .02). Early ART also predicted lower CD4+ T-cell activation than with later ART (5.3% vs 7.5%; P = .06). Early ART predicted 4.8-fold lower DNA levels than achieved with later ART (P = .005), and lower cell-associated RNA levels (difference in signal-to-cutoff ratio (S/Co), 3.2; P = .035).
Conclusions. ART initiation <6 months after infection is associated with lower levels of T-cell activation and smaller HIV DNA and RNA reservoir size during long-term therapy.
J Antimicrob Chemother. 2013 May;68(5):1169-78. doi: 10.1093/jac/dks533. Epub 2013 Jan 20.
Hocqueloux L1, Avettand-Fènoël V, Jacquot S, Prazuck T, Legac E, Mélard A, Niang M, Mille C, Le Moal G, Viard JP, Rouzioux C; AC32 (Coordinated Action on HIV Reservoirs) of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS).
Abstract
OBJECTIVES: To characterize viro-immunological outcomes following long-term combined antiretroviral therapy (cART) initiated during primary HIV infection (PHI) or chronic HIV infection (CHI) and to identify factors predictive of optimal viro-immunological responder (OVIR) status.
METHODS: This was a prospective, single-centre cohort study of HIV-1-infected patients on effective cART. Total cell-associated HIV DNA levels and T cell counts before and during treatment were used to identify factors predictive of OVIR status {i.e. low HIV DNA level [<2.3 log10 copies/10(6) peripheral blood mononuclear cells (PBMCs)], together with normalization of the absolute/relative CD4+ T cell counts and CD4+/CD8+ ratio}.
RESULTS: A total of 307 patients were enrolled, of whom 35 started cART during PHI (<4 months post-infection) and 272 during CHI. HIV DNA decay was modelled with a non-linear mixed-effects model that showed two phases of HIV DNA decay, both of which were significantly more pronounced in the PHI group. At the end of follow-up, after a median of 4 years of viral suppression (<50 copies/mL), HIV DNA levels were lower in the PHI group than in the CHI group (median = 2.15 versus 2.84 log10 copies/10(6) PBMCs; P< 0.0001). Immune reconstitution was more rapid and sustained in the PHI group (median = 883 versus 619 CD4+ cells/mm(3); 41% versus 31% CD4+; CD4+/CD8+ 1.31 versus 0.77; all P< 0.0001). Finally, OVIR status was obtained in 19/35 (54%) and 7/272 (3%) patients in the PHI and CHI groups (P< 0.0001), respectively. In a logistic regression analysis, cART initiation during PHI (OR = 16, 95% CI = 3.5-72.3) and HIV DNA level <3.3 log10 before treatment (OR = 4.8, 95% CI = 1.2-19.3) were independently predictive of OVIR status.
CONCLUSIONS: Initiating cART during PHI represents a major opportunity to reduce HIV reservoirs and achieve optimal immune reconstitution.
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