Date Published: November 7, 2017
Publisher: Public Library of Science
Author(s): Timothy J. Henrich, Hiroyu Hatano, Oliver Bacon, Louise E. Hogan, Rachel Rutishauser, Alison Hill, Mary F. Kearney, Elizabeth M. Anderson, Susan P. Buchbinder, Stephanie E. Cohen, Mohamed Abdel-Mohsen, Christopher W. Pohlmeyer, Remi Fromentin, Rebecca Hoh, Albert Y. Liu, Joseph M. McCune, Jonathan Spindler, Kelly Metcalf-Pate, Kristen S. Hobbs, Cassandra Thanh, Erica A. Gibson, Daniel R. Kuritzkes, Robert F. Siliciano, Richard W. Price, Douglas D. Richman, Nicolas Chomont, Janet D. Siliciano, John W. Mellors, Steven A. Yukl, Joel N. Blankson, Teri Liegler, Steven G. Deeks, Linda-Gail Bekker
Abstract: BackgroundIt is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.Methods and findingsColorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.ConclusionsWe report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.
Partial Text: The development of a cure for HIV infection is a major public health objective . Despite the ability of antiretroviral therapy (ART) to significantly reduce disease-related morbidity and mortality in HIV-1 infection, viral reservoirs persist indefinitely in latently infected cells . HIV persists during ART primarily within circulating and tissue-resident, long-lived memory CD4+ T cells that harbor integrated HIV DNA; these cells are not cleared with ART and are a source of viral rebound when treatment is discontinued . A major HIV eradication strategy involves aborting the initial seeding of these long-lived reservoirs by the very early initiation of ART [4,5]. For example, initiation of ART in a perinatally infected infant at 31 hours of life led to significant reductions in the viral reservoir and a significant time off ART (>2 years) before eventual viral recrudescence [6,7]. However, the impact of extremely early ART on HIV persistence and seeding the viral reservoir with the potential to prevent establishment of lifelong infection in adults is unknown.
We report 2 cases of extremely early HIV diagnosis and initiation of ART at the threshold when plasma viremia begins to expand exponentially (the end of the so-called “eclipse phase” and beginning of Fiebig stage I). These stages of HIV infection precede the time when acute HIV infection becomes clinically apparent and are theoretically the earliest time when ART can be initiated in an adult [12,13]. To the best of our knowledge, PrEP Participant A is the earliest documented case of adult HIV infection followed by immediate initiation of ART with the exception of successful post-exposure ART prophylaxis, and it would be very challenging to initiate therapy any earlier. Despite the complete or near-complete loss of detectable HIV in blood and a variety of tissues, HIV rebounded in this person 225 days following cessation of ART. Although identifying hyperacute infection is rare, our group has previously reported that 15.6% of patients referred to our HIV clinic for newly diagnosed infection had detectable plasma HIV-1 RNA but negative HIV-specific antibody test results . These data include individuals taking part in a rapid treatment initiation study and may overestimate the incidence of acute infection identified during Fiebig stage I. Excluding participants in this study, 6.3% of individuals presented with positive plasma HIV-1 RNA and no detectable HIV-specific antibodies at the time of diagnosis .