Important news has unfolded this week regarding possible additional cases of HIV cures and remission. Yesterday, the London Patient (LP) courageously publicly identified himself as Adam Castillejo in an excellent, thoughtful and empathetic article in the New York Times by Apoorva Mandivilli. While his name is now known, I’ll follow his preference to go by the acronym LP here. Following this story, a scientific update was published in Lancet HIV today (open access), timed to coincide with a poster presentation at the Conference on Retroviruses and Opportunistic Infections (CROI)—a conference that was due to occur in Boston this week, but is now ongoing in a virtual format due to concerns over coronavirus. The same poster session also featured new information on the similar case of the Düsseldorf patient, along with a report on an infant treated early with ART in whom treatment was subsequently interrupted without HIV rebound (which has echoes of the HIV remission described in the Mississippi baby in 2013).
The Lancet HIV paper describes the latest results from extensive studies of LP. The embargo on the publication was lifted at 8:30am ET today, so there are a number of excellent online articles reporting in detail on the findings, including those by Simon Collins for HIV i-Base and Ben Ryan for POZ Magazine. Simon Collins was the first to ever report on LP, after noticing a reference made to the case by Ian Gabriel at a British HIV Association conference in October 2018. LP also released a statement which is quoted extensively in an article by Eagle Radio.
LP has now been off antiretroviral therapy (ART) for 2.5 years and the major take home message from the science is that no evidence of intact, replication-competent HIV could be found in multiple samples of blood, cerebrospinal fluid, semen, gut and lymph nodes. Rare examples of extremely low-level positive signals for HIV DNA fragments were detected in memory CD4 T cells and samples from an axillary lymph node, but this represented a minority of samples from multiple replicates. It was not possible to sequence any HIV genes from these positive samples. The researchers suggest the results could be explained by detection of fragmentary, defective HIV DNA or false positives. Similarly rare low-level positive readings for HIV DNA and RNA were reported in some samples from Timothy Brown back in 2012. Antibody responses to HIV are waning, as was also observed in Brown.
The researchers collaborated with mathematical modeler Alison Hill to explore the probability that LP is cured of HIV. The modeling takes into account donor chimerism, which refers to the proportion of cells in LP that are from the stem cell donor (who was homozygous for the CCR5Δ32 mutation). The model's output indicated that if greater than 90% of the cells in LP are from the donor, then a lifelong HIV cure is almost certain. Measures of the peripheral blood showed that donor chimerism was approximately 99%, so even accounting for the possibility of lower levels in tissues, the paper concludes that a cure has probably been achieved. Nevertheless, viral load testing will continue twice a year for up to 60 months after ART was interrupted, then be switched to yearly for a further 60 months.
As articulated in an accompanying commentary by Jennifer Zerbato and Sharon Lewin, certainty remains elusive when it comes to defining HIV cures. The most important factor is time. Much as confidence in Timothy Brown’s HIV cure has grown the longer he has gone without HIV rebound, the same will be true for LP. But as Zerbato and Lewin note: “We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication.”
In the poster session scheduled for 2:30-4:00pm ET at CROI today (for which the embargo has just lifted), Björn-Erik 0. Jensen provided the latest information on the Düsseldorf patient, who might represent a third individual cured of HIV after receipt of a stem cell transplant from a donor homozygous for the CCR5Δ32 mutation. Follow up is considerably shorter in this case, at just 15 months after ART interruption. Mirroring the findings in both LP and Timothy Brown, the researchers have detected traces of HIV DNA in some samples from lymph nodes and the gastrointestinal tract, but not found any evidence of replication-competent HIV. Antibody responses to HIV are declining.
The same poster session also featured a report by Gloria Heresi from the University of Texas Health Science Center, describing a child experiencing apparent ongoing HIV remission for more three years after an ART interruption. The case closely parallels that of the Mississippi baby, who appeared to have possibly been cured by very early initiation of ART after birth but eventually rebounded after an interruption in treatment that lasted a little over 27 months.
For reasons that are not explained, the mother was untreated at the time of the birth and had a viral load of 14,400 copies the day after delivery. ART regimens were initiated in the infant after 33 hours, but subsequently stopped by the mother at 13 months of age. Viral load has remained <20 copies/mL since that time and the HIV antibody test has been negative from 15 months of age onward (the child is now 4 years of age).
While the mechanisms at work are unknown and further analyses and follow up will be needed, the case may indicate that early restriction of the HIV reservoir by ART can lead to longer periods of HIV remission than was seen in the Mississippi baby. This could be encouraging news for the IMPAACT P1115 trial, which is testing whether early initiation of treatment in HIV-exposed newborns can subsequently facilitate HIV remission, at least for some participants.
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