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Persistent Low Level 'Non-Suppressible' HIV Viremia
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Here in this report is collection of recent research on this subject including publications & CROI orals over past few years plus comments from leading eminent clinicians/researchers: 2 publications from 2020 & 2023, along with 2 commentaries; there were 2 CROI abstracts from 2019 & 2023.
"A small group of people, however, could not suppress despite great adherence to the HIV medications they are taking. So what is being reported is that this appears "not necessarily to be clinically meaningful" if a person develops low level detectable virus without drug resistance, so they haven't "failed therapy". From a researcher: "It is not being reported that people are undetectable then detectable at a very low level and then they feel therapy with drug resistance. So there is no report of meaningful clinical failure. We are also debating whether this new phenomena people switching to a higher setpoint after years of undetectable is either uncommon or super rare. Because it's obviously not very often seen. Its not infectious virus. And even if there is some infectious virus there, there is no resistance seen over years, so it is coming out of cells but not able to get back in and evolve resistance"."
"In conclusion, we demonstrate that proviruses with 5'-L defects, when in favorable genomic and immunological conditions, are a frequent cause of persistent NSV despite effective ART. Although incapable of causing viral rebound, these proviruses contribute to variable levels of viremia and complicate ART management (84), leading to additional testing, unnecessary ART changes and intensifications, and causing anxiety and frustration in patients and clinical care providers. Our work reveals additional complexity in residual viremia and should prompt the development of assays that would allow detection of 5'-L defects."
Comment: "I think we need more data to support this but if someone has not developed NSV for >20 years of suppression, the chances of developing NSV are very low, but it does not exclude the risk of NSV."
Comment: "If you look through the levels of viremia, in the papers, in many cases it is unclear how stably undetectable at what level and for how long they were.
a PWH who has been <20 for many years and suddenly has a VL of say 43
Or even say 143
What to do:
• Examine adherence >>> likely OK
• Repeat VL
• Try to get resistance test if VL sufficient
I have managed this situation dozens of times
I have never seen treatment failure evolve
Almost always VL becomes UD again
It is reassuring to know that in the very rare cases where VL persists, it might be NSV
But it does not change management
But the overall population of people with this kind of low-level viremia
(non-suppressible viremia NSV) seems to be small
Each large center may have 1 or 2 such people per year or so
Most of low level viremia IS Suppressible (better adherence), or is a BLIP (not durable).
Assuming HIV drug resistance is not measured, most of low level viremia that appears in clinical practice in people previously suppressed is suppressible (with better adherence), or is a so-called "blip," a transient surge of viremia that is not durable. Blips may be in some cases due to an immune stimulus, but are often not explained.
Measuring the unique mutation described in the 5' leader sequence is technically difficult, and so it may not happen that a commercial entity would be able to license a test to measure this for clinical management.
More often clinicians like myself would just observe the patient, encourage adherence, look for drug resistance, and if things were stable and LLV persisted with evidence of adherence then assume this was true NSV
And reassure the patient that drug failure was very unlikely to evolve"
Another comment: "This is a very interesting and well done paper. From a clinical perspective it informs what may be going on in at least a subset of the relatively large number of people who have persistent low level viremia while on stable regimen. We all have such patients in our practice and anecdotally over many years in the past we have all tried to intensify or modify therapy without any change. As a result of this, along with other data it has become the standard, and endorsed by guidelines, that typically one should not do anything other than reassure these individuals with viremia that is above limits of detection but less than 200 copies/mL. Although some of these people may go on to fail, the majority do not and it has been hypothesized that we were measuring release of virus from reservoir without rounds of replication. This study is consistent with that assumption, with additional data showing that some of this virus we measure is not replication competent, which is not surprising. The patient with relatively high level viremia is particularly interesting and frankly not something I have seen in my clinical practice over the years.
Detectable infectious virus does not necessarily suggest resistance and failure is likely. If ART is effective, new rounds of infection will not occur in this setting and modifications in therapy are not necessary. My sense is that in clinical practice, VL repeatedly between 200 and 1000 will prompt resistance testing and either addressing issues of adherence and/or drug-drug or drug-food interactions, or modifying therapy typically results in viral suppression. While more data is always interesting, I am not sure that having access to an assay that defines whether plasma virus is infectious or noninfectious would change management strategy for the overwhelming majority of individuals. Of course, if such an assay was readily available with reasonable turnaround time, this hypothesis could be tested before considering its use in the clinic."
3rd Comment: Nonsupressible viremia is a real thing that is uncommon to detect. Most PWH actually have it, I think it is just on the order of 1 copy per mL or less. However, if there is a large enough pool of cells that are expressing virus then it becomes detectable and anxiety provoking (and described many times). The commentary by Ron Swanstrom in JCI is very help. Many people have described this phenomenon over the years. What is new in this paper is the high level of viremia in one person and the 5' deletion that one would only detect with full length sequencing – that is detected in some of the PWH in the paper. Jon Li had a presentation at CROI describing the same thing. These are non-infectious particles that contain RNA (so show up on assay) but lack an envelope (so maybe not cleared as quickly by antibody binding?? (theory)).
While it is impossible to prove a negative all the data suggest in the setting of good adherence and drug levels there is no ongoing sustained replication in PWH like described (and of course not in the people with the 5' deletion). As you know people have argued about this forever."
From Swanstrom, Joseph Commentary, March 2023:
Nonsuppressible viremia during HIV-1 therapy meets molecular virology
The authors estimate that NSV occurs at a frequency of about 1 in 250 cases of people on suppressive therapy (10).
HIV-1 replication can be suppressed with antiretroviral therapy (ART), but individuals who stop taking ART soon become viremic again. Some people experience extended times of detectable viremia despite optimal adherence to ART. In this issue of the JCI, White, Wu, and coauthors elucidate a source of nonsuppressible viremia (NSV) in treatment-adherent patients - clonally expanded T cells harboring HIV-1 proviruses with small deletions or mutations in the 5'-leader, the UTR that includes the major splice donor site of viral RNA. These mutations altered viral RNA-splicing efficiency and RNA dimerization and packaging, yet still allowed production of detectable levels of noninfectious virus particles. These particles lacked the HIV-1 Env surface protein required for cell entry and failed to form the mature capsid cone required for infectivity. These studies improve our understanding of NSV and the regulation of viral functions in the 5'-leader with implications for rationalized care in individuals with NSV.
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JCI 2020, Halvas et al: HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus
Comment, Janet & Robert Siliciano: Nonsuppressible HIV-1 viremia: a reflection of how the reservoir persists
at CROI 2023: VIRAL AND HOST MEDIATORS OF PERSISTENT LOW-LEVEL VIREMIA
https://www.croiwebcasts.org/console/player/51668?mediaType=slideVideo&
JCI Jan 5 2023, Jennifer White: Clonally expanded HIV-1 proviruses with 5'-leader defects can give rise to nonsuppressible residual viremia
Commentary JCI, Sara Joseph & Ron Swanstrom: Nonsuppressible viremia during HIV-1 therapy meets molecular virology
CROI 2019:
NONSUPPRESSIBLE VIREMIA ON ART FROM LARGE CELL CLONES CARRYING INTACT PROVIRUSES.....Elias Halvas - Across the 10 individuals referred, median plasma HIV-1 RNA was 97.5 cps/mL (range 40 to 356 cps/mL) after a median of 10 years on ART. abstract: webcast:
https://www.croiwebcasts.org/console/player/41059?mediaType=audio&
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