Low level viral load on effective ART is linked to clonal expansion of reservoir: not affected by modifying ART

Researchers investigating new and persistently detectable viral load in four people with a previous history of suppressive ART report that this is caused by clonal expansion of reservoir cells. All cases included people having excellent adherence and no evidence of drug resistance. [1]

The paper also reports new findings that links the cause of viraemia to clones carrying proviruses with 5’-Leader defects.

These cases had many years on suppressive ART and became a clinical challenge due to a subsequent unexplained extended period of detectable viral load that was unresponsive to treatment changes.

Viral load increased to levels where guidelines currently recommend changing treatment,

The four participants (P1–4) had been living with HIV for more than 15 years (range 15-32 years) and had been undetectable on long-term ART from 7 to 27 years, with good CD4 counts. Treatment changes, including intensification had not been successful.

• P1 had persistently detectable viremia for more than four years, with a median plasma viral load of 80 copies/mL (range 37-156).
• P2 had intermittent periods of detectable viremia for more than ten years, with a median of 75 copies/mL (range <20-300).
• P3 had persistently detectable viremia for over four years, with a median of 123 copies/mL (range 26-857).
• P4 was the most extreme example, with a median viral load of 2979 copies/mL (range 1145-5138) for almost two years.

The results have important implications for clinical management of viral rebound that are not currently covered in HIV treatment guidelines that recommend modifying ART in an attempt to resuppress viral load.

As well as not being effective, this risk undermining the relationship of trust between people living with HIV and their doctor, if the default assumption is that this is caused by poor adherence.

1. In these cases, treatment modification including intensification, as currently recommended in treatment guidelines will not have any impact on resupressing viral load.
2. The lack of viral evolution in these cases includes the reassurance that drug resistance is not a concern.
3. Recovered virus was inducible but produced non-infectious virions containing viral RNA but lacking envelope.
4. That without an easy way to test residual low level viral load, it isn’t possible to identify such cases, which might be as common as 1 in 250 people on otherwise stable ART.

The study was published as an online open access paper in the Journal of Clinical Investigation in January.

Comment

Similar cases presented at CROI 2019 were restricted to levels of viraemia that were between 50 to 200 copies/mL when treatment changes would not necessarily have been recommended. [2, 3, 4]

This paper is notable for including higher levels of viraemia >1000 copies/mL when treatment is definitely recommended to be changed.

Low level viral load (>50–1000 copies/mL) is a cause of significant stress and anxiety to people living with HIV who expect their viral load to be undetectable (<50 copies/mL) for both their own health and as protection for their partners.

This highlights the need for an easy test to identify the source of rebound viral load.

Without this test, it might be possible to use lack of impact from ART intensification as a way to return to previous ART, without continued worry about low level viraemia.

This is clearly an area that needs further research.

By Simon Collins, HIV i-Base

Reference

1. White JA et al. Clonally expanded HIV-1 proviruses with 5’-Leader defects can give rise to nonsuppressible residual viremia, J Clin Invest. 2023. DOI: 10.1172/JCI165245. (5 January 2023).
   www.jci.org/articles/view/165245
2. Collins S. Viral reservoir can explain persistent low level viraemia with good adherence on ART. HTB (12 March 2019).
   i-base.info/htb/35801
3. Halvas EK et al. Nonsuppressible viremia on ART from large cell clones carrying intact proviruses. CROI 4 – 7 March 2019, Seattle. Oral abstract 23.
   www.croiconference.org/sessions/nonsuppressible-viremia-art-large-cell-clones-carrying-intact-proviruses (abstract)
   www.croiwebcasts.org/console/player/41059 (webcast)
4. Halvas EK et al. HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus. J Clin Invest. 2020; 130(11):5847-5857. doi: 10.1172/JCI138099. (2 November 2020.
   www.ncbi.nlm.nih.gov/pmc/articles/PMC7598056