HTB

Lack of virological impact of treatment intensification in suppressed patients supports latent viral reservoir as source of residual viraemia

Simon Collins, HIV i-Base

Frank Maldarelli from the US HIV Drug Resistance Programme, and colleagues, presented results from a small treatment intensification study looking to clarify the source of residual viraemia in patients with viral load suppressed to <50 copies/mL. [1]

This group has previously reported that long term suppression < 50 copies/mL still results in 80% patients have viraemia >1 copy/mL (when tested on an assay with this sensitivity), but that median levels are only 3.1 copies/mL once patients have been on stable treatment for 60 weeks, and that no further suppression occurred from week 60 to 120. This study also found that the level at week 60 correlated with pre-treatment viral load but not with choice of treatment regimen. [2] They concluded that “these data suggest that the persistent viraemia on current antiretroviral therapy is derived, at least in part, from long-lived cells that are infected prior to initiation of therapy”.

The new study intensified treatment for 30 days in 6 patients who had been suppressed to <50 copies/mL for at least the previous year on standard 3-drug regimens but who still had detectable virus using a 1 copy/mL assay. The four patients on PI-based therapy intensified with efavirenz and the two patients on NNRTI-based therapy added lopinavir/r. Doses were modified appropriately to allow for ARV drug interactions.

These patients (5 men, 1 woman) had been diagnosed a mean 9 years (range 4-16) and on treatment for a mean of 4 years (range 1-10). Mean baseline viral was 4.5 copies/mL.

No significant changes occurred in viral load or CD4 count over the 30 day intensification period, and treatment was well tolerated with no serious side effects reports. Mean viral load during and after intensification were 5.2 and 5.3 copies/mL respectively, showing no impact of the intervention. This was supported by individual responses of the 6 patients that were all included in the poster.

The researchers concluded that failure to find a decrease from intensification in this study was inconsistent with the idea that persistent vireamia at low levels was the result of ongoing complete cycles of replication and that the results supported the source being from latently infected reservoirs.

COMMENT

This study supports research first presented at the resistance workshop several years ago by Lisa Frenkel, who found that 8/11 children with generally suppressed viraemia had no evolution of viral divergence since starting treatment, implying ongoing viraemia was seeded from latently infected cells rather than a partially activated reservoirs as suggested by others.

This has been one of the theoretical foundations behind the drive to achieve suppression to <50 copies/mL. rather than at any higher (or lower) level.

The absence of viral evolution shows effective treatment stopping, rather than slowing, HIV progression, with a clearly different and more important impact on clinical outcome.

References:

  1. Maldarelli F et al. Intensification with efavirenz or lopinavir/r does not reduce residual HIV-viraemia in patients on standardised ARV therapy. XVII IHDRW 2008, Sitges. Abstract 72.
  2. Maldarelli F et al. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathogens 3(4): e46. doi:10.1371/journal.ppat.0030046.
    http://www.plospathogens.org/article/info:doi%2F10.1371%2Fjournal.pp at.0030046
  3. Tobin NL, Frenkel L et al. Evidence that low-level viremias during effective HAART result from two processes: expression of archival virus and replication of virus. J Virology, Aug. 2005, p. 9625-9634.
    http://jvi.asm.org/cgi/content/abstract/79/15/9625

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