The dynamics of HIV proliferation in the viral reservoir might be the explanation for why viral load fails to become undetectable, especially when adherence is good.
Such cases are often reported as a management challenge in the absence of drug resistance at baseline and when ART is started in very early infection. Anecdotally, replication in the viral reservoir has been suggested as a possible mechanism to explain this and this hypothesis is now supported by results from an oral presentation at CROI 2019.
Elias Halvas from the University of Pittsburgh and colleagues presented results that amplified HIV in 10 participants with persistent low level viral load for > 6 months on ART (>50 to <200 copies/mL).
Median viral load and CD4 count was 98 copies/mL and 542 cells/mm3, and at baseline (pre-ART) was 189,000 copies/mL and 212 cells/mm3, respectively. Median cell associated HIV DNA and RNA at the time of the analysis was 1458 and 166 copies/million PBMCs respectively and was detectable in all ten participants.
The study used single-genome sequencing on plasma RNA, cell-associated DNA, and p24+ culture supernatants from quantitative viral outgrowth assays (qVOA). Phylogenetic analysis and integration site analysis was able to show the lack of viral evolution or variation in integration sites.
Although 1/10 participant was excluded due to drug resistance linked to ongoing HIV replication, all other sequences confirmed lack of viral evolution and the viral source was from clonal replication.
This showed that low level viral load was not the result of ongoing viral replication linked to suboptimal adherence or ART but was due to cell proliferation in the viral reservoir.
The study also concluded that the finding might have implications for cure-related research as this clonal reservoir might lead to more rapid viral rebound if ART is stopped in context of an analytic treatment interruption.
These finding have important clinical implications as management of such cases often focuses on intensifying treatment or other modifications to ART.
These results are also important for HIV positive people as intermittent adherence is often proposed as the likely cause.
The PARTNER study provided limited data that low level viral load (<200 copies/mL) is not seen as a risk from HIV transmission (as this threshold was the definition for undetectable in PARTNER).
By Simon Collins
Halvas EK et al. Nonsuppressible viremia on ART from large cell clones carrying intact proviruses. CROI 4 – 7 March 2019, Seattle. Oral abstract 23.