Impact of sub-optimal HIV viral control on activated T cells

Abstract

Objective: HIV viral load (VL) monitoring is generally conducted 6–12 monthly in low- and middle-income countries, risking relatively prolonged periods of poor viral control. We explored the effects of different levels of loss of viral control on immune reconstitution and activation. Design: Two hundred and eight participants starting protease inhibitor (PI)-based second-line therapy in the EARNEST trial (ISRCTN37737787) in Uganda and Zimbabwe were enrolled and CD38+/HLA-DR+ immunophenotyping performed (CD8-FITC/CD38-PE/CD3-PerCP/HLA-DR-APC; centrally gated) in real-time at 0, 12, 48, 96 and 144 weeks from randomization. Methods: VL was assayed retrospectively on samples collected every 12–16 weeks and classified as continuous suppression (<40 copies/ml throughout); suppression with transient blips; low-level rebound (two or more consecutive VL >40, <5000 copies/ml); high-level rebound/nonresponse (two or more consecutive VL >5000 copies/ml). Results: Immunophenotype reconstitution varied between that defined by numbers of cells and that defined by cell percentages. Furthermore, VL dynamics were associated with substantial differences in expression of CD4+ and CD8+ cell activation markers, with only individuals with high-level rebound/nonresponse (>5000 copies/ml) experiencing significantly greater activation and impaired reconstitution. There was little difference between participants who suppressed consistently and who exhibited transient blips or even low-level rebound by 144 weeks (P > 0.2 vs. suppressed consistently). Conclusion: Detectable viral load below the threshold at which WHO guidelines recommend that treatment can be maintained without switching (1000 copies/ml) appear to have at most, small effects on reconstitution and activation, for patients taking a PI-based second-line regimen.

Long-term efficacy and safety of a treatment strategy for HIV infection using protease inhibitor monotherapy: 8-year routine clinical care follow-up from a randomised, controlled, open-label pragmatic trial (PIVOT)

“…9,23 Other possible long-term adverse consequences of viral rebound include those mediated through pathways involving increased immune activation, that might affect immunological recovery or increase clinical events linked to inflammatory or immune responses. 24,25 However, the short-term, low-level viral rebound episodes typical of this strategy are unlikely to have had a major impact on levels of immune activation 26 ; consistent with our finding of equivalent longterm increase in CD4 cell counts in the groups. There was a small numerical excess of death, serious AIDS and non-AIDS events in the PI-mono group that was not statistically significant.…”