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 CD38Ý/HLA-DRÝ 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 CD4Ý and CD8Ý 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
| Original language | English |
|---|---|
| Journal | AIDS |
| Early online date | 23 Jan 2023 |
| Publication status | E-pub ahead of print - 23 Jan 2023 |
Bibliographical note
Note: This work was supported by the European and Developing Countries Clinical Trials Partnership (EDCTP, Grant Code: IP.2007.33011.003) with contributions from the Medical Research Council, UK; Institito de Salud Carlos III, Spain (Grant A107/90015); Irish Aid, Ireland; Swedish International Development Cooperation Agency (SIDA), Sweden; Instituto Superiore di Sanita (ISS), Italy; The World Health Organisation; and Merck, USA. Substantive in-kind contributions were made by the Medical Research Council Clinical Trials Unit, UK [MC_UU_12023/23], CINECA, Bologna, Italy, Janssen Diagnostics, Beerse, Belgium; GSK/ViiV Healthcare Ltd., UK; Abbott Laboratories, USA. Trial medication was donated by AbbVie, Merck, Pfizer, GSK and Gilead.Impact: This study demonstrates that the main drivers
of immune reconstitution and activation are most likely
viral, rather than being driven by specific ART
combinations. These findings suggest that
the current WHO viral load threshold for switching to
second-line of 1000 copies/ml should avoid the most
deleterious effects of high-level rebound, given that it is
mostly identified through annual viral load.
Keywords
- Infection and immunology