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NO RESIDUAL VIRUS REPLICATION IN A RANDOMISED TRIAL OF DOLUTEGRAVIR INTENSIFICATION
Thomas A. Rasmussen1, James McMahon2, J. Judy Chang3, Jennifer Audsley3, Ajantha Solomon3, Surekha Tennakoon3, Ashanti Dantanarayana3, Tim Spelman3, Tina Schmidt2, Stephen J. Kent3, Vincent Morcilla4, Sarah Palmer4, Julian Elliott2, Sharon R. Lewin3
1Aarhus University Hospital, Aarhus, Denmark,2Alfred Hospital, Melbourne, VIC, Australia,3Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia,4University of Sydney, Westmead, NSW, Australia
Whether residual virus replication (RVR) persists in HIV-infected individuals on suppressive antiretroviral therapy (ART) remains controversial. One strategy used to demonstrate RVR is to intensify ART with an integrase inhibitor and measure an early increase in 2-long terminal repeat (2-LTR) circles. Two previous studies with raltegravir demonstrated RVR in a subset of individuals on ART. Here we investigated the effects of dolutegravir.
In a randomised, placebo-controlled, double-blinded clinical trial, HIV-infected adults with virological suppression for >3 years were randomly assigned 1:1 to dolutegravir 50 mg or placebo daily for 56 days in addition to background ART. The primary outcome measure was the level of 2-LTR circles in CD4+ T cells at day 7. Cell-associated unspliced (CA-US) HIV RNA, total and integrated HIV DNA, and plasma HIV RNA using a single copy assay (SCA) were quantified by real-time PCR; T cell expression of HLA-DR, CD38 and PD-1 by flow cytometry, and plasma levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), d-dimer and soluble CD14 (sCD14) by ELISA. We used repeated-measures analysis of variance (ANOVA) as the protocol-defined primary analysis. Student's t-test or rank sum test, were used to compare changes from baseline to specific time points across study arms.
We enrolled 40 HIV-infected individuals; 21 were allocated to dolutegravir and 19 to placebo with 14 and 11% receiving a protease-inhibitor based ART regimen respectively. All participants completed the study. There was no significant difference in the primary endpoint, 2-LTR circles in peripheral blood CD4+ T cells, as assessed by repeated-measures ANOVA over 7 days (p=0.17) or any other time point (Figure). Median (IQR) 2-LTR circles fold-change from baseline to day 7 was -0.17 (-0.90 to 0.90) in the dolutegravir and -0.26 (-1.00 to 1.17) in the placebo groups. We found no consistent difference in the levels of CA US HIV-RNA, total and integrated HIV DNA (Figure), SCA, T cell activation markers or plasma levels of sCD14, d-dimer, IL-6 or hs-CRP. PD-1 expression in CD4+ T cells declined slightly after 56 days in placebo recipients compared to dolutegravir (p=0.03).
In a randomised, double-blinded, placebo-controlled trial of dolutegravir intensification, there was no evidence of RVR on ART.