Dolutegravir Impact on Residual Replication (DIORR)
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Investigator, Outcomes Assessor
Primary Purpose: Treatment
|Official Title:||Dolutegravir Impact on Residual Replication: Dolutegravir Intensification Study|
- Level of residual HIV replication in circulating CD4+ T cells [ Time Frame: day 7 of treatment ]Change in the level of 2-LTR circles as measured by polymerase chain reaction (PCR) in the dolutegravir arm versus the placebo arm after 7 days of treatment
- Level of Human Leukocyte Antigen D-related (HLA-DR) [ Time Frame: time points to day 84 (28 days after treatment) ]Change in level of Human Leukocyte Antigen D-related (HLA-DR), a marker of T cell activation from baseline within and across study arms.
- Level of Programmed cell death-1 receptor (PD-1) [ Time Frame: time points to day 84 (28 days after treatment) ]Change in level of Programmed cell death-1 receptor (PD-1), a marker of T cell activation from baseline within and across study arms.
- Level of Cluster of Differentiation 38 (CD-38) [ Time Frame: time points to day 84 (28 days after treatment) ]Change in level of Cluster of Differentiation 38 (CD-38), a marker of T cell activation, from baseline within and across study arms.
- Level of residual HIV replication in circulating CD4+ T cells in a protease inhibitor -containing regimen [ Time Frame: time points up to day 84 (28 days after treatment) ]Change in the level of 2-LTR circles as measured by polymerase chain reaction (PCR) in the dolutegravir arm versus the placebo arm in those participants on regimen which includes a protease inhibitor
|Actual Study Start Date:||September 28, 2015|
|Estimated Study Completion Date:||September 30, 2017|
|Primary Completion Date:||September 16, 2016 (Final data collection date for primary outcome measure)|
Active Comparator: Intensification
Oral dolutegravir 50 mg once daily for 8 weeks added to their current ART regimen.
Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir.
Other Name: Tivicay®, S/GSK1349572
Placebo Comparator: Placebo
Oral placebo once daily for 8 weeks added to their current ART regimen.
A film-coated tablet identical in appearance to the active drug tablet but not containing any dolutegravir or any other active ingredient
ART effectively suppresses HIV-1 viremia but in most patients, virus rebounds within 2-3 weeks of stopping ART. ART is unable to cure HIV due to the persistence of virus as long-lived latently infected cells, residual virus replication and anatomical reservoirs. Understanding the contribution of residual virus replication to virus persistence on ART is important because first, no interventions aimed at eliminating latency will be effective in the presence of residual virus replication; second, residual virus replication may contribute to persisting immune activation which has been associated with all-cause mortality.
Numerous studies have demonstrated that intensifying a suppressive ART regimen with an additional antiretroviral drug does not alter the frequency of latently infected cells or low-level viremia. However, in studies that have intensified ART with the integrase inhibitor raltegravir, an increase in circularised HIV episomes containing 2 copies of the viral long terminal repeat (2-LTR) circles within 2 weeks of intensification, was observed in ~30% of study participants. 2-LTR circles have a short half- life, which may explain why an increase in 2-LTR circles was only observed in studies that measured 2-LTR circles within 2 weeks of raltegravir intensification. In these two randomized controlled trials, the level of 2-LTR circles increased transiently in patients randomized to intensification with raltegravir as compared with placebo and this effect was more pronounced in subjects receiving a protease inhibitor (PI)-containing ART regimen. Other studies have failed to demonstrate an increase in 2-LTR circles following raltegravir intensification but this is likely because sampling was delayed beyond 2 weeks.
One possible explanation for the additional effect observed with raltegravir intensification is the extensive penetration of this compound into gastrointestinal (GI) tissue where it reaches concentrations 39- to 650-fold higher than those in plasma.
To date, raltegravir is the only integrase inhibitor that has been investigated in ART intensification trials. Dolutegravir (DTG) is a recently licensed once-daily integrase inhibitor that is non-inferior to raltegravir and with a similar safety profile, however DTG levels in GI tissue is only 17% of that in plasma. DTG has not been investigated in intensification studies, so whether adding dolutegravir to a suppressive ART regimen is able to inhibit residual replication is currently unknown.
Thus, there are several unresolved issues related to residual viral replication in the presence of ART and the potential benefit of integrase inhibitors in this context: How frequent is this phenomenon and does it occur more frequently in patients receiving a PI-containing regimen? Given that raltegravir does seem to impact residual replication in approximate 30% of HIV infected patients on ART when assessed early after intensification, what is the effect of DTG in this setting? Finally, what are the dynamics of 2-LTR levels in blood in the early phases after intensification with an integrase inhibitor? To address those questions, the investigators have designed a randomized, controlled study to compare the impact of intensification with DTG or placebo in HIV-infected patients on suppressive ART. In this study, the investigators will closely define the effects of dolutegravir intensification on 2-LTR levels in circulating CD4+ T cells.
Study participants will be in the study for up to 133 days. The duration of participation is calculated from the initial screening visit to the last study visit (visit 9), with 9 visits in total.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02500446
|Melbourne Sexual Health Centre|
|Carlton, Victoria, Australia, 3053|
|Prahran, Victoria, Australia, 3010|
|Principal Investigator:||Sharon Lewin||Doherty Institute for Immunity and Infection|