Ignite Creation Date:
2024-05-06 @ 7:17 AM
Last Modification Date:
2024-10-26 @ 11:46 AM
Study NCT ID:
NCT02500446
Status:
COMPLETED
Last Update Posted:
2017-11-20
First Post:
2015-06-30
Brief Title:
Dolutegravir Impact on Residual Replication
Sponsor:
University of Melbourne
Organization:
University of Melbourne
Study Overview
Official Title:
Dolutegravir Impact on Residual Replication Dolutegravir Intensification Study
Status:
COMPLETED
Status Verified Date:
2017-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
DIORR
Brief Summary:
Several studies have suggested that despite suppressive combination antiretroviral therapy ART in people who are HIV-positive in some individuals there may be on-going viral replication Clarifying the extent of on-going viral replication on ART is important for the development of HIV-1 curative strategies and for reducing HIV-1 associated immune activation The investigators hypothesize that treatment intensification with dolutegravir will inhibit residual virus replication in HIV-1 infected patients on ART The primary objective of this study is to determine the effects of dolutegravir intensification on residual virus replication in circulating cluster of differentiation 4 CD4 T cells
Detailed Description:
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
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None