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Inflammation and Co-Infections in D²EFT (i2-D²EFT)

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ClinicalTrials.gov Identifier: NCT04183738
Recruitment Status : Withdrawn (In the context of COVID-19 pandemic.)
First Posted : December 3, 2019
Last Update Posted : November 10, 2020
Sponsor:
Collaborators:
Frederick National Laboratory for Cancer Research
UNITAID
National Institute of Allergy and Infectious Diseases (NIAID)
ViiV Healthcare
Janssen Pharmaceutica
Information provided by (Responsible Party):
Kirby Institute

Brief Summary:

i2-D²EFT substudy is an observational cohort nested within the parent D²EFT study (NCT03017872). D²EFT goal is to compare the standard of care second-line antiretroviral therapy in people living with HIV whose first-line non nucleoside reverse transcriptase-based regimen failed, to two simpler regimens. Approximately 1,000 participants will be enrolled in D²EFT.

Commencing a second-line ART is an important moment when the level of inflammation in participants may be elevated due to first-line ART failure; this level of inflammation should then decrease with the commencement of a new second-line treatment and would be expected to normalise by 48 weeks of second-line treatment, if successful.

The investigators propose to study other factors which can influence the decrease of inflammation. The investigators hypothesise that co-infections may play a role in persistent inflammation. The key-infections of interest will be common frequent infections encounter throughout the world: Human Herpes virus 8, Epstein-Barr virus, Cytomegalovirus and Human papillomavirus, tuberculosis, malaria and other key opportunistic infections. Possible changes of level of inflammation (using the serum level of Interleukin 6) in approximately 200 participants of the D²EFT study will be investigated and measured. The hypothesis is that the presence of other infections than HIV may influence the level of inflammation in participants in therapeutic success.


Condition or disease Intervention/treatment Phase
HIV-infection/Aids Human Herpesvirus 4 Infections Cytomegalovirus Infections Human Herpesvirus 8 Infection Human Papilloma Virus Drug: NRTIs Drug: Darunavir Drug: Ritonavir Drug: Dolutegravir Phase 4

Detailed Description:
i2-D²EFT substudy an observational cohort nested within the parent open label phase III/IV randomised controlled trial of simplified second-line therapy, D²EFT (NCT03017872). Participants consenting to D²EFT study will be randomised within the three arms: either ritonavir-boosted darunavir plus two nucleosides or dolutegravir plus two predetermined nucleosides (tenofovir disoproxil fumarate plus lamivudine or emtricitabine) or ritonavir-boosted darunavir plus dolutegravir. Enrolment into the i2-D²EFT substudy is voluntary and optional for participants in D²EFT. Parameters relevant to i2-D²EFT substudy including demographics, arm of randomised ART, HIV history, physical examination, immunological and virological results, episodes of co-infections and adverse events due to any infection or malignancies at required time points will be collected as part of D²EFT study. Substudy specific assessments performed at baseline and at weeks 48 include sample collection for IL-6 dosage plus EBV/CMV/HHV8 testing, and optional anal/cervical HPV screening.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Observational cohort nested within the parent open label phase III/IV randomised controlled trial of simplified second-line therapy, D²EFT.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Impact of Co-infections on Inflammation in Patients Commencing Second-line Antiretroviral Therapy. A Sub-study of D²EFT (Dolutegravir and Darunavir Evaluation in Adults Failing Therapy)
Estimated Study Start Date : February 1, 2021
Estimated Primary Completion Date : December 19, 2022
Estimated Study Completion Date : December 19, 2022


Arm Intervention/treatment
Active Comparator: SOC
darunavir/ritonavir 800/100mg + 2 NRTIs po od
Drug: NRTIs

In SOC arm, choice of NRTIs determined by clinician, guided by either genotypic resistance testing or use of a protocol-specified algorithm for N(t)RTI selection.

In D2N arm, NRTIs are predetermined.

Other Name: Nucleoside/Nucleotide Reverse Transcription Inhibitors

Drug: Darunavir
800mg tablet by mouth once daily for 96 weeks.
Other Name: Prezista

Drug: Ritonavir
100mg tablet by mouth once daily for 96 weeks.
Other Name: Norvir

Experimental: DOL
darunavir/ritonavir 800/100mg + dolutegravir 50mg po od
Drug: Darunavir
800mg tablet by mouth once daily for 96 weeks.
Other Name: Prezista

Drug: Ritonavir
100mg tablet by mouth once daily for 96 weeks.
Other Name: Norvir

Drug: Dolutegravir
50mg tablet by mouth once daily for 96 weeks.
Other Name: Tivicay

Experimental: D2N
dolutegravir 50mg + tenofovir + emtricitabine or lamivudine po od
Drug: NRTIs

In SOC arm, choice of NRTIs determined by clinician, guided by either genotypic resistance testing or use of a protocol-specified algorithm for N(t)RTI selection.

In D2N arm, NRTIs are predetermined.

Other Name: Nucleoside/Nucleotide Reverse Transcription Inhibitors

Drug: Dolutegravir
50mg tablet by mouth once daily for 96 weeks.
Other Name: Tivicay




Primary Outcome Measures :
  1. Change from baseline in IL-6 level at week 48 [ Time Frame: At week 0 and week 48 ]
    To compare the change of a biomarker of inflammation (IL-6) in participants who achieve HIV virological suppression (defined as peripheral blood viral load below 50 copies/mm3 at week 48) across the three study arms according to the presence (or not) of active key-co-infections (HHV8, EBV, CMV, HPV) at baseline and week 48, and the occurrence (or not) within these 48 weeks of any infection (co-infections or opportunistic infections).

  2. Change from baseline of presence/absence of active key co-infections at week 48 [ Time Frame: At week 0 and week 48 ]
    Active key-co-infections (HHV8, EBV, CMV, HPV) at baseline and week 48, and the occurrence (or not) within these 48 weeks of any infection (co-infections or opportunistic infections).


Secondary Outcome Measures :
  1. Prevalence of HHV8, EBV and CMV and of cervical and anal HPV [ Time Frame: At week 0 ]
    To describe the prevalence of HHV8, EBV and CMV (defined by serological assays) and of cervical and anal HPV (defined by tissue HPV deoxyribonucleic acid (DNA) detection) at baseline, in the D2EFT cohort, by geographic region, route of HIV transmission, and other demographic and disease variables.

  2. Occurrence of active HHV8, EBV and CMV [ Time Frame: At week 48 ]
    To compare the occurrence of active HHV8, EBV and CMV (defined by a detectable peripheral blood viral load) in participants with and without HIV virological suppression at 48 weeks, across the three arms of D²EFT.

  3. Change from baseline in rates of detection of cervical and anal HPV infection at week 48 [ Time Frame: At week 0 and week 48 ]
    To compare rates of detection of cervical and anal HPV infection (defined by tissue HPV DNA detection) between baseline and week 48 in participants with and without HIV virological suppression at 48 weeks across the three arms of D²EFT.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Fulfil the eligibility criteria for D²EFT randomisation;
  • Being able to give a written informed consent for the i2-D²EFT sub-study.

Exclusion Criteria:

  • Unwilling to comply with the i2-D²EFT protocol requirements.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04183738


Sponsors and Collaborators
Kirby Institute
Frederick National Laboratory for Cancer Research
UNITAID
National Institute of Allergy and Infectious Diseases (NIAID)
ViiV Healthcare
Janssen Pharmaceutica
Investigators
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Principal Investigator: Mark Polizzotto, MD, PhD Kirby Institute, UNSW Sydney, Australia
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Responsible Party: Kirby Institute
ClinicalTrials.gov Identifier: NCT04183738    
Other Study ID Numbers: 2019-10-i2-DEFT
18Q065 ( Other Grant/Funding Number: NIAID via Leidos )
First Posted: December 3, 2019    Key Record Dates
Last Update Posted: November 10, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kirby Institute:
HIV
IL-6
EBV
CMV
HHV8
HPV
inflammation
co-infections
opportunistic infections
AIDS and non-AIDS defining cancers
Additional relevant MeSH terms:
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Infections
Communicable Diseases
HIV Infections
Cytomegalovirus Infections
Coinfection
Acquired Immunodeficiency Syndrome
Epstein-Barr Virus Infections
Papilloma
Inflammation
Disease Attributes
Pathologic Processes
Blood-Borne Infections
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Neoplasms, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Herpesviridae Infections
DNA Virus Infections
Slow Virus Diseases
Tumor Virus Infections
Ritonavir
Darunavir