Inflammation and Co-Infections in D²EFT

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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HIV-infection/Aids, Human Herpesvirus 4 Infections, Cytomegalovirus Infections, Human Herpesvirus 8 Infection, Human Papilloma Virus

Intervention / Treatment
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* Drug: NRTIs
* Drug: Darunavir
* Drug: Ritonavir
* Drug: Dolutegravir


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SOC<br>darunavir/ritonavir 800/100mg + 2 NRTIs po od | Drug: NRTIs<br>* 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.<br>* Other names: Nucleoside/Nucleotide Reverse Transcription Inhibitors;Drug: Darunavir<br>* 800mg tablet by mouth once daily for 96 weeks.<br>* Other names: Prezista;Drug: Ritonavir<br>* 100mg tablet by mouth once daily for 96 weeks.<br>* Other names: Norvir;|
| Experimental: DOL<br>darunavir/ritonavir 800/100mg + dolutegravir 50mg po od | Drug: Darunavir<br>* 800mg tablet by mouth once daily for 96 weeks.<br>* Other names: Prezista;Drug: Ritonavir<br>* 100mg tablet by mouth once daily for 96 weeks.<br>* Other names: Norvir;Drug: Dolutegravir<br>* 50mg tablet by mouth once daily for 96 weeks.<br>* Other names: Tivicay;|
| Experimental: D2N<br>dolutegravir 50mg + tenofovir + emtricitabine or lamivudine po od | Drug: NRTIs<br>* 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.<br>* Other names: Nucleoside/Nucleotide Reverse Transcription Inhibitors;Drug: Dolutegravir<br>* 50mg tablet by mouth once daily for 96 weeks.<br>* Other names: Tivicay;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in IL-6 level at 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). | At week 0 and week 48 | 
| Change from baseline of presence/absence of active key co-infections at 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). | At week 0 and week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of HHV8, EBV and CMV and of cervical and anal HPV | 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. | At week 0 | 
| Occurrence of active HHV8, EBV and CMV | 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. | At week 48 | 
| Change from baseline in rates of detection of cervical and anal HPV infection at 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. | At week 0 and week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EBV, HIV, IL-6, CMV, HHV8, HPV, inflammation, co-infections, opportunistic infections, AIDS and non-AIDS defining cancers