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

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)

Frederick National Laboratory for Cancer Research, UNITAID, National Institute of Allergy and Infectious Diseases (NIAID), ViiV Healthcare, Janssen Pharmaceutica

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.

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.

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

HIV, IL-6, EBV, CMV, HHV8, HPV, inflammation, co-infections, opportunistic infections, AIDS and non-AIDS defining cancers

Observational cohort nested within the parent open label phase III/IV randomised controlled trial of simplified second-line therapy, D²EFT.

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.

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).

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).

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.

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.

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.

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.