DORAvirine Versus DOlutegravir Based Antiretroviral Regimens in Treatment-naïve People Living With HIV-1 Infection

Obesity will be defined as having BMI≥30 kg/m² for Caucasian and African population and BMI≥27.5 kg/m² for Asian populations.

Proportion of subjects with newly measured HOMA≥2 as compared to baseline HOMA will be calculated with the following formula (glucose levels in mmol/L, insulin levels in mIU/L): HOMA =(glucose ×insulin)÷22.5

Proportion of subjects with hypertension newly detected compared to baseline. Hypertension will be defined as either being prescribed new anti-hypertension medication and/or by having diastolic blood pressure >90 mmHg AND/OR systolic blood pressure >140 mmHg during visit and confirmed during subsequent visit > 15 days after.

Proportion of subjects in virologic success defined as achieving HIV-1 RNA <50 copies/mL at week 96 under allocated treatment using the FDA snapshot algorithm with a window period of 90 to 102 weeks; subjects not achieving viral success will be described according to the FDA snapshot recommendation

Proportion of confirmed virological failures. Virological failure will be defined as 1) confirmed HIV-1 RNA ≥ 200 copies/mL after initial response with HIV-1 RNA < 50 copies/mL at any time during the study or 2) non-response defined as either confirmed HIV-1 RNA ≥ 200 copies/mL at Week 24 or Week 36 (or any other unscheduled visit in-between) or confirmed HIV-1 RNA ≥ 50 copies/mL at Week 48, Week 72 and Week 96 (or any other unscheduled visit in-between).

Frequency of HIV-1 drug resistances in participants with a confirmed virological failure.

Drug resistances will be defined according to the last version of the ANRS algorithm and to the last version of the Stanford algorithm.

Proportion of subjects achieving HIV 1 RNA<200 copies/mL under allocated treatment

Proportion of subjects achieving HIV 1 RNA<1000 copies/mL under allocated treatment

Frequency of RT and integrase mutations at baseline and impact on the virological response

Combined overweight and obesity will be defined as having BMI≥25 kg/m² for Caucasian and African populations and BMI≥23 kg/m² for Asian populations

Proportion of subjects with ≥10% absolute weight gain from baseline

Absolute weight gain will be calculated by simply subtracting the follow-up weight from baseline weight measured according to protocol procedures

Proportion of subjects with diabetes newly detected compared to baseline. Diabetes will be defined as either being prescribed new medication for diabetes mellitus and/or having a fasting glycemia ≥1.26 g/L during visit and confirmed during subsequent visit > 15 days after and/or in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L).

Any adverse event of any grade and those graded 3-4

Change from baseline in waist and hip circumferences and waist-to-hip ratio

Change from baseline in fasting glycemia and insulin

Change from baseline in fasting serum lipids. The fasting serum lipids analyzed will be total cholesterol, HDL, LDL and triglycerides.

Change from baseline in estimated glomerular filtration rate. Estimated glomerular filtration rate (eGFR) will be calculated using the CKD-EPI equation

Change from baseline in cardiovascular parameters (blood pressure profile, electrocardiographic and echocardiographic damages). These cardiovascular parameters assessments will be measured through an electrocardiogram, a transthoracic echocardiography and an ABPM, a 24-hour blood pressure Holter.

Change from baseline in mean patient CAP and LSM measurements and occurrence of: Liver steatosis defined by CAP ≥ 263 dB/m2, and clinically significant liver fibrosis and cirrhosis defined by LSM ≥ 8.0 kPa and LSM ≥ 12.5 kPa, respectively

Change from baseline in mean patient CAP and LSM measurements and occurrence of: MASLD defined by the presence of liver steatosis with at least one cardiometabolic risk-factor (overweight/obesity; pre-or diabetes; hypertension; hypertriglyceridemia or low-HDL; and MASH defined by the presence of at least CSF in people with MASLD.

Changes from baseline in Fib-4, VCTE and FAST scores and presence at baseline or occurrence of: CSF defined as Fib-4 ≥ 2.67 and FAST score > 0.67 (high probability of MASH)

Change from baseline in EQ-5D-3L, HIVTSQ, DASS-21, PSQI, WHOQOL HIV-BREF scores

Proportion of subjects with AIDS (defined as having CDC stage 3/C or WHO stage 4), tuberculosis, IRIS or death

DOR, DTG and M9 trough plasma concentration in samples taken pre-dose

DOR, DTG and M9 trough plasma concentration in samples taken pre-dose

DOR, DTG and M9 trough plasma concentration in samples taken pre-dose

DOR, DTG and M9 trough plasma concentration in samples taken pre-dose

Change from baseline in CD4 cell count, CD4 percentage, CD8 cell count, CD8 percentage, CD4/CD8 ratio

Adherence to ART by (1) pill count (considering a pill count adherence ratio <95% as sub-optimal adherence), (2) 4-days and 1-month recall questions at every trial visit, (3) by TFV-DP quantification in dried blood spots (LC/MS). ARV pill burden will also be an endpoint in order to study the relation between adherence and ARV pill burden.

Type and frequency of alleles variants in the gene coding for CYP3A5/4

Impact of CYP3A5/4 mutations on pharmacokinetics of DOR, DTG and M9

Virological response and side-effects depending on CYP3A5/4 mutations

Assess additional polymorphism of UGT1A1

Cost-effectiveness measured by (1) Incremental health benefits of using one regimen compared to the other (in DALYs and QALYs), (2) Incremental economic costs of using one regimen compared to the other (USD), (3) Budget impact of changing from one regimen to the other (USD)

Change from baseline in truncal fat distribution. Truncal fat repartition will be measured by the proportion of fat tissue using DEXA-scanner assessment

Change from baseline in adipose tissue markers (adiponectin, leptin) and immune activation markers (sCD14, sCD163). Measurement will be made on stored serum samples by immunonephelometry or ELISA.

Change from baseline (by abdominal subcutaneous surgical biopsy) in fat pathology, gene expression and global transcriptome analysis (RT-PCR and RNAseq). Measurement will be made on an abdominal fat tissue biopsy sample fixed for immunohistochemistry (Red Sirius, collagen 6, fibronectine, TFG-beta, alpha-SMA) and frozen for gene expression analysis by RT-PCR of markers of adipogenesis (PPARG, CEPBA), beiging (PRDM16, PGC1A), lipogenesis (FAS), adipocyte function (GLUT4), fibrosis (COL4, COL6, FN, TGFB, LOX, ASMA) and mDNA level (mDNA gene and nDNA).