Efficacy and Safety of Doravirine in the Rapid Initiation

Protocol number: FH-96

Primary objective: To evaluate the antiviral activity of DOR/3TC/TDF at week 48 in HIV.

Secondary objectives:

• To evaluate the antiviral activity of DOR/3TC/TDF at < 200 coIPes/mL at week 48, using the intention-to-treat analysis (FDA snapshot analysis) for the exposed population (ITT-E). 2. To evaluate the antiviral activity of DOR/3TC/TDF at week 48 using an observed analysis (only including patients with available virological data).

• To evaluate the antiviral activity of DOR/3TC/TDF in the subgroup of participants with baseline ITINN mutations that do not confer resistance to doravirine, (according to the list of mutations defined in the exclusion criteria) by calculating the proportion of patients with viral load <200 coIPes/mL and <50 coIPes/mL at week 48.

• To evaluate the antiviral activity of DOR/3TC/TDF at <200 coIPes/mL and <50 coIPes/mL at week 24.

• To evaluate the safety and tolerability of DOR/3TC/TDF. 6. To evaluate the antiviral activity of DOR/3TC/TDF at week 48 in patients with a baseline viral load >100,000 coIPes/mL.

• Immune response: to evaluate immune recovery (CD4, CD8 and CD4/CD8 T-cell counts at weeks 24 and 48.

• To evaluate the development of HIV-1 resistance in patients experiencing virological failure while undergoing treatment with DOR/3TC/TDF.

• To assess changes in weight, BMI, and liIPd profile (total cholesterol, HDL, LDL and triglycerides) at weeks 24 and 48.

Study population: Subjects will be HIV-1 infection patient without ARV experience (naïve) within 30 days of diagnosis, willing to start ARV therapy in a rapid initiation setting, with ≥ 18 years of age, and who meet all inclusion criteria and do not meet any of the exclusion criteria.

Study design: Phase IV, multicenter, non-randomized, single-arm, open-label study describing the antiviral efficacy, safety, and tolerability of DOR/3TC/TDF therapy as rapid initiation therapy in subjects with HIV-1 infection who have not received prior treatment.

Regimens: Doravirine 100 mg; Lamivudine 300 mg; Tenofovir disoproxil 245 mg. Thirteen bottles. (Trade name: DELSTRIGO - MSD). Duration: 48 weeks.

Sample size: 100 subjects

Inclusion criteria

• Subject has to voluntarily signed and dated an informed consent form, approved by an institutional ethics committee.
• ≥18 years of age.
• Not previously exposed to ARV (naïve). Subject may have received oral PrEP and PEP within the last 6 months and injectable PrEP and PEP within the last year.
• Have a received an HIV diagnosis within 30 days prior to selection. Defined as: Having confirmed HIV-1 infection. HIV-1 positive result is considered if the HIV1 RNA in plasma is ≥ 1000 copies/mL or two HIV antibody tests (using two different tests) are positive.

NOTE: Participants may be included without knowing their baseline viral load. If baseline viral load results are less than 1000 copies/mL, the volunteer's participation will be suspended and they will be considered to have failed the screening test. A viral load brought by the subject may be considered if it was performed within the last 30 days prior to the SCR visit.

• CD4+ T-cell count: No limit.
• Subjects able to meet the protocol requirements.

Exclusion criteria

• History of hypersensitivity to doravirine, tenofovir, or lamivudine.
• Severe hepatic impairment (Child-Pugh C).
• Active HCV infection requiring specific treatment during study participation at the time of eligibility assessment. If HCV is diagnosed during the study and the participant requires treatment, the decision on whether to continue in the study will be at the investigator's discretion.
• A woman may be eligible to enter and participate in the study if she is not pregnant (confirmed by a negative urine pregnancy test at the time of screening/baseline). If the baseline visit is scheduled on a different day than the SCR, the urine pregnancy test will be repeated) or breastfeeding and if at least one of the following conditions applies:

• Women without reproductive capacity, defined as premenopausal women with tubal ligation or hysterectomy, or documented bilateral oophorectomy; or as postmenopausal women with 12 months of spontaneous amenorrhea, and women ≥ 45 years of age without hormone replacement therapy.
• Women with reproductive capacity who agree to adopt one of the contraceptive options in Appendix 2 for at least 30 days after the last dose of study medication and/or completion of the follow-up visit.

The chosen contraceptive method must be used consistently, according to the approved product label. All study participants must be advised on safer sex practices, including the use of effective barrier methods, and the choice of effective contraceptive method must be documented in the eCRF (Electronic Case Report Form).

• The subject's general health status, in the investigator's oIPnion, interferes with the requirements of the study.
• Has a diagnosis of an active opportunistic infection defining AIDS or a malignant neoplasm within 30 days prior to evaluation (except Kaposi's sarcoma with fewer than 10 skin lesions).
• Is participating or has participated in a clinical study in the last 6 months.
• Creatinine clearance (CrCl) ≤50 mL/min according to the Cockcroft-Gault equation.
• Any verified Grade 4 abnormality (except liIPds: HDL, LDL, total cholesterol, triglycerides).
• History or presence of allergy to study drugs or their components, or to drugs in their class.
• Subjects taking any medication during the study, including over-the-counter medications and herbal preparations, without the approval of the study physician.
• Mutations resistant to doravirine, 3TC, or TDF, according to the list described below:

DOR mutations (INNTI):

Doravirine (INNTI) Primary: the presence of one or more ART-resistant mutations will be grounds for exclusion.

Mutations: V106A/M, F227C/V, L234I, Y188L, Y318F, M230I/L. Secondary: the presence of one or more RAMs will be grounds for exclusion. Mutations: A98G, V108I, G190E, H221Y, P225H, F227L, P236L. Others: the presence of five or more RAMs will be grounds for exclusion. Mutations: V90I, L100I, K101E/H/P, K103N/R/S, V106I, I135T, Y181C/I/V, E138A/G/K/Q/R, V170F/T, G190A/Q/S, Y188C/H, F227I, V245E, K311R.

NRTI (TDF) Relevant mutations: Presence of one or more RAM Mutations: K65R, insertion 69, K70R/E, Q151M,

NRTI (3TC) Relevant mutation Presence of IM184V