Efficacy and Safety of the ACC017-Based Antiretroviral Regimen in Treatment-Experienced Adults With HIV-1 Harboring Non-Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations

Efficacy and Safety of the ACC017-Based Antiretroviral Regimen in Treatment-Experienced Adults With HIV-1 Harboring Non-Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

This trial is a randomized, double-blind, placebo-controlled clinical study conducted in treatment-experienced adults with NNRTI-resistant HIV-1, designed to preliminarily evaluate the efficacy, safety, and resistance profile of the core drug ACC017 in this population.

The study consists of two treatment phases: a functional monotherapy period (double-blind phase) and an extended optimized treatment period (open-label phase).

The first phase is the functional monotherapy period (W1-W2). After initial screening, eligible participants will return to the hospital on D1 for final eligibility review and baseline examinations. Those who pass the review will be randomized in a 2:1 ratio to either ACC017 tablets (N=8, 40 mg, once daily [QD]) or matching placebo (N=4), replacing the core NNRTI drug in the failing background regimen while maintaining the original backbone NRTIs unchanged. Treatment will continue for 2 weeks.

The second phase is the extended optimized treatment period (W3-W16). All participants who complete the functional monotherapy period will receive ACC017 tablets (40 mg QD) in combination with an optimized backbone regimen (i.e., ACC017 replaces the core NNRTI drug in the failing background regimen, while the investigator adjusts the backbone drugs based on HIV genotypic resistance test results to ensure at least one backbone NRTI remains sensitive, if applicable). Treatment will continue for 14 weeks.

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for this trial:

1. Voluntarily sign the informed consent form before screening and be able to comply with the protocol procedures or agreed requirements;
2. Age ≥18 years (inclusive) at the time of signing the informed consent, regardless of gender;
3. Diagnosed with HIV-1 infection before screening, having received the current first-line antiretroviral therapy (i.e., one NNRTI combined with two NRTIs) for at least 6 months (changes in treatment regimen due to tolerability issues or other adverse reactions are acceptable), with treatment interruption ≤4 weeks before screening (if applicable);
4. Before and at screening, no prior use of INSTI, PI, or other novel antiretroviral drugs (including but not limited to fusion inhibitors [FI] or capsid inhibitors [CAI]), including for pre-exposure prophylaxis (PrEP) and/or post-exposure prophylaxis (PEP);
5. At least one HIV-1 RNA test result ≥400 copies/mL within 8 weeks before screening, and confirmed HIV-1 RNA ≥400 copies/mL at screening (with ≥7 days between the two tests); or at least one HIV-1 RNA test result ≥50 copies/mL to <400 copies/mL within 8 weeks before screening, and confirmed HIV-1 RNA ≥1000 copies/mL at screening (with ≥7 days between the two tests);
6. Within 8 weeks before or at screening, documented NNRTI resistance mutations in the resistance test results (as interpreted by the Stanford HIVdb database, including "low-level resistance [L]," "intermediate resistance [I]," and "high-level resistance [H]") (if two test results exist, the most recent one shall prevail);
7. At screening, based on resistance test results, at least one fully active NRTI backbone drug is available for optimized background therapy in the trial (as interpreted by the Stanford HIVdb database, including "susceptible [S]" and "potential low-level resistance [P]");
8. Participants agree not to modify their antiretroviral treatment regimen-including but not limited to the composition, dosage, or frequency of regimen drugs-without the investigator's consent from the time of signing the informed consent until the end of the study.

Exclusion Criteria:

Participants will be excluded from this trial if they meet any of the following criteria:

1. The investigator judges that the participant has poor treatment compliance or protocol adherence, or any other condition that makes them unsuitable for participation, or that participation may not maximize the participant's health interests;
2. At screening, female participants are pregnant or breastfeeding, or male/female participants engaging in heterosexual activity plan to conceive (including sperm/egg donation) from 1 month before signing informed consent until 1 month after the last dose of the study drug, or are unable/unwilling to use effective contraception (including one or more non-pharmacological contraceptive methods or abstinence from heterosexual activity);
3. At screening or within 4 weeks before screening, participants are in the acute phase of HIV-1 infection or have concurrent opportunistic infections or other serious AIDS-defining conditions;
4. At screening or within 8 weeks before screening, resistance testing shows documented INSTI major resistance mutations, including but not limited to N155H and Q148H (as interpreted by the Stanford HIVdb database, including "low-level resistance [L]," "intermediate resistance [I]," and "high-level resistance [H]");
5. At screening, the investigator determines the presence of uncontrolled clinically significant diseases (including cardiovascular, respiratory, digestive, endocrine/metabolic, neuropsychiatric, hematologic, or immune system disorders), such as resting systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, NYHA Class III or IV heart failure, etc.;
6. At screening, ALT >5× upper limit of normal (ULN), or ALT >3×ULN with total bilirubin (TBIL) >1.5×ULN or direct bilirubin (DBIL) >ULN, or other laboratory abnormalities graded ≥3 per CTCAE v5.0;
7. At screening, creatinine clearance <50 mL/min (calculated by Cockcroft-Gault formula);
8. At screening, concurrent active hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection; or active syphilis infection requiring or having completed syphilis treatment <7 days prior (as judged by the investigator);
9. Before screening, underwent major gastrointestinal surgery (except uncomplicated appendectomy or cholecystectomy), or the investigator judges that elective surgery may be required during the trial;
10. Screening for the past 5 years, having suffered from malignant tumors (including cervical carcinoma in situ treated with cervical conization, or surgically cured basal cell carcinoma, squamous cell carcinoma, and/or carcinoma in situ [excluding Bowen's disease]);
11. Known history of allergy to the investigational drug, chemically similar drugs, or excipients; or a history of allergic diseases requiring medication control (such as asthma, urticaria, atopic dermatitis [eczema], etc.) prior to screening.
12. Within 5 years prior to screening, have a history of substance, alcohol, or other substance use disorders (excessive, inappropriate, or addictive use of substances, alcohol, or other substances for non-medical reasons, resulting in social, psychological, and physiological impairments).
13. Use of any prohibited medication as specified in the protocol within 14 days before the first dose of the investigational drug;
14. Before screening, intolerance to venipuncture, history of needle or blood phobia, or blood donation (including component donation) or significant blood loss (≥400 mL) or transfusion within 3 months before screening, or planned donation during the trial;
15. Within 3 months prior to screening, have participated in any interventional clinical trials, including but not limited to drugs, vaccines, or medical devices (referring to subjects who have signed the informed consent form and received the investigational drug/device or placebo).