Effectiveness and Safety of Darunavir/Cobicistat Plus Lamivudine Compared With Darunavir/Cobicistat Plus Tenofovir Alafenamide/Emtricitabine in Virologically Suppressed People Living With HIV at 24 and 48 Weeks of Follow-up

Effectiveness and Safety of Darunavir/Cobicistat Plus Lamivudine Compared With Darunavir/Cobicistat Plus Tenofovir Alafenamide/Emtricitabine in Virologically Suppressed People Living With HIV at 24 and 48 Weeks of Follow-up

A single-center, open-label, randomized pilot clinical trial between March 2025 and March 2026 at the Hospital de Infectología "La Raza" National Medical Center in Mexico City. Eligible participants were adult males (≥18 years) with HIV-1 infection who had maintained virological suppression (HIV-1 RNA <50 copies/mL) for 48 weeks on either DRV/c + 3TC or DRV/c + TDF/FTC prior to enrollment (TLALOC-1 trial), and had an estimated glomerular filtration rate (eGFR) by CKD-EPI ≥60 mL/min/1.73 m². The primary endpoints were virological efficacy and safety at 24 weeks.

This was a phase IV, open-label, single-center pilot clinical trial conducted from March 2025 to March 2026 at the HIV Clinic of the "La Raza" Infectious Diseases Hospital, National Medical Center, in Mexico City. This tertiary care center provides services to patients with social security coverage. The study protocol was approved by the Local Health Research Committee of the Mexican Social Security Institute (3502) and the Research Ethics Committee (35028; R-2025-3502-183). Written informed consent was obtained from all participants to mantained DRV/c + 3TC or switching from TDF/FTC to TAF/FTC.

Study population: Eligible participants were adult males ≥18 years old living with HIV-1 who had maintained virological suppression on either dual therapy with DRV/c + 3TC or triple therapy with DRV/c + TDF/FTC for 48 weeks prior to enrollment (TLALOC-1 trial), and had an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m² calculated by the CKD-EPI equation.

Exclusion criteria in TLALOC-1 included history of prior virological failure, baseline genotypic resistance mutations to any component of the study regimens, active malignancy, or coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV).

Treatment allocation:This was a non-randomized study. Participants already receiving DRV/c + 3TC (1 tablet of DRV/c 800/150 mg and two tablets of 3TC of 150 mg each) continued on the same dual regimen. Participants receiving DRV/c + TDF/FTC switched the nucleoside backbone from TDF/FTC to TAF/FTC 10/200 mg while continuing DRV/c.

Outcomes: For this preliminary analysis, the primary efficacy endpoint was the proportion of participants with HIV-1 RNA ≥50 copies/mL at week 24. (TLALOC-2 continues recruitment; the primary endpoint for the full study is effectiveness and safety at 48 and 96 weeks of follow-up). This was confirmed in two consecutive determinations, according to the FDA Snapshot algorithm. Participants were classified into three mutually exclusive categories.

1. HIV-1 RNA ≥50 copies/ml at week 24, discontinuation of the study drug before week 24 due to lack of efficacy, or discontinuation for reasons other than lack of efficacy, adverse events, or death with the last available HIV-1 RNA value ≥50 copies/ml.
2. HIV-1 RNA <50 copies/ml at week 24.
3. No virological data, participants who discontinued the study drug before week 24 due to adverse events or death; participants who discontinued treatment for reasons other than lack of efficacy, adverse events or death, with the last available HIV-1 RNA value less than 50 copies/ml; or participants who were still receiving the study drug but with missing HIV-1 RNA data at week 24.

Safety was assessed through physical examinations and laboratory tests. AEs were defined as any unfavorable and unintended sign including abnormal laboratory findings, symptom, or disease temporally associated with the use of the study treatment, regardless of causality. The incidence and severity of AEs were graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Corrected Version 2.1, July 2017) and assessed at baseline, week 12, and week 24.

Secondary endpoints included change in CD4+ cell count from baseline to week 24, and changes in renal function parameters, including estimated GFR (calculated using the CKD-EPI formula with cystatin C), urinary phosphorus excretion fraction, urinary uric acid excretion fraction, and serum creatinine levels.

Procedures: Laboratory assessments were performed at baseline and at weeks 4, 12, and 24. Tests included complete blood count, blood chemistry, liver function tests, fasting lipid profile, biomarkers of renal and bone metabolism (serum creatinine, cystatin C, estimated glomerular filtration rate [eGFR], urinary and serum electrolytes), CD4+ cell count, and HIV-1 RNA viral load (RT-PCR, M2000, Abbott).

Adherence was assessed using the AIDS Clinical Trials Group (ACTG) adherence questionnaire, administered at each visit. Treatment satisfaction and symptom burden were evaluated with the HIV Treatment Satisfaction Questionnaire (HIVTSQ) and the HIV Symptom Distress Module (HIV-SDM). Neuropsychological status was assessed at baseline and at weeks 12 and 24 using the Hospital Anxiety and Depression Scale (HADS-A and HADS-D), the Patient Health Questionnaire-9 (PHQ-9), and the Insomnia Severity Index (ISI). Safety was monitored at every visit through direct questioning and clinical evaluation, with AEs categorized by organ system according to DAIDS criteria.

Statistical analysis: Baseline and 24-week follow-up outcomes were analyzed. Continuous variables were expressed as means with standard deviations or medians with interquartile ranges, depending on normality assessed by the Kolmogorov-Smirnov test. Categorical variables were presented as frequencies and percentages.

Between-group comparisons of continuous variables were performed using the independent Student's t-test in case of normal distribution or Mann-Whitney U test in case of non-normal distribution. Within-group changes from baseline to week 24 were analyzed with paired t-tests or Wilcoxon signed-rank tests, as appropriate. Associations between categorical variables were evaluated using the chi-square test or Fisher's exact test. Variables showing statistical significance in bivariare analyses were further examined using binary logistic regression model. For safety analyses, baseline characteristics were summarized using descriptive statistics for all participants who received at least one dose of study medication. A p-value ≤0.05 was considered statistically significant. All analyses were performed using SPSS software (version 29; IBM Corp., Armonk, NY, USA).

Ethical considerations: The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was approved by the Health Research Ethics Committee 3502 of the Hospital de Infectología "La Raza" National Medical Center (protocol number R-2025-3502-183). All participants received detailed information about the study purpose, procedures, potential risks, and benefits, and were informed of their right to withdraw at any time without affecting their standard medical care.

Inclusion Criteria:

• Virologically suppressed men living with HIV, transitioning from a DRV/c (800 mg/150 mg) + TDF/FTC (300 mg/200 mg) regimen for at least 48 weeks prior to the study
• Viral suppression for 48 weeks prior to the study
• Agree to participate in the study by signing a written informed consent form
• Age ≥18 years
• Glomerular filtration rate (GFR) by CDK-EPI ≥60 mL/min
• Beneficiaries of the Mexican Social Security Institute (IMSS) treated at the Infectious Diseases Hospital of the "La Raza" National Medical Center

Exclusion Criteria:

• Withdrawal of informed consent
• Loss of coverage
• Failure to attend sample collection within the required timeframe