Highlight
– In the PASO‑DOBLE multicentre Spanish trial, dolutegravir 50 mg plus lamivudine 300 mg (DTG/3TC) was non‑inferior to bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg (BIC/FTC/TAF) for maintenance of virological suppression at 48 weeks (non‑inferiority margin 4%).
– Virological failure was rare in both arms (2% DTG/3TC vs 1% BIC/FTC/TAF) and trial discontinuations for adverse events were uncommon.
– Adverse events were generally mild or moderate; grade 3–4 events were numerically more frequent with BIC/FTC/TAF.
Background
Over the past decade, integrase strand transfer inhibitor (INSTI)–based regimens have become preferred options for many people living with HIV because of potency, tolerability, and high genetic barrier to resistance. Two common, guideline‑endorsed maintenance strategies are a two‑drug regimen of dolutegravir plus lamivudine (DTG/3TC) and single‑tablet three‑drug regimens such as bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). DTG/3TC offers potential advantages including reduced nucleoside exposure, fewer drug components, and cost benefits, while BIC/FTC/TAF provides the established backbone of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a high‑potency INSTI.
Despite widespread uptake, direct, fully powered head‑to‑head comparisons of these two commonly used maintenance strategies in people with sustained virological suppression have been limited. PASO‑DOBLE was designed to address this evidence gap and inform clinical decision‑making around regimen switching.
Study Design
PASO‑DOBLE is a randomised, multicentre, open‑label, non‑inferiority trial conducted at 30 sites in Spain. Adults (≥18 years) with HIV‑1 infection, no history of virological failure, and sustained plasma HIV‑1 RNA <50 copies/mL for at least 24 weeks on a once‑daily oral antiretroviral regimen (with no prior exposure to dolutegravir or bictegravir) were eligible. Participants with prior exposure to certain antiretrovirals (eg, efavirenz, cobicistat) could be enrolled provided they met virological and safety criteria.
Participants were randomised 1:1 to switch to either:
- dolutegravir 50 mg + lamivudine 300 mg once daily (DTG/3TC), or
- bictegravir 50 mg / emtricitabine 200 mg / tenofovir alafenamide 25 mg once daily (BIC/FTC/TAF).
Randomisation used block permutation and was stratified by baseline use of tenofovir alafenamide and sex assigned at birth. The primary endpoint was the proportion of participants with plasma HIV‑1 RNA ≥50 copies/mL at week 48 in the intention‑to‑treat exposed population (all who received at least one dose). The predefined non‑inferiority margin was 4%.
Key Findings
Between July 14, 2021, and March 24, 2023, 553 participants initiated study treatment (277 DTG/3TC; 276 BIC/FTC/TAF). Baseline demographics and clinical characteristics were balanced across arms (details in the full paper).
Primary efficacy
At week 48 the proportion with plasma HIV‑1 RNA ≥50 copies/mL was:
- DTG/3TC: 6 of 277 (2%)
- BIC/FTC/TAF: 2 of 276 (1%)
The absolute difference was 1.4% (95% CI −0.5 to 3.4; p=0.16), meeting the prespecified non‑inferiority criterion. Virological suppression was therefore preserved with DTG/3TC to a degree consistent with BIC/FTC/TAF in this population.
Resistance and virological failure
Virological failure was uncommon in both groups. The report did not identify widespread emergence of integrase or NRTI resistance; however, as with all switch trials, the population excluded persons with prior viral failure and therefore the findings are most directly applicable to people with sustained suppression and no historical resistance.
Safety and tolerability
Adverse events (AEs) occurring in ≥10% of participants in either group included infections, musculoskeletal complaints, gastrointestinal events, metabolic disturbances, and psychiatric events. Most AEs were mild to moderate and judged unrelated to study drugs. Numerically more grade 3–4 adverse events occurred in the BIC/FTC/TAF arm (10 participants, 3%) than in the DTG/3TC arm (3 participants, 1%; p=0.049).
Very few participants discontinued therapy for adverse events (1 in DTG/3TC; 2 in BIC/FTC/TAF). There were no deaths reported through 48 weeks.
Other outcomes
The trial reported on safety categories broadly; detailed subgroup analyses (eg, by baseline TAF use, sex, age, comorbidities, weight changes, renal or bone biomarkers) were not fully detailed in the summary and should be reviewed in the full publication for nuanced interpretation. The open‑label design may have influenced reporting of subjective AEs (eg, psychiatric symptoms).
Expert Commentary and Interpretation
PASO‑DOBLE adds an important, pragmatic, and relatively large head‑to‑head comparison of two widely used maintenance strategies in adults with sustained viral suppression. The finding that DTG/3TC is non‑inferior to BIC/FTC/TAF supports the existing evidence base for dual‑therapy maintenance in selected patients and provides data directly relevant to clinicians and their patients when considering a regimen switch.
Clinical implications to consider when applying these results:
- Patient selection: The trial enrolled people without prior virological failure and without prior exposure to dolutegravir or bictegravir. The results therefore best apply to suppressed patients without historical resistance or adherence challenges.
- HBV coinfection: Lamivudine has activity against hepatitis B virus but offers insufficient long‑term HBV suppression alone; switching to DTG/3TC is not recommended for people with chronic HBV unless appropriate HBV therapy is maintained. BIC/FTC/TAF contains two agents active against HBV (FTC and TAF) and may be preferred when HBV treatment is required.
- Pregnancy and women of childbearing potential: Although dolutegravir and bictegravir are both INSTIs with high potency, safety considerations in early pregnancy and family planning remain relevant; local guidance should be consulted for regimen selection around conception and pregnancy.
- Long‑term toxicities and comorbidities: One motivation for dual therapy is reducing cumulative NRTI exposure, potentially favouring bone and renal parameters. Conversely, TAF is associated with favourable bone and renal profiles compared with tenofovir disoproxil fumarate (TDF) but with potential modest impacts on weight and lipids; the net clinical tradeoffs require individualised assessment.
- Adverse events: The numerical excess of grade 3–4 events in the BIC/FTC/TAF arm warrants attention but must be contextualised by event types and baseline risks; causality was not uniformly established.
Study strengths include randomisation, multicentre real‑world recruitment, and a prespecified non‑inferiority design. Limitations include open‑label design, single‑country conduct (Spain) which may affect generalisability to regions with different comorbidity or resistance patterns, and restriction to individuals without prior failure or integrase exposure. Long‑term outcomes beyond 48 weeks (including weight trajectories, metabolic parameters, and rare safety signals) require continued follow‑up.
How this fits with prior evidence
Previous randomised trials have established DTG/3TC as an effective option in both treatment‑naive (GEMINI) and switch (TANGO and other switch studies) settings for appropriately selected patients. BIC/FTC/TAF has been consistently shown to be highly effective as a single‑tablet three‑drug regimen in both treatment‑naive and switch populations. PASO‑DOBLE complements these data by directly comparing the two regimens in a maintenance context and showing that, at 48 weeks, the dual therapy strategy preserves suppression at rates comparable to the three‑drug single‑tablet option.
Practical considerations for clinicians
When counselling patients about switching maintenance regimens, clinicians should discuss:
- Virological history and archived resistance tests: Ensure no prior failure or known resistance that would compromise the chosen regimen.
- Comorbidities: HBV status, renal disease, bone disease, cardiovascular risk, psychiatric history, and concomitant medications that might interact (eg, drug‑drug interactions with integrase inhibitors or TAF).
- Patient values: Pill burden preferences, concerns about long‑term toxicities, cost or insurance coverage, and pregnancy plans.
- Monitoring plan: Baseline labs (HIV RNA, HBV serology, renal function, lipids, weight), and scheduled follow‑up including HIV RNA checks to detect viral rebound early.
Conclusion
PASO‑DOBLE provides high‑quality randomised evidence that, among adults with sustained suppression and no prior virological failure, switching to dolutegravir plus lamivudine maintains virological suppression at 48 weeks and is non‑inferior to bictegravir/emtricitabine/tenofovir alafenamide. Both regimens were well tolerated and discontinuations for adverse events were uncommon. These data support shared decision‑making: clinicians and patients can consider DTG/3TC as a validated maintenance option when clinical circumstances and patient preferences align, while recognising contexts (eg, HBV coinfection, prior resistance) where a three‑drug regimen may be preferable.
Funding and trial registration
Funding: ViiV Healthcare, CIBER de Enfermedades Infecciosas (CIBERINFEC), and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS).
ClinicalTrials.gov: NCT04884139.
Selected references
Ryan P, Blanco JL, Masia M, et al.; PASO‑DOBLE study group. Maintenance therapy with dolutegravir and lamivudine versus bictegravir, emtricitabine, and tenofovir alafenamide in people with HIV (PASO‑DOBLE): 48‑week results from a randomised, multicentre, open‑label, non‑inferiority trial. Lancet HIV. 2025 Jul;12(7):e473–e484. doi:10.1016/S2352-3018(25)00105-5. PMID: 40489982.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at: https://clinicalinfo.hiv.gov (accessed 2025).
European AIDS Clinical Society (EACS) Guidelines. Available at: https://www.eacsociety.org (accessed 2025).
Author disclosures
This article is a scientific interpretation of the PASO‑DOBLE trial results intended for clinicians and policy makers. The primary trial investigators disclosed funding sources in the original publication. Clinicians should consult the full paper and local guidelines before changing clinical practice.