PASO-DOBLE Journal Club

The Lancet HIV published the PASO-DOBLE study in July 2025. This is an article I have been waiting to be published. It is finally here! This post is a journal club breaking down the PASO-DOBLE trial and what change it may bring to our clinical practice.

Background/Overview

Title: 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

Citation: Ryan P, Blanco J, Masia M, et al. 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;12:e473-84.

Objective: to prospectively compare the 48-week results of dolutegravir and lamivudine versus bictegravir, emtricitabine, and tenofovir alafenamide as maintenance therapies for people with HIV

Background: There are several single tablet regimens available for the treatment of HIV. Biktarvy (bictegravir-emtricitabine-tenofovir alafenamide) is a first-line option recommended in the guidelines. Biktarvy contains a second-generation integrase strand transfer inhibitor (INSTI) and two nucleoside reverse transcriptase inhibitors (NRTIs). The use of second-generation INSTIs and the NRTI tenofovir alafenamide has been associated with greater weight gain than other regimens. A more recent single tablet regimen, Dovato, contains a different second-generation INSTI, dolutegravir, and only one NRTI, lamivudine. Dovato is also a first-line option in the guidelines. Although both options are single tablet regimens that can increase patient adherence, optimization of HIV therapy is paramount in the HIV population, and comparing two first-line options can provide insight on when or if one regimen should be preferred over another.

Primary Efficacy Measure: proportion of people with HIV with RNA ≥50 copies per mL at week 48

Key Secondary Efficacy Measure(s):

• Change in weight and the proportion of participants with >5% weight change at 48 weeks.
• Changes in concentrations of fasting glucose, insulin, glycated haemoglobin (HbA1c), and plasma lipids, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) value, liver function tests, fibrosis-4 index score, and eGFR value
• Proportion of people who needed to start lipid-lowering, anti-diabetic, or anti-hypertensive medications

Safety Outcomes:

• Adverse events occurring in >10% of participants

Participants:

Sex assigned at birth was collected via hospital files; gender was self-reported.

Design: phase 4, randomised, multicentre, parallel-group, open-label, non-inferiority trial conducted over 96 weeks at 30 hospitals in Spain

Intervention:

• Biktarvy (bictegravir-emtricitabine-tenofovir alafenamide) PO once daily
• Dovato (dolutegavir-lamivudine) PO once daily

Duration: 48 weeks; participants screened between July 2021 and March 2023.

Statistical Analysis: It was determined that if 2% of participants in each group had HIV RNA ≥ 50 copies/mL at week 48, a sample size of 520 participants would be required to achieve at least 90% power for non-inferiority with a one-sided alpha of 0.025.

• Non-inferiority was established if the upper bound of the 95% CI for the difference between the dolutegravir group and bictegravir group was less than 4%.

This study was also powered to detect a difference in weight change with a sample size of 504 participants for 80% power to detect a 1 kg weight difference with a one-sided alpha of 0.025.

Results

Dolutegravir group: 277 participants; Bictegravir group: 276 patients

Baseline demographics:

• 73% Male; 27% Female
• 73% White; 24% Latino
• Median age: 50 years (IQR 40∙0–57∙3)
• Median duration of
  • Antiretroviral exposure: 11.4 years
  • Virological suppression: 100.5 months
  • Previous antiretroviral therapy: 66.2 months
• Median weight: 72·8 kg (IQR 63·0–82·4)
  • 50% overweight or obese
• 35% tenofovir disoproxil fumarate (TDF) at baseline
• 20% abacavir at baseline

There were no differences in baseline diet among participants with available data at week 48.

Additional weight change data:

• >5% weight change was similar between groups when the previous regimens contained tenofovir alafenamide
  • Tenofovir alafenamide: 22% BIC, 18% DTG
• >5% weight change was higher in the bictegravir group when the previous regimens contained abacavir or tenofovir disoproxil fumarate
  • Abacavir: 31% BIC, 21% DTG
  • Tenofovir disoproxil fumarate: 41% BIC, 20% DTG
• >5% weight in the bictegravir group was lower than in the dolutegravir group with regimens containing no NRTIs (eg, protease inhibitor monotherapy)
• Changes in BMI categories over time showed more participants meeting criteria for overweight or obesity in the bictegravir group than in the dolutegravir group

Strengths:

• Phase 4, randomised, multicentre, parallel-group
• Comparison trial between two first-line agents
• Powered to detect a difference in weight
• Both TDF and efavirenz use in previous regimens were fairly balanced, as expected from a randomised clinical trial. Both of these medications are known to have weight-suppressing effects.

Limitations:

• Excluded pregnancy or in people with hepatitis B
• Open-label design could introduce bias due to the absence of masking for participants and investigators
• Only stratified participants by sex assigned at birth and tenofovir alafenamide use at baseline
• Not representative of some races or ethnicities, such as Black or African

Authors’ conclusions:

In summary, switching from antiretroviral regimens deserving optimisation to dolutegravir and lamivudine or bictegravir, emtricitabine, and tenofovir alafenamide in people with HIV with virological suppression showed similarly high levels of virological efficacy, no emergence of resistance, and few discontinuations due to adverse events at 48 weeks. Switching to bictegravir, emtricitabine, and tenofovir alafenamide was associated with greater weight gain than switching to dolutegravir and lamivudine, although weight gain with each of the study regimens was greater than expected in the general population. These results provide further evidence that could be useful in shared decision making between physicians and people living with HIV regarding switching to oral antiretroviral therapy.

Recommendation/Extra information:

• Dovato and Biktarvy have previously shown non-inferior efficacy to standard triple therapies in clinical trials
• At 48 weeks, non-inferiority (4% margin) of Dovato versus Biktarvy was shown in the PASO DOBLE study
• The bictegravir group showed greater weight gain and clinically significant weight gain (considered as >5% from baseline) than the dolutegravir group
• These findings add value to existing evidence suggesting that, in people with HIV with virological suppression, switching to Biktarvy might be associated with higher weight gain than switching to Dovato, particularly when tenofovir disoproxil fumarate or abacavir are components in the discontinued regimen
• Both study regimens are convenient and effective options for switching antiretroviral regimens, although weight gain with both regimens was greater than expected in the general population
• Special note! If a patient has chronic hepatitis B or is unprotected, Dovato does not provide adequate coverage, and Biktarvy (with its tenofovir component) is recommended if deciding between the two regimens

Cost (per Lexidrugs Online 2025):

• Biktarvy 50-200-25 mg (per each): $168.64
• Dovato: 50-300 mg (per each): $123.83

Special Considerations/Populations:

• "Discontinuation of tenofovir disoproxil fumarate or abacavir alone or introduction of tenofovir alafenamide alone does not fully explain the different results observed in the proportions of participants with weight gain >5% between the two groups. The fact that the introduction of tenofovir alafenamide in people with HIV who had reached virological suppression was associated with greater weight gain only when tenofovir disoproxil fumarate or abacavir were discontinued suggests that both interventions might be necessary and interdependent. Of note, regimens containing tenofovir alafenamide plus a second-generation integrase inhibitor have been associated with the greatest weight gain in people with HIV and naive to antiretroviral therapy in randomised clinical trials and cohort studies."

Final Thoughts

• My last thought on Biktary vs Dovato is one that was not mentioned in the background of the trial by the study authors. In practice, I see and suggest switching to Dovato from Biktarvy in patients with declining renal function. Since both regimens are single tablets with fixed doses, it can be difficult to continue when CrCl declines <30 mL/min without being on hemodialysis.
• Biktarvy cannot be broken into individual components, as there is no formulation of bictegravir by itself. In addition, the available formulation of tenofovir alafenamide by itself on the market is only approved for Hepatitis B (Vemlidy), but is used off-label for HIV in special circumstances.
• Dovato, on the other hand, can be broken into its components, with dolutegravir (Tivicay) on the market, and lamivudine (generic) is available as well. Dolutegravir does not require renal adjustments, and lamivudine can be renally adjusted down to a CrCl <5 mL/min.
• If a patient's CrCl falls below 30 mL/min and is on Biktarvy, one option is to switch to the individual components of Dovato, with a renally adjusted lamivudine dose. Dovato also provides a tenofovir-free regimen, which can have long-term effects on bone density and kidney function (although much less than the TDF formulation).

*Information presented on RxTeach does not represent the opinion of any specific company, organization, or team other than the authors themselves. No patient-provider relationship is created.