Efficacy and Durability of Two- vs. Three-drug Integrase Inhibitor-Based Regimens in Virologically Suppressed HIV-Infected Patients

Data From Real-Life ODOACRE Cohort

Massimiliano Fabbiani; Barbara Rossetti; Arturo Ciccullo; Letizia Oreni; Filippo Lagi; Luigi Celani; Manuela Colafigli; Andrea De Vito; Maria Mazzitelli; Alex Dusina; Miriam Durante; Francesca Montagnani; Stefano Rusconi; Amedeo Capetti; Gaetana Sterrantino; Gabriella D'Ettorre; Simona Di Giambenedetto


HIV Medicine. 2021;22(9):843-853. 

In This Article

Abstract and Introduction


Objectives: The aim of the present study was to compare the efficacy and durability of treatment switch to two-drug (2DR) vs. three-drug (3DR) integrase inhibitor (InSTI)-based regimens in a real-life setting.

Methods: Within the ODOACRE cohort, we selected adult patients with HIV RNA < 50 copies/mL switching to an InSTI-based 2DR or 3DR. Survival analyses were performed to estimate the probability of virological failure (VF, defined as one HIV RNA > 1000 copies/mL or two consecutive HIV RNA > 50 copies/mL) and treatment discontinuation (TD, defined as any modification, intensification or interruption of the regimen), and to evaluate their predictors.

Results: Overall, 1666 patients were included, of whom 1334 (80%) were treated with a 3DR (19.9%, 25.0% and 55.1% elvitegravir-, raltegravir- and dolutegravir-based, respectively) and 332 (20%) with a 2DR (79.2% dolutegravir + lamivudine and 20.8% dolutegravir + rilpivirine).

Over a median (interquartile range) follow-up of 100 (52–150) weeks, 52 (3.1%) patients experienced VF with an incidence of 1.5/100 person-year of follow-up (PYFU). The estimated 96-week probability of VF was similar for the 2DR and 3DR groups (2.3% vs. 2.8%, P = 0.53), but it was higher for elvitegravir (4.9%) and raltegravir (5.0%) than for dolutegravir (1.5%) (P = 0.04).

Four hundred (24%) patients discontinued their InSTI-based regimen, with an incidence of 11.3/100 PYFU. At 96 weeks, 3DRs showed a higher probability of TD for any reason (20.6% vs. 11.2%, P < 0.001) and TD for toxicity (9.0% vs. 6.6%, P = 0.02) when compared with 2DRs. A higher risk of TD for central nervous system toxicity was observed for dolutegravir than for elvitegravir and raltegravir (4.0% vs. 2.5% vs. 0.6%, P = 0.005).

Conclusions: In virologically suppressed HIV-infected patients, 2DRs showed an efficacy similar to 3DRs but with better tolerability.


Combined antiretroviral therapy (ART) has dramatically changed the prognosis of HIV infection since available ART regimens allow viral replication to be suppressed in most patients, thus reducing AIDS-related morbidity and mortality.[1,2]

In recent years, integrase strand transfer inhibitors (InSTIs) have become the reference antiretroviral drug class. This is mainly due to their efficacy and improved tolerability with respect to older drug classes; in particular, a rapid viral decay has been observed in patients treated with InSTIs, with lower impact on lipid profile, improved gastrointestinal tolerability, and good renal, hepatic and bone safety.[3] Moreover, recent reports seem also to suggest a benefit of InSTIs in terms of immunological recovery when in comparison to protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors.[4] Indeed, a more convenient inflammatory profile has been observed in patients switched to InSTIs.[5–7] As a consequence, InSTI-based regimens are currently recommended by major international guidelines as first-line therapy[8,9] and they are increasingly used for treatment optimization in order to improve short- and long-term tolerability, reduce drug–drug interactions and improve convenience (e.g. reduced pill burden and/or dosing frequency) of ART.[10–13]

Traditionally, InSTIs are combined with two nucleos(t)ide reverse transcriptase inhibitors in a three-drug regimen (3DR). The InSTI-based 3DRs have shown good efficacy and durability both in clinical trials[14,15] and in real-life settings.[16–18] Recently, dolutegravir, a last-generation InSTI characterized by a high genetic barrier, has been evaluated for the treatment of HIV infection in two-drug regimens (2DRs) with encouraging results. In the GEMINI trials, dolutegravir + lamivudine showed long-term, non-inferior efficacy compared with a dolutegravir-based 3DR in treatment-naïve patients.[19] In treatment-experienced virologically suppressed patients, the TANGO trial showed that treatment switch to dolutegravir + lamivudine was non-inferior in maintaining virological suppression at weeks 48 and 96 compared with a tenofovir alafenamide (TAF)-based 3DR regimen.[20,21] Moreover, in the setting of virological suppression, SWORD trials demonstrated that virological efficacy was maintained through 3 years in a high proportion of subjects after treatment switch to a 2DR based on dolutegravir + rilpivirine.[22] Also data from clinical practice suggest a good efficacy of treatment switch to a dolutegravir-based 2DR.[23–28] Moreover, preliminary findings did not demonstrate a detrimental effect of 2DRs on virological control in reservoirs and on inflammatory profile.[7,29–32] However, very few studies comparing 2DRs and 3DRs in a real-life setting are available.[33–35]

In our study, we aimed to evaluate efficacy and durability of treatment switch to 2DR vs. 3DR InSTI-based regimens in virologically suppressed HIV-infected patients treated during routine clinical practice.