Effectiveness and Safety of Dolutegravir Two-Drug Regimens in Virologically Suppressed People Living With HIV

A Systematic Literature Review and Meta-Analysis of Real-World Evidence

Y S Punekar; D Parks; M Joshi; S Kaur; L Evitt; V Chounta; M Radford; D Jha; S Ferrante; S Sharma; J Van Wyk; A de Ruiter


HIV Medicine. 2021;22(6):423-433. 

In This Article

Abstract and Introduction


Objectives: Dolutegravir (DTG) is widely recommended within three-drug regimens. However, similar efficacy and tolerability have also been achieved with DTG within two-drug regimens in clinical trials. This study evaluated the real-world effectiveness and discontinuations in people living with HIV-1 (PLHIV) switching to DTG with lamivudine (3TC) or rilpivirine (RPV).

Methods: This was a one-arm meta-analysis utilizing data from a systematic literature review. Data from real-world evidence studies of DTG + RPV and DTG + 3TC were extracted, pooled and analysed. The primary outcome was the proportion of patients with viral failure (VF; ≥ 50 copies/mL in two consecutive measurements and/or ≥ 1000 copies/mL in a single measurement) at week 48 (W48) and week 96 (W96). Other outcomes included virological suppression (VS; < 50 copies/mL) and discontinuations (W48 and W96). Estimates were calculated for VF, VS as per snapshot (VSS) and on treatment analysis (VSOT), and discontinuations.

Results: Pooled mean estimates of VF for DTG + 3TC and DTG + RPV were 0.8% [95% confidence interval (CI): 0.4–1.3] and 0.6% (95% CI: 0.0–1.6), respectively, at W48. VSS rate at W48 was 85.0% (95% CI: 82.3–87.5) for DTG + 3TC regimen and 92.4% (95% CI: 85.0–97.7) in the DTG + RPV regimen. The DTG + 3TC and DTG + RPV regimens led to discontinuations in 13.6% (95% CI: 11.1–16.2) and 7.2% (95% CI: 2.1–14.4) of patients, respectively, at W48. Similar results were observed at W96.

Conclusions: Treatment with DTG + 3TC or DTG + RPV in clinical practice provides a low rate of VF and a high rate of VS when initiated in virologically suppressed PLHIV with diverse backgrounds.


Current guidelines recommend a three-drug combined antiretroviral therapy (ART) regimen consisting of an integrase strand inhibitor (INSTI) and two nucleoside/nucleotide reverse transcriptase inhibitors for treatment-naïve and virologically suppressed people living with HIV-1 (PLHIV).[1–4] However, the European Acquired Immune Deficiency Syndrome (AIDS) Clinical Society (EACS) and US Department of Health and Human Services (DHHS) guidelines now also recommend the use of two-drug regimens in switch patients due to their efficacy.[1,4] Furthermore, two-drug regimens are of interest as several ART agents are associated with the risk of well-established, long-term toxicities, including reduced bone mineral density, renal failure or chronic kidney disease, cardiovascular disease and diabetes.[5–11] In addition, the high prevalence of co-morbidities associated with HIV leads to polypharmacy, thus increasing the risk of drug–drug interactions and serious adverse drug events.[12,13]

Considering the lifetime requirements for PLHIV, risks associated with long-term drug exposure[14] may be mitigated, at least partly, by reducing exposure to ART agents where possible. INSTIs have been shown to be the most efficacious core agents[15,16] and are the preferred agent according to EACS and DHHS guidelines, with dolutegravir (DTG) being the preferred INSTI according to the World Health Organization (WHO) for both first- and second-line therapy.[1–4] DTG is a once-daily INSTI approved for the treatment of adults with HIV-1 (who do not have documented or suspected resistance to INSTIs) in combination with other ART agents.[16,17] DTG is considered to be among the most effective INSTIs and, therefore, is the core agent for the majority of triple ART regimens.[15,16,18] In addition to the clinical value of DTG forming part of three-drug regimens, several clinical trials and meta-analyses have shown that DTG-containing two-drug ART regimens, particularly the combinations of DTG with lamivudine (3TC) or rilpivirine (RPV), have similar efficacy in achieving and maintaining virological suppression (VS) in PLHIV. This is achieved whilst reducing the number of ART agents and potential risk of drug–drug interactions owing to the simplified regimen compared with triple ART regimens.[14,19–24]

Two multicentre, double-blind, randomized, phase III trials demonstrated non-inferiority of DTG + 3TC vs. DTG + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for achieving VS in treatment-naïve PLHIV (GEMINI-1 and GEMINI-2).[20,21] In these 48-week studies, the tolerability profiles were considered similar between the two regimens.[20] The combination of DTG and RPV was non-inferior compared with the triple ART regimen in the maintenance of VS over 48 weeks in patients who switched to the two-drug ART regimen from their current triple ART regimen in the open-label, parallel-group, multicentre, phase III, randomized, non-inferiority studies, SWORD-1 and SWORD-2.[25] In addition, a recent randomized phase III study evaluated the efficacy and safety of switching to DTG + 3TC from a tenofovir alafenamide (TAF)-based regimen (TANGO study). Results showed that switching to DTG + 3TC was not inferior to continuing a TAF-containing regimen at week 48 {W48; snapshot virological failure: < 1% vs. < 1%; adjusted difference= −0.6% [95% confidence interval (CI): −1.3–0.2]}. The safety profile of the DTG + 3TC regimen was similar to that seen with the TAF-based regimen.[26,27]

These clinical trials are encouraging the use of these two-drug ART regimens in clinical practice, and the EACS and DHHS now recommend the use of DTG + 3TC for naïve patients and DTG with 3TC or RPV in virologically suppressed switch patients. Furthermore, a plethora of real-world evidence using cohort, case–control, claims-database studies, and case series have been conducted to investigate DTG two-drug regimens in routine clinical practice. Here we present the results of a one-arm meta-analysis with the objective of providing an estimate of the real-world effectiveness and tolerability (as measured by discontinuation rate) of DTG when used as part of a two-drug regimen with either 3TC or RPV in treatment-experienced PLHIV.