Effectiveness of Integrase Strand Transfer Inhibitors in HIV-infected Treatment-Experienced Individuals Across Europe

Barbara Rossetti; Massimiliano Fabbiani; Domenico Di Carlo; Francesca Incardona; Ana Abecasis; Perpetua Gomes; Anna Maria Geretti; Carole Seguin-Devaux; Federico Garcia; Rolf Kaiser; Sara Modica; Adrian Shallvari; Anders Sönnerborg; Maurizio Zazzi


HIV Medicine. 2022;23(7):774-789. 

In This Article

Abstract and Introduction


Objectives: To explore the effectiveness and durability of integrase strand transfer inhibitor (INSTI)-based regimens in pre-treated subjects.

Methods: Treatment-experienced individuals starting an INSTI-based regimen during 2012–2019 were selected from the INTEGRATE collaborative study. The time to virological failure [VF: one measurement of viral load (VL) ≥ 1000 copies/mL or two ≥ 50 copies/ml or one VL measurement ≥ 50 copies/mL followed by treatment change] and to INSTI discontinuation were evaluated.

Results: Of 13 560 treatments analysed, 4284 were from INSTI-naïve, non-viraemic (IN-NV) individuals, 1465 were from INSTI-naïve, viraemic (IN-V) individuals, 6016 were from INSTI-experienced, non-viraemic (IE-NV) individuals and 1795 were from INSTI-experienced, viraemic (IE-V) individuals. Major INSTI drug resistance mutations (DRMs) were previously detected in 4/519 (0.8%) IN-NV, 3/394 (0.8%) IN-V, 7/1510 (0.5%) IE-NV and 25/935 (2.7%) IE-V individuals. The 1-year estimated probabilities of VF were 3.1% [95% confidence interval (CI): 2.5–3.8] in IN-NV, 18.4% (95% CI: 15.8–21.2) in IN-V, 4.2% (95% CI: 3.6–4.9) in IE-NV and 23.9% (95% CI: 20.9–26.9) in IE-V subjects. The 1-year estimated probabilities of INSTI discontinuation were 12.1% (95% CI: 11.1–13.0) in IN-NV, 19.6% (95% CI: 17.5–21.6) in IN-V, 10.8% (95% CI: 10.0–11.6) in IE-NV and 21.7% (95% CI: 19.7–23.5) in IE-V subjects.

Conclusions: Both VF and INSTI discontinuation occur at substantial rates in viraemic subjects. Detection of DRMs in a proportion of INSTI-experienced individuals makes INSTI resistance testing mandatory after failure.


Effective combination antiretroviral therapy (ART) has radically reduced AIDS-related morbidity and mortality in people living with HIV (PLWH), leading to improved quality of life and life expectancy similar to age-matched HIV-negative people.[1–3] Based on individual and public health benefits consequent to early initiation of ART, together with increased safety and tolerability of antiretroviral strategies, ART is now recommended for all PLWH.[4–6] Indeed, although eradication of HIV infection cannot be achieved with current ART, durable plasma HIV RNA suppression minimizes the risk of emergent drug resistance and contributes to restoring immunological function.[7–10] Due to proven efficacy, safety and ease of administration, integrase strand transfer inhibitors (INSTIs) are recommended for the treatment of HIV infection in many settings.[11–13] The effectiveness of INSTIs, as shown by rapid viral load (VL) decay, long-term maintenance of stable suppression of plasma HIV-RNA and good tolerability, results in relatively few treatment discontinuations.[14,15] The rapid virological suppression associated with INSTIs is of utmost importance to prevent HIV transmission.[7] There appears to be limited circulation of INSTI-resistant strains; however, drug resistance may emerge at virological failure of any antiretroviral, leading to reduced treatment options for future ART approaches.[16,17] Selection of drug resistance mutations depends on different factors, including adherence to therapy, forgiveness and genetic barrier of the ART regimen.[18–21] Currently, two first-generation INSTIs, raltegravir (RAL) and elvitegravir (EVG), and two second-generation INSTIs with a higher barrier to resistance, dolutegravir (DTG) and bictegravir (BIC), are available.[22–25] Raltegravir, the first INSTI developed, has the longest safety track record and is available only as a multi-tablet antiretroviral regimen, increasing pill burden and possibly complicating adherence.[26] Elvitegravir/cobicistat is available as a boosted single-tablet regimen (STR), has substantial drug–drug interactions and must be administered with food.[27,28] Dolutegravir and BIC are both co-formulated as STRs, with different nucleoside reverse transcriptase inhibitor (NRTI) backbones, abacavir/lamivudine (3TC) and tenofovir alafenamide/emtricitabine, respectively. Indeed, the choice between these STRs may be driven by the preferred NRTI backbone.[29–36] A newer INSTI, cabotegravir, administered as a once-monthly or bi-monthly, injectable, long-acting drug in combination with rilpivirine (RPV) has been recently approved for virologically suppressed PLWH.[37–40] All the compounds in the class, except for cabotegravir, are indicated for first-line ART and for treatment switch in PLWH under successful ART, without INSTI resistance-related mutations.[4–6] Moreover, INSTIs, particularly second-generation formulations, are being increasingly used in pre-treated patients, either as salvage at treatment failure or as switch in virologically suppressed PLWH. Thus, analysis of INSTI resistance in real life settings is important, particularly because emergent resistance at failure of first-generation INSTIs can impact response to higher genetic barrier second-generation INSTIs.[16–18,41,42] Overall, a thorough understanding of INSTI effectiveness and drug resistance dynamics is crucial for better management and scale-up of antiretroviral therapy. This study aimed to estimate the risk of and time to virological failure as well as treatment discontinuation of INSTI-based regimens in treatment-experienced PLWH across Europe and to investigate potential predictors of either outcome.