Transmitted Drug Resistance to NRTIs and Risk of Virological Failure in Naïve Patients Treated With Integrase Inhibitors

A Borghetti; A Ciccullo; F Lombardi; G Baldin; S Belmonti; M Prosperi; F Incardona; E Heger; V Borghi; A Sönnerborg; M Zazzi; A De Luca; S Di Giambenedetto


HIV Medicine. 2021;22(1):22-27. 

In This Article

Abstract and Introduction


Objectives: Nucleoside reverse transcriptase inhibitor (NRTI) transmitted drug resistance mutations (TDRMs) could increase the risk of virological failure (VF) of first-line integrase strand transfer inhibitor (InSTI)-based regimens.

Methods: Patients starting two NRTIs (lamivudine/emtricitabine plus abacavir/tenofovir) plus raltegravir or dolutegravir were selected from the EuResist cohort. The role of NRTI genotypic susceptibility score and of specific TDRMs in VF (i.e. two consecutive viral loads > 50 HIV-1 RNA copies/mL or a single viral load ≥ 200 copies/mL after 3 months from antiretroviral therapy start) was evaluated in the overall population and according to the InSTI employed.

Results: From 2008 to 2017, 1095 patients were eligible for the analysis (55.5% men, median age 39 years). In all, 207 VFs occurred over 1023 patient-years of follow-up. The genotypic susceptibility score (GSS) had no effect on the risk of VF in the overall population. However, the presence of M184V/I independently predicted VF of raltegravir- but not dolutegravir-based therapy when compared with a fully-active backbone [adjusted hazard ratio (aHR) = 3.09, P = 0.035], particularly when associated with other non-thymidine analogue mutations (aHR = 27.62, P = 0.004). Higher-zenith HIV-RNA and lower nadir CD4 counts independently predicted VF.

Conclusions: NRTI backbone TDRMs increased the risk of VF with raltegravir-based but not dolutegravir-based regimens.


Raltegravir and dolutegravir are the reference first- and second-generation integrase strand transfer inhibitors (InSTIs), respectively. InSTIs are the mainstay in the management of chronic HIV infection, representing the recommended initial regimens for most people with HIV according to international guidelines.[1,2]

Despite high intrinsic InSTI potency, the presence of NRTI transmitted drug resistance-associated mutations (TDRMs) could negatively affect the efficacy of standard three-drug regimens with two NRTIs plus an InSTI in naïve patients,[3] advising for genotypic resistance testing before starting antiretroviral therapy (ART). However, in a previous study on a multicentre Italian cohort,[3] the rate of TDRMs to NRTIs was low, and only 11 out of 160 patients (6.8%) experienced virological failure (defined as a plasma HIV-1 RNA> 200 copies/mL after week 24), eight of whom were on a raltegravir-based regimen. Conversely, data from registrational clinical trials on dolutegravir in naïve patients[4] did not suggest increased risk of virological failure in patients with a history of resistance to at least two classes of antretrovirals. Moreover, in the recently published DAWNING clinical trial[5] comparing the use of dolutegravir with lopinavir/ritonavir-based regimens in patients failing their first-line therapy with an NNRTI + two NRTIs, dolutegravir showed superior virological efficacy. Interestingly, the presence of NRTIs resistance mutations seemed to be protective even against virological failure compared with the presence of two fully active NRTIs, possibly due to lower adherence in the NRTI resistance-free cases.

Our aim was to investigate and compare the impact of NRTI TDRMs on the virological outcome in a multinational cohort of HIV-1-infected, naïve individuals starting a standard InSTI-based three-drug regimen composed of two NRTIs (abacavir or tenofovir plus lamivudine or emtricitabine) plus either raltegravir or dolutegravir.