Transmitted Drug Resistance to Integrase-Based First-Line Human Immunodeficiency Virus Antiretroviral Regimens in Mediterranean Europe

Abstract

Objective To study the prevalence of transmitted drug resistance (TDR) to INSTIs and NRTIs, and of clinically relevant resistance (CRR), in newly-diagnosed people with HIV (PWH) naïve to antiretroviral therapy (ART) in Europe. Methods MeditRes HIV is a consortium that includes ART naïve PWH newly diagnosed in France, Greece, Italy, Portugal, and Spain during the years 2018-2021. Reverse transcriptase (RT) and Integrase (INSTI) sequences were provided by participating centers. To evaluate the prevalence of surveillance drug resistance mutations (SDRM) we used the CPR tools from Stanford HIV-website. To evaluate clinically relevant resistance (CRR), defined as any resistance level >= 3, we used the Stanford v.9.1HIVDB Algorithm. Results We included 2705 PWH, 72% men, median age of 37 (IQR, 30-48); 43.7% infected by non-B subtypes. The prevalence of INSTI-SDRMs was 0.30% (T66I, T66A, E92Q, E138T, E138K, Y143R, S147G and R263K, all n = 1), and of NRTI-SDRMs was 5.77% (M184V n = 23, 0.85%; M184I n = 5, 0.18%; K65R/N n = 3, 0.11%; K70E n = 2, 0.07%; L74V/I n = 5, 0.18%; any TAMs n = 118, 4.36%). INSTI-CRR was 2.33% (0.15% dolutegravir/bictegravir; 2.29% raltegravir/elvitegravir), and 1.74% to first-line NRTIs (0.89% tenofovir/tenofovir alafenamide fumarate; 1.74% abacavir; 1.07% lamivudine/emtricitabine). Conclusions We present the most recent data on TDR to integrase based first-line regimens in Europe. Given the low prevalence of CRR to second generation integrase inhibitors and to first-line NRTIs, in the years 2018-2021 it is unlikely that newly diagnosed PWH in MeditRes countries would present with baseline resistance to a first-line regimen based on second generation integrase inhibitors.

Transmitted drug resistance to antiretroviral drugs in Spain during the period 2019–2021

“…2 In recent years, clinical guidelines have recommended first-line treatment with second-generation integrase inhibitors, which have a high genetic barrier and therefore make it more difficult to develop resistance. 4,5 Although the first integrase inhibitor-associated TDR were described in 2011, 3,6,7 it is worth noting that the prevalence of TDR to these remains very low despite the fact that the use of these drugs has increased. 8,9 The Spanish cohort of HIV-infected naïve individuals (CoRIS) provides a large amount of clinical, demographic, and virological information, making it an excellent scenario for monitoring TDR to different antiretroviral drugs in Spain.…”

“…1,2 The use of antiretroviral therapy to which the virus is resistant can lead to problems, such as lengthening the time it takes to achieve virological suppression and increasing the risk of developing resistance to active treatments. 3 Given the importance of identifying TDR in advance, different clinical guidelines, such as those of the US Department of Health and Human Services, the European AIDS Clinical Society, the IAS-USA, and the Spanish AIDS Study Group (GESIDA), recommend studying transmitted resistance to reverse transcriptase (RT) inhibitors and protease inhibitors (PI) as part of the initial clinical evaluation of newly diagnosed people living with HIV (PLWH). 2 In recent years, clinical guidelines have recommended first-line treatment with second-generation integrase inhibitors, which have a high genetic barrier and therefore make it more difficult to develop resistance.…”

“…This risk is particularly high with nonnucleoside reverse transcriptase inhibitor (NNRTI)‐based therapies 1,2 . The use of antiretroviral therapy to which the virus is resistant can lead to problems, such as lengthening the time it takes to achieve virological suppression and increasing the risk of developing resistance to active treatments 3 …”

“…In recent years, clinical guidelines have recommended first‐line treatment with second‐generation integrase inhibitors, which have a high genetic barrier and therefore make it more difficult to develop resistance 4,5 . Although the first integrase inhibitor‐associated TDR were described in 2011, 3,6,7 it is worth noting that the prevalence of TDR to these remains very low despite the fact that the use of these drugs has increased 8,9 …”

Future of Antiretroviral Drugs and Evolution of HIV-1 Drug Resistance

“…These worrying findings, in a context where pre-therapeutic genotypic resistance testing is rarely available, have conducted to a change in the WHO guidelines in 2019 with the introduction of the 2nd generation INSTI, dolutegravir (DTG), as the third agent of the first-line regimen. Despite the very low prevalence of TDR to 2nd generation INSTI [ 9 ] and the absence of integrase polymorphisms impacting DTG susceptibility, epidemiological surveys remain crucial. Indeed, virological monitoring of PWH often remains limited, due to restricted access to plasma viral load testing and even more to genotyping, hampering the detection of drug resistance mutations (DRM) in the treated population and the potential transmission of these DRMs to newly infected patients, which would severely and negatively impact HIV infection care.…”