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Clinically Relevant Transmitted Integrase Resistance Low in Mediterranean Countries
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HIV Drug Therapy/Glasgow 2020, October 5-8, 2020
Mark Mascolini
Transmitted mutations that may confer clinically meaningful resistance to integrase inhibitors (InSTIs) or current nucleos(t)ides (NRTIs) in antiretroviral-naive people could be detected in fewer than 2.5% of 1844 people tested in France, Greece, Italy, Portugal, and Spain [1]. This analysis of people diagnosed with HIV in 2018 and 2019 offered reassurance that newly infected people in these countries are unlikely to harbor HIV resistant to regimens consisting of second-generation InSTIs and frequently prescribed NRTIs.
InSTI-based regimens are preferred first-line therapy in Europe, the United States, and elsewhere. But most guidelines do not recommend testing antiretroviral-naive people for integrase mutations. Because current thinking favors quick prescription of a first regimen in newly infected people, it would be valuable to know how likely these people are to carry mutations conferring resistance to InSTIs and first-line NRTIs.
To address these questions, researchers working with the MeditRes HIV consortium checked virus in newly infected people for resistance mutations in integrase and reverse transcriptase. To calculate the prevalence of surveillance drug resistance mutations* (SDRM), they used Calibrated Population Resistance tools available via the Stanford v8.9-1 HIVDB algorithm [2]. They defined clinically relevant resistance as a resistance level at or above Stanford level 3, which indicates low-level resistance.
The 1844 study participants had a median age of 40 (interquartile range [IQR] 30 to 54), 79% were males, and 60% were men who have sex with men. Median viral load stood at 5.01 log10 copies (about 102,000 copies) and median CD4 count at 330 (IQR 162 to 505). Almost half of viruses sequenced for mutations (47.2%) were not subtype B (the originally predominant subtype in Europe). CRF02_AG was the most frequent non-B subtype (20%).
Four of 1844 participants (0.22%) had InSTI-related SDRMs, while 45 (2.45%) had clinically relevant integrase mutations. Frequency of clinically relevant InSTI-related mutations was higher for those conferring resistance to raltegravir (2.4%) or elvitegravir (2.4%) than to bictegravir (0.05%) or dolutegravir (0.05%).
Sixty-six of 1844 participants (3.6%) had NRTI-related SDRMs, including any thymidine analog mutation (2.44%), 2 or more thymidine analog mutations (0.76%), M184V (0.86%) (which confers resistance to lamivudine [3TC] and emtricitabine [FTC]), and K65R (0.1%) (which confers resistance to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF).
Thirty-one of 1844 people (1.7%) had clinically relevant NRTI-related mutations, including 27 (1.46%) conferring resistance to abacavir, 18 (0.97%) conferring resistance to 3TC and FTC, and 14 (0.76%) conferring resistance to TDF and TAF.
Because of very low rates of transmitted virus conferring resistance to second-generation InSTIs (bictegravir and dolutegravir) and first-line NRTIs in 2018 and 2019, the researchers proposed "it is very unlikely that a newly diagnosed patient in MeditRes countries would present with baseline resistance to a first-line regimen based on second-generation InSTIs."
*Surveillance drug resistance mutations have "caused or contributed to HIV-1 drug resistance; . . . did not occur in the absence of antiretroviral (ARV) drug pressure; and . . . were valid for all [HIV-1] subtypes."[3] The list is intended to inform epidemiologic surveillance, not to manage individual patients.
References
1. de Salazar A, Fuentes A, Serrano-Conde E, et al. Integrase-based first-line HIV antiretroviral treatment in the Mediterranean Resistance (MeditRes) HIV collaboration. HIV Drug Therapy/Glasgow 2020, October 5-8, 2020. Abstract O322.
2. Stanford University HIV Drug Resistance Database. https://hivdb.stanford.edu/
3. Shafer RW, Rhee SY, Bennett DE. Consensus drug resistance mutations for epidemiological surveillance: basic principles and potential controversies. Antivir Ther. 2008;13:59-68. https://hivdb.stanford.edu/pages/surveillance.html
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