Factors associated with HIV-1 resistance to integrase strand transfer inhibitors in Spain: Implications for dolutegravir-containing regimens

Abstract

Integrase strand transfer inhibitor (INSTI)-containing regimens in HIV-1-infected patients have experienced a global increase. Recently, WHO has emphasized the need to fast-track the transition to dolutegravir (DTG)-based antiretroviral (ARV) treatments. However, continued surveillance of INSTI resistance is recommended. In this study, clinical, epidemiological, and virological features associated with INSTI resistance diagnosed in Spain were analyzed. Samples collected between 2008 and 2021 from HIV-1-infected patients were analyzed in integrase, protease, and reverse transcriptase using Sanger population sequencing. ARV drug resistance was evaluated with the Stanford University HIVdb program. Among 2,696 patients, 174 (6.5%) had INSTI resistance, all of them to first-generation INSTIs, and 71 (2.6%) had also resistance to second-generation INSTIs. Of these, only 5 individuals were exposed to DTG as the only INSTI, in whom resistance development was associated with poor treatment adherence and/or resistance to other ARV classes. Of newly HIV-1-diagnosed individuals, 0.92% harbored INSTI-resistant viruses, with low prevalences maintained along time, and only one had low-level resistance to DTG. Persons who inject drugs, age over 39 years, resistance to other ARV classes, and longer time from diagnosis were associated with INSTI resistance (p < 0.001). Non-subtype B INSTI-resistant viruses lacked the Q148H + G140S resistance pathway and showed lower INSTI resistance levels than subtype B viruses. In conclusion, INSTI resistance is uncommon and associated with long-term infections, older age and additional resistance to other ARV drug classes, and is rare in newly diagnosed HIV-1 infections. Our results also support the preferential use of DTG-containing regimens in first-line treatments, although surveillance of INSTI resistance is encouraged.

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

“…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 …”

“…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.…”

Comprehensive Analysis of HIV-1 Integrase Resistance-Related Mutations in African Countries

“…The rare mutation E92G was present in South Africa; G118, previously described as a DTG-resistance pathway in non-B subtypes, was present in South Africa; the extremely rare mutation G140R was present in South Africa; and the less common mutation Y143H was present in Uganda and Botswana. The appearance of INSTI resistance mutations in the pre-INSTI era, as found in our study, might be explained by low retention in care and poor treatment adherence in SSA, while the decline in the frequency of DRMs in the INSTI era likely reflects the availability of ART regimens and improved adherence in treatment-experienced populations [ 37 , 39 ].…”

“…Estimates of INSTI-DRMs are limited within SSA [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. Most reports indicate that primary INSTI DRMs are rare, and very few INSTI accessory resistances can be detected prior to the initiation of INSTI therapy, possibly due to transmitted INSTI resistances and the cumulative natural occurrence of mutations without selective drug pressure [ 27 , 39 ]. DRMs such as G118R, E138K/A/T, G140S/A/C/R, Q148H/R/K, S153 F/Y, N155H, and R263K have been identified as being associated with DTG resistance [ 34 ].…”

“…These mutations, which have been shown to occur before initiation of cART with different prevalences depending on the subtypes, could facilitate viral evolution of resistance under drug-selective pressure. M50I has been shown to increase DTG resistance in combination with R263K [ 39 ]. Here, we show a high prevalence of the M50I in HIV subtypes circulating in SSA over forty years, particularly in subtype C and in HIV groups N, O, P, and U, with a higher increase in groups N, O, P, and U in 2008–2023.…”