OBJECTIVE:To assess the prevalence and patterns of treatment-emergent resistance-associated mutations (RAMs) in people with HIV (PWH) with ≥1 prior regimen experiencing virologic failure (VF) with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), dolutegravir/lamivudine (DTG/3TC), or cabotegravir/rilpivirine (CAB + RPV) in an observational setting. DESIGN:A noninterventional, multicenter, retrospective, observational study was conducted between January 1, 2022 and December 31, 2024 using a national French multicenter database of genotypic resistance assays performed at confirmed VF. METHODS:VF was defined as 2 consecutive HIV-1 plasma viral loads of >50 copies/mL. Genotypic resistance assays were performed using Sanger sequencing. Treatment-emergent RAMs were characterized using the 2024 ANRS algorithm. Clinical history, virologic history, and demographic data were collected from medical records during standard clinical follow-up. RESULTS:A total of 6523 PWH were followed over 3 years. The prevalence of VF during follow-up was 6% with B/F/TAF, 5% with DTG/3TC, and 5% with CAB + RPV. The prevalence of treatment-emergent RAMs at VF were 3% with B/F/TAF, 15% with DTG/3TC, and 32% with CAB + RPV. Dual treatment-emergent integrase strand transfer inhibitor (InSTI) and nucleoside reverse transcriptase inhibitor (NRTI) RAMs were observed with B/F/TAF and DTG/3TC, while dual treatment-emergent nonnucleoside reverse transcriptase inhibitor (NNRTI) and InSTI RAMs were observed with CAB + RPV. CONCLUSIONS:The overall prevalence of VF was low for all regimens. B/F/TAF was associated with a numerically lower prevalence of RAMs at VF compared with DTG/3TC and CAB + RPV. These observational findings highlight the importance of monitoring resistance patterns to optimize HIV treatment outcomes.

BACKGROUND:The aim of this study was to evaluate changes in prevalence of resistance to integrase strand transfer inhibitors (INSTIs) in relation to changes in their use over 16 years in people living with HIV (PLWHIV) treated with antiretrovirals (ARVs) and in virological failure. MATERIALS AND METHODS:We analysed the use of different INSTIs (for ≥3 months during the study year) in ARV-treated PLWHIV in an academic centre and the HIV INSTI resistance profiles in RNA in case of virological failure (2008-24; analysed using the ANRS-MIE algorithm v33). RESULTS:During the studied period (2008-24), INSTI use increased from 3.3% to 71.2%. Raltegravir use peaked at 21.5% in 2013 and then declined to 2.5% in 2024. Elvitegravir followed a similar trend, increasing to 15.7% in 2018 and then decreasing to 1.5% in 2024. Dolutegravir increased steadily from 6.3% in 2014 to 39.3% in 2023 and bictegravir from 2.0% in 2018 to 28.0% in 2024. Cabotegravir, first noted in 2020 (0.3%), will reach 3.8% in 2024. The proportion of patients with INSTI-resistant viruses was initially high for raltegravir (47.8% in 2008), before decreasing. By 2024, resistance was 2.7% for dolutegravir, cabotegravir and bictegravir, but remained higher for raltegravir (8.5%) and elvitegravir (9.8%). CONCLUSIONS:Although the use of INSTIs has increased over time with differences in the duration of use, we did not observe a corresponding increase in the proportion of ARV-treated PLWHIV who experienced virological failure with INSTI-resistant viruses during the study period.

This case of HIV-1-seronegative infection due to very early treatment demonstrates that even in the absence of sufficient HIV replication to generate detectable immunity, a competent reservoir can accumulate, allowing replication to resume despite 20 months of effective treatment and the disappearance of molecular evidence of infection.

OBJECTIVES:This study aimed to gain a better understanding of the role of insertional mutations in the integrase (IN)-coding sequence of 13 HIV-1-infected people. RESULTS:Here, we present the first documentation of amino acid insertion in the IN-coding sequence of HIV-1-infected people at positions 168, 253, 255 and 260. The consequences of these mutations in terms of viral replication and resistance to INSTIs were analysed using virological and biochemical assays and 3D modelling. Analysis of viral genomes by quantitative PCR demonstrated that insertional mutations reduce reverse transcription efficiency and had different impacts on viral integration. Taken together, we showed that mutants were delayed in their replication. Virological assays using two potent strand-transfer inhibitors (INSTIs), raltegravir and dolutegravir, demonstrated that no resistance to INSTIs was observed. CONCLUSIONS:Our study has revealed that the mutations observed in people living with HIV-1 do not confer resistance to anti-integrase compounds but are detrimental to viral replication.

BACKGROUND:Recent studies have shown progress in understanding the evolution of HIV antiretroviral resistance-associated mutations (RAMs) in the reservoir, particularly M184V, but data on non-nucleoside reverse transcriptase (RT) inhibitors RAMs (NNRTI-RAMs) remain limited. This study aimed to describe the evolution of NNRTI-RAMs in the reservoir, with or without M184V. MATERIALS AND METHODS:This single-centre retrospective study included people living with HIV-1 (PLWHIV) who had one or more NNRTI-RAMs detected in plasma genotype, and who had blood samples collected after at least 1 year of virological suppression on antiretroviral therapy. RT NGS was performed at two time points during virological suppression: DNA1 (2019) and DNA2 (2024). RESULTS:Of 49 PLWHIV with NNRTI-RAMs, 40 had an M184V mutation in their previous HIV-1 RNA genotypes. At DNA1, NNRTI-RAMs and M184V were present in 44.9% (n = 22/49) and 65.0% (n = 26/40) of PLWHIV, respectively. In univariate analysis, NNRTI-RAM clearance at DNA1 was associated with shorter duration of replication under an NNRTI regimen at virological failure (VF) (5 versus 37 months, P = 0.013), longer duration between RNA and DNA1 genotypes (14 versus 9 years, P = 0.010) and older age (60 versus 55 years, P = 0.037). Only replication duration remained associated with the persistence of NNRTI-RAMs (P = 0.041) in multivariate analysis. Past M184V in RNA genotypes was not associated with NNRTI-RAM persistence at DNA1 or DNA2 (P = 0.477 and P = 0.711, respectively). No significant evolution of NNRTI-RAMs was observed between DNA1 and DNA2 (P > 0.999). CONCLUSIONS:In virologically suppressed PLWHIV, NNRTI-RAMs and M184V in the HIV blood reservoir decreased without evidence of interaction between their evolution.

Background:Attachment inhibitor fostemsavir (FTR) and postattachment inhibitor ibalizumab (IBA) are used in people with HIV-1 (PWH) who are highly treatment experienced and harboring multidrug-resistant viruses, and real-world data remain limited. We describe population characteristics and pharmacovirologic outcomes of PWH initiating FTR- or IBA-based regimens. Methods:We conducted a French retrospective observational study within the AIDS Research National Agency | Emerging Infectious Diseases virology and pharmacology network. Virologic failure (VF) was defined as 2 consecutive plasma viral loads (VLs) ≥50 copies/mL; nonvirologic response was considered a VL decrease <1 log10 copies/mL or failure to achieve virologic suppression. Results:Among 70 PWH receiving FTR-based treatment, 50% were virologically suppressed at initiation; median VL among viremic cases was 3.6 log10 copies/mL. Resistance to at least 2 antiretrovirals was observed among participants by inhibitor class: 96%, nucleoside reverse transcriptase inhibitor; 94%, nonnucleoside reverse transcriptase inhibitor; 74%, protease inhibitor; and 64%, integrase strand transfer inhibitor. The genotypic susceptibility score was ≤1 in 47%, and median follow-up was 20 months. Eight VFs and 8 nonvirologic responses occurred. At failure, emergence of FTR resistance-associated mutations occurred in 1 case. Suboptimal temsavir concentrations were observed in 2 of 8 participants in failure. Eleven PWH who were viremic initiated IBA-based treatment: the genotypic susceptibility score was ≤1 in 4, and median follow-up was 7 months with 5 VFs and 2 nonvirologic responses. One new resistance mutation (N74D, capsid) was detected at VF; suboptimal plasma concentrations of oral antiretrovirals were observed in 3 of 5 participants. Conclusions:PWH receiving FTR or IBA had extensive multidrug resistance and limited therapeutic options. Among PWH who were viremic and initiating FTR- and IBA-based regimens, virologic success was achieved in 63% and 36%, respectively, and maintained in 91% who were virologically suppressed and starting an FTR-based regimen.

BACKGROUND:Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with moderate plasma protein binding and good potential for anatomical sanctuary penetration. MATERIALS AND METHODS:Adding doravirine to existing antiretroviral therapy (ART) regimens has led to virological success in two groups of people living with HIV (PLWHIV): those with recent virological rebound (n = 84) and those with prolonged low-level viremia (LLV, n = 39). Doravirine was added without any modification to the other ART drugs. RESULTS:After 6 months, 88% of PLWHIV in the recent failure group had achieved virological success, compared to 33% of those in the LLV group. Efficacy was closely tied to the genotypic susceptibility score (GSS), with higher success rates in patients whose regimens retained two or more active drugs. Doravirine resistance mutations were uncommon but occurred more frequently in the LLV group. No significant associations were found between treatment response and CD4 count, nadir, VL zenith or duration of suppression. CONCLUSIONS:These findings support the use of doravirine add-on strategies to rescue virological control without changing the full regimen, particularly when a full regimen change is not feasible and when GSS is favourable. The study highlights the potential of doravirine in tailored salvage therapy strategies.

ABSTRACT There is limited data on lenacapavir (LEN) use, the newest capsid inhibitor, in observational settings. We describe population characteristics and pharmaco-virological outcomes of people with HIV-1 (PWH) who initiated LEN-based treatment. We conducted a national retrospective observational study of PWH initiating LEN-based treatment in France after its approval (December 2022). Virological failure (VF) was defined as two consecutive viral loads (VLs) ≥50 c/mL, and a non-virological response as a VL decrease of <1 log 10 c/mL or still >50 c/mL at W24. Ninety-six PWH were included; 49 were virologically suppressed at initiation. Median follow-up on LEN was 12 months (IQR = 8–17). Genotypic susceptibility score was <1 in 59 cases (61%). Twelve participants (12.5%) discontinued LEN-based treatment. Among the virologically suppressed and viremic PWH at initiation, 94% and 64% had VL <50 c/mL at the last follow-up visit, respectively. VF occurred in 8 PWH (3 in virological success and 5 viremic at baseline), and a non-virological response was observed in 12 PWH. Capsid sequence at VF was available for eight subjects, showing the emergence of N74D mutation in one. LEN plasma concentrations were available for 13 of the 20 PWH presenting with VF or non-response with adequate concentrations in 90% of cases. Twenty-four participants received cabotegravir + LEN, 18 having VL <50 c/mL at the last follow-up visit. Our observational findings confirm that LEN-based regimens are effective among heavily treatment-experienced individuals with advanced resistance. In this population, LEN-based treatments were associated with high rates of sustained virological suppression and a low incidence of capsid emergent resistance.

OBJECTIVES:Rilpivirine, a non-nucleoside reverse transcriptase inhibitor for preventing mother-to-child HIV transmission, may have reduced plasma exposure in the second and third trimesters due to increased metabolism/elimination in pregnant women, potentially compromising its efficacy. The study aimed to evaluate maternal rilpivirine plasma concentrations during pregnancy and postpartum. METHODS:A multicenter, cross-sectional, cohort was conducted from 2020 to 2023. Pregnant women living with HIV-1 receiving rilpivirine 25 mg once-daily containing regimen were enrolled. Plasma concentrations of rilpivirine were determined throughout pregnancy and postpartum. A population pharmacokinetic approach was performed to analyze the plasma concentrations. Rilpivirine trough plasma concentrations (C24h) were estimated using individual parameters and interpreted using an efficacy threshold of 48 ng/ml (# four-fold protein adjusted EC50). RESULTS:Seventy-two (97% sub-Saharan African) pregnant women were enrolled: median age 34 years old (interquartile range 25-75%; 28-38). All were receiving triple-therapy, including emtricitabine/tenofovir (as tenofovir disoproxil fumarate or tenofovir alafenamide fumarate)-associated nucleoside reverse transcriptase inhibitors. Overall, 222 plasma concentrations were determined. There was no effect of gestational age or trimester on pharmacokinetic parameters to improve the between-occasion variabilities. Median rilpivirine estimated C24h were 79 ng/ml (interquartile range 25-75%; 55-105). Among the 72 women, 14% of them presented C24h<48 ng/ml. Only one woman presented >200 copies/ml viral load during her pregnancy. CONCLUSIONS:In our study, no significant effect of pregnancy on rilpivirine pharmacokinetic parameters was reported. No dose adjustment for orally-administered rilpivirine should be recommended in this setting.

BACKGROUND:The S147G mutation is associated with high-level resistance to the integrase strand transfer inhibitor (INSTI) elvitegravir. In several poorly documented cases, it was also selected in patients on dolutegravir. Given the widespread use of dolutegravir, further studies of S147G are required. METHODS:We consulted the HIV-1 resistance databases of French laboratories to identify all cases of S147G emergence. We collected immunological and virological parameters, history of treatment and INSTI resistance mutations. Mann-Whitney and Fisher's exact tests were performed. RESULTS:We retrospectively identified 88 cases of S147G selection, from 2015 to 2022, in 22 laboratories. The most frequent HIV-1 subtypes were Clade B (55.7%) and CRF02_AG (21.6%). At the time of resistance genotyping, the median viral load was 5860 copies/mL (IQR 1011-24  525) and the median CD4 cell count was 412 cells/mm3 (228-560). S147G emerged on dolutegravir (48%), elvitegravir (36%) and raltegravir (10%) treatments. S147G was associated with a larger median number of other INSTI mutations on dolutegravir than on elvitegravir [3.0 (2.0-4.0) versus 2.0 (1.0-2.0); P = 0.0002] and was never observed with Q148H or G118R. On dolutegravir, S147G was associated principally with T97A (62%), N155H (59%), E138K (50%), L74I/M (38%) and Q148R (33%). CONCLUSIONS:In this French study, S147G emerged principally in patients on dolutegravir regimens, in association with up to five other INSTI resistance mutations. This accumulation of mutations suggests a replicative advantage on HIV strains under dolutegravir selection pressure, suggesting that caution is required when interpreting dolutegravir resistance in the presence of such S147G resistance patterns, even in patients prescribed dolutegravir twice daily.

BACKGROUND:We aimed to determine how non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance profiles have changed over the last decade in people living with HIV (PLWHIV) experiencing virological failure on all antiretroviral treatments, including different NNRTIs. MATERIALS AND METHODS:We analysed the use of the different NNRTIs in PLWHIV treated with antiretroviral drugs at an academic centre and the HIV NNRTI resistance profiles observed in cases of virological failure over the last 10 years (2014-23). We used the latest ANRS-MIE algorithm (v33; https://hivfrenchresistance.org/) to analyse the resistance mutation profiles of the HIV reverse transcriptase sequences. RESULTS:During this period, the frequency of NNRTI use remained high, fluctuating slightly between 43.5% (n = 1782/4094) and 39.9% (n = 1758/4421). The use of efavirenz (10.8%-1.5%), nevirapine (7.0%-1.2%), and etravirine (11.0%-1.1%) decreased, whereas the use of rilpivirine (14.7%-26.3%) and doravirine (available from 2018, rising to 9.7% in 2023) increased. These trends were statistically significant for etravirine (P = 0.033) and rilpivirine (P < 0.001). Resistance rates for efavirenz, nevirapine and rilpivirine remained above 15% (efavirenz: 17.3%-16.6%, nevirapine: 16.9%-15.4% and rilpivirine: 17.6%-16.1%). This reflects significant cross-resistance between these three NNRTIs. By contrast, resistance rates were lower for etravirine (7.8%-6.0%) and doravirine (4.9%-4.6%), probably due to differences in their resistance profiles and higher genetic barriers to resistance. CONCLUSIONS:The NNRTI class of antiretroviral drugs remains widely used. Changes in the usage of drugs from this class have not altered the ecology of NNRTI resistance in antiretroviral drug-treated PLWHIV with virological failure during the studied period.

BACKGROUND:Doravirine is licensed in patients living with HIV (PWH) harbouring no prior resistance to any NNRTIs. We aimed to evaluate in real life the efficacy of doravirine with prior NNRTI virological failure and NNRTI resistance-associated mutations (RAMs). METHODS:This observational study included PWH switched to a doravirine-containing regimen between 30 September 2019 and 1 May 2022, with an HIV-1 RNA of ≤50 copies/mL and past NNRTI-RAMs. The main outcome was the proportion of participants with virological failure at Week 48 and Week 96. Secondary outcomes evaluated the rate of viral suppression and transient virological blip, RAMs in the case of virological failure and side effects. RESULTS:A total of 102 patients were analysed, mostly men (63%), with a median age of 59 years (IQR 51-63). The median time since HIV-1 diagnosis was 26 years (IQR 16-31), on ART for 22 years (IQR 14-26) and virally suppressed for 7 years (IQR 1-11).Of the patients analysed, 25/102 (25%) had documented historical RAMs to doravirine, 9/25 (36%) showing possible resistance and 16/25 (64%) showing major resistance. The resistance profile primarily (21/23) consisted of the K103N, Y181C and/or G190A/E reverse transcriptase substitutions. Median time since the last detection of NNRTI-RAMs was 12 years (5-17). Over 2 years follow-up, no virological failure occurred, neither at Week 48 (0/87; 0%) nor Week 96 (0/86; 0%). CONCLUSIONS:This is the first real-world study to provide new insight about the use of doravirine-containing regimens as a treatment in long-term suppressed patients whose viruses harboured specific NNRTI-RAMs in their history.

BACKGROUND:Second-generation integrase strand transfer inhibitors (InSTIs) have a high barrier to resistance and potent antiretroviral activity. They are recommended as first- or second-line (FL and SL) options in two- and three-drug regimens (2DR and 3DR) in international treatment guidelines. However, there are limited real-world data on emerging resistance at the time of virological failure (VF) with these regimens. OBJECTIVES:The Virostar-1 study objective is to analyse the emergence of resistance-associated mutations (RAMs) over 3 years with DTG-based 2DRs and DTG- or bictegravir (BIC)-based 3DRs in people living with HIV (PLWH) experiencing a VF (FL or SL). METHODS:Retrospective analysis of genotypic resistance detected at the time of a FL or SL VF with BIC/FTC/TAF, DTG/ABC/3TC, DTG/3TC and DTG/RPV between 2019 and 2022 was conducted from a French multicentre database. VF was defined as two consecutive HIV-1 plasma viral loads > 50 c/mL. Sanger assays were performed at VF within standard clinical care. Resistance mutations were reported using the ANRS algorithm. Selection biases prevent group comparisons. RESULTS:During the period, N = 5986 PLWH were followed either in FL or SL. The VF rate was overall low: BIC/FTC/TAF, 6.8%; DTG/ABC/3TC, 7.5%; DTG/3TC, 5.1%; and DTG/RPV, 2.1%. Some emergent InSTI or NRTI RAMs were detected with BIC/FTC/TAF 4%, DTG/ABC/3TC 8.5%, DTG/3TC 18% and 39% emergent NNRTI RAMs with DTG/RPV. However, a complete absence of dual resistance against NRTIs and InSTIs was observed. CONCLUSIONS:We detected rare emergent InSTI RAMs and few emergent NRTI RAMs in PLWH failing DTG- or BIC-based regimens in FL or SL. The observed rates of emergent RAMs at VF were 4% with BIC/FTC/TAF, 8.5% with DTG/ABC/3TC, 18% with DTG/3TC and 39% with DTG/RPV.

IntroductionMolecular surveillance is an important tool for detecting chains of transmission and controlling the HIV epidemic. This can also improve our knowledge of molecular and epidemiological factors for the optimization of prevention. Our objective was to illustrate this by studying the molecular and epidemiological evolution of the cluster including the new circulating recombinant form (CRF) 94_cpx of HIV-1, detected in 2017 and targeted by preventive actions in 2018.MethodsIn June 2022, 32 HIV-1 sequence databases from French laboratories were screened to identify all individuals who had acquired CRF94_cpx or a similar strain, whatever the date of diagnosis. Phylogenetic analyses were performed with the sequences identified, and biological parameters were collected at the time of diagnosis and after the start of treatment to analyse the evolution of the cluster. Full genomes were sequenced to characterize the new strains.ResultsWe analysed 98 HIV-1 isolates: 63 were CRF94, three were unclassifiable, and the other 32 formed a new cluster containing a new recombinant, CRF132_94B, derived from CRF94 and a subtype B strain. At least 95% of the individuals in both the CRF94 and CRF132 clusters were men who have sex with men (MSM), most of whom had acquired HIV less than 12 months before diagnosis. The number of CRF94 diagnoses declined drastically after 2018, but CRF132 strains spread widely between 2020 and 2022, into a different area of Ile-de-France region and within a younger population nevertheless aware of pre-exposure prophylaxis. Higher viraemia, lower CD4 cell counts and delayed treatment efficacy suggested that CRF94 was more virulent than CRF132, possibly due to the F subtype fragment of the vif gene.ConclusionsThese findings highlight the role of the MSM transmission cluster in spreading HIV and new variants. They show also the benefits of cluster surveillance for improving the targeting of preventive interventions, detecting the emergence of new strains and enriching our knowledge on virulence mechanisms. However, these investigations require support with sufficient resources dedicated to a regional or national programme to be responsive and effective.

Journal Article Ultra-rapid selection of the N74D capsid inhibitor resistance mutation after 3 weeks on lenacapavir Get access Marc Wirden, Marc Wirden INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Sorbonne Université, Paris, F75013, FranceDepartment of Virology, AP-HP, Pitié Salpêtrière Hospital, Paris, France Corresponding author. E-mail: marc.wirden@aphp.fr https://orcid.org/0009-0003-3723-4142 Search for other works by this author on: Oxford Academic PubMed Google Scholar Cecile Pouderoux, Cecile Pouderoux Department of Infectious Diseases, AP-HP, Pitié Salpêtrière Hospital, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Gilles Peytavin, Gilles Peytavin Pharmacology Department, AP-HP, Bichat Claude-Bernard University Hospital, Paris, France https://orcid.org/0000-0002-4359-537X Search for other works by this author on: Oxford Academic PubMed Google Scholar Basma Abdi, Basma Abdi INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Sorbonne Université, Paris, F75013, FranceDepartment of Virology, AP-HP, Pitié Salpêtrière Hospital, Paris, France https://orcid.org/0000-0002-9139-0010 Search for other works by this author on: Oxford Academic PubMed Google Scholar Antoine Fayçal, Antoine Fayçal INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Sorbonne Université, Paris, F75013, FranceDepartment of Infectious Diseases, AP-HP, Pitié Salpêtrière Hospital, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Romain Palich, Romain Palich INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Sorbonne Université, Paris, F75013, FranceDepartment of Infectious Diseases, AP-HP, Pitié Salpêtrière Hospital, Paris, France https://orcid.org/0000-0003-0047-0101 Search for other works by this author on: Oxford Academic PubMed Google Scholar Marc Antoine Valantin, Marc Antoine Valantin INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Sorbonne Université, Paris, F75013, FranceDepartment of Infectious Diseases, AP-HP, Pitié Salpêtrière Hospital, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Sophie Seang, Sophie Seang INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Sorbonne Université, Paris, F75013, FranceDepartment of Infectious Diseases, AP-HP, Pitié Salpêtrière Hospital, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Christine Katlama, Christine Katlama INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Sorbonne Université, Paris, F75013, FranceDepartment of Infectious Diseases, AP-HP, Pitié Salpêtrière Hospital, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Vincent Calvez, Vincent Calvez INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Sorbonne Université, Paris, F75013, FranceDepartment of Virology, AP-HP, Pitié Salpêtrière Hospital, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Valerie Pourcher, Valerie Pourcher INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Sorbonne Université, Paris, F75013, FranceDepartment of Infectious Diseases, AP-HP, Pitié Salpêtrière Hospital, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Anne-Geneviève Marcelin Anne-Geneviève Marcelin INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), Sorbonne Université, Paris, F75013, FranceDepartment of Virology, AP-HP, Pitié Salpêtrière Hospital, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Antimicrobial Chemotherapy, dkae115, https://doi.org/10.1093/jac/dkae115 Published: 17 April 2024

Introduction:We assessed the kinetics of the clearance of integrase strand transfer inhibitors resistance mutations (INSTIs-RMs) and associated factors from people living with HIV (PWH) displaying suppressed viral replication after virological failure (VF) on an INSTI regimen. Patients and methods:We included PWH with HIV-RNA viral loads ≤20 copies/mL for at least 5 years in whom INSTIs-RM had been identified at least once in a prior RNA resistance genotyping test. HIV DNAs were sequenced by Sanger sequencing (SS) and ultra-deep sequencing (UDS; detection threshold: 5%) every year over the preceding 5 years. Results:We included 39 PWH in the study. Most (95%) had experienced VF on a raltegravir-containing regimen. The past INSTIs-RMs were not detected in the peripheral blood mononuclear cells of 35 of the 39 (90%) PWH by SS at the end of follow-up. In a longitudinal analysis (2017-21) based on UDS, the previously detected INSTIs-RMs were not detected in 29 of the 35 (83%) PWH. In multivariable analysis, the duration of viral replication and the level of HIV-RNA during prior VF were significantly associated with the persistence of INSTIs-RM, with odds ratios of 1.05 per week of replication (95% CI, 1.00-1.11; P = 0.024) and 8.26 per log10 copies/mL (95% CI, 1.46-46.59; P = 0.017). Conclusions:We observed a clear trend towards the clearance of archived INSTIs-RM after a long period of virological control leading to changes in the resistance profile in cellular DNA, raising the possibility of studies assessing the recycling of INSTI classes even in the presence of a history of resistance.

Objectives Resistance associated mutations (RAMs) are archived in the HIV reservoir and can re-emerge with an inappropriate ART use limiting treatment options. However, recent studies, using ultra-deep sequencing (UDS), showed a decrease of quasispecies harbouring RAMs, suggesting that recycling some antiretrovirals could be considered. The aim of this study was to characterize, in HIV treated PLWHIV, the M184V mutation decrease kinetics in proviral DNA and associated factors of M184V mutation clearance over time.Methods UDS was performed on HIV-DNA from blood cells at different time points to quantify the percentage of M184V positive quasispecies. The sequence reads were analysed with a minimum coverage set at 50 and an ambiguity filter at 5% or 2%.Results At 2.5 years after the first time point, the M184V lost was observed in 50% of PLWHIV. Moreover, univariate analyses highlight that a higher nadir CD4 count and a lower zenith HIV1 RNA viral load were correlated with a faster clearance of the mutation. In multivariate analysis, a higher zenith was negatively associated with the M184V clearance at the 5% threshold. Interestingly, lamivudine/emtricitabine presence in the ART therapy regiment during the 5 years was not associated with the persistence of the M184V.Conclusions Our study provides new information concerning the clearance speed of M184V mutation over time in PLWHIV with fully suppressed viremia, opens the discussion about the duration needed to consider a lamivudine/emtricitabine recycling and reinforces the association of the nadir and zenith values with the M184V mutation clearance.