Despite rising NNRTI resistance among pretreatment people with HIV, overall population prevalence of pretreatment HIV drug-resistant viraemia decreased due to increasing ART uptake and viral suppressi...

Study was halted early but the novel NNRTI is now being tested with a lower dose of islatravir.

Tenofovir/lamivudine/dolutegravir (TLD) is widely prescribed worldwide. We report virologic and resistance outcomes for patients initiating or switching to TLD.

This study included PWLHs with past virological failure on NNRTIs. NNRTI RAMs were slowly cleared from proviral DNA. RAM persistence was associated with th

In the blood mononuclear cells of persons living with HIV (PLWHs) with a history of virological failure (VF), some viral strains, archived as proviral DNA, can harbor mutations conferring resistance to antiretrovirals.

Gilead/MSD's once-weekly oral medicine for HIV has been shown to achieve high rates of viral suppression in phase 3, setting up regulatory filings.

This study included PWLHs with past virological failure on NNRTIs. NNRTI RAMs were slowly cleared from proviral DNA. RAM persistence was associated with th

Antiretroviral drug resistance limits treatment options for people with human immunodeficiency virus (HIV) 1 and may reduce the effectiveness of preexposure prophylaxis. Novel treatment options with enhanced efficacy and more convenient formulations have become available from 2016 to 2021. Large-scale studies of trends in the prevalences of plasma RNA drug resistance mutations (DRMs) since 2018 are lacking, and there have been no systematic studies of trends in proviral DNA DRMs.MethodsWe retrospectively analyzed deidentified HIV-1 plasma RNA and proviral DNA sequences from specimens submitted to a reference laboratory between January 2018 and May 2024. We analyzed the annual prevalence of DRMs with a Stanford HIV Drug Resistance Database score of ≥30 for nucleoside and nonnucleoside reverse-transcriptase inhibitors (NRTIs and NNRTIs), protease inhibitors, and integrase strand transfer inhibitors (INSTIs).ResultsThe prevalence of resistance declined for both RNA and DNA sequences. Single-class and dual-class NRTI + NNRTI resistance declined but was higher for DNA (NRTI + NNRTI, declined from 6.1% to 3.5% for RNA and from 12.1% to 7.8% for DNA). Rilpivirine DRMs remained low, with prevalences of 6.3% (RNA) and 10.2% (DNA) in 2024. The doravirine DRM prevalences in 2024 were 2% (RNA) and 2.9% (DNA). INSTI and dual-class NRTI + INSTI resistance also declined, but the prevalence of integrase DRM R263K increased.ConclusionsPrevalence of NRTI and NNRTI resistance has declined, consistent with increased use of regimens with higher resistance barriers, improved tolerability, and more convenient dosing. Proviral DNA resistance trends were correlated with those for RNA. Continued advances in antiretroviral therapy efficacy, durability, and tolerability may lead to increased rates of virologic suppression and further reduce the incidence of archived resistance mutations in proviral DNA.

In the blood mononuclear cells of persons with HIV (PWHs) with a history of virological failure (VF), some viral strains, archived as proviral DNA, can harbor mutations conferring resistance to antiretrovirals.MethodsThis single-center, retrospective study included French PWHs older than 18 years with a history of VF on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen and at least one NNRTI resistance-associated mutation (RAM) detected by Sanger sequencing at the time of VF. Next-generation sequencing targeting the reverse transcriptase gene, in combination with proviral DNA quantification, was performed on at least one whole blood sample after years of virological suppression on other antiretroviral regimens. Multivariate analysis identified factors associated with NNRTI RAM persistence.ResultsIn total, 79 PWHs were included. Samples were collected after a median of 10 years of virological suppression and 16 years after VF. Non-nucleoside reverse transcriptase inhibitor RAMs were not detected in the DNA in 39% of patients, and persistence was associated with a higher proviral DNA load and a higher HIV-1 RNA level at the time of VF. The mutational viral load tended to decrease over time (as assessed in 62 people with two samples collected at 3-year intervals).ConclusionsIn contrast to other mutations such as M184V and INSTI RAMs, NNRTI RAMs tended to persist within the HIV-1 DNA reservoir. However, clearance of these archived mutations from the cellular reservoir was observed in some cases (low proviral DNA load, short duration of viral replication, and low HIV RNA level while taking failing NNRTIs).

Despite rising NNRTI resistance among pretreatment people with HIV, overall population prevalence of pretreatment HIV drug-resistant viraemia decreased due to increasing ART uptake and viral suppressi...

Bictegravir–lenacapavir STR demonstrated non-inferior efficacy to complex regimens, with a similar safety profile and increased treatment satisfaction. Bictegravir–lenacapavir offers new opportunities...

Doravirine/islatravir (DOR/ISL) is a 2-drug, single-tablet regimen in clinical development for once-daily treatment of adults living with HIV-1. We examined the impact of baseline resistance-associated mutations (RAMs) in proviral DNA on the response to DOR/ISL (100/0.25 mg) in virologically suppressed participants in three phase 3 studies.MethodsSamples were collected pre-dose from participants in studies P051 (NCT05631093), P052 (NCT05630755), and P054 (NCT05766501) to evaluate RAMs in proviral DNA at baseline. The prevalence of baseline non-nucleoside reverse transcriptase inhibitor (NNRTI) RAMs and M184I/V, and their impact on virologic suppression (HIV-1 RNA <50 copies/mL) at week 48, as well as on types of viremia (confirmed HIV-1 RNA ≥200 copies/mL, low-level viremia, and transient viremia), was examined. Samples from participants with confirmed HIV-1 RNA ≥200 copies/mL or who discontinued from treatment with HIV-1 RNA ≥200 copies/mL were assessed for viral drug resistance.ResultsAmong 1227 participants who switched to DOR/ISL, 323 (26.3%) had baseline NNRTI RAMs and 70 (5.7%) had baseline M184I/V. At week 48, DOR/ISL maintained HIV-1 RNA <50 copies/mL in ≥88% of participants with and/or without NNRTI RAMs and/or M184I/V detected in proviral DNA at baseline. The percentage of participants in each viremia category was comparable with regard to the presence or absence of NNRTI RAMs and/or M184I/V. No treatment-emergent resistance to DOR or ISL was observed in the 7 participants who met criteria for postbaseline resistance testing.ConclusionsBaseline NNRTI RAMs and M184I/V in proviral DNA did not impact virologic outcomes through 48 weeks after switching to DOR/ISL (100/0.25 mg).Clinical Trials RegistrationClinicalTrials.gov: NCT05631093, NCT05630755, NCT05766501.

This study reveals high rates of HIV-1 drug resistance mutations in individuals failing first-line NNRTI-based regimens across multiple low- and middle-inc

While surveillance drug resistance mutations (SDRMs) remain essential for monitoring transmitted drug resistance (TDR), the clinical impact of transmitted resistance for current first-line regimens has become increasingly important. We aimed to update estimates of TDR in Spain and assess its clinical impact over time.MethodsThis is a nationwide observational study within the CoRIS cohort. We estimated the prevalence of SDRMs and clinically meaningful resistance (CMR) among antiretroviral therapy (ART)–naïve individuals with baseline genotypic resistance testing in 2022–2023 and evaluated annual trends in CMR to first-line regimens from 2007 to 2023. Clinically meaningful resistance was defined as Stanford HIVDB resistance level ≥ 3.ResultsIn 2022–2023, 1028 individuals were included; 82.8% were male, 63.2% MSM, and 72.2% subtype B. Surveillance drug resistance mutation prevalence was 14.4% (95% CI 12.2%–16.9%), driven mainly by NNRTI-SDRMs, while INSTI-SDRMs remained rare [0.5% (95% CI 0.1%–1.5%)]; CMR to recommended first-line regimens was very low. Over 2007–2023, CMR declined markedly, coinciding with adoption of second-generation integrase inhibitors. Rilpivirine-associated resistance mutations were detected in 7.0%, largely due to E138A (4.8%). M184V was detected in 0.8%; 6 of 8 cases occurred in persons with current or prior oral pre-exposure prophylaxis (PrEP), although numbers were small.ConclusionsIn Spain, TDR remains stable, but its clinical impact on first-line regimens has markedly declined. These findings support Test & Treat strategies and immediate ART initiation with contemporary triple- or dual-drug regimens, while highlighting the need for targeted resistance assessment for rilpivirine-containing regimens and further research on prior PrEP exposure and selected NRTI resistance patterns.

AbstractIntroductionFailure in the prevention of mother-to-child HIV transmission (PMTCT) and pediatric treatment challenges led to pretreatment drug resistance (PDR) and acquired drug resistance (ADR) in children with HIV (CWHIV).MethodInterventional and observational data published between 2010 and 2024 on PDR and ADR in CWHIV were included and analyzed by random effects models.ResultsOverall, 72 studies encompassing 9973 children were included. The prevalence (95% CI) of PDR was 32.48% (26.08–39.21), and high among those who failed PMTCT prophylaxis (43.23% [32.94–53.82]) versus those without PMTCT-intervention (P < .01) and driven by nonnucleoside reverse transcriptase inhibitors (NNRTI) mutations (28.38% [18.74–39.08]; P = .013). The prevalence of ADR was 61.43% (49.82–72.45), driven by NNRTI-mutations (65.17% [53.95–75.63]; P < .001). INSTI-ADR was low (5.53% [2.49–9.53]) but emerging.ConclusionThere are high burdens of PDR and ADR among CWHIV, suggesting the need to phase out pediatric NNRTIs used for either PMTCT or treatment. Emerging INSTI resistance among CWHIV highlights the relevance of drug-resistance surveillance strategies.Prospero registration NoCRD42023470034.

Longer-term outcome data following second-line antiretroviral therapy initiation in resource-limited settings is limited, especially in regions where genotypic resistance is inaccessible. This analysis evaluated extended efficacy and tolerability data from the D2EFT study.MethodsD2EFT is a completed, multicenter, phase IIIB/IV, randomized, open-label trial in 14 low- and middle-income countries. People with HIV who had failed first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens were switched to one of ritonavir-boosted darunavir plus two nucleoside reverse transcriptase inhibitors (DRV/r+2NRTIs), ritonavir-boosted darunavir plus dolutegravir (DTG+DRV/r), or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine (DTG+TDF/XTC), with or without pre-switch genotyping. Here we report virological suppression at 96 weeks, defined as HIV RNA <50 copies/mL in a modified intention-to-treat population.ResultsBetween November 2017 and January 2022, 1190 participants were screened, 828 were randomized and 826 were included in the analysis. At week-96, the proportions of participants with HIV RNA <50 copies/mL were 191/251 (76.1%) in DRV/r+2NRTIs, 215/251 (85.7%) in DTG+DRV/r and 231/283 (81.6%) in DTG+TDF/XTC. The treatment differences (95% CIs) in proportions achieving virological suppression were 9.6% (2.7, 16.4) in DTG+DRV/r and 9.0% (1.4, 16.6) in DTG+TDF/XTC, compared to DRV/r+2NRTIs. Intermediate or high-level dolutegravir resistance was identified in 3/27 (13%) of virological failures in individuals taking DTG+TDF/XTC, but in no one taking DTG+DRV/r. No darunavir resistance was observed.ConclusionsAfter 96 weeks of follow-up, DTG+DRV/r and DTG+TDF/XTC demonstrated virological superiority over DRV/r+2NRTIs after first-line NNRTI-failure. However, emerging dolutegravir resistance, which was observed only in individuals taking DTG+TDF/XTC, requires ongoing global surveillance.

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.MethodsWe 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.ResultsAmong 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.ConclusionsPWH 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.