We aimed to assess the kinetics of drug-resistant viral variants (DRVs) harboring the M184V mutation in proviral DNA of long-term virally suppressed patients, and factors associated with DRV persistence. Human immunodeficiency virus (HIV) DNA from blood cells stored in 2016 and 2019 was sequenced using Sanger and ultradeep sequencing (SS and UDS; detection threshold 1%) in antiretroviral therapy (ART)-treated patients with HIV RNA < 50 copies/mL for at least 5 years, with past M184V mutation documented in HIV RNA. Among 79 patients, by combining SS and UDS, M184V was found to be absent in 26/79 (33%) patients and persistent in 53/79 (67%). M184V-positive patients had a longer history of ART, lower CD4 nadir, and higher pretherapeutic HIV RNA. Among 37 patients with viral sequences assessed by UDS, the proportion of M184V-positive DRVs significantly decreased between 2016 and 2019 (40% vs 14%, P = .005). The persistence of M184V was associated with duration and level of HIV RNA replication under lamivudine/emtricitabine (3TC/FTC; P = .0009 and P = .009, respectively). While it decreased over time in HIV DNA, M184V mutation was more frequently persistent in HIV DNA of more treatment-experienced patients with longer past replication under 3TC/FTC.

Lenacapavir is a very recent first-in-class capsid inhibitor approved for HIV-1 treatment.¹ It is a long-acting antiretroviral intended for dosing twice a year by subcutaneous injection. In combination with other antiretrovirals, lenacapavir is indicated in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance or safety considerations. Because lenacapavir is the first and only compound of its class, this drug is expected to be fully active regardless of previous treatment history. To date, several resistance mutations (RM) have been identified in the capsid protein (L56I, M66I, Q67H, K70N, N74D/S and T107N).² They have been selected in vitro or in vivo during virological failures in the CAPELLA or CALIBRATE studies.^3,4 None of these mutations was found to be polymorphic and therefore likely to be present before lenacapavir intake.⁵ However, the selection of these mutations is sufficiently frequent in the context of lenacapavir treatment failure to estimate that this drug presents a low genetic barrier to resistance. Therefore, given the risk of developing resistance in situations of functional monotherapy, careful consideration should be given to having good adherence and active drugs in addition to lenacapavir in the treatment regimen. The present clinical case reports the very rapid selection of resistance after only 3 weeks on lenacapavir.

In this observational study, we aimed to evaluate whether bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) administered 5 or 4 days a week is able to maintain viral suppression in people living with HIV (PLHIV). We enrolled 85 patients who initiated intermittent B/F/TAF between 28 November 2018 and 30 July 2020: median (IQR) age 52 years (46–59), duration of virological suppression 9 years (3–13), CD4 633/mm³ (461–781). Median follow-up was 101 weeks (82–111). The virological success rate (no virological failure [VF]: confirmed plasma viral load [pVL] ≥ 50 copies/mL, or single pVL ≥ 200 copies/mL, or ≥50 copies/mL with ART change) was 100% (95%CI 95.8–100) and the strategy success rate (pVL < 50 copies/mL with no ART regimen change) was 92.9% (95%CI 85.3–97.4) at W48. Two VF occurred at W49 and W70, in 2 patients self-reporting poor compliance. No resistance mutation emerged at time of VF. Eight patients presented strategy discontinuation for adverse events. There was no significant change in the CD4 count, residual viraemia rate, neither body weight during follow-up, but a slight increase in CD4/CD8 ratio (p = 0.02). In conclusion, our findings suggest that B/F/TAF administered 5 or 4 days a week could maintain the control of HIV replication in virologically suppressed PLHIV while reducing cumulative exposition of ART.

APOBEC3 editing activity contributes to sequences variation and viral diversification. We aimed to characterize virological and clinical factors associated with G-to-A mutations and stop codons in the HIV-1 reservoir, markers of APOBEC3 footprints, in order to better understand HIV-1 diversity among virologically suppressed HIV-1-infected patients. Immuno-virological and clinical factors were compared between 92 patients harbouring G-to-A mutations and stop codons (APOBEC+) in the reverse transcriptase gene and 92 patients without G-to-A mutations (APOBEC–) and stop codons in their DNA genotypes. Patients were predominantly men (74.5%) and were mostly infected by B-subtype (69.0%), with 44.1% and 55.9% in APOBEC+ and APOBEC– groups, respectively. At time of HIV DNA genotypes, the total cell-associated HIV-1 DNA load was 2.34 log₁₀ copies/10⁶ cells (IQR 1.85–2.67) and 33.2% of them had a detectable ultrasensitive plasma viral load. Hypermutated sequences were identified in 28.2% of the APOBEC+ group. The median total cell-associated HIV-1 DNA level was significantly lower in APOBEC+ than APOBEC– group: 2.13 log₁₀ copies/10⁶ cells (IQR 1.60–2.60) versus 2.52 log₁₀ copies/10⁶ cells (IQR 2.19–2.71) (P < 0.001), respectively. Presence of G-to-A mutations and stop codon was independently associated with HIV-1 subtype non-B (P = 0.017). These results show an independent association between the presence of G-to-A mutations and stop codons with HIV-1 subtype non-B and low proviral DNA that could be explained by the APOBEC3 footprints and restriction of DNA synthesis and integration. However, further investigations are needed to study the contribution of Vif amino acid variability among HIV-1 subtypes.

Objective: Most studies about HIV-1 molecular evolution have shown the lack of viral evolution on effective antiretroviral therapy (ART), although controversial results have been documented. We therefore aimed to look for evidence of HIV-1 evolution in patients who initiated ART at the time of primary HIV-1 infection (PHI). Design: We included retrospectively 20 patients diagnosed at PHI, treated at the time of acute infection and with subsequent effective long-term suppressive ART (HIV Viral Load <20 cp/mL during at least 5 years without any blips). Methods: Longitudinal blood samples were deep sequenced using Illumina Miseq. Drug-resistance-associated mutations (DRAMs) were retained at 2% cutoff and interpreted using the latest ANRS resistance algorithm. Viral evolution was established when temporal structure on maximum-likelihood phylogenetic tree and significant change over time of HIV-1 genetic diversity measured as the average pairwise distance (APD) was observed. Results: Emergences or disappearances of DRAMs were detected in the blood cells during follow-up despite sustained virological control. In all patients, tree topologies showed an absence of segregation between sequences and blood viral populations from all time-points were intermingled. Comparison of the APD showed the absence of significant viral diversity at the time of primary infection and afterwards during 5 years of full virological control under ART. Conclusion: Despite a slight variation of minority resistance-associated mutation variants, there was no clear evidence of viral evolution during a prolonged period of time in this population of highly controlled adult patients treated at time of PHI.

There are concerns about neutralizing antibodies’ (NAbs’) potency against severe acute respiratory syndrome coronavirus 2 variants. Despite decreased NAb titers elicited by BNT162b2 vaccine against VOC202012/01 and 501Y.V2 strains, 28/29 healthcare workers (HCWs) had an NAb titer ≥1:10. In contrast, 6 months after coronavirus disease 2019 mild forms, only 9/15 (60%) of HCWs displayed detectable NAbs against 501Y.V2 strain.