The European AIDS Clinical Society (EACS) 2025 surveyed a rapidly diversifying antiretroviral (ARV) treatment landscape in HIV. From first-in-class mechanisms to ultra–long-acting regimens and real-world outcomes in highly treatment-experienced populations. This article highlights the session PS09: “New Drugs in the Pipeline” from EACS 2025.
Summaries are derived from presentations and discussions during EACS 2025 PS09 – “New Drugs in the Pipeline”.
Co-chairs: Caroline Solas (Aix-Marseille Université) & Gordana Dragović (University of Belgrade)
Speakers: Anne-Geneviève Marcelin, Peter Leone, Charlotte Charpentier, Onyema Ogbuagu, Rebecka Papaioannu Börjesson
Across talks, three themes stood out:
- Potent novel mechanisms (e.g., capsid inhibition and nucleoside reverse transcriptase translocation inhibitors [NRTTIs])
- Extended-interval dosing (weekly oral to twice-yearly injectable/infusible strategies)
- Implementation challenges (resistance selection, pharmacokinetic [PK] variability at higher body weight, hepatitis B virus [HBV] co-infection management, and the need for susceptibility testing with broadly neutralising antibodies [bNAbs]).
Simplification and pharmacokinetic precision: Chairs’ perspective
Chair, Dr Caroline Solas (La Timone University Hospital, Marseille, France) opened with the rationale for simplification, both in pill count (robust two-drug regimens) and dosing frequency (weekly oral, 2–6-monthly injectables/infusions).
Chair, Dr Gordana Dragović (University of Belgrade, Serbia) emphasised pharmacokinetic (PK) variability as a key determinant of success for long-acting strategies and highlighted the importance of therapeutic drug monitoring where available.
Mechanisms and formats shaping the next antiretroviral therapy (ART) era
Dr Anne-Geneviève Marcelin (Sorbonne Université, Paris, France) reviewed two cornerstone innovations:
- Islatravir (NRTTI): the first in its class, combining translocation inhibition and delayed chain termination for dual-mechanistic activity. Its 186-hour intracellular half-life supports weekly or longer dosing, and it retains potency against resistant variants.
- Lenacapavir (capsid inhibitor): a multimodal agent that targets the viral capsid through over-stabilisation and interference with uncoating, assembly, and release. It demonstrates favourable PK allowing infrequent dosing and no cross-resistance with existing ARV classes.
Combination approaches:
- Once-daily regimens: early data support lenacapavir + bictegravir and doravirine + islatravir, both demonstrating non-inferiority at Week 48 versus controls.
- Once-weekly oral: islatravir + lenacapavir maintained efficacy to Week 48; islatravir + ulonivirine (a long-half-life non-nucleoside reverse transcriptase inhibitor [NNRTI]) showed promising Week-24 activity.
- Long-acting injectables: modelling supports a 4-month cabotegravir (intramuscular [IM]) formulation exceeding exposures of the current 2-month IM regimen; 6-month candidates such as ViiV’s VH184 and cabotegravir prodrug are in development.
- Broadly neutralising antibodies (bNAbs): N6LS (CD4 binding site) and Gilead’s tabivuskal/zansekibart pair achieved high suppression rates when baseline susceptibility was confirmed.
Clinical note: Many long-acting combinations lack HBV-active agents. When switching suppressed patients who have hepatitis B surface antigen (HBsAg) positivity or hepatitis B core antibody (anti-HBc) alone, clinicians must define a clear HBV management strategy to prevent reactivation.
Twice-yearly HIV therapy: Lenacapavir with dual bNAbs
Dr Onyema Ogbuagu (Yale School of Medicine, New Haven, CT, USA) discussed the twice-yearly regimen lenacapavir plus two broadly neutralising antibodies (bNAbs; teropavimab and zirlovimab).
In a phase-2, open-label, randomised switch trial, adults suppressed for ≥12 months and phenotypically susceptible to both bNAbs received lenacapavir + teropavimab + zirlovimab (every 26 weeks) versus continued oral antiretroviral therapy (ART).
- Efficacy: Around 90% maintained HIV-1 RNA <50 copies/mL at Week 52, with CD4 counts rising by ~30 cells/µL.
- Virologic rebound: Observed in three cases (two due to bNAb resistance; one lenacapavir Q67H mutation). All re-suppressed on bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF).
- Pharmacokinetics: All rebounders had low drug exposures and body weight >100 kg, suggesting a need to consider weight-adjusted dosing.
- Safety: No grade ≥3 treatment-related adverse events (AEs) or discontinuations occurred.
Route matters: Intravenous vs subcutaneous long-acting delivery
Prof. Peter Leone (University of North Carolina, Chapel Hill, NC, USA) presented the EMBRACE phase-2b study, comparing N6LS (a bNAb) administered every 4 months with monthly cabotegravir versus continued oral ART.
- Safety: Intravenous (IV) N6LS caused only mild, transient injection-site reactions (ISRs), while subcutaneous (SC) N6LS produced more ISRs (~51%, 16% grade 3) due to large-volume infusion, all resolving quickly.
- Next steps: A phase-3 trial evaluating twice-yearly IV N6LS with bimonthly cabotegravir is planned, with results expected mid-2026.
Key takeaway: Route and injection volume significantly influence tolerability and adherence potential.
Real-world evidence of lenacapavir
Prof. Charlotte Charpentier (Bichat-Claude Bernard Hospital, Paris, France) presented findings from a national retrospective cohort (n = 94) assessing post-approval lenacapavir use. The data showed:
- Resistance: 45% had nucleoside reverse transcriptase inhibitor (NRTI) resistance, 54% NNRTI, 29% protease inhibitor (PI), and 22% integrase strand transfer inhibitor (INSTI) resistance. Half had ≥2 fully exhausted classes.
- Outcomes: 94% maintained suppression if suppressed at baseline; 64% achieved suppression if viremic. One case (5.3%) of lenacapavir resistance was linked to optimised background therapy (OBT) non-adherence.
- Pharmacokinetics: Most participants had adequate trough levels.
Interpretation: Lenacapavir-based regimens remain durable and effective in multi-class resistance when paired with adherent OBT.
Salvage therapy strategies: Fostemsavir in multi-drug-resistant HIV
Dr Rebecka Papaioannu Börjesson (IRCCS San Raffaele Scientific Institute, Milan, Italy) presented data from Italy’s PRESTIGIO registry (Program for Resistance Evaluation and Salvage Therapy in Global Infectious Observations).
- Cohort: 52 participants (40 viraemic, 12 non-viraemic); ART duration ~25–29 years.
- Virology: 80% of viraemic patients achieved suppression over 2.3 years. Failures (20% viraemic; 8% non-viraemic) were often low-level viremia.
- Immunology: Modest CD4/CD8 recovery observed.
- Persistence: 21% discontinued by 16 months; 4-year continuation ~67%.
Clinical implication: Fostemsavir provides a stable backbone in heavily treatment-experienced populations; pairing with lenacapavir or bNAbs may enhance long-term outcomes.
Practice takeaways: What matters most?
- Mechanisms matter: NRTTI and capsid inhibition redefine the ART landscape.
- Interval matters: Dosing now spans from weekly oral to twice-yearly injection; route selection influences adherence.
- Susceptibility matters: Baseline bNAb sensitivity testing is essential before therapy initiation.
- PK matters: High body weight (>100 kg) can reduce exposure; dose adjustments may be warranted.
- OBT and co–infections matter: Ensure adherence to active background therapy and HBV prophylaxis when switching regimens.
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This content has been developed independently by Touch Medical Media for touchINFECTIOUS DISEASES. Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Summaries are derived from presentations and discussions during EACS 2025 PS09 – “New Drugs in the Pipeline.”
Session: European AIDS Clinical Society (EACS) 2025. PS09 “New Drugs in the Pipeline”. EACS 2025 Congress; 17–21 Oct 2025; Barcelona, Spain. Available at: https://allintheloop.info/Agenda/EACS/EACS2025/View_agenda/560287 (accessed 28 Oct 2025).
Editor: Katey Gabrysch, Editorial Director.
Disclosures: The content was developed and edited by human editors. No fees or funding were associated with its publication. touchINFECTIOUS DISEASES utilize AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat).
Cite: EACS 2025 round-up: New mechanisms and extended dosing shape the HIV drug pipeline. touchINFECTIOUS DISEASES. 28 October 2025
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