Redefining HIV Management: Emerging Antiretroviral Drug Classes and Immunologic Strategies Shaping the Future of HIV Treatment, Prevention

Over the past 3 decades, antiretroviral therapy (ART) has transformed HIV from a universally fatal infection into a manageable chronic disease. Modern integrase strand transfer inhibitor (INSTI)–based regimens achieve virologic suppression in over 90% of treated individuals, resulting in life expectancy comparable to that of the general population.^1,2 Despite these advances, important limitations remain. With daily oral ART, people with HIV face challenges with adherence and stigma; meanwhile, lifelong therapy contributes to pill fatigue, polypharmacy, and risk of drug resistance.³

The next generation of antiretroviral development, therefore, has shifted to prioritize factors beyond antiviral potency alone. ART research and development now greatly considers patient-centered outcomes, progressing toward less frequent dosing to improve patients’ quality of life, fewer active ingredients to minimize toxicity, and the mission of functional cure or remission strategies through targeting HIV reservoirs. The current manufacturing pipeline reflects this paradigm shift. Investigational therapies include nucleoside reverse transcriptase translocation inhibitors (NRTTIs), capsid inhibitors, broadly neutralizing antibodies (bNAbs), immune modulators, and T cell–engaging biologics. To combat the threat of emerging resistance, pharmaceutical manufacturers have directed attention toward novel antiretroviral drug classes. A key advancement in ART can be seen in the form of the NRTTI islatravir (ISL). As a first-in-class agent, ISL inhibits HIV-1 replication via several mechanisms, notably reverse transcriptase translocation blockade, which produces immediate chain termination and induces structural changes in viral DNA, resulting in delayed chain termination.⁴ ISL exhibits differentiated resistance patterns compared with nucleoside reverse transcriptase inhibitors, which is attributed to the agent’s different mechanism of action.⁵ Previously placed on hold in 2021 due to inducing dose-dependent lymphopenia at a weekly dose of 20 mg, manufacturers have shifted to lower ISL doses.⁶ Rockstroh et al and Carr et al evaluated daily ISL 0.75 mg and observed continued occurrences of lymphocyte depletion, necessitating early trial cessation in Rockstroh et al and noting the need for further dose reductions in the future.^7,8

Several combination products are currently in development with this agent for the purposes of HIV treatment, including doravirine (DOR) 100 mg/ISL 0.25 mg (MK-8591A), ulonivirine (ULO) 200 mg/ISL 2 mg (MK-8591B), and lenacapavir (LEN) 300 mg/ISL 2 mg.^9-12 Notably, ULO/ISL and LEN/ ISL are being developed as once-weekly oral formulations, potentially enabling oral intermittent ART and representing a major shift from daily adherence requirements. The ISLEND-1 (NCT06630286) and ISLEND-2 (NCT06630299) phase 3 trials evaluated the efficacy of LEN/ISL. The novel investigational combination maintained a high rate (94.2%) of viral suppression (HIV-1 RNA < 50 copies/mL) in virologically suppressed adults at 48 weeks compared with standard of care.^13,14 Adverse events (AEs) were reported in 80.8% of participants in the LEN/ISL arm compared with 76.9% of participants in the BIC/FTC/ TAF (bictegravir, emtricitabine, and tenofovir alafenamide) group, with the most frequent AEs including upper respiratory tract infection, COVID-19, and diarrhea. Grade 3 or 4 AEs were observed in 7.7% of LEN/ISL participants, compared with 1.9% in BIC/FTC/TAF, and none of these AEs were attributed to the study drug by the investigators. These regimens may address a critical barrier to ART for those patients unable or unwilling to receive injections but who struggle with daily therapy. With a Prescription Drug User Fee Act date of April 28, 2026, DOR 100 mg/ ISL 0.25 mg is anticipated to be the first available in clinical practice. In Orkin et al and Colson et al, virologically suppressed adults randomly assigned to once-daily DOR/ISL (100 mg/0.25 mg) maintained high rates of viral suppression through 48 weeks and met noninferiority criteria compared with continuing BIC 50 mg/FTC 200 mg/TAF 25 mg or other standard oral ART.^15,16

Importantly, the lower 0.25-mg ISL dose demonstrated improved hematologic safety, with no participants in either trial discontinuing DOR/ISL as a result of protocol-defined lymphocyte depletion. Treatment-related AEs occurred in higher percentages in participants receiving DOR/ ISL than in participants continuing baseline ART in both trials. The most common treatment- related AEs were diarrhea, fatigue, headache, pruritus, and dizziness. Other previous pipeline uses of ISL include the ISL prodrug GS-1614; however, the agent is not currently being investigated due to prioritization of other long-acting agents.¹⁷ In the pursuit of novel drug classes, beyond ISL, the most recent innovation in HIV therapeutics is the capsid inhibitor class, pioneered by LEN. Unlike traditional antiretrovirals that target viral enzymes (reverse transcriptase, protease, or integrase), capsid inhibitors interfere with multiple stages of the viral life cycle, including capsid assembly, nuclear import, and virion maturation. LEN is under evaluation in multiple ongoing clinical trials to extend existing formulation frequencies and study it in combination with other antiretrovirals. In addition to weekly oral LEN 300 mg/ ISL 2 mg, the ARTISTRY-1 (NCT05502341) and ARTISTRY-2 (NCT06333808) phase 3 trials investigated LEN 50 mg in combination with BIC 75 mg as a daily dose.¹⁸ Early data in late 2025 from these multicenter, double-blind trials demonstrated tolerability and statistical noninferiority when compared with complex ART regimens and BIC/FTC/TAF, respectively, with the higher BIC dose providing exposure consistent with BIC 50 mg in BIC/FTC/ TAF. In ARTISTRY-1, drug-related AEs were reported in 14% of participants in the BIC/LEN group and 2% in the complex regimen group; 2% of BIC/LEN participants discontinued therapy due to nausea, dizziness, headache, alopecia, and fatigue. A BIC/ LEN single-tablet regimen may further transform HIV treatment by offering an additional option for sustained virologic suppression with a next-generation antiretroviral strategy. Furthermore, the efficacy of LEN has prompted the development of additional capsid inhibitors. Novel oral capsid inhibitor agents in the pipeline include VH4011499, GS-3107, and GS-4182, a weekly oral prodrug of lenacapavir.^19-22 Moreover, the WONDERS1 (NCT06544733) and WONDERS2 (NCT06613685) trials are evaluating the novel INSTI and capsid inhibitor combination of GS-1720 650 mg and GS-4182 300 mg as an oral weekly formulation. ^21,22 However, the US Food and Drug Administration placed a clinical hold on GS-1720/GS-4182 in June 2025 due to safety signals of absolute lymphocyte depletion.²³ While the manufacturer has expressed intent to continue to pursue both agents, no trials have been announced investigating the agents at lower doses. While manufacturers are seeking to improve medication adherence and patient autonomy via less frequent dosing, the latent HIV reservoir continues to be a key area of research with the mission of achieving long-term HIV remission or a potential cure. In particular, bNAbs have served as a promising area of cure-directed research. Studies have demonstrated that bNAbs bind conserved epitopes on the viral envelope, neutralizing a broad range of viral strains and enabling immune-mediated clearance of infected cells.²⁴ Importantly, bNAbs offer pharmacologic advantages in the form of long halflives, no CYP drug interactions, and minimal organ toxicity.²⁵

Current bNAbs in development are teropavimab (TAB), zinlirvimab (ZAB), VH3810109, and VH4527079.^26-30 For purposes of their role in clinical practice, manufacturers are combining TAB 2550 mg and ZAB 2550 mg, both given intravenously, with LEN 927 mg, given subcutaneously, seeking a complete 6-month injectable regimen for virologically suppressed individuals.²⁹ While still early in investigation, no serious treatment-emergent AEs occurred during the pilot study of TAB/ZAB/LEN, and virologic suppression was maintained in 8 of 10 participants at week 26.²⁷ In addition, the phase 1 ENTRANCE trial (NCT07053384) is investigating the use of subcutaneous or intravenous VH3810109 every 4 months with or without fostemsavir to reduce the size and activity of the HIV viral reservoir.²⁷ These multimechanistic approaches reflect a growing consensus that an HIV cure will likely require a combination of immunologic and antiviral therapy.

Beyond neutralization, some investigational agents aim to activate immune-mediated clearance of latent HIV. The phase 2a agent vesatolimod stimulates toll-like receptor 7 (TLR7), activating innate immunity and inducing interferon responses with the goal of activating latent HIV reservoirs to allow immune clearance of infected cells.³¹ Meanwhile, a bispecific antibody, the bispecific T-cell engager GS-8588, simultaneously binds HIV-infected cells via gp120 envelope protein and cytotoxic T cells to enable immune-mediated destruction of viral reservoirs.³² This agent is currently in phase 1 trials. When combined with bNAbs, these agents may enhance reservoir reduction, providing an opportunity for a potential HIV functional cure. In alignment with the goals of less frequent dosing and long-term control of HIV treatment in the form of novel ART, preexposure prophylaxis (PrEP) strategies and investigational agents continue to push the boundary of dosing intervals in the pursuit of ultra-long-acting options. The PURPOSE-365 trial is evaluating the pharmacokinetics and the safety and tolerability of a yearly dose of LEN 3000 mg administered intramuscularly for PrEP.³³ An ongoing phase 1 trial (NCT06786520) is also evaluating ultra -long-acting cabotegravir administered every 4 months in healthy volunteers at 800 mg, 1200 mg, and 1600 mg.³⁴ Lastly, the EXPrESSIVE phase 3 clinical trials (NCT07044297) are currently assessing the safety and efficacy of MK-8527 11 mg, an investigational once-monthly, oral NRTTI for HIV PrEP.³⁵ Together, these investigational approaches signal a transition from daily therapy to much less frequent medication administration, positioning ultra-long-acting antiretrovirals as a cornerstone of future HIV prevention.

The HIV treatment pipeline represents a transition from chronic suppression to durable remission and, potentially, cure (TABLE). Capsid inhibitors are poised to become foundational agents enabling ultralong- acting therapy. Additionally, broadly neutralizing antibodies, TLR7 agonists, and T cell–engaging biologics are pushing the field toward eradication strategies. In the near future, HIV management may no longer rely on daily pills. Instead, patients could receive therapy a few times per year. While challenges in cost, resistance, and implementation remain, the diversity and innovation of current investigational therapies mark one of the most transformative periods in HIV pharmacotherapy since the advent of combination ART. The ART pipeline suggests that the next milestone in HIV medicine will not merely be better treatment, but the realistic possibility of long-term viral control.

References

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2.Lambert-Niclot S, Boyd A, Fofana D, et al. INSTI-based triple regimens in treatment-naïve HIV-infected patients are associated with HIV-RNA viral load suppression at ultralow levels. Open Forum Infect Dis. 2019;6(5):ofz177. doi:10.1093/ofid/ofz177

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8.Rockstroh JK, Paredes R, Cahn P, et al Doravirine/islatravir (100/0.75 mg) once-daily compared with bictegravir/emtricitabine/tenofovir alafenamide as initial HIV-1 treatment: 48-week results from a phase 3, randomized, controlled, double-blind, noninferiority trial. Clin Infect Dis. 2025;81(2):322-332. doi:10.1093/cid/ciaf077

9.A phase 3, randomized, active-controlled, double-blind clinical study to evaluate a switch to doravirine/islatravir (DOR/ISL) once daily in participants with HIV-1 who are virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) (MK-8591A-052). ClinicalTrials.gov. Updated November 18, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT05630755

10.A phase 3, randomized, active-controlled, open-label clinical study to evaluate a switch to doravirine/islatravir (DOR/ISL 100 mg/0.25 mg) once daily in participants with HIV-1 who are virologically suppressed on antiretroviral therapy (ART) (MK-8591A-051). ClinicalTrials.gov. Updated November 21, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT05631093

11.A phase 2, randomized, double-blind, active-controlled clinical study to evaluate doravirine/islatravir (DOR/ISL) once daily in treatment-naïve participants with HIV-1 infection (MK-8591A-011). ClinicalTrials.gov. Updated May 2024. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT05393271

12.Dose-ranging, switch study of islatravir (ISL) and ulonivirine (MK-8507) once-weekly in virologically suppressed adults with human immunodeficiency virus type 1 (HIV-1) (MK-8591-013). ClinicalTrials.gov. Updated October 2023. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT04564547

13.A phase 3, randomized, double-blind, active-controlled study to evaluate a switch to an oral weekly islatravir/lenacapavir regimen in people with HIV-1 who are virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). ClinicalTrials.gov. Updated November 13, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT06630286

14.Study to compare an oral weekly islatravir/lenacapavir regimen with standard of care in virologically suppressed people with HIV-1. ClinicalTrials.gov. Updated November 14, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT06630299

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16.Colson AE, Mills AM, Ramgopal MN, et al. Switch to fixed-dose doravirine (100 mg) and islatravir (0·25 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, multicentre, randomised, controlled, double-blind, non-inferiority trial. Lancet. 2026;407(10528):611-621. doi:10.1016/S0140-6736(25)01948-8

17.Calibr announces license agreement with Gilead to develop a long-acting HIV antiviral agent for treatment in combination with lenacapavir. News release. Scripps Research. January 4, 2024. Accessed February 23, 2026. https://www.scripps.edu/news-and-events/press-room/2024/20240104-calibr-gilead-hiv-antiviral.html

18.Mounzer K, Slim J, Ramgopal M, et al. Efficacy and safety of bictegravir plus lenacapavir: 48-week outcomes in people with HIV-1 who are virologically suppressed on complex antiretroviral regimens at baseline. Open Forum Infect Dis. 2025;12(11):ofaf615. doi:10.1093/ofid/ofaf615

19.Thakkar N, Griesel R, Pierce A, et al. Clinical pharmacokinetics and safety of orally administered VH4011499, a new HIV-1 capsid inhibitor, in adults without HIV. Infect Dis Ther. 2025;14(5):1011-1025. doi:10.1007/s40121-025-01129-y

20.A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of GS-3107 coadministered with encequidar in healthy participants. Australian and New Zealand Clinical Trials Registry. Registered December 3, 2025. Accessed February 18, 2026. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12625001353482

21.Study of oral weekly GS-1720 and GS-4182 compared with Biktarvy in people with HIV-1 who have not been treated (WONDERS2). ClinicalTrials.gov. Updated November 21, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT06613685

22.Study of oral weekly GS-1720 and GS-4182 versus Biktarvy in people with HIV-1 who are virologically suppressed (WONDERS1). ClinicalTrials.gov. Updated November 21, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT06544733

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26.A study to assess the safety and pharmacokinetics of a human monoclonal antibody (VH4527079) in healthy adults and persons with HIV. ClinicalTrials.gov. Updated August 13, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT06652958

27.A study to investigate the use of VH3810109 with or without fostemsavir (FTR) to reduce the size and activity of the viral reservoir in people living with HIV. ClinicalTrials.gov. Updated August 19, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT07053384

28.Leone PA, Losos J, Wannamaker P, et al. VH3810109 (N6LS) broadly neutralizing antibody safety, pharmacokinetics, and anti-drug antibody incidence in adults without HIV: phase 1 SPAN study results. Antimicrob Agents Chemother. 2025;69(9):e0025825. doi:10.1128/aac.00258-25

29.A study of teropavimab and zinlirvimab in combination with capsid inhibitor lenacapavir in virologically suppressed adults with HIV-1 infection. NCT05729568. ClinicalTrials.gov. Updated July 15, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT05729568

30.Eron JJ, Cook PP, Mehrotra ML, et al. Lenacapavir plus 2 broadly neutralizing antibodies, teropavimab and zinlirvimab, for people with HIV-1 highly susceptible to either teropavimab or zinlirvimab. J Infect Dis. 2025;231(6):1440-1444. doi:10.1093/infdis/jiaf159

31.A phase 1b, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of GS-9620 (vesatolimod) in antiretroviral treated HIV-1 infected controllers. Updated April 21, 2021. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT03060447

32.Gupta S. Safety, tolerability, and pharmacokinetics of GS-8588 in people with HIV-1 who are virologically suppressed on antiretroviral therapy. All IN for Health Research Studies. Updated March 12, 2025. Accessed February 18, 2026. https://research-studies.allinforhealth.info/us/en/listing/12239/safety-tolerability-and-pharmacokinetics/

33.Study of lenacapavir as a once-yearly injection for HIV pre-exposure prophylaxis (PrEP). ClinicalTrials.gov. Updated January 12, 2026. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT07047716

34.A study to evaluate the pharmacokinetics, safety, and tolerability of cabotegravir ultra long-acting (CAB ULA) following switch from cabotegravir long-acting (CAB LA) in healthy adults. ClinicalTrials.gov. Updated June 19, 2025. Accessed February 18, 2026. https://clinicaltrials.gov/study/NCT06786520

35.A Clinical Study of MK-8527 to Prevent Human Immunodeficiency Virus Type 1 (HIV-1) (MK-8527-011) ClinicalTrials.gov. Updated March 9, 2026. Accessed March 17, 2026. https://clinicaltrials.gov/study/NCT06045507

36.Pipeline: advancing innovative therapies. Gilead Sciences Inc. Updated February 12, 2026. Accessed February 23, 2026. https://www.gilead.com/science/pipeline

37. Driving innovation: ViiV Healthcare’s long‑acting pipeline. ViiV Healthcare. Updated February 2025. Accessed February 23, 2026. https://viivhcmedinfo.com/our-pipeline/