Long-Acting Antiretroviral Therapies for HIV Treatment and Prevention

ContagionContagion, June 2021 (Vol. 06, No. 3)
Volume 06
Issue 03

More treatment options and modalities are now available for patients.

In January, the FDA approved cabotegravir/rilpivirine(Cabenuva®), the first long-acting medication used for treating HIV infection. Several long-acting modalities are currently under investigation for both HIV treatment and prophylaxis, including oral, injectable, implant, antibody therapy, and vaginal ring.

Long-acting formulations are being developed to overcome barriers—primarily, adherence—presented by daily oral therapy. Encouraging results regarding adherence comes from the phase IIb LATTE-2 study (NCT02120352) evaluating long-acting cabotegravir-rilpivirine for HIV treatment where 99% of participants preferred to continue with injectable therapy compared with 78% on oral treatment.1 The purpose of this article is to provide an overview of the various ART therapies being studied and are available for prevention and treatment of HIV.

Cabotegravir/rilpivirine (Cabenuva®)


Figure 1.

Cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), were approved and co-packaged as the first injectable treatment option for adults with HIV-1 (Figure 1). Following an oral lead-in therapy, the cabotegravir/rilpivirine long-acting extended-release injectable suspensions are currently administered once monthly and are expected to replace the current regimen for those who are infected, have no history of treatment failure, and are virologically suppressed (HIV-1 RNA < 50 copies/mL). This long-acting injectable was approved based on the results of the phase III FLAIR (NCT02938520) and ATLAS (NCT02951052) studies, which evaluated virologic suppression in antiretroviral (ART)-naive and ART-experienced individuals, respectively.2,3


In addition to the previously mentioned clinical trials (ATLAS, FLAIR) examining long-acting cabotegravir in the treatment of HIV, injectable cabotegravir is also being studied for pre-exposure prophylaxis (PrEP) in the HPTN 083 (NCT02720094) and HPTN 084 (NCT03164564) studies.4,5,6

Promising results emerged using injectable cabotegravir every two months for PrEP in the HPTN 083 study, which enrolled cisgender men and transgender women who have sex with men.4 As with the ATLAS and FLAIR studies, an oral lead-in therapy was utilized. The study was halted early due to the superiority of injectable cabotegravir versus oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC).4 Of the 52 HIV infections seen in HPTN 083, 13 infections were in the cabotegravir arm (0.41% incidence rate) compared to 39 infections in the TDF/FTC arm (1.22% incidence rate).

The interim analysis for the phase III HPTN 084 study, which enrolled HIV-uninfected women at increases risk for HIV, showed that women in the cabotegravir arm had an 89% lower risk of HIV infection compared with those receiving TDF/FTC.5,6 In addition, HPTN 084 showed superior efficacy for long-acting injectable cabotegravir in an interim review meeting, with the HIV incidence rate in those receiving cabotegravir at 0.21% compared with 1.79% in those receiving oral TDF/FTC. Because of the positive study outcomes at that point, it was recommended to stop the blinded phase and offer subjects in both arms of the study long-acting cabotegravir once available.5,6


A dapivirine intravaginal ring (IVR) for HIV-1 prevention is currently on the World Health Organization’s prequalification list following the positive opinion from the European Medicines Agency in July 2020.7 The dapivirine intravaginal silicone ring is designed to slowly release dapivirine over the course of one month to reduce the risk of HIV acquisition.

In two phase III studies, the dapivirine IVR was shown to be well tolerated and reduced HIV-1 acquisition risk by 30% compared with placebo.8 The HOPE study (NCT02858037), an open-label extension of the ASPIRE study (NCT01617096), aimed to assess the uptake and use of the IVR in women who had participated in the ASPIRE study and remained HIV-1 negative. Acceptance of the dapivirine IVR was high; 92.2% of women accepted the ring at enrollment, and 97.9% of follow-up visits were completed. Adherence was also measured by testing residual dapivirine amounts in the rings; overall, 89.3% of the returned rings had more than 0.9 mg of dapivirine released, which indicated use.8

Due to its cost effectiveness, acceptability, and feasibility, the IVR will provide benefit to sexually active at-risk women.9 Studies that include IVRs with both contraceptive and HIV preventative medications are underway.


One of the most promising long-acting oral antiretrovirals is islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI).10 Islatravir’s long intracellular half-life in peripheral blood mononuclear cells (PBMCs) allows for extended dosing intervals.11

Interim results from a phase IIa study (NCT04003103) comparing once-monthly islatravir 60 mg tablets, 120 mg tablets, and placebo for PrEP showed no serious adverse events or deaths; in addition, the drug was well-tolerated. Tissue kinetics showed rapid and sustained distribution to cervical, rectal, and vaginal tissues, with both tested doses achieving trough concentrations above the prespecified threshold (0.05 pmol/106 cells).11

Based on the favorable results from this phase II study, two phase III studies will compare islatravir once monthly at the 60 mg dose to current PrEP therapy: TDF/FTC in cisgender women (IMPOWER-022) (NCT04644029) and TDF/FTC or tenofovir alafenamide (TAF)/FTC in men who have sex with men (MSM) and in transgender women who have sex with men (IMPOWER-024) (NCT04652700).12,13 Additionally, islatravir is being investigated as part of a combination regimen with doravirine for once daily treatment in the ILLUMINATE study (NCT04223778).14

Islatravir’s high binding affinity to reverse transcriptase combined with its long half-life (~ 190 hours in PBMCs) makes it suitable for implant formulations. A stent using a drug-eluting polymeric matrix was tested in preclinical and clinical studies. Importantly, few adverse effects were seen aside from implant site pain, tenderness, and erythema.15 In pharmacokinetic simulation studies, the 62 mg implant projects a concentration above the aforementioned target threshold (0.05 pmol/106 cells) at 12 months, with concentrations not falling below the threshold until approximately 16 months.16 Other implants being studied include tenofovir alafenamide and cabotegravir.


Lenacapavir acts as a capsid inhibitor, with additional in vitrodata showing disruption of multiple stages in HIV’s life cycle; thus, lenacapavir has the potential to work against HIV strains that have developed resistance to multiple other classes.17 In the phase II/III CAPELLA study (NCT04150068), 36 adults with multidrug resistant HIV received either placebo or daily lenacapavir for 14 days as an add-on to a failing regimen. At the end of 14 days, the lenacapavir cohort met the primary endpoint (0.5 log10 copies/mL decrease in viral load; 88%) compared with the placebo group (17%).18

The aforementioned subcutaneous injectable formulation of lenacapavir displays a long half-life and is being investigated as a twice-yearly injectable for PrEP. A phase Ib study showed sustained therapeutic concentrations following a single 900 mg dose administered in three 1 mL injections (also studied were two 1.5 mL injections).19

For treatment purposes, interim efficacy results from the CAPELLA study showed high rates of viral suppression through 26 weeks in study participants receiving lenacapavir injection (following the 2-week oral lead-in) in combination with an optimized background regimen in treatment-experienced people living with HIV (PLWH).18 Nineteen of the 26 subjects followed through the 26 weeks achieved viral suppression, with an average CD4 count increase of 72 cells/mm3. Gilead Sciences, Inc and Merck have announced plans to co-develop lenacapavir and islatravir as a combination injectable regimen; a coformulated oral regimen is also being studied.


Broadly neutralizing monoclonal antibodies (bNAbs) are potential agents for long-acting HIV prevention due to their ability to decrease viral load by neutralizing many strains of the pathogen and possibly reducing the viral reservoir. VRCO1 was discovered in the blood of a PLWH and is directed at the HIV-1 envelope protein CD4-binding site. This bNAb was manufactured for the Antibody Mediated Prevention (AMP) studies (NCT04801758, NCT04860323) to assess its ability to prevent HIV-1 acquisition.20

The two double-blind, placebo-controlled phase IIb AMP studies enrolled more than 4000 patients collectively. HPTN 081 (NCT02568215) enrolled cisgender women, and HPTN 085 (NCT02716675) enrolled MSM and transgender persons who have sex with men.21,22 HVTN 703/HPTN 081 (NCT04860323) included heterosexual women from sub-Saharan Africa, and HVTN 704/HPTN 085 (NCT04801758) included men and transgender persons from the Americas and Europe who have sex with men.20

In each study, subjects were randomized to receive VRC01 by intravenous infusion at a dose of 10 mg/kg or 30 mg/kg every eight weeks or a control infusion every eight weeks. The outcome of both studies was to compare documented HIV-1 infection by week 80. Overall, acquisition of HIV-1 was not significantly lower with VRC01 compared with placebo in either study.23

Unfortunately, viruses in persons receiving the bNAb showed greater resistance. Furthermore, as compared to other potential long-acting modalities, cost—as well as the necessity of intravenous infusions—may preclude the use of bNAbs for the immediate future. Instead, bNAbs may have a place in vaccine design and development.24 Future studies will examine combinations of bNAbs and bNAb-based vaccines.


The modalities currently under study, once realized, will allow a wide variety of options for both treatment and prophylaxis (Table). Adherence, which is especially challenging for at-risk populations, could improve dramatically. Daily adherence to an oral regimen would be replaced by longer intervals between clinic visits—reducing dosing frequency, pill fatigue, and oral absorption issues (eg, drug-drug interactions, short bowel syndrome) as well as the potential avoidance of HIV-related stigma.

Table 1.

Table 1.

However, the potential impact that delayed clinic visits could have on resistance to long-acting formulations in a real-world setting requires further study. Other barriers also will need to be overcome for long-acting formulations to reach their full potential, such as cost effectiveness, co-treating comorbidities (eg, hepatitis B, substance abuse), and ensuring overall availability to at-risk populations.

Eric F. Egelund is a clinical assistant professor at the University of Florida College of Pharmacy in Jacksonville. His research interests include infectious disease pharmacokinetics, specifically those used for the treatment of tuberculosis, nontuberculous mycobacteria, and HIV.

Jessica Huston is a clinical assistant professor at the University of Florida College of Pharmacy in Jacksonville. Huston’s experience in clinical research and the pharmaceutical industry includes having served as a subinvestigator on numerous clinical trials.


  1. Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017;390(10101):1499-1510. doi:10.1016/S0140-6736(17)31917-7
  2. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135. doi:10.1056/NEJMoa1909512
  3. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. doi:10.1056/NEJMoa1904398
  4. Marzinke MA, Grinsztejn B, Fogel JM, et al. Characterization of HIV infection in cisgender men and transgender women who have sex with men receiving injectable cabotegravir for HIV prevention: HPTN 083 [published online ahead of print, 2021 Mar 19]. J Infect Dis. 2021;jiab152. doi:10.1093/infdis/jiab152.
  5. Clement ME, Kofron R, Landovitz RJ. Long-acting injectable cabotegravir for the prevention of HIV infection. Curr Opin HIV AIDS. 2020;15(1):19-26. doi:10.1097/COH.0000000000000597
  6. Evaluating the Safety and Efficacy of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women. ClinicalTrials.gov. Updated August 4, 2021. Accessed April 14, 2021. https://clinicaltrials.gov/ct2/show/NCT03164564
  7. Vaginal ring to reduce the risk of HIV infection for women in non-EU countries with high disease burden. News release. European Medicines Agency. July 24, 2020. Accessed April 10, 2021. https://www.ema.europa.eu/en/news/vaginal-ring-reduce-risk-hiv-infection-women-non-eu-countries-high-disease-burden
  8. Baeten JM, Palanee-Phillips T, Mgodi NM, et al; MTN-025/HOPE Study Team. Safety, uptake, and use of a dapivirine vaginal ring for HIV-1 prevention in African women (HOPE): an open-label, extension study. Lancet HIV. 2021;8(2):e87-e95. doi:10.1016/S2352-3018(20)30304-0
  9. WHO recommends the dapivirine vaginal ring as a new choice for HIV prevention for women at substantial risk of HIV infection. World Health Organization. January 26, 2021. Accessed April 14, 2021. https://www.who.int/news/item/26-01-2021-who-recommends-the-dapivirine-vaginal-ring-as-a-new-choice-for-hiv-prevention-for-women-at-substantial-risk-of-hiv-infection.
  10. Schürmann D, Rudd DJ, Zhang S, et al. Safety, pharmacokinetics, and antiretroviral activity of islatravir (ISL, MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel trial. Lancet HIV. 2020;7(3):e164-e172. doi:10.1016/S2352-3018(19)30372-8.
  11. Hillier S, Bekker LG, Badal-Faesen, et al. Trial design, enrollment status, demographics, and pharmacokinetics (PK) data from a blinded interim analysis from a phase 2a trial of Islatravir once monthly (QM) for HIV pre‐exposure prophylaxis (PrEP). Presented at: HIV Research for Prevention (R4P) // Virtual; February 4, 2021. https://onlinelibrary.wiley.com/doi/10.1002/jia2.25659. Accessed April 30,2021.
  12. Oral ISL QM as PrEP in Cisgender Women at High Risk for HIV-1 Infection (MK-8591-022) (Impower-022). ClinicalTrials.gov. Updated April 12, 2021. Accessed April 14, 2021. https://clinicaltrials.gov/ct2/show/NCT04644029.
  13. Oral Islatravir (MK-8591) Once-Monthly as Preexposure Prophylaxis (PrEP) in Men and Transgender Women Who Have Sex With Men and Are at High Risk for HIV-1 Infection (MK-8591-024) (Impower-024). ClinicalTrials.gov. Updated April 12, 2021. Accessed April 14, 2021. https://clinicaltrials.gov/ct2/show/NCT04652700.
  14. Safety and Efficacy of a Switch to Doravirine/Islatravir in Participants With HIV-1 (MK-8591A-017)). ClinicalTrials.gov. Updated March 9, 2021. Accessed March 25, 2021. https://clinicaltrials.gov/ct2/show/NCT04223778.
  15. Matthews RP, Zang X, Barrett S, et al. Next-generation islatravir implants projected to provide yearly HIV prophylaxis. Presented at: CROI 2021; March 6-10, 2021; virtual.https://www.croiconference.org/abstract/next-generation-islatravir-implants-projected-to-provide-yearly-hiv-prophylaxis/. Accessed April 30, 2021.
  16. Matthews RP, Barrett SE, Patel M, et al. First-in-human trial of MK-8591-eluting implants demonstrates concentrations suitable for HIV prophylaxis for at least one year. Presented at: 10th International AIDs Society Conference on HIV Science (IAS); July 21-24, 2019; Mexico City, Mexico. http://programme.ias2019.org/Abstract/Abstract/4843. Accessed April 30, 2021.
  17. Link JO, Rhee MS, Tse WC, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020;584(7822):614-618. doi:10.1038/s41586-020-2443-1
  18. Segal-Maurer S, Castagna A, Berhe M, et al. New weapons against SARS-CoV-2 and HIV. Presented at: Conference on Retroviruses and Opportunistic Infections (CROI) 2021; March 6-10, 2021; virtual. https://www.croiconference.org/abstract/potent-antiviral-activity-of-lenacapavir-in-phase-2-3-in-heavily-art-experienced-pwh/. Accessed April 30, 2021.
  19. Begley R, Lutz J, Rhee M, et al. GS-6207 Sustained delivery formulation supports 6-month dosing interval. Presented at: 23rd International AIDS Conference; July 6-10, 2020; virtual. https://www.natap.org/2020/IAC/IAC_51.htm. Accessed April 30, 2021.
  20. Corey L, Gilbert PB, Juraska M, et al; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 Study Teams. Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition. N Engl J Med. 2021;384(11):1003-1014. doi:10.1056/NEJMoa2031738
  21. Evaluating the Safety and Efficacy of the VRC01 Antibody in Reducing Acquisition of HIV-1 Infection in Women. ClinicalTrials.gov. Updated March 5, 2021. Accessed April 10, 2021. https://clinicaltrials.gov/ct2/show/NCT02568215
  22. Evaluating the Safety and Efficacy of the VRC01 Antibody in Reducing Acquisition of HIV-1 Infection Among Men and Transgender Persons Who Have Sex With Men. ClinicalTrials.gov. Updated February 21, 2021. Accessed April 14, 2021. https://clinicaltrials.gov/ct2/show/NCT02716675
  23. Corey L, Gilbert PB, Mgodi NM, et al. VRC01 antibody prevention of HIV. Presented at: HIVR4P // Virtual; January 27-28, 2021. https://onlinelibrary.wiley.com/doi/10.1002/jia2.25659. Accessed April 30,2021.
  24. Burton DR, Hangartner L. Broadly neutralizing antibodies to HIV and their role in vaccine design. Annu Rev Immunol. 2016;34:635-659.doi:10.1146/annurev-immunol-041015-055515
Related Videos
© 2024 MJH Life Sciences

All rights reserved.