What’s Next? A Look at the Future of HIV Treatment and Prevention

Over the past four decades, treatment and prevention for human immunodeficiency virus (HIV) has evolved from taking many intolerable medications multiple times per day to only taking one daily tablet. As each new therapy was developed, a common treatment goal was simple: create an effective medication with fewer side effects.

Now that there are many well-tolerated, single tablet regimens, what is next?

As times have progressed, HIV research has begun to focus on 2 main objectives: (1) long-acting treatment options to help improve patient adherence and (2) new mechanisms of action for highly-resistant patients. Resistance occurs when the virus forms mutations that prevent a medication from working as intended. If a patient is not taking their medication as often as prescribed, the virus can begin to develop these mutations.

Image 1 provides an overview of the HIV life cycle, featuring the various drug targets that are currently available or in development. Each class of medications works to stop replication of the virus or prevent incorporation into the human host cell, thus reducing viral load and preventing disease progression.

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Image 1: HIV Life Cycle

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New Drug Approval – Cabenuva^®

The newest HIV treatment that has been FDA-approved is a long-acting injection, Cabenuva^® (cabotegravir + rilpivirine), which is administered into the muscle once every month.

Recent data from the ATLAS-2M study has shown promising results that could extend dosing frequency to every 2 months. ViiV Healthcare, the manufacturer of Cabenuva^®, submitted a supplemental new drug application (sNDA) in February of 2021 to include this new dosing regimen. This sNDA allows a manufacturer to request approval for new packaging, dosages, or indications of an already approved drug. Additionally, clinical trials are being conducted to evaluate the safety and efficacy of one of the active ingredients, cabotegravir, as a long-acting option for pre-exposure prophylaxis (PrEP), or prevention, of HIV infection.

HIV Medications Currently Being Studied

Another long-acting medication, islatravir, is currently being developed in multiple formulations. Oral tablets are being studied as daily or weekly doses for treatment and monthly doses for prevention. Phase 1 study results of an islatravir implant were recently presented at the Conference on Retroviruses and Opportunistic Infections (CROI) on March 8, 2021. The data showed the implant placed under the skin could prevent HIV infection for up to one year – this data supports the pursuit of Phase 2 studies. Although insertion and removal would necessitate a low-risk medical procedure, an implant could benefit patients in many ways. This formulation provides a more consistent and predictable release of drug to ensure long-term effectiveness. The islatravir implant can also be removed if a patient has a side effect and wants to stop treatment at any point.

Leronlimab is a monoclonal antibody being studied in clinical trials. It is a once weekly injection under the skin to be used alone after achieving viral suppression using oral therapy or in addition to oral therapy for resistant patients. Interestingly enough, it is also being investigated to treat COVID-19 and metastatic breast cancer due to its targets within the immune system. In the case of HIV, leronlimab blocks a receptor (CCR5) on human CD4 T-cells, a type of cell in the immune system, which protects healthy CD4 T-cells from viral infection.

Commonly, subcutaneous injections can be self-administered by a patient at home because they are given under the skin rather than into the muscle. This therapy, being an injection that is given under the skin, could provide patients with the option to take longer-acting medication without having to go to the doctor’s office for each injection.

Broadly neutralizing antibodies (bnAbs) such as VRC01, VRC07, UB-421, PGT-121, GS9722, 3BNC117, 10-1074, and N6 are molecules in varying phases of clinical trials being studied for prevention, treatment, and cure research. The goal for these antibodies is to recognize and neutralize (inactivate) different strains of HIV. Current study results are promising; however, it is likely multiple bnAbs will need to be used together in order to provide an effective regimen that does not require daily oral therapy.

As seen in Image 1, there are many different points within the HIV life cycle where a medication can act. There are two novel mechanisms of action in development that primarily target the end of the life cycle: capsid inhibition and maturation inhibition. A capsid inhibitor interferes with the transportation of viral genetic information. A maturation inhibitor blocks the assembly of HIV particles to form immature virus that is unable to infect other cells. Expansion to new drug classes is necessary in order to provide more options for resistant HIV variants.

The investigational capsid inhibitor, lenacapavir, would be administered as a subcutaneous injection every 6 months in combination with oral therapy.  The maturation inhibitor, only known by the sponsor company’s molecule identification number (GSK3640254), is a capsule taken daily and it shows potential as another effective option for patients with longstanding treatment history and limited options remaining due to resistance.

Lastly, a biologic medication called combinectin could prevent viral entry using 3 unique approaches. This once weekly or monthly subcutaneous injection has been in development for multiple years; however, the first in-human study was terminated in February of 2021. So, at this time, combinectin is no longer being studied.

What does this all mean?

As advances in research continue, patients can expect to see more treatment options to choose from based on their own personal preferences such as drug formulation, dosing frequency, tolerability, and convenience. Novel long-acting formulations can help to improve adherence. Currently, if a patient stops taking their daily medication for even a short amount of time, it could jeopardize the treatment’s effectiveness and it could also limit choices for future medication options. For patients with hard-to-treat HIV variants, new drug targets would provide alternative options when there is resistance to other drug types.

With more patient-specific options for treatment and prevention, we come closer to ending the HIV epidemic. HIV’s long-standing history as a global health concern forces the attention of research and development toward these innovative therapies in order to improve quality of life for affected individuals and continue working toward a cure.

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References:

1. ViiV Healthcare Submits Supplemental New Drug Application to US FDA for Expanded Use of Cabenuva (cabotegravir, rilpivirine) as an HIV Treatment for Use Every 2-Months. ViiV Healthcare website. Accessed March 27, 2021. https://viivhealthcare.com/en-us/us-news/us-articles/2021/viiv-healthcare-submits-supplemental-new-drug-application-to-us-fd-for-expanded-use-of-cabenuva/.
2. Future Directions for HIV Treatment Research. National Institute of Allergy and Infectious Disease website. Accessed March 27, 2021. https://www.niaid.nih.gov/diseases-conditions/future-hiv-treatment.
3. HIV Pipeline Report – March 2020. HIV i-Base website. Accessed March 25, 2021. https://i-base.info/hiv-pipeline-report-march-2020/.
4. Clinicaltrials.gov. Safety and Efficacy Study of Injectable Cabotegravir Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), For Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women Who Have Sex with Men. NCT 02720094. https://clinicaltrials.gov/ct2/show/NCT 02720094.
5. Clinicaltrials.gov. Evaluating the Safety and Efficacy Study of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women. NCT03164564. https://clinicaltrials.gov/ct2/show/NCT03164564.
6. Clinicaltrials.gov. Oral Islatravir Once-Monthly as Preexposure Prophylaxis in Cisgender Men and Transgender Women Who Have Sex with Men, and Are at High Risk for HIV-1 Infection. NCT04652700. https://clinicaltrials.gov/ct2/show/NCT04652700.
7. Clinicaltrials.gov. Dose-Ranging, Switch Study of Islatravir (ISL) and MK-8507 Once-Weekly in Virologically-Suppressed Adults With HIV-1. NCT04564547. https://clinicaltrials.gov/ct2/show/NCT04564547.
8. Drug Database: Leronlimab. ClinicalInfo website. Accessed March 27, 2021. https://clinicalinfo.hiv.gov/en/drugs/leronlimab/patient.
9. Joshi SR, Fernando D, Igwe S, et al. Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next-generation HIV-1 maturation inhibitor. Pharmacol Res Perspect. 2020 Dec;8(6):e00671. doi: 10.1002/prp2.671.
10. Clinicaltrials.gov. Evaluation of the Safety, Tolerability and Pharmacokinetics (PK) of GSK3732394 First-Time-in-Human (FTIH) Study. NCT03984812. https://clinicaltrials.gov/ct2/show/NCT03984812.