Exciting alternatives: An overview of long-acting HIV treatment, prevention
Click Here to Manage Email Alerts
An estimated 1.2 million people in the United States live with HIV, of whom 13% do not know their status. Although HIV incidence declined overall by 9% in 2019, there were still 36,801 new HIV diagnoses.
HIV affects everyone, but racial and ethnic minorities and gay, bisexual and other men who have sex with men continue to be disproportionately affected. In the 1980s, the average life expectancy for someone receiving an AIDS diagnosis was approximately 1 year. In 2022, people living with HIV are expected to live a nearly normal life span.
Source: Adobe Stock
From multiple-tablet regimens — leading to a high pill burden, suboptimal dosing and drug toxicities — to single-tablet regimens, the substantial progress made in antiretroviral drug discovery and development is substantial. Acknowledging that even single-tablet regimens may pose challenges to achieving viral suppression in many patients — including pill fatigue, tolerability, toxicity concerns and HIV-related stigma — the focus has now shifted to long-acting (LA) ART.
Why long acting?
In the absence of a cure or effective vaccine, ART must be relied on for HIV treatment and prevention. LA ARTs are a promising alternative for those desiring less frequent ART dosing. The tradeoff of discomfort associated with injectable administration may become more attractive the less one must be injected.
There are, however, some barriers to optimal implementation that need to be considered, such as cold chain requirements and operational needs for long-acting injectables. Despite that, LA ARTs are safe, effective and offer a viable option for HIV treatment and prevention that warrant more attention.
Current options
The first-ever LA ART for the treatment of HIV-1 approved in North America and Europe was cabotegravir/rilpivirine. Cabotegravir is an integrase strand inhibitor (INSTI) and rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI), and when combined, the therapy has been shown to be noninferior to daily oral ART with high patient satisfaction.
Even though administered intramuscularly at monthly or every-2-month intervals, uptake in low- and middle-income countries may be limited due to the fact that long-acting rilpivirine requires cold chain preservation, the occurrence of HIV resistance and decreased concentrations with concomitant use of rifampin, a common antituberculosis agent.
This agent is well tolerated, with the most common adverse reaction being injection site reactions.
Cabotegravir monotherapy demonstrated preventive efficacy and has been approved for HIV PrEP, helping the 2022-2025 National HIV/AIDS Strategy’s goal of preventing new HIV infections. When initiating cabotegravir for HIV PrEP, it must be administered monthly for the first two doses, followed by every-2-month dosing. Oral lead-in therapy may be pursued to ensure tolerability, and similar to cabotegravir/rilpivirine in combination, it is well tolerated, with the most common adverse reaction being injection site reactions.
Similar uptake challenges are faced with cabotegravir prevention therapy. Another alternative for HIV PrEP is dapivirine monotherapy, available as a vaginal ring that needs to be replaced every 28 days. It has been approved for use in Zimbabwe and South Africa. The European Medicines Agency (EMA) recognizes it as a reasonable option for women who may not be candidates for oral alternatives. The International Partnership for Microbicides (IPM) withdrew its new drug application for FDA consideration because of the unlikelihood of approval in the U.S., a move that primarily affected women of racial and ethnic minority groups in a country where they are already disproportionately affected and may benefit the most.
Current pipeline
Lenacapavir is the first in its class to inhibit the HIV capsid protein and has been shown to be safe and effective in achieving viral load suppression among heavily treatment-experienced patients living with HIV. It is a unique alternative because it inhibits HIV at different stages, its unique subcutaneous formulation and its frequency of administration being every 6 months. The EMA recently approved lenacapavir for use, achieving a major milestone in addressing a critical unmet need for patients living with multidrug-resistant HIV. The FDA rejected a new drug application for lenacapavir in the U.S. in March, citing concerns about the glass vials in which the drug would be stored.
Islatravir, another first in its class, is a nucleoside reverse transcriptase translocation inhibitor with a unique formulation in the form of a subdermal implant administered once yearly. Reports of decreases in total lymphocyte and CD4 counts with an unclear mechanism led the FDA to place clinical holds on trials evaluating islatravir for HIV treatment and prevention. Although it is unclear what the future holds for islatravir, there is still hope for it to move forward in clinical trials and be available as an alternative for patients who need it around the world.
Minority/underserved populations
There is no doubt that LA ART shows promise for the management of patients living with HIV. Globally, HIV continues to disproportionally affect racial and ethnic minorities. An estimated 38.4 million individuals live with HIV globally, of whom the vast majority are in low- and middle-income countries. Of those with HIV in the U.S., 40.3% are Black/African American and 24.7% are Hispanic/Latino patients, despite these groups accounting for only 13.4% and 18.5% of the total U.S. population, respectively. This highlights that current treatment and prevention efforts are not reaching individuals who are disproportionately affected and could benefit the most. As more LA ARTs become available, it will be important to understand how they will be perceived and accepted by these patient populations.
A study conducted by Dandachi and colleagues evaluated the acceptability and preferences for LA ART among patients living with HIV. The majority of patients included were African American (63%) and Hispanic (26%), and the study found that 41% of patients preferred to take oral medications as opposed to injectables. This study suggests that uptake of LA ART will require extensive education regarding safety and efficacy of LA ART. Not only that, but increasing uptake of LA ART, and increasing HIV-related care overall, will require a coordinated and multidisciplinary approach to meet unique local and cultural needs.
Community partnerships have been shown to be effective in achieving goals related to the HIV care continuum. Specifically, faith-based organizations, academic institutions and private and public stakeholders can all aid in increasing dialogue around HIV using a community-based advocacy approach. Racial concordance among patients and providers has been associated with reduced time to receipt of ART and increased medication adherence. This can be achieved by training more minority clinicians to provide HIV care and fostering a culturally sensitive workforce. Engagement in care, especially during the first year after receiving an HIV diagnosis, predicts future engagement. The earlier patients are linked to care, the more likely they are to remain in care, which is of extreme importance for patients on LA ART.
Conclusion
Having options is a must, and LA ARTs offer exciting alternatives to patients with barriers to accessing oral therapies. With variable dosing schedules, LA ARTs will have a place in the care of patients living with HIV or at risk for acquiring HIV. Education, community partnerships, minority representation and engagement and retention in care all need to be in place to ensure acceptance and uptake of LA ARTs among those at higher risk and who could benefit the most.
- References:
- Apretude. Prescribing information. ViiV Healthcare; 2021.
- Boyd MA, Cooper DA. Lancet. 2017; doi:10.1016/S0140-6736(17)31962-1.
- Cabenuva. Prescribing information. GlaxoSmithKline; 2022.
- Chandiwana NC, et al. AIDS. 2021;doi:10.1097/QAD.0000000000003102.
- Dandachi D, et al. AIDS Care. 2021;doi:10.1080/09540121.2020.1764906.
- European Medicines Agency. Dapivirine vaginal ring 25 mg: Opinion on medicine for use outside EU. https://www.ema.europa.eu/en/opinion-medicine-use-outside-EU/human/dapivirine-vaginal-ring-25-mg. Published July 5, 2021. Accessed Sept. 10, 2022.
- European Medicines Agency. Sunlenca. European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/sunlenca. Published June 22, 2022. Accessed Sept. 10, 2022.
- Gilead receives complete response letter from U.S. FDA for investigational lenacapavir due to vial compatibility issues. https://www.gilead.com/news-and-press/press-room/press-releases/2022/3/gilead-receives-complete-response-letter-from-us-fda-for-investigational-lenacapavir-due-to-vial-compatibility-issues. Published March 1, 2022. Accessed Sept. 28, 2022.
- HIV.gov. Drug database: Dapivirine. Accessed Sept. 10, 2022. https://clinicalinfo.hiv.gov/en/drugs/dapivirine/patient.
- HIV.gov. Drug database: Islatravir. https://clinicalinfo.hiv.gov/en/drugs/islatravir/patient. Accessed Sept. 1, 2022.
- HIV.gov. Global statistics. https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics. Published Aug. 3, 2022. Accessed Sept. 10, 2022.
- HIV.gov. Impact on racial and ethnic minorities. https://www.hiv.gov/hiv-basics/overview/data-and-trends/impact-on-racial-and-ethnic-minorities. Published Jan. 26, 2022. Accessed Sept. 5, 2022.
- HIV.gov National HIV/AIDS Strategy (2022-2025). https://www.hiv.gov/federal-response/national-hiv-aids-strategy/national-hiv-aids-strategy-2022-2025. Published Dec. 14, 2021. Accessed Sept. 1, 2022.
- HIV.gov. A timeline of HIV and AIDS. https://www.hiv.gov/hiv-basics/overview/history/hiv-and-aids-timeline. Published April 29, 2022. Accessed Sept. 1, 2022.
- HIV.gov. U.S. statistics. Published June 2, 2021. Accessed Sept. 1, 2022. https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics.
- International Partnership for Microbicides. IPM statement on US Food and Drug Administration review of dapivirine vaginal ring. https://www.ipmglobal.org/content/ipm-statement-us-food-and-drug-administration-review-dapivirine-vaginal-ring. Accessed Sept. 10, 2022.
- Merck announces clinical holds on studies evaluating islatravir for the treatment and prevention of HIV-1 Infection. https://www.merck.com/news/merck-announces-clinical-holds-on-studies-evaluating-islatravir-for-the-treatment-and-prevention-of-hiv-1-infection/. Published Dec. 13, 2021. Accessed Sept. 1, 2022.
- National HIV curriculum. HIV in racial and ethnic minority populations. https://www.hiv.uw.edu/go/key-populations/minority-populations/core-concept/all. Accessed Sept. 5, 2022.
- National Institute of Allergy and Infectious Diseases. Antiretroviral drug discovery and development. Accessed Sept. 1, 2022. https://www.niaid.nih.gov/diseases-conditions/antiretroviral-drug-development.
- Segal-Maurer S, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2115542.
- Tseng A, et al. Br J Clin Pharmacol. 2015;doi:10.1111/bcp.12403. https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bcp.1240.
- For more information:
- Michael J. Parisi Mercado, PharmD, MPH, is a current PGY2 infectious diseases resident at the University of Minnesota Medical Center.
- Jennifer Ross, PharmD, BCIDP, is an infectious diseases clinical pharmacist at M Health Fairview – University of Minnesota Medical Center. Ross can be reached at jross13@fairview.org.
Collapse
Read more about
Click Here to Manage Email Alerts