By Susan Swindells* and Mark Harrington
This issue of TAGline explores the exciting opportunities and challenges that come with the development of long-acting formulations for the prevention and treatment of infectious diseases. For many years to date, patients and providers have welcomed long-acting medications for other conditions such as schizophrenia, osteoporosis, and contraception. These delivery systems improve adherence, which leads to improved clinical outcomes. 1,2,3
The terms “long-acting” or “extended release” describe applications for multiple routes of administration, including oral, topical, and parenteral (which refers to implants and intravenous, intramuscular, subcutaneous injections). Generally, to be considered a long-acting technology (LAT), a drug should have dosing once weekly or less often orally, once monthly or less often by injection, or every six months by implant.4 Encouraging data from large clinical trials for HIV treatment recently led to the approval of long-acting cabotegravir and rilpivirine by the U.S. Food and Drug Administration. 5,6 Ongoing community engagement and equitable access, however, are critical for this new strategy to fulfill its promise.
A serious concern regarding equity and access for novel long-acting antiretroviral agents will be the price. According to the U.S. Department of Health and Human Services, the monthly average wholesale price of cabotegravir plus rilpivirine for HIV treatment (sold as Cabenuva by ViiV Healthcare) ranges from $4,752 to $7,218 depending on dose — or as much as $86,616 per year.7 Comparator oral regimens’ annual average whole sale price costs range from $23,532 for all-generic efavirenz/TDF/FTC to $48,876 for bictegravir/cobicistat/TAF/FTC.8 It’s not yet clear whether ViiV or other co-developers of long-acting injectable therapies intend to market these formulations globally or, if so, what prices will be required to make them maximally accessible (including the cost of supply chain, delivery, storage, administration, and pharmacovigilance).
Alongside ongoing efforts to develop other long-acting drugs for HIV prevention and treatment,9 other infectious diseases are now receiving attention. Unitaid10 (is a global health initiative for innovations to prevent, diagnose, and treat major diseases in low- and middle-income countries, with an emphasis on tuberculosis (TB), malaria, and HIV. To that end, Unitaid is funding a consortium based at the University of Liverpool and including TAG called Longevity.11 This project is developing a pipeline of long-acting medicines for malaria, TB, and hepatitis C virus (HCV) and infrastructure for sustainable translational capacity.
Each disease and each potential long-acting intervention poses a series of questions specific to the disease and proposed intervention. There are a number of shared, cross-cutting issues, among them community acceptability and involvement, how best to design the studies and in which groups of people, regulatory issues, manufacturing, cost, delivery, accessibility, and affordability. The introduction of safe and effective long-acting interventions could help speed the end of the HIV, HCV, malaria, and TB pandemics.
Affected communities are central to success in the development, approval, and safe distribution of LATs for HIV, HCV, malaria, and TB. Their involvement, participation, and endorsement of LAT research is key. To that end, TAG, in partnership with AfroCAB and the LONGEVITY team including the University of Nebraska Medical Center (UNMC), is supporting the development of a Long-Acting Technologies Community Advisory Board (LAT-CAB). Recruited in 2021, the new LAT-CAB is now engaging this novel research area of great potential, as described in this edition by Bryn Gay and Joelle Dountio Ofimboudem of TAG with Kenly Sikwese of the AfroCAB.
Annette Gaudino and Suraj Madoori go on to explore how the health care delivery and policy landscape must be substantially altered in order to create enabling environments for the successful, effective use of LATs. Zooming in on the U.S. HIV epidemic, Abraham Johnson explores the issues of health equity raised by the advent of research into and regulatory approval of long-acting agents for preventing and treating HIV. Gaudino and Madoori emphasize that combatting racism and strengthening affected community involvement are essential every stage of the struggle to end HIV. Richard Jefferys reviews recent data indicating that when used for HIV prevention, current LA-PrEP (using injectable cabotegravir) can in rare cases miss early HIV infection that is undetectable using standard laboratory HIV antibody (serology) assays.
David Branigan describes the paradoxical situation of using injectable agents in the TB space, after years of successfully struggling to end the use of toxic, antiquated, and unnecessary daily injectable treatments for drug-resistant TB. All stakeholders — including policymakers, national health and regulatory authorities, TB clinics, and communities where TB is prevalent — must become fully conversant with the potential for new, safe, and effective long-acting injectables for TB chemoprophylaxis or curative treatment.
Erica Lessem’s interview with David Thomas of Johns Hopkins University explores the exciting possibility of what could be a one-shot, single injectable cure for HCV infection. Joelle Dountio Ofimboudem outlines the potential of LA-malaria chemoprophylaxis or mass treatment to enable a significant step forward in global efforts to eliminate malaria, particularly in sub-Saharan Africa.
As the world continues to struggle with mainly uncontrolled and continuously evolving SARS-CoV-2, the importance of prompt drug, diagnostic, and vaccine development, sufficient funding, and deep community involvement has become clearer than ever. These elements were crucial in developing safe and effective vaccines to prevent infection, severe disease and death from SARS-CoV-2/COVID-19; and they will be just as essential in the upcoming work to roll out safe and effective LATs for HIV, HCV, malaria, and TB.
* Susan Swindells MBBS is Professor of Internal Medicine at the University of Nebraska Medical Center.
Endnotes
1 Kaplan G, Casoy J, Zummo J. Impact of long-acting injectable antipsychotics on medication adherence and clinical, functional, and economic outcomes of schizophrenia. Patient Prefer Adherence. 2013 Nove 13;7:1171–80. doi: 10.2147/PPA.S53795.
2 Fobelo Lozano MJ, Sanchez-Fidalgo S. Adherence and preference of intravenous zoledronic acid for osteoporosis versus other bisphosphonates. Eur J Hosp Pharm. 2019 Jan;26(1):4–9. doi: 10.1136/ejhpharm-2017-001258.
3 Winner B, Peipert JF, Zhao Q, et al. Effectiveness of long-acting reversible contraception. N Engl J Med. 2012 May 24;366(21):1998–2007. doi: 10.1056/NEJMoa1110855.
4 Owen A, Rannard S. Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: insights for applications in HIV therapy. Adv Drug Deliv Rev. 2016 Aug 1;103:144–156. doi: 10.1016/j.addr.2016.02.003.
5 Orkin C, Arasteh K, Gorgolas Hernandez-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020 Mar 19;382(12):1124–35. doi: 10.1056/NEJMoa1909512.
6 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 Mar 19;382(12):1112-23. doi: 10.1056/NEJMoa1904398.
7 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/ AdultandAdolescentGL.pdf. Last updated 16 August 2021; accessed 20 August 21; Table 22b. Monthly Average Prices of Commonly Used Antiretroviral Drugs (Last updated June 3, 2021; last reviewed June 3, 2021), page L-33. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-new-guidelines.
8 Ibid., pp. L32-33.
9 Scarsi KK, Swindells S. The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?. J Int Assoc Provid AIDS Care. 2021;20:23259582211009011. doi: 10.1177/23259582211009011.
10 Unitaid. https://unitaid.org/#en. Accessed 8 September 2021.
11 University of Liverpool Centre of Excellence for Long-acting Therapeutics – Longevity Project. https://www.liverpool.ac.uk/centre-of-excellence-for-long-acting-therapeutics/longevity/). Accessed 8 September 2021.