Long Acting injectable antiretrovirals: more than just a change in formulation

Since the first approved drug, azidothymidine (AZT), became available, the management of people with human immunodeficiency virus (HIV) has been transformed. Numerous innovations have led to significant advances in care and reduced the burden of HIV patients. These include the simplification of oral treatments (with the grouping of antiretroviral drugs in a single tablet), the reduction of treatments (from dual therapy to triple therapy), and the appearance of new galenic forms. For example, since the end of 2021, a dual injectable sustained-release antiretroviral therapy is available on the market in France. This injectable LA treatment illustrates how a change in dosage form can profoundly change the care pathway of HIV-positive patients.

What is injectable LA?

This type of new injectable LA therapy is based on the combination of known antiretrovirals used in current oral treatments in tablet form. By modifying their galenic form, these combinations of molecules can now be administered intramuscularly and act in a prolonged mode of action, allowing continuous delivery of the drug for two months. Various clinical trials have shown that switching to an injectable solution is just as effective as daily triple therapy.
For the moment, the only injectable LA combination available in France is that between cabotegravir (an integrase inhibitor) and rilpivirine (a non-nucleoside reverse transcriptase inhibitor), but other combinations could be developed. For example, lenacapavir, a capsid inhibitor, has shown promising results and is being tested as a subcutaneous injection once every six months.

Benefits of LA for HIV+ patients

Improved adherence to treatment

Even though it has been simplified by the “all-in-one” treatments such as the “Single-Tablet Treatment Regimen” (STR), taking a daily oral tablet can be perceived as restrictive. Indeed, oral antiretroviral treatments require strict compliance, with one or more tablets taken at a fixed time each day. For these patients, a decrease in adherence can lead to rapid health repercussions, especially for certain therapeutic classes such as non-nucleoside reverse transcriptase inhibitors.
LA injectable therapies would therefore provide a new solution for patients to improve adherence (less restrictive injections than taking daily tablets). These advantages are particularly interesting in the case of “travelling” patients, as injectable LA therapy allows them to limit the risk of forgetting to take the drug or to travel without worrying about running out of tablets.

More serenity in patients’ daily lives

Acceptance of the disease can also be an issue for HIV-positive people. They have to learn to live with the virus and can go through a difficult emotional journey while undergoing treatment. Taking a pill every day can be a constant reminder of one’s HIV-positive status and a source of suffering.
Taking pills in the presence of others can also make the patient fear disclosure of their status, stigmatization related to the virus and add anxiety and stress. For these patients, spacing out the time they take their treatment can make their lives more comfortable and serene.

Long Acting issues and future prospects

The issue of eligibility of target patients

However, not all patients are eligible for injectable LA. Indeed, this type of combination is currently only recommended for stabilized patients: the injectable combination is therefore not indicated as a first-line treatment for newly diagnosed HIV-positive patients, who are preferentially oriented towards oral therapies.
Another eligibility parameter concerns patient follow-up. Switching to injectable LA treatment implies a longer follow-up of the patient, and therefore a greater risk of losing sight of the patient. This spacing may be a barrier for the physician, who may fear that some patients will not show up for the next appointment.

Complexity of treatment delivery and administration

In the case of injectable LA dual therapy already marketed in France, injections of the two antiretrovirals are given in hospital for the first three months of treatment, at the rate of one injection per month. At the end of this period, injections are given every two months and follow-up can be done in the city: the patient must then collect his or her treatment from a pharmacy and receive the injection via an approved nurse.
It is conceivable that this type of management, combining city and hospital care, will constitute a new standard for patients undergoing injectable LA treatment. However, this process can be perceived as complex and restrictive, particularly when patients have to travel to the hospital, are unable to administer the treatment themselves and have to use a registered nurse.

The prospects for LA: towards injectable PrEP?

This new dosage form could also be extended to other therapeutic strategies, such as pre-exposure prophylaxis (PrEP). Authorized since 2016 in France, PrEP consists of using prevention as treatment, allowing HIV-negative people at high risk of contracting HIV to take a preventive antiretroviral treatment in order to block the transmission of the virus. The only approved combination therapy includes two nucleoside reverse transcriptase inhibitors: emtricitabine and tenofovir disoproxil. The treatment is available in oral tablet form.
As of December 2021, the Food and Drug Administration (FDA) is the first national agency to approve PrEP injection as an alternative to the tablet. The treatment consists of a cabotegravir-based extended-release injectable suspension.

Forty years after the discovery of HIV, it is clear that the challenges of the care pathway are similar to those of chronic diseases: compliance, quality of life, city-hospital link, etc. The appearance of new formulations makes it possible (without deteriorating clinical indicators) to propose new management methods to improve patients’ quality of life. The latest advances once again raise the issues associated with the organization of the care pathway (synergies with nurses, understanding of the issues of the disease by the patient, follow-up “far from the specialist”, etc.), up to the appearance of new advances in the context of HIV/AIDS research (for example, recent clinical trials with a messenger RNA vaccine, which aim to finally be able to propose a curative solution).

About the author, 

Hervé, Consultant in Alcimed’s Healthcare team in France