What Clinicians Need to Know About the Development of Long-Acting Formulations

Abstract

We encourage readers of this Supplement to find articles that are relevant to the current and future practice of infectious diseases medicine. Access to long-acting products and formulations in low- and middle-income countries remains a key determinant of the impact of these advances on global health.

When thinking about the potential impact of long-acting formulations on the treatment and prevention of infectious diseases, it is important to first define what is meant by “long-acting.” In most clinical circumstances, the concept of long-acting is a relative one, based on the frequency of dosing of other treatments available for the same disease. For example, although intramuscular procaine penicillin G has an apparent half-life in plasma of 3.4 hours, and might be considered long-acting when compared to the 30 minute half-life of unaltered penicillin G, neither compares to the 672 hour apparent half-life of intramuscular benzathine penicillin G [1]. For human immunodeficiency virus (HIV) treatments, long-acting benchmarks of ≥ 1 week, ≥1 month, and ≥ 6 months were proposed for oral, injectable, and implantable strategies, respectively, largely based on clinical benefit and patient preference [2].

For contemporary audiences, the term long-acting (LA) generally implies a formulation that incorporates a slow or extended release depot or device. Strategies for creating LA products could involve the unmodified original drug of interest, as is the case in the penicillin example above, or the identification of a novel small molecule or prodrug specifically designed for compatibility with LA delivery. This is how we will be using the term “long-acting” in this overview and in the accompanying Supplement of Clinical Infectious Diseases.

This Supplement was inspired by the ongoing efforts of the Long-Acting Extended-Release Antiretroviral Research Resource Program (LEAP), which is supported by grants from the National Institutes of Health (NIH). LEAP is a first-of-its-kind research support program that provides access to a broad set of scientific resources including a dedicated website, academic and industrial investigators, regulatory experts, and representatives of communities affected by HIV, tuberculosis, and viral hepatitis. This Supplement draws on the expertise of LEAP collaborators to give the clinician a comprehensive look at the current state of LA anti-infectives, including preclinical and clinical scientific topics, and regulatory, global health, and community perspectives.

In this Supplement, the reader can expect thoughtful, expert consideration of the general principles of producing and approving long-acting treatments, as well as detailed discussions of individual examples including the treatment and prevention of HIV, tuberculosis, and chronic hepatitis B and hepatitis C virus infections. Additional articles describe barriers to the uptake of novel LA formulations in high- and low-income countries, and their use in infants, children, and women who become pregnant. There are detailed discussions of recently approved products like LA-cabotegravir and LA-rilpivirine, as well as products in advanced clinical development such as lenacapavir and anti-HIV monoclonal antibodies. Readers can find more resources relevant to developing long-acting treatments at the LEAP website, www.longactinghiv.org.

Infectious diseases care providers have a long history of using long-acting antimicrobial therapies. In addition to the penicillin example, pegylation of interferon-alpha extends its half-life and allows weekly dosing for chronic hepatitis B and hepatitis C virus infections [3]. However, the most important example may be the recent success of treating HIV infection with intramuscular cabotegravir and rilpivirine given every 4 or 8 weeks [4]. Indeed, intramuscular cabotegravir every 8 weeks vastly outperformed daily oral tenofovir and emtricitabine in preventing HIV acquisition and was recently approved for that application as well [5]. This underscores the potential value of long-acting antimicrobial treatments for other diseases, and raises the question of what other medications should be adapted for LA applications.

The primary advantages of long-acting medications are improved convenience and adherence, which may produce better clinical results. Compared to daily use of tenofovir to prevent HIV infection, women prefer monthly cabotegravir injections, resulting in higher adherence and fewer HIV infections [5]. Additionally, compared with daily oral treatment, many people living with HIV, especially young adults, welcome the option of a long-acting regimen [6]. But potential users had concerns as well, especially if their oral regimen was tolerable and effective. Perceived disadvantages could include fear of injections (particularly with more frequently than four-week intervals), concerns about possible side effects, additional costs, and lower efficacy. Parents of children with HIV expressed varying levels of enthusiasm depending on their child's age and acceptability of injections.

The advantages of long-acting medicines are especially salient in long-term use of medications for asymptomatic conditions, and in populations where the daily use of oral formulations might increase stigma or be challenging because of socioeconomic factors. By improving adherence, long-acting treatments might also reduce selection of antimicrobial resistance, because intermittent and incomplete exposure to drugs is the most important driving factor for resistance.

Infectious diseases providers will also recognize that medications used to treat an infection might be used to prevent the same infection, as is the case with meningococcal meningitis, bacterial endocarditis, and malaria, as well as HIV. In the case of LA formulations, antimicrobial chemoprophylaxis could replace a vaccine in controlling the spread of disease in a population. The example of tenofovir and cabotegravir just mentioned is again instructive. Although sadly there is no vaccine approved to prevent HIV, long-acting cabotegravir is a highly effective and safe alternative, recognizing the need for multiple injections to maintain protection. If used broadly in at-risk populations, cabotegravir's epidemiologic effect would be similar to that of an HIV vaccine. However, long-acting treatments as prevention must be affordable to sustain their effectiveness in the population.

There are additional examples of medications used to prevent infections for which we do not have highly effective vaccines: oseltamivir to prevent influenza, artemether-lumefantrine or atovaquone to prevent malaria, or isoniazid and rifapentine to prevent tuberculosis. Long-acting formulations of these or similar medications could have immediate public health impact like that of a vaccine. In the case of malaria, where humans are an obligate life-cycle intermediary, just a few courses of LA drug administration to most individuals in an endemic region could interrupt local transmission [7]. The case can be made to use LA antimicrobials to prevent other conditions demanding long-term treatment such as chronic viral hepatitis, endocarditis, or other sexually transmitted infections.

Long-acting formulations are used successfully in other common non-infectious conditions, paving the way for increasing use for infectious diseases in addition to HIV. Long-acting reversible contraceptives (LARC), which include intra-uterine devices and subdermal hormonal implants, are gaining popularity due to both their convenience and high efficacy in preventing unintended pregnancy. In the Contraceptive CHOICE cohort study, 9256 women aged 14–45 years were offered their choice of contraceptive method without charge [8]. Seventy-five percent of the cohort chose LARC, and continuation rates for participants who chose LARC were higher than for those who chose short-acting methods. Also in the field of women's health, adherence over time to oral bisphosphonates for the treatment or prevention of osteoporosis is notoriously low. Several studies have shown that patients overwhelmingly prefer a once-yearly injectable product (intravenous zoledronic acid) [9]. Finally, in the realm of psychiatry, the discontinuation rate for oral antipsychotics is 26%–44%, and this is one of the most common causes of relapse in schizophrenia. Long-acting injectable antipsychotic treatment is associated with lower rates of relapse, treatment discontinuation, and hospitalization when compared to oral therapy but also increased cost-effectiveness, functionality, quality of life, and patient satisfaction [10].

Various chemical and/or physical processes are needed to create sustained-release depots and/or prodrugs optimized for delivery into muscle or subcutaneous tissue, typically by injection or implantation, or in some cases by ingestion. As a consequence, creation of an LA product is substantially more complex than that of an oral one. This can lead to increased costs and time required for approval, and this, in turn, can make investment in an LA alternative seem risky to those in the pharmaceutical industry. This may explain, in part, why there are not more LA anti-infectives available today.

Product sterilization is critical for any parenteral formulation, and this is especially true for LA injections or implanted devices. For nanoparticle formulations, sterile filtering or radiation could alter the make-up of the final product and change its pharmacologic properties, sometimes in a radical way. This further complicates the manufacturing process. Compared to oral formulations like tablets or capsules, the same manufacturing line cannot be readily altered to switch from one active pharmaceutical ingredient to another. In the case of generic drug manufacturing, the company may be limited in its ability to invest in the requisite infrastructure, increasing reluctance to switch from oral to LA parenteral products. This represents a potential barrier to availability of generic LA products for use in low- and middle-income countries. This is especially unfortunate given the importance of generic formulations in those regions, as exemplified by the way that generic antiretrovirals have revolutionized the global management of the HIV epidemic.

There are notable downsides to long-acting treatments, the most serious being adverse drug reactions. Discontinuation of the drug can be challenging (eg, removal of an implant) or impossible (after intramuscular injection of a long-acting treatment). Teratogenicity is also an important consideration because pregnancy might occur or be recognized only after the LA treatment is administered. Tolerability is not necessarily better with long-acting treatments, especially for systemic drug effects. Some people have aversions to injections, and the physical evidence of an implant can be unpleasant and possibly enhance stigmatization. Long-acting approaches are more challenging to administer in the clinic than prescribing or dispensing of oral formulations.

An important drawback for LA formulations of anti-infective drugs is the possibility of developing drug resistance at the end of a long dosing interval, or after the product is discontinued (also referred to as the pharmacokinetic “tail” phase). Concentrations of some nanoformulated drugs like cabotegravir are detectable in plasma for many months after a single injection and could be low enough to promote the emergence of resistant variants of HIV [2]. Indeed, new cabotegravir resistance has been reported, albeit rarely, in participants in HIV treatment and prevention trials [4, 5]. Strategies to avoid resistance must include coverage with oral anti-infectives in the case of missed or late doses, use of more than 1 active agent, or possibly use of drugs where resistant organisms would have significantly reduced fitness [7].

Despite the fact that long-acting injections are more complicated to administer and manage than writing prescriptions, there is a high level of interest and enthusiasm for this approach from the affected community in the case of HIV. HIV providers, particularly in low- and middle-income countries, have expressed reservations about the many practical issues, including scheduling, staffing and training health workers, ordering and inventory management, and the necessary monitoring to make sure patients come in for their injections on time. Rollout in the United States is also problematic because of more complex billing and reimbursement from insurance companies and pharmacy plans. Finally, it remains to be seen whether or not use of long-acting antiretroviral therapy will improve patient adherence to lifelong therapy [11]. On the other hand, participants in the phase 3 trials with cabotegravir and rilpivirine for HIV treatment expressed very high levels of treatment satisfaction and preference for injectable treatment as compared to continuing oral therapy. Multiple surveys across diverse community groups, including some in low- and middle-income countries, also reflect high levels of interest. Reasons cited usually include convenience, freedom from having to remember to take daily oral therapy, and decreased fear of stigma [11].

Demand for long-acting cabotegravir by African community groups is gaining momentum [12]. They argue that, although data from Uganda and 6 other sub-Saharan African countries were crucial for cabotegravir approval as pre-exposure prophylaxis in the United States, and the World Health Organization was expected to issue safety guidelines for its use in July 2022, people from the region may have to wait years before a generic version is available at an affordable price. Access to long-acting products and formulations in low- and middle-income countries remains a key determinant of the impact of these advances on global health.

We encourage readers of this Supplement to find articles that are relevant to the current and future practice of infectious diseases medicine. Although we believe this is the first time this journal has devoted so much space to this topic, we also believe this is just the beginning of what is likely to be a new era in the control of these diseases.

Notes

Acknowledgments. The authors would like to thank Jane McKenzie-White for expert assistance in organizing and managing the publication of this Supplement.

Financial support. The preparation of this manuscript was supported in part by NIH National Institute of Allergy and Infectious Diseases (NIAID) grant number R24 AI118397, Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP), www.longactinghiv.org, awarded to Johns Hopkins University.

Supplement sponsorship. This article appears as part of the supplement “Long-Acting and Extended-Release Formulations for the Treatment and Prevention of Infectious Diseases,” sponsored by the Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP).