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Impact of long-acting therapies on the global HIV epidemic
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AIDS Dec 2021
In conclusion, long-acting antiretroviral agents have great potential to improve the way we both treat and prevent HIV. The two-drug combination of long-acting injectable cabotegravir and rilpivirine is likely to be approved in sub-Saharan Africa by the end of 2022, with a wider number of investigational long-acting antiretroviral formulations in clinical development that could be better adapted for use in LMICs. However, challenges include managing side effects, drug–drug interactions, use in pregnancy, and long-lasting drug concentrations after discontinuation of the formulations that could lead to the development of drug resistance. In addition, affordability, acceptability, and ability to deliver at scale must be anticipated. These products are likely to revolutionize the treatment and prevention of HIV, and this approach to drug delivery holds great promise for other infectious diseases as well.
Abstract
Long-acting antiretroviral drugs have emerged as exciting treatment and preexposure prophylaxis (PrEP) options for people with HIV and at risk of HIV. Long-acting regimens may improve dosing convenience, tolerability and cost compared with current daily-based oral therapy. They can also circumvent stigma associated with oral therapy for both treatment and PrEP, thereby improving adherence and outcomes. Yet, multiple challenges remain, many specific to low-income and middle-income countries (LMICs), where the epidemic is most concentrated and HIV prevention and treatment options are limited. To optimize the use of long-acting formulations, key outstanding questions must be addressed. Uncertain costing, scale-up manufacturing, complex delivery systems and implementation challenges are potential barriers when considering the scalability of long-acting ARVs for global use.
Introduction
Current oral antiretroviral regimens are extremely effective at suppressing HIV with minimal toxicity. Wherever fixed-dose combinations are available, they offer the simplicity of once-daily single-tablet dosing and have enabled vast scale-up of antiretroviral therapy (ART) in low-income and middle-income countries (LMICs) during the last 15 years [1]. However, these gains might be threatened in the absence of sustained viral suppression [2]. Among the most common reasons for lack of adherence are forgetting, being away from home, and a change in daily routine [3]. Depression, pill fatigue, alcohol and substance use, secrecy/stigma, and health service-related barriers (e.g. distance to clinic, stockouts) are also reported [4].
Long-acting (LA) antiretrovirals with infrequent dosing, for example, weekly oral or long-acting parenterally administered agents, may be useful in circumstances where daily oral therapies are not feasible, difficult to administer, and/or when adherence may be inadequate [5,6]. Limitations of such approaches to drug delivery include the management of toxicities, given that exposure to these agents is not easily reversed; and prevention of drug resistance, when these drugs are discontinued, and drug concentrations are slowly reduced below targets over time. New agents with long-acting anti-HIV-1 activity and older antiretrovirals in modified delivery systems are being tested in both treatment of chronic infection and PrEP for people at high risk of infection [7–9].
These approaches appear to be especially attractive for people complaining of pill fatigue, including adolescents, women during pregnancy and the postpartum period, and for those experiencing HIV-associated stigma [3,10]. However, in higher income countries, disparities in access are barriers to uptake of long-acting ART and PrEP for women and black MSM [11–14]. Due to high tuberculosis (TB) and hepatitis B (HBV) burdens, as well as cold chain requirements, currently available long-acting formulations, are not ideal for LMICs. Other barriers to the optimal implementation of long-acting antiretrovirals in LMICs, include the increased frequency of the injection appointments, provider concerns of identifying appropriate candidates for LA ART and operational challenges of the availability of single use needles [15,16]. As these formulations, are shown to be safe, well tolerated, more user-friendly, and economically viable, they are likely to gain broader appeal.
Current pipeline of long-acting antiretroviral therapy for treatment and prevention
Current clinical and experimental long-acting technologies can be classified as oral, parenteral, transdermal or implantable approaches (Fig. 1). Parenteral (intramuscular or subcutaneous) and implantable technologies have already proven clinically successful for other indications, while other approaches may be less invasive but are at earlier stages of development [9,17,18]. For HIV prevention, the pipeline is advancing quickly, with a diversity of long-acting options being developed [19], including the recently reported results of long-acting cabotegravir in preventing HIV among MSM and in cisgender women, and the recent approval of a monthly vaginal ring of dapivirine [20,21]. In the HIV treatment pipeline, a number of initiatives are looking into long-acting products, with multiple candidates at different stages of development (Table 1), and other products in a diverse number of platforms entering this dynamic pipeline that hold promise to radically change the way ART is taken [22–24].
The first long-acting injectable combination (cabotegravir with rilpivirine) shown to be noninferior to daily oral ART, with high patient satisfaction in research to date has recently approved been approved for use in North America and Europe [25–28]. This is an important landmark in ART development but its use may be limited in LMICs as long-acting rilpivirine requires cold chain preservation, two separate vials for injection every 8 weeks, occurrence of drug resistance, and there is interaction with anti-TB therapy [29,30]. New classes of antiretrovirals can now be formulated in long-acting forms, including capsid inhibitors, and nucleoside reverse transcriptase translocation inhibitors, such as islatravir [31,32]. In terms of biotherapeutic research, HIV broadly neutralizing antibodies (bnAbs) are becoming attractive strategies for treatment and prevention.
The first monoclonal antibody (ibalizumab) was approved in March 2018 for treatment-experienced patients with multidrug-resistant HIV [33]. A rapidly growing number of HIV bnAbs are in development now, including combinations of different bnAbs and second-generation products, which might bring about important advantages for LMICs scaled use [5,34].
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