Long-acting antiretrovirals: Are they the future of HIV treatment or will the future pass them by?
As research progresses on long-acting antiretroviral therapy (LA-ART) for HIV — also sometimes referred to as extended-release (ER) antiretroviral therapy — experts disagree about the impact it will have on clinical care. There is both optimism and pessimism regarding LA-ART, and sometimes they come from the same person, as was the case at CROI 2017 in Seattle, Washington.
At this major gathering of HIV researchers and clinical experts, Charles W. Flexner, M.D., a professor of medicine at Johns Hopkins University, gave a presentation in which he refuted what he regarded as five common LA-ART myths — while retaining his own healthy dose of scepticism about LA-ART’s ultimate value for people living with HIV.
People with Chronic Illnesses Prefer Taking Pills
Among perceived downsides to LA-ART is the need for current drug candidates to be administered via injection, which could lower demand. However, “[p]arenteral therapy is widely accepted for a number of very serious chronic diseases” including Type 1 diabetes and rheumatoid arthritis, Flexner countered, suggesting there is little reason to expect the case would be different with HIV.
Flexner cited results from a survey he led in 2013 that found widespread approval of injectable therapy among people living with HIV. In his study, the majority of respondents said they “probably” or “definitely” would want to receive parenteral treatment. That preference held regardless of the proposed dosing schedule, although acceptance was particularly high (84%) when the theoretical dosing of an injectable regimen was only once per month.
Other surveys show very similar results, Flexner said. “The enthusiasm for injectable therapy is very high in our patients, especially in high-income and middle-income countries. In fact, my experience is that our patients are more enthusiastic about this form of therapy than health care providers are.”
The advantages of LA-ART are obvious, Flexner said: infrequent dosing; the potential for lower doses than oral medications using nanoformulations; and the prevention of poor adherence on oral antiretrovirals, thanks in part to the likelihood of directly observed therapy, tissue targeting of the injectable therapy and the countering of fill fatigue with periodic injections.
Flexner also offered that less-frequent treatment dosing could protect HIV-positive people’s health privacy and reduce stigma by eliminating their need to fill prescriptions and carry or store pills.
There are not enough good drug candidates for LA/ER
Much of the attention placed on LA-ART for HIV has thus far centred on the experimental integrase inhibitor cabotegravir and a new formulation of the NNRTI rilpivirine (available commercially as Edurant). Research to date suggests that, while the combination of these two drugs has promise as a maintenance regimen, it may not be potent enough to prescribe to people who have not yet achieved virological control.
However, “There are a lot of antiretrovirals being developed for long-acting administration,” Flexner said. “In fact, I would say this is the hottest area in antiretroviral development right now.”
Although cabotegravir and LA-rilpivirine are the only two candidates in Phase 3 study, Flexner listed several undergoing Phase 2 trials, including ibalizumab, PRO 140, albuvirtide and a quartet of broadly neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117 and 10-1074). Yet more are in Phase 1 trials or at a pre-clinical stage, including the long-studied NRTI EFdA and the capsid inhibitor GS-CA1.
In addition to these candidates, Flexner discussed the possibility of reformulating existing, approved antiretrovirals, such as lopinavir, ritonavir (Norvir) and tenofovir (Viread), to greatly increase their half life (a process Flexner jokingly referred to as “extendification”) and enhance their concentration in lymphatic tissue. He also noted the potential for novel, long-acting prodrugs of existing antiretrovirals such as dolutegravir (Tivicay, DTG) or lamivudine (3TC, Epivir).
LA/ER means intramuscular injection
Although the long-acting regimen of cabotegravir and rilpivirine has been tested as an intramuscular injection, “We’re beginning to learn that there’s lots of ways to create a long-acting formulation,” Flexner said. The most obvious alternate delivery method is implants.
“If we can prevent pregnancy for three years with a single implant, I’m beginning to think we can suppress HIV with a single implant for this duration of time,” Flexner said. As examples, he pointed to recently published research on a silicone-based implant that releases tenofovir alafenamide (Vemlidy) over the course of months, as well as on an implantable form of EFdA that could achieve desired drug concentrations for a year or more.
In favour of the implantable approach, Flexner said, is that an implant allows for a consistent, predictable release of a drug (potentially for years) that is not dependent on the choice of injection sites, and it can still be removed in cases of drug toxicity or a necessary change in treatment.
Flexner acknowledged potential drawbacks as well, including challenges to insertion (which would require a specialized device) and removal (which would require minor surgery), drug regulation (an implant would have to be approved as both a drug and a medical device) and future generic formulation approval. “But I don’t think those problems are insurmountable,” Flexner said.
Dosing for LA/ER for infants and children will be nearly impossible
When it comes to paediatric dosing of LA-ART, Flexner acknowledges a steep hill to climb. “I recognize that this is one of the most difficult things we face in developing these formulations,” Flexner said, “but I don’t think it’s impossible. In particular, I think cutting-edge technology can be used to make this happen.”
For example, Flexner cited a process called physiologically based pharmacokinetic (PBPK) modelling, which follows a “bottom-up” approach: Rather than measuring drug plasma concentrations and working backward to construct a model of how the human body is handling a drug, PBPK modelling separates the body into component parts and known pharmokinetic factors, and it then adds in relationships and other variables that are intended to more closely mimic human physiology.
The value in this approach, Flexner said, is that it would move the clinical community away from the potential pitfalls of empiric drug dosing. The approach was recently tested as a predictor of LA-rilpivirine dosing in children, both at CROI 2017 and CROI 2016.
LA/ER will always be too expensive for low- and middle-income countries
“I hear this a lot: How are you ever gonna deliver this in places where the epidemic needs it the most?” Flexner said.
The answer, Flexner offered, may lie within the very science that is driving much of LA-ART development: nanotechnology. “Better technology can actually lead to lower costs,” Flexner said.
By way of example, Flexner pointed to research presented at CROI 2017 exploring the use of nanotechnology to reduce orally administered doses of efavirenz (Sustiva, Stocrin) and lopinavir. The pilot study found that the tested approach reduced the drug dose by 50% without falling below therapeutic levels — and saved a projected $243 million per year in active pharmaceutical ingredient use.
Despite his optimistic rebuttal of five key criticisms of LA-ART, Flexner admitted that many obstacles remain to its widespread use in HIV. “I don’t want to leave you with the impression that all the problems are solved,” he said. On the contrary, a number of vital questions remain, including:
- How to make injections more tolerable by decreasing their volume.
- How to eliminate the need for an induction-maintenance approach involving oral medications.
- How to prevent and manage adverse events.
- How to address pharmacokinetic issues, such as the drugs’ long activity tail and variability.
- How to devise rational dosing strategies for special populations, including children and pregnant women.
Flexner said that these questions, among others, are being examined by the Long-Acting/Extended Release Antiretroviral Resource Program (LEAP), a U.S. National Institutes of Health-funded effort to support and centralize investigations into LA/ER antiretrovirals. Flexner is LEAP’s principal investigator.
That said, Flexner concluded his talk with a prediction that HIV will not be the field in which long-acting drugs most dramatically change the treatment paradigm. “I think these formulations are not gonna have their biggest impact on HIV,” he said. “I think, in the long term, they’re gonna have their biggest impact on other infectious diseases. Imagine what a long-acting, extended-release formulation can do for the control of tuberculosis, hepatitis C virus, hepatitis B, malaria and epidemics like Ebola.”
“This is no longer science fiction: This is today.”