"As we look at this question [of] where do long-acting antiretrovirals fit into the armamentarium," Dieffenbach said, "we have to ask ourselves the question: What problems are long-acting or sustained-release formulations solving, and what problems or concerns are the introduction of these type of formulations actually creating?"
For Dieffenbach, the answer appears to boil down to one word: adherence. Adherence encapsulates both the promise and the peril of LA-ART, even as a range of new drug candidates move through the development pipeline.
The promise, of course, is that by dramatically reducing the frequency at which a person is required to take HIV medications, we reduce the person's risk of missed doses that can potentially lead to treatment failure. Poor adherence to therapy not only leads to a risk for declining health in an individual living with HIV; it also facilitates low-level viral replication that can lead to HIV drug resistance. The worldwide prevalence of HIV drug resistance is on the rise, Dieffenbach said -- and a relative lack of widespread drug-resistance testing only exacerbates the problem, even as we witness increasing global distribution of a new generation of integrase inhibitors that sport a high barrier to resistance, alongside excellent potency and minimal toxicity.
Dieffenbach pointed to an abundance of literature on female contraceptive patches, implants, and injections as evidence that less-frequent dosing can improve adherence. What is less certain at this point is what dosing frequency -- via what method of administration -- is going to be optimal for HIV.
And therein lies the peril of LA-ART. While Dieffenbach noted the potential for non-daily medication dosing to improve adherence, he acknowledged that it could potentially worsen the very problem it's trying to solve: "Long-acting, sustained-release formulations can not eliminate adherence challenges; they simply increase the urgency of getting patients back for redosing," he said. "It changes the risk profile."
A truly effective LA-ART regimen, therefore, would have a "reasonably long" elimination phase, Dieffenbach said. Each dose would have to walk a tightrope between toxicity and efficacy, giving people with HIV a reliably long window of time during which they could receive a new dose before the prior dose lost its ability to suppress the virus. And an infrastructure would need to exist around the therapy that helped to ensure a person with HIV got his or her next LA-ART dose before the virus had a chance to rebound.