How Long for Long-Acting Antiretrovirals? A Top HIV Clinical Development of 2017

It has been fascinating to observe the evolution in HIV clinicians' thinking on long-acting injectable antiretrovirals (LA-ART). It was not that long ago that LA-ART was largely dismissed as suiting only a small niche of patients while most were assumed content with their one- or two-pill daily HIV regimens. However, interest in long-acting injectables has trended with data from clinical trials -- particularly, the LATTE-2 study -- showing high levels of viral suppression maintenance and high patient satisfaction on intramuscular (IM) rilpivirine (RPV) and cabotegravir (CAB).

Certainly, a downer for the LA-ART-curious was the suggestion at the 48-week analysis of higher rates of virologic failure with the every-eight-week dosing of IM RPV+CAB compared with the every-four-week IM RPV+CAB and daily oral administration of these medications. However, five of the eight protocol-defined virologic failures at that time-point had low-level viremia (< 200 copies/mL), which might have been incidental.

Reassurance could be found in the 96-week data cut demonstrating viral suppression being maintained in 100 (87%) of 115 patients in the four-week group and 108 (94%) of 115 patients in the eight-week group compared with 47 (84%) of 56 patients receiving oral treatment. Three patients (1%) experienced protocol-defined virological failure (two in the eight-week group and one in the oral treatment group). According to the paper:

[O]f the two patients in the 8-week group, a mixture emerged for one at integrase codon 269 (R269R/G), which did not decrease cabotegravir susceptibility. The second patient harboured virus with treatment-emergent reverse transcriptase mutations K103N, E138G, and K238T, with phenotypic resistance to efavirenz, rilpivirine, and nevirapine, and an integrase mutation Q148R, with phenotypic resistance to raltegravir, elvitegravir, and cabotegravir, while remaining sensitive to dolutegravir.

Injection-site reactions to the two 2 mL (every four-week) or two 3 mL (every eight-week) IM shots were not uncommon but were mostly mild to moderate and did not lead to discontinuation of study product.

Related: Long-Acting HIV Treatment: 5 Myths and Realities

The Bottom Line

There is a growing realization that LA-ART might be less a fringe therapy and more the Apple Macintosh 128K of a new wave of alternative HIV therapies for which no pill-taking is required. Injections six times a year will certainly appeal to many of the pill-fatigued. Other uses will follow, given the creativity of the HIV treating community. That dosing of RPV+CAB can conceivably be done every eight weeks after the oral lead-in period required to demonstrate tolerability breathes added life into the concept.

Importantly, in addition to clinical trials, implementation science-type studies are needed to guide how clinicians and patients envision LA-ART integrating into their lives. Outside-the-box thinking will be needed to develop strategies supporting adherence to shots and off-ramps when they are no longer wanted or indicated. Patients coming to clinic just for their injection and a lollipop? It's no longer a long shot. Get ready.

Top 10 Clinical Developments of 2017
0. Introduction
1. The Cost of Cuts in HIV Spending
2. Awakening to the Opioid Crisis
3. Does It Work to Pay People to Come to Clinic?
4. Bictegravir -- It's Coming
5. A Better Second Chance
6. More Real World Test for Dual Antiretroviral Therapy
7. Heart Attacks in HIV Often Not Due to Atherosclerosis
8. How Long for Long-Acting Antiretrovirals?
9. ART Resistance Spreads
10. We Order Too Many CD4 Cell Counts, but Should We Really Stop?

David Alain Wohl, M.D., is a professor of medicine in the Division of Infectious Diseases at the University of North Carolina (UNC). He is site leader of the UNC AIDS Clinical Trials Unit at Chapel Hill, director of the North Carolina AIDS Education and Training Center (AETC), and co-directs HIV services for the North Carolina state prison system. In 2014, he became co-director of the UNC-Duke Clinical RM Ebola Response Consortium.