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Professor of HIV
Queen Mary, University of London
Lead for HIV Research
Barts Health NHS Trust
The Royal London Hospital
London, United Kingdom
Chloe Orkin, MBChB, FRCP, MD, has disclosed that she has served on an advisory board/panel or speakers bureau for and has received funds for research support from Gilead Sciences, GlaxoSmithKline, Janssen, MSD, and ViiV Healthcare.
Long-Acting ART: Another New Paradigm for HIV Therapy
As we know, there is great interest from both patients and their doctors in long-acting HIV treatment. In March 2020, long-acting (LA) injectable cabotegravir (CAB) plus rilpivirine (RPV) was licensed in Canada, so for Canadian patients with HIV, LA ART access is now a reality. At CROI 2020, one of the most eagerly anticipated presentations of the conference was on the phase III ATLAS 2M study comparing every-4-week vs every-8-week dosing of intramuscular injectable LA CAB plus RPV for maintaining virologic suppression. Dr. Edgar Overton presented this study to an eerily empty and silent auditorium, but the findings have since generated much excitement and also much discussion.
ATLAS-2M: Switch to LA Injectable CAB Plus RPV Every 2 Months Is Noninferior to Switch to Monthly Injections in Virologically Suppressed Patients at Week 48
Before considering the ATLAS-2M trial, it is important to recall the preceding ATLAS trial. This open-label phase III noninferiority trial randomized virologically suppressed patients with no previous treatment failure to either monthly intramuscular injections of LA CAB plus RPV (n = 308) or to continue baseline oral ART (n = 308). All patients in the injectable ART arm received a 4-week lead-in of oral CAB plus RPV. The results demonstrated that injectable LA CAB plus RPV was noninferior to continued baseline oral ART for the primary endpoint of HIV-1 RNA ≥ 50 copies/mL at Week 48 by FDA snapshot with < 2% of patients experiencing virologic nonresponse in either treatment arm. An analysis of patient-reported outcomes found that treatment acceptance was significantly higher with LA vs oral ART (P < .001), and 97% of patients in the LA treatment arm indicated that they preferred LA treatment to daily oral therapy.
Following the positive results from ATLAS, investigators for the ATLAS-2M trial randomized 1045 participants with virologic suppression on their current regimen to either every-4-week or every-8-week dosing of injectable LA CAB plus RPV. The enrolled participants were derived from 3 different cohorts: ATLAS study participants who had already been receiving injectable LA CAB plus RPV every 4 weeks through at least Week 52 (constituting < 40% of ATLAS-2M study population), ATLAS study participants who had received continued oral ART in that trial, and patients receiving standard-of-care oral ART outside of the ATLAS trial. The ATLAS-2M results demonstrated that every-8-week LA CAB plus RPV dosing met the primary endpoint of noninferiority to every-4-week LA CAB plus RPV dosing for the FDA snapshot outcome of virologic failure (HIV-1 RNA ≥ 50 copies/mL) at Week 48. Most (98%) ISRs were grade 1/2 in severity and resolved in a median of 3 days. The every-8-week dose interval had a comparable safety profile to every 4 week dosing. Unsurprisingly, participants preferred the every-8-week dosing regimen—94% of those who had previously received every-4-week dosing preferred every-8-week dosing.
The scientific discussion for ATLAS-2M has centered on the confirmed virologic failure (CVF) outcomes. Although the rate was very low overall, it was numerically different between arms, at 1.5% for every-8-week vs 0.4% for every-4-week dosing. Resistance outcomes were similar to those observed at Week 48 in the ATLAS and FLAIR studies in that patients who experienced virologic failure almost invariably did so with INSTI and NNRTI mutations. Among the 10 patients with CVF across treatment arms in ATLAS-2M, 9 achieved viral suppression with a switch to fully active oral ART and all maintained phenotypic sensitivity to dolutegravir.
FLAIR: Switch to LA Injectable CAB Plus RPV Following Oral Induction in ART-Naive Patients Noninferior to Continued Oral DTG/ABC/3TC at Week 96
The other notable LA CAB plus RPV study presented at CROI 2020 was the FLAIR Week 96 data. The headline result is that LA CAB plus RPV (n = 283) remained noninferior to oral ART (n = 283) at Week 96, with no further cases of virologic failure and similar safety outcomes compared with the Week 48 results. The strong preference for LA CAB plus RPV injectable treatment over oral dolutegravir/abacavir/lamivudine was also maintained at Week 96.
Other Up-and-Coming Long-Acting Agents
Another up-and-coming LA drug to watch out for is GS-6207, a first-in-class capsid protein inhibitor. We learned that it is versatile! Not only is it very effective in driving down viral load when injected subcutaneously, but it can also be used orally, and data were presented at CROI 2020 on both subcutaneous and oral administration. Based on the latest findings, it looks like it may be suitable for weekly dosing with an appropriate partner. The good news is that it can be dosed without regard to food.
In summary, my take-home message is that LA ART is here—and here to stay. We have lots to look forward to with this new strategy, including the exciting investigational drug islatravir (formerly MK-8591), a nucleoside reverse transcriptase translocation inhibitor with a novel mechanism of action being developed for both HIV treatment and prevention and in several different formulations, including as a subdermal implant and for weekly oral dosing. Watch this space!
How do you anticipate incorporating LA injectable HIV therapy into your clinical practice? Join the discussion by posting a comment. If you provide HIV care in Canada and have already begun to incorporate this new paradigm into your clinical practice, we are particularly interested in your thoughts and experiences.