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Division of Infectious Diseases
University of Toronto
Division of Infectious Diseases
St. Michael's Hospital
Darrell Tan, MD, FRCPC, PhD, has disclosed that he has received funds for research support from AbbVie, GlaxoSmithKline, and Gilead Sciences.
Canada was the first country to approve long-acting (LA) injectable cabotegravir (CAB) plus rilpivirine (RPV) in 2020 to treat virologically suppressed patients with HIV, and several other countries have now followed suit. Data presented at the Virtual 2021 Conference on Retroviruses and Opportunistic Infections (CROI 2021) highlighted the continued focus on developing HIV treatments with novel delivery options and mechanisms of action. Here are my takeaways from some of these presentations.
ATLAS-2M: Switch to Injectable LA CAB Plus RPV Every 8 Weeks vs Every 4 Weeks
LA CAB plus RPV is approved for 4-week dosing intervals in Canada and the United States and 8-week dosing intervals in Europe. ATLAS-2M compared 4-week dosing to 8-week dosing of LA CAB plus RPV in patients who were enrolled on the ATLAS study (LA CAB plus RPV arm or continued oral antiretroviral therapy [ART] arm) and patients outside of the ATLAS study who were virologically suppressed on standard-of-care oral ART (N = 1045). As a reminder, the 48-week 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. The Week 96 data presented at CROI 2021 demonstrated continued noninferiority of LA CAB plus RPV administered every 8 weeks compared with every 4 weeks: 91.0% of patients and 90.2% of patients, respectively, had HIV-1 RNA <50 copies/mL.
The adverse event profile was as expected; we continue to see mostly mild injection-site reactions. Of note and particular importance, only 1 person in the every-8-week arm withdrew between Week 48 and Week 96 for injection-related reasons, suggesting that after patients become used to this injectable regimen, they are likely to stick with it.
Although LA CAB plus RPV is approved in Canada, it is not yet publicly reimbursed. Therefore, my colleagues and I have not been prescribing it routinely as part of clinical care yet—our experience remains mostly limited to ongoing trials. We await data from the SOLAR trial, another large phase IIIb trial, which is evaluating the noninferiority of switching to 8-weekly LA CAB plus RPV from bictegravir/emtricitabine/tenofovir alafenamide in patients who are virologically suppressed.
It was also notable that the resistance profiles for the 8 patients in ATLAS-2M who experienced virologic failure with RPV resistance associated mutations on LA CAB plus RPV were distinct from resistance profiles of next-generation NNRTIs. This suggests that if patients experience failure on LA CAB plus RPV but prefer LA options, they could still be a good candidate for the once-weekly oral MK-8507, a new NNRTI with data also presented at the meeting. I think one of the big questions with LA CAB plus RPV continues to be: What is the mechanism of failure? A small number of pre-exposure prophylaxis failures were reported with LA CAB in HPTN 083 at CROI 2021, further begging this question.
So far, we do not know the mechanism of failure in patients with on-time injections, but there is some valuable information from previous studies, such as data from HIV Glasgow that evaluated predictors of failure with LA CAB plus RPV. In that analysis, high body mass index and having the HIV subtype A1/A6 were among the factors that, when seen in combination, predicted a virologic breakthrough on this regimen. Those data may be helpful to clinicians as they consider who would be the best candidates for LA CAB plus RPV.
Population Pharmacokinetic Modeling of LA RPV Every 8 Weeks for Managing Dose Interruptions
Another study that was quite interesting and pertains directly to the ATLAS-2M study findings was an analysis that attempted to simulate the impact of missed doses or delayed doses in the every-8-week schedule—a very important pragmatic question. Even if the clinical trial shows great efficacy, we know that real life is more complicated than a rigorously run clinical trial.
Encouragingly, the simulated pharmacokinetic profiles suggest that delays of up to 1 week in the timing of administration of an every-8-week dose had minimal impact on the RPV simulated plasma concentration after a person was at steady state. This finding is important because it may help the every-8-week dosing schedule line up better with real calendar time. People think in terms of months of the year and tend not to think and count their lives in terms of multiples of 4 weeks, even though that is how we design clinical trials. Knowing that there is a bit of room in the dosing schedule could be quite pertinent when we think about how we might administer this regimen in the clinic.
CAPELLA: Lenacapavir for Treatment of Heavily ART–Experienced Patients
Data were also presented from an ongoing phase II/III trial investigating the novel, first-in-class capsid inhibitor lenacapavir for treatment of HIV in heavily ART–experienced patients with multiclass resistance and virologic failure. Data from an oral lead-in phase demonstrated that lenacapavir resulted in a significant decline in HVI-1 RNA (-1.93 log10) when added to the failing ART regimen. The subsequent portion of the trial investigated the administration of lenacapavir subcutaneously every 6 months in combination with an optimized background regimen, and preliminary analyses demonstrated that 19 of 26 patients (73%) had an HIV-1 RNA <50 copies/mL at Week 26.
Although we fortunately no longer have many patients who experience treatment failure with multiclass resistance, it is important that we not forget about those individuals. Many heavily ART–experienced patients were pioneers in the HIV community and in HIV activism, and it is great to see new options in the pipeline for them.
Resistance Profile of the Novel NNTRI MK-8507
Finally, we saw data on the resistance profile of the novel once-weekly NNRTI MK-8507. Previous phase I data support once-weekly dosing of MK-8507. Data presented at CROI 2021 demonstrate that MK-8507 has activity against some of the classic NNRTI mutations (K103N, Y181C, and G190A) that we know compromised earlier drugs in this class. Data also demonstrated activity across HIV subtypes, which is encouraging. In Canada, we see mostly subtype B HIV, but we also treat people from all over the world presenting with various subtypes of HIV.
The resistance pathway and profile of MK-8507 was similar to doravirine and distinct from rilpivirine. Obviously, we always treat for success, but the principle of planning for what may be available to that patient in the future is one that we have applied since the beginning of antiretroviral therapy. Knowing that there is cross-resistance to an existing next-generation NNRTI, doravirine, has some implications for how we might choose to recommend these NNRTI class drugs today to preserve options for our patients in the future. MK-8507 100 mg is advancing into phase II study in combination with the investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir for once-weekly dosing based on data showing that islatravir is active against variants selected for by MK-8507 in vitro.
Many patients are happy with their oral regimens, particularly those who receive 1 pill once daily, and are not interested in injections (self-administered or administered in the clinic). However, if taking pills every day poses a challenge, a once-weekly oral option that could be taken on the weekend when life may be less hectic could be a great option.
How do you anticipate incorporating LA ART into your clinical practice? Join the discussion by posting a comment. We are particularly interested in your thoughts and experiences if you provide HIV care in Canada and have already begun to incorporate this new paradigm into your clinical practice.