Virologic Failure With Long-Acting ART in Real-World Settings: Perspectives From Australia

Key Takeaways:

• Several IDWeek and HIV Glasgow 2022 presentations evaluating virologic outcomes among people switched to long-acting injectable cabotegravir (CAB) plus rilpivirine (RPV) in real-world settings demonstrated low rates of virologic failure that were comparable to those observed in randomized clinical trials (~1%).

The most important function of any antiretroviral therapy (ART) is to fully suppress HIV replication. With currently available second-generation integrase inhibitor (INSTI)-based therapies in Australia, virological failure is no longer tolerated. Through this lens, the recently approved long-acting injectable combination of cabotegravir (CAB) plus riplivirine (RPV) is being scrutinized to determine whether the results seen in the clinical trials (FLAIR, ATLAS, and ATLAS-2M) are being replicated in real-world settings.

In the clinical trials, confirmed virological failure (CVF) was detected in 1% to 2% of participants who switched from a suppressive ART to long-acting CAB plus RPV. To me, a primary concern for HIV healthcare professionals going forward is that if there is a 2% failure rate with this regimen given every 2 months in the idealized world of clinical trial sites, will it be worse when the rest of us begin administering this therapy in our clinics? 

Reassuringly, this fear has not been confirmed based on data presented to date. In this commentary, I will review several presentations from IDWeek 2022 and HIV Glasgow 2022 that examined virologic failure rates with long-acting CAB plus RPV in more real-world settings. 

OPERA Cohort
At IDWeek 2022, Sension and colleagues presented data from the OPERA cohort of medical sites within the United States, evaluating outcomes for 383 people with HIV who had switched from daily oral ART to long-acting CAB plus RPV over the course of 1 year beginning in January 2021 with follow-up through March 2022. The results demonstrated that ≤5 individuals experienced CVF in each of the analysis groups separated by HIV-1 RNA levels at the time of switch. The investigators noted that Health Insurance Portability and Accountability (HIPAA) rules in the United States prevented them from providing the exact number of people with CVF in each group because it represented ≤5 observations. 

CARISEL Study
Also at IDWeek 2022, De Wit and colleagues presented results from the European experience with use of long-acting CAB plus RPV in the CARISEL study. CARISEL is an open-label, implementation-effectiveness phase IIIb study of switching patients to long-acting CAB plus RPV every 2 months at 18 clinic sites across Belgium, France, Germany, the Netherlands, and Spain.

In this analysis, investigators randomized clinical study sites to compare a standard implementation approach involving virtual injection training, educational resources, and regular support (standard arm) vs a more intensive implementation strategy involving face-to-face injection training, educational resources, and a continuous quality improvement program (enhanced arm).

Among the 430 people with HIV enrolled and switched to long-acting CAB plus RPV every 2 months, there was only 1 case of CVF and 1 case of suspected virologic failure, both in the enhanced arm (<1%). One could speculate that perhaps all the extra support in the enhanced arm made the clinicians a bit overconfident in selecting eligible patients for long-acting CAB plus RPV? 

CARLOS Cohort
At the HIV Glasgow 2022 meeting, Jonsson-Oldenbüttel and colleagues presented results from the German experience of long-acting CAB plus RPV in CARLOS, a 3-year cohort study of people with HIV who switched from suppressive daily oral ART to long-acting CAB plus RPV every 2 months in Germany.

In the virologic efficacy analysis (n = 200), 4 individuals (2.0%) had HIV-1 RNA >50 copies/mL at Month 6, including 2 participants with single HIV-1 RNA ≥200 copies/mL and 2 participants with HIV-1 RNA ≥50 copies/mL. However, there was only 1 case of CVF (0.5%), which occurred in a person who had HIV-1 subtype B, a BMI of 23 kg/m², and on-time injections. This patient’s virus demonstrated emergent INSTI and NNRTI resistance-associated mutations at CVF.

There was 1 other patient who experienced virologic failure, but it was discovered post hoc that they had been switched to long-acting CAB plus RPV off-label because they had experienced previous NNRTI virologic failure. 

Blip vs Failure?
When do we abandon injectable therapy because of detectable viremia? Sustained and increasing HIV-1 RNA levels represent new viral replication and the risk of developing resistance mutations, whereas blips are occasional releases of old virus from the latent reservoir and do not represent ongoing replication. Knowing which is which is often difficult and causes anxiety, especially in the context of a 2-drug regimen that harbors the risk of resistance to both components when true virologic failure occurs, thus also risking the loss of both the NNRTI and INSTI drug classes.

Latham and colleagues interrogated the FLAIR and ATLAS-2M databases to assess the frequency and implications of viral blips. The investigators reported at HIV Glasgow 2022 that viral blips (single HIV-1 RNA between 50-200 copies/mL) occurred at a similar frequency with long-acting injectable CAB plus RPV given every month vs daily oral 3-drug therapy (16% vs 17%, respectively) through Week 96 in FLAIR. In ATLAS-2M, rates of viral blips were 8% with every-2-month dosing and 9% with monthly dosing of long-acting CAB plus RPV through Week 152. In both studies, there did not appear to be a correlation between viral blips and CVF, which occurred in 1% of participants in each arm of FLAIR through Week 96 and in <1% (monthly dosing) to 2% (every-2-month dosing) of participants in ATLAS-2M through Week 152. Virologic efficacy rates were generally similar between treatment groups in each study, regardless of the occurrence or absence of viral blips. 

In summary, the results of these analyses reveal CVF rates of ~1% with a switch to long-acting CAB plus RPV in more real-world settings, an important finding that will hopefully allay concerns about the potency of switching to this long-acting 2-drug injectable option. These findings are especially relevant as many patients seem enthusiastic and eager to move away from daily pill taking, with Spreen and colleagues reporting at HIV Glasgow 2022 high ongoing levels of satisfaction through 152 weeks among 1045 participants receiving long-acting CAB plus RPV every 1 or 2 months in ATLAS -2M.

Your Thoughts?
How are you considering the latest real-world data on switching from suppressive ART to long-acting ART for your eligible and interested patients? Join the discussion and share your experiences by posting a comment.