Released: April 21, 2020
Expiration: April 20, 2021
Laura Waters, MD:
One of the most highly anticipated antiretroviral treatment studies at CROI 2020 was ATLAS-2M (Capsule Summary).[1] ATLAS-2M is a randomized trial investigating long-acting injectable cabotegravir (CAB) plus rilpivirine (RPV) in 1045 adults from 3 groups: patients already receiving long-acting CAB plus RPV in the original ATLAS trial (n = 654; 63%), patients receiving standard-of-care oral ART in the original ATLAS trial, and patients receiving standard-of-care oral ART outside of the original ATLAS study. After an oral lead-in phase for patients not already receiving long-acting CAB plus RPV, patients were randomized to long-acting injectable CAB plus RPV either every 4 weeks (Q4W), which is the regimen that has been studied the most, or every 8 weeks (Q8W).
Laura Waters, MD:
Virologic outcomes in this previously suppressed population were good and very similar between the 2 treatment arms. Indeed, at Week 48, 94.3% and 93.5% of patients in the Q8W and Q4W arms, respectively, remained suppressed. The adjusted treatment differences were small and well within the CIs for noninferiority, indicating that long-acting CAB plus RPV Q8W was noninferior to CAB plus RPV Q4W.
Josep M. Llibre, MD, PhD:
Virologic failure with the Q8W dosing strategy was 1.5%, and it appears that some of the patients who experienced failure had 2-class resistance. In the ATLAS and FLAIR trials evaluating long-acting injectable CAB plus RPV,2,3 the very few people who experienced virologic failure also selected for mutations which conferred resistance to RPV and mutations associated with INSTI resistance. Post hoc analysis of HIV-1 DNA in peripheral blood mononuclear cells in ATLAS-2M demonstrated the presence of preexisting major RPV resistance in 5 patients with virologic failure and preexisting major INSTI resistance in 1 patient with virologic failure in the Q8W dosing arm. The investigators noted that an analysis of factors contributing to virologic failure, including drug concentrations and baseline resistance, is ongoing.
By contrast, the development of INSTI resistance was not observed in patients who experienced virologic failure in the SWORD trials evaluating a switch to oral DTG plus RPV.4 Indeed, the observation of significant INSTI resistance at failure is unexpected with later-generation INSTIs. It is also notable that 5 patients who experienced virologic failure in ATLAS-2M had the L74I polymorphism, and this may open the door to selecting mutations with high level resistance to INSTIs. Since 3 of these patients had subtype A or A1 HIV, these data raise concerns about the use of this regimen in people with subtype A HIV.
Laura Waters, MD:
I agree; it seems that this regimen works well for the great majority of people, but I would not currently recommend it for people with subtype A HIV.
Laura Waters, MD:
The results from ATLAS-2M are similar to those from ATLAS and FLAIR in that injection-site reactions (ISRs) were quite common, although the frequency appeared to decrease over time.2,3 However, as also observed in the previous studies, withdrawals due to ISRs were very infrequent, indicating that people are willing to tolerate this low-grade adverse event in order to receive an injectable long-acting treatment. Pain was the most common ISR event, and there were no significant differences in the frequency of ISRs between the 2 study arms in ATLAS-2M.
Josep M. Llibre, MD, PhD:
The rates of all adverse events and treatment-related adverse events were higher that typically observed with oral therapy. This regimen requires 2 injections because the drugs are not coformulated, but the study showed that patients were very happy not to take pills every day and, therefore, did not consider this to be a substantial limitation. However, there is a potential selection bias in that these individuals were highly motivated to receive long-acting injectable therapy in a clinical trial; the patient preference results may not be applicable to the broader patient population.
Laura Waters, MD:
I will be interested to see the results from a study looking at thigh administration since this may be a more straightforward way to administer these drugs, rather than into the gluteus medius, and could also offer the option for self-administration of the regimen. Considering that individuals throughout the world are tending to gain weight rather than lose weight, factors such as needle length and anatomical location may be challenging. I would, therefore, imagine that injecting into the thigh would be an easier site to get right.
Laura Waters, MD:
It will be important to better understand what is driving the difference in virologic failures between the Q8W and Q4W dosing. Although it is a very small difference in these Week 48 data, we should have a low tolerance of virologic failure and resistance in a previously suppressed population.
As such, I eagerly await additional analyses, particularly around the pharmacology, where it would be reassuring to confirm whether drug exposures with the Q8W regimen were sufficient throughout the dosing period. In addition, we need to learn more about whether genetic polymorphisms may affect responses, whether body mass index has an impact on drug absorption and drug levels, and whether patient sex plays a role.
Many patients in my clinic in the United Kingdom are very interested in the prospect for a long-acting injectable HIV treatment. A monthly injection would represent important progress, and it is also encouraging that the future will likely bring additional, less-frequent options, like the every-2-month regimen studied here, and implants. However, we may need to choose the right people for less frequent dosing to ensure that we do not risk losing viral suppression and diminishing their treatment options with dual-class resistance. My current intention would be to take a cautious approach and not use Q8W dosing unless the patient was already suppressed on Q4W injectable therapy.
Josep M. Llibre, MD, PhD:
The regimen studied here is quite attractive for the right person, with only 6 doses required per year. In Spain, ARVs are received in the hospital pharmacy, so people could receive a shot in the hospital pharmacy or even in ambulatory healthcare.
Laura Waters, MD:
I agree. As long-acting therapy becomes available, we will learn the best ways to implement the administration of these injections, which will vary of course from one patient population to the next.
In March 2020, shortly after CROI 2020, Canada became the first country to approve long-acting CAB plus RPV for use as a switch regimen in virologically suppressed patients, delivered by IM injection once per month. This approval should soon yield real-world data to help inform implementation approaches.
For some patients, we may be able to link the injection to other services they might be accessing, such as drug dependency services, mental health services, and perhaps regular contraceptive injections.
Finally, I think we are going to need to move away from hospital-focused treatment and explore how to safely deliver these treatments in the community. With a Q8W dosing schedule, it may be very important to ensure that people are able to attend for their injections on time and do not miss dosing cycles.
Laura Waters, MD:
The BRAAVE study investigated the efficacy of BIC/FTC/TAF in black PWH who were virologically suppressed, and the investigators evaluated the effect of preexisting drug resistance on outcomes.5 In this study, 495 patients were randomized 2:1 to either switch to BIC/FTC/TAF or to continue their baseline regimen of any 2 NRTIs plus a third agent. A total of 13% of patients in the switch to BIC/FTC/TAF arm and 16% in the continued baseline ART arm had baseline NRTI resistance, most of which was M184V/I. NNRTI resistance was observed in 21% and 19% of BIC/FTC/TAF and continued baseline ART participants, respectively, and PI resistance was observed in 11% and 15%, respectively. Baseline genotypic resistance analysis included use of historical genotyping reports when available and HIV-1 proviral DNA genotype testing.
At Week 24, the investigators found that, regardless of baseline NRTI resistance, including M184V/I, virologic suppression rates were very high and similar in both treatment arms. This is certainly reassuring and helps support the idea that we may now have options outside of the PI class for patients with NRTI resistance.
Laura Waters, MD:
I would like to point out a couple of considerations when interpreting these data. First, I think we need to be cautious not to extrapolate these data from people who were virologically suppressed at baseline to people with virologic failure and resistance. I hope that data on this will be forthcoming, but currently I do not think BIC/FTC/TAF has been challenged in that setting.
Second, although Week 24 data are important and often reflect Week 48 and longer-term results, I think it is still too early to say that this is a safe regimen in people with resistance.
Josep M. Llibre, MD, PhD:
I think this study is important to help us understand the impact of the archived M184V/I mutation. It is reassuring to see that 100% of patients with preexisting M184V/I maintained virologic suppression through 24 weeks after a switch to BIC/FTC/TAF. Therefore, it appears that the impact of the archived mutations is very limited with this regimen.
Laura Waters, MD:
One other thing to note is that, like some of the other BIC/FTC/TAF studies that we have seen, the preexisting resistance was a mixture of historical genotypes and proviral DNA sequencing, and there is still some debate about whether resistance by proviral sequencing means the same as that observed with historical genotypes. A small pilot study from Spain evaluated a different strategy, switching to a 2-drug regimen of DTG/lamivudine, in patients with a history of the M184V/I mutation that persisted on proviral DNA next-generation sequencing (but not on proviral DNA Sanger sequencing).6 The basis for this study is the idea that archived resistance may actually become unimportant or even disappear completely over time. I think we will learn more over time about how best to utilize both historical genotypes and our current tests to see whether or not old resistance remains an issue for people who have been suppressed for many years.
Josep M. Llibre, MD, PhD:
Yes, that is a good point. Actually, that study from Spain reported 48-week and 96-week data at CROI 2020,7 and they have not seen any cases of virologic failure. However, the prevalence of the M184V/I mutation was relatively low and they excluded people with majority M184V. It is quite clear that, upon virologic suppression, the M184V/I mutation suffers a progressive waning and will likely disappear. Therefore, if it has been a long time since failure and selection of the M184V/I mutation, this mutation will probably have disappeared or have a very low impact on future treatment. Without longer-term data, however, my current recommendation is for patients with historical FTC resistance to stay on a 3-drug regimen, including TAF or TDF.
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