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New Data on Investigational ART
My Take on 4 Interesting Investigational ART Studies From HIV Glasgow 2020 Virtual

Released: November 11, 2020

Expiration: November 10, 2021

Alexandra Calmy
Alexandra Calmy, MD, FMH, PhD
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The HIV Glasgow 2020 Virtual conference included new data on investigational and emerging long-acting (LA) ART strategies that provide a more complete picture of critical aspects of these evolving HIV treatment approaches, including factors associated with risk of virologic failure and new dosing strategies.

ATLAS, FLAIR, ATLAS-2M: Pooled Analysis of Injectable LA CAB Plus RPV
Margolis and colleagues performed an analysis of factors associated with confirmed virologic failure (CVF) using Week 48 data from 3 phase III trials evaluating LA injectable (intramuscular) cabotegravir (CAB) plus rilpivirine (RPV), including every-4-week dosing in FLAIR and ATLAS, and every-4-week or every-8-week dosing in ATLAS-2M. This report is particularly relevant to European clinicians at this time because the EMA approved LA CAB plus RPV on October 16, 2020. Investigators used a logistic regression model to examine factors known or thought to affect virologic outcomes, including drug pharmacokinetics, body mass index (BMI), dosing intervals, sex at birth, and HIV subtype. Overall, LA CAB plus RPV regimens across the 3 trials maintained virologic suppression in 94% (1531/1636) of patients at Week 48, with an approximate 1% rate of CVF (17/1636). Thirteen patients with CVF were included in the multivariable analysis, and most of these patients had multiple factors with a potential influence on virologic efficacy. When specific factors were examined, 4 were demonstrated to be associated with a significantly increased odds of CVF, 3 of which were baseline factors: RPV resistance associated mutations at baseline (odds ratio OR: 37.24; 95% CI: 8.44 to > 99.00; P < .001), post hoc Week 8 RPV trough concentration (OR: 4.17; 95% CI: 1.59-11.11; P = .004), A6/A1 HIV subtype (OR: 6.59; 95% CI: 1.82-25.26; P = .005), and high baseline BMI (OR: 1.13; 95% CI: 1.03-1.25; P = .014). An important and unique feature of this analysis is that it also evaluated the effect of a combination of factors. I found it striking that a single baseline factor in isolation was not strongly associated with CVF, but CVF was strongly affected by ≥ 2 of the 3 identified baseline factors. When either 0 or 1 baseline factor was present, the CVF rate at 48 weeks was < 0.5%. By contrast, the CVF rate among patients with ≥ 2 baseline factors was 26%. These factors (BMI ≥ 30, baseline mutations, and HIV subtype) are all parameters that can easily be evaluated at baseline in most settings in Europe. The results suggest that the presence of > 1 of these factors could serve to indicate that a patient may not be an ideal candidate for LA CAB plus RPV. This study paves the way for future analyses as it suggests not to focus on whether a patient bears a single deleterious mutation or other single factor but instead to consider a broader view that takes into account multiple factors.

P011: Islatravir Plus DOR vs DOR/3TC/TDF in Treatment-Naive Adults
Molina and colleagues presented Week 96 virologic outcomes from the international, randomized, double-blind phase IIb dose-ranging P011 trial comparing different daily oral doses of the investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir in combination with doravirine (DOR) vs DOR/lamivudine (3TC)/tenofovir disoproxil fumarate (TDF) in treatment-naive adults (N = 121). Week 24 and Week 48 results have previously been reported, demonstrating the virologic efficacy and safety of islatravir. The combination of islatravir and DOR continued to be generally well tolerated and effective through Week 96, with only 1 additional case of protocol-defined virologic failure identified between Week 48 and Week 96. In this trial, all patients who experienced protocol-defined virologic failure had HIV-1 RNA levels that were too low for resistance testing (confirmatory levels were all < 80 copies/mL). These data support the durability of viral suppression with this daily oral 2-drug combination. However, islatravir also holds the potential to be a LA ARV agent, based on potency and pharmacokinetic data. At the current time, a LA (once monthly) oral formulation is under investigation for use as HIV pre-exposure prophylaxis (NCT04003103), and a study opened in September 2020 that will evaluate islatravir in combination with MK-8507 as a once-weekly switch regimen for patients with virologic suppression on their current ART (NCT04564547). We hope that the COVID-19 context will not impede or prevent recruitment and/or conduct of this study.

Single Doses of MK-8507, a Novel NNRTI, Reduced HIV-1 RNA for at Least 1 Week
Ankrom and colleagues evaluated the efficacy, pharmacokinetics, and safety of single oral doses of MK-8507, a novel NNRTI, in treatment-naive patients (N = 18). The primary endpoint was an HIV-1 RNA decrease of a least 1 log10 copies/mL, and participants were to initiate standard-of-care ART 7 days after the MK-8507 dose. The results showed that single oral MK-8507 doses of 40 mg, 80 mg, or 600 mg reduced HIV-1 RNA by > 1 log10 copies/mL from baseline to Day 7. Among 14 patients who initiated standard ART at 7 days following MK-8507 dosing, there were no cases of viral rebound. Four patients did not initiate standard ART until more than 14 days after their single oral MK-8507 dose. Among those 4 patients, 1 experienced viral rebound with emergence of the RT resistance mutation F227C 10 days after receiving a single 600-mg dose of MK-8507.

These results support the viral efficacy of orally administered MK-8507 through 7 days post dosing. However, they raise the question of what the term “long acting” means to patients. I suspect that most of my patients would not consider once-weekly dosing as truly long acting. Nonetheless, I think it would be good to have another NNRTI option that does not require daily dosing to provide patients with as many options as possible. Qualitative surveys will be needed to gauge if patients would be receptive to a once-weekly option. Oral administration may be appealing for patients who do not want the constraints of monthly or every-2-month visits to a health care center.

Lenacapavir Resistance Analysis in a Phase Ib Clinical Proof-of-Concept Trial
Margot and colleagues presented resistance data from a phase Ib clinical trial of lenacapavir, the first-in-class inhibitor of HIV-1 capsid function (N = 39). No polymorphisms that would preclude the use of lenacapavir were identified in this study. Two individuals developed the Q67H mutation 10 days after a single 20-mg or 50-mg dose. In the phase II trial, lenacapavir will be studied as a sustained-delivery subcutaneous formulation for dosing every 6 months. I think that these results are quite exciting as this is a truly very long–acting drug. Which drug(s) will be used in combination with lenacapavir to form a complete HIV regimen is not yet known.

Considerations for LA ART
Although the benefit of LA therapies for patients is universal, real-world trials are needed to address key remaining questions:

  • What happens if patients miss an appointment for their LA dose?
  • What if patients require the use of a drug that has unfavorable drug–drug interactions with a LA ART regimen?
  • Will the quality-of-life benefits experienced by patients in the randomized trials translate into real-world settings?
  • Will patients and doctors forget that they have the LA drugs in their system when providing other therapies that could result in drug–drug interactions
  • How will health systems and HIV clinics adapt to the burden of more frequent patient visits when many places currently provide ART monitoring visits at 6-month intervals?

These presentations from HIV Glasgow 2020 covered a spectrum of LA HIV treatments, providing a broader view of the investigational pipeline, including options with dose intervals ranging from once weekly to every 1, 2, or 6-months and various formulations that include oral, intramuscular injection, and subcutaneous injection.

Your Thoughts
What are your thoughts about the findings from these studies related to LA ART? Join the discussion by posting a comment and share your experiences of what your patients are telling you they would most like to see with LA ART strategies.

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In addition to safety and efficacy, which of the following aspects of LA ART do you feel is or will be most important to your patients with HIV?
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