Two month injection from ViiV

[venom_X]

Just read this press release from ViiV, what folks takes are on here with regard to the two-drug injection every two months?

From the clinical trial info, I found that the RNA detection limit in the ATLAS-2M study is set to <50 copies, then it is not differentiating those with non-detected with low level viral replication with <50 copies. It could be that ViiV's claim is based on this to be non-inferior to daily 3-drug regimes. My fear is that if the criteria is set to 1 copy ultrasensitive assay, then the 2 month injection will be inferior to daily 3-drug regimes. I think they should also look at the CD4 count and CD4/CD8 ratio between 2 month arm and daily arm of the study. Any thoughts?

ATLAS-2M study:

https://clinicaltrials.gov/ct2/show/NCT03299049

https://www.gsk.com/en-gb/media/press-releases/viiv-healthcare-reports-positive-phase-iii-study-results-of-investigational-long-acting-injectable-hiv-treatment-regimen-administered-every-two-months/

ViiV Healthcare, the global specialist HIV company majority owned by GSK, with Pfizer Inc. and Shionogi Limited as shareholders, today announced positive headline results from its global phase III ATLAS-2M study of the investigational, long-acting, injectable, 2-drug regimen (2DR) of ViiV Healthcare’s cabotegravir and Janssen’s rilpivirine for the treatment of HIV. The study was designed to demonstrate the non-inferior antiviral activity and safety of long-acting cabotegravir and rilpivirine administered every eight weeks (two months) compared to every four weeks (monthly) over a 48-week treatment period in adults living with HIV-1 infection whose viral load is suppressed and who are not resistant to cabotegravir or rilpivirine.

The study met its primary endpoint, showing that the long-acting regimen of cabotegravir and rilpivirine, injected every two months, was non-inferior to cabotegravir and rilpivirine administered every month at Week 48. Non-inferiority was assessed by comparison of the proportions of participants with plasma HIV-RNA ≥ 50 copies per milliliter (c/mL) using the FDA Snapshot algorithm at Week 48 (Intent-to-Treat Exposed [ITTE] population). Overall safety, virologic response and drug resistance results for the every-two-months injectable regimen were consistent with results from the phase III ATLAS study.

Kimberly Smith, M.D., Head of Research & Development at ViiV Healthcare, said: “We are excited to report that for the first time since the AIDS epidemic started more than 30 years ago, our ATLAS-2M study has demonstrated that it is possible to maintain suppression of the HIV virus with an injectable regimen containing two drugs administered every two months. This is further progress in our efforts to reduce the number of medicines a person living with HIV must take while also reducing the frequency of treatments. The ATLAS-2M study results mean that people living with HIV could maintain viral suppression with six total treatments per year, instead of a daily oral treatment 365 times per year. Approval of this regimen would mark a significant change in the HIV treatment paradigm.”

Detailed results from the ATLAS-2M study will be presented at an upcoming scientific meeting.

This investigational, long-acting, injectable regimen is being co-developed as a collaboration with Janssen Sciences Ireland UC and has been submitted to regulatory authorities in the United States, Canada and Europe. A Priority Review Designation for the once-monthly injectable regimen was granted by the FDA with an expected action date of December 29, 2019.
About ATLAS-2M (NCT03299049)

The ATLAS-2M study is a phase III, randomised, open-label, active-controlled, multicentre, parallel-group, non-inferiority study designed to assess the non-inferior antiviral activity and safety of long-acting cabotegravir and rilpivirine administered every eight weeks compared to long-acting cabotegravir and rilpivirine administered every four weeks over a 48-week treatment period in 1,045 adults living with HIV-1.[1] Subjects were required to be virally suppressed for six months or greater, on first or second regimen, with no prior failure. The primary outcome measure for the study is the proportion of participants with HIV-RNA ≥ 50 c/mL at Week 48 using the FDA Snapshot algorithm (Intent-to-Treat Exposed [ITT-E] population).

ATLAS-2M is part of ViiV Healthcare’s extensive and innovative clinical trial programme for 2-drug regimens. The study is being conducted at research centres in Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden and the United States.

For further information please see https://clinicaltrials.gov/ct2/show/NCT03299049.
About rilpivirine long-acting

Rilpivirine long-acting is an investigational, prolonged-release suspension for intramuscular injection being developed by Janssen Sciences Ireland UC and is not approved by regulatory authorities anywhere in the world.

[Jim Allen]

My fear is that if the criteria is set to 1 copy ultrasensitive assay

Why fear? VL between 0 - 50 has no clinical difference so nothing to fear there, in addition, you would not be forced to take it, neither is it the first injectable combination to be tested, or from ViiV. Relax.

I think they should also look at the CD4 count and CD4/CD8 ratio between 2 month arm and daily arm of the study. Any thoughts?

All the meds do is suppress the virus ... not much more to it. If you took the counts from all the people on the same drug currently say Tivicay/Truvada combo the difference within the same treatment group alone would be vast, it's a not a telling or relevant measurement.

[harleymc]

Why would CD4 counts which have a very variable time lag from cd4 suppression, and can vary hugely hour to hour be any meaningful data points?

My doctors are more interested, as am I, in having my viral load supressed.  I don't bother to collect my CD4 count and they are only tested irregularly. 

[Jim Allen]

The POZ.com Write-up:

https://www.poz.com/article/longacting-injectables-can-given-every-month

In short:

As reported at this year’s Conference on Retroviruses and Opportunistic Infections, results from the Phase III ATLAS trial showed that 92.5% of people randomly assigned to switch to the injectable regimen had undetectable HIV (less than 50 copies) 48 weeks later, as did 95.5% of those who stayed on their oral regimen. Likewise, the FLAIR trial saw similar rates of viral suppression in people new to treatment, 93.6% and 93.3%, respectively.

The Phase III ATLAS-2M trial was a head-to-head comparison in which participants were randomly assigned to receive cabotegravir and rilpivirine injections either every four weeks or every eight weeks.

ViiV and Janssen announced in press releases that the study met its primary endpoint, showing that the efficacy of the injectable cabotegravir/rilpivirine combo was similar at 48 weeks regardless of whether it was administered once a month or every other month. In other words, cabotegravir/rilpivirine given every eight weeks was found to be noninferior to administration every four weeks.

The companies did not provide viral suppression rates or other detailed data at this time, indicating that these would be presented at an upcoming scientific conference.

[venom_X]

Why fear? VL between 0 - 50 has no clinical difference so nothing to fear there, in addition, you would not be forced to take it, neither is it the first injectable combination to be tested, or from ViiV. Relax.

Hi Jim,

I was reading several research including this one in PLOS:

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050065

"A detectable VL <48 copies/mL was independently and significantly associated with subsequent viral rebound, and is cause for clinical concern."

[MarkintheDark]

Guess I'll jump in, having participated in the ViiV study for almost three years, albeit monthly.  I've remained UD, though I've also only occasionally ventured >150-200 on my CD4 absolute.  Low 200s currently.

The study cited is but one and from 2012.  In the subsequent seven years more studies have been done, this gist of which, as I understand them, is that a possible cause for concern is consistent >50 copies - <200 copies.  The breakpoint for virologic failure is >200 copies.  A good breakdown from NIH is here:
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/15/virologic-failure

While it certainly may be an option to explore down the road as the injectables become available as standard therapy, we're simply not there yet.  That's to say, worrying about a treatment that's not even generally available yet is kinda pointless if you're current ART is working.

[Jim Allen]

I still don't get the concern/fear as this is not a treatment on the market yet neither do I predict you will you be forced to take it, in addition, plenty of treatments were benchmarked to the same criteria

I'll add that blipping between 0-50 & 50-200 whilst having preexisting low-level resistance or poor adherence resulting in rebound at some stage is not new and does explain part of this study. Generally, with good adherence and no preexisting resistance, there is no clinical difference between 0-50.

I had a quick scan of the study and 10 people out of 778 (5.5%) experienced viral rebound >1000 copies/mL had blips <48 copies/mL beforehand.  Resistance would explain some of it and this was in part answered from all groups, 53 rebounded. Only 22 had interpretable resistance testing and 9 showed evidence of drug resistance. Ideally, this should be checked before starting treatment. The question of adherence under the group was not answered 

If you are really interested in blipping there is more to read, I think this 3 page decent Q&A on this topic provides good insights when fully read.

https://www.healio.com/infectious-disease/hiv-aids/news/online/%7B8373ca63-674d-4015-ac35-f4da653c7415%7D/qa-understanding-persistent-low-level-viremia-in-people-with-hiv

Low-level blips & treatment

https://www.poz.com/article/viral-blips-raise-risk-hiv-treatment-failure
http://www.aidsmap.com/Spanish-study-gives-reassurance-small-HIV-blips-do-not-predict-treatment-failure/page/3085173/

4289 individuals - very low level viraemia (20-49 copies/ml) was not associated with subsequent virological failure when compared to persistent suppression below 20 copies/ml

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308904/

3550 participants blips of 500–999 copies/mL were associated with virologic rebound, whereas blips of 50–499 were not.

In addition, there is the theory that no resistance and good adherence micro blip are due to a release from the viral reservoir perhaps including defective copies being released.

Defective copies - 90℅ or more of HIV in reservoirs are rejects
https://www.sciencedaily.com/releases/2016/08/160808150523.htm

Viral blips (50 - 500 copies) during suppressive antiretroviral treatment are associated with high baseline HIV-1 RNA levels
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915053/

[Mightysure]

I dont think there's any statistical difference between  20 copies and 50. While some labs can quantify VL down to 20 copies, 50 is still pretty much the standard.
But I think getting bogged down in this misses the point of the article as they would consider a VL of 49 the same as 0 and studies have consistently shown little difference in outcome with VL in that range.

We're getting closer to FDA approval of an HIV treatment that only doses 12x per year and eventually 6x! During the early years, some people took upwards of 40 pills a day!