DOLUMONO study - Dolutegravir monotherapy fails

[Jim Allen]

The good news is dolutegravir + lamivudine currently still looks good and on track.

http://hivinsite.ucsf.edu/insite?page=hmq-1704-04

http://www.aidsmap.com/Dolutegravir-monotherapy-fails-to-maintain-HIV-viral-suppression-but-dolutegravir-lamivudine-looks-good/page/3122291/

The DOLUMONO study included 104 people at multiple centres in the Netherlands. Just over 90% were men and the median age was 46 years. At baseline they were on combination ART with HIV RNA < 50 copies/ml for more than six months, never more than 100,000 copies/ml, a CD4 count never less than 200 cells/mm3, no drug resistance and no history of virological failure.

Participants were randomly assigned to switch to 50mg once-daily dolutegravir monotherapy immediately, or to continue on their current combination regimen for 24 weeks then switch to dolutegravir monotherapy.

At week 24, the dolutegravir regimen appeared as effective as continued combination therapy: 98% and 100% in the respective arms maintained undetectable viral load, defined in this analysis as > 200 copies/ml.

But with longer follow-up, results began to diverge. Looking at the entire study population who switched to dolutegravir monotherapy either immediately or after 24 weeks, the viral suppression rate fell to 92% at week 48. This was significantly lower than the 98% suppression rate seen in a similar group of people who were not in the randomised study and stayed on continuous combination therapy through week 48 (p = 0.03).

By the time 77 people in the dolutegravir monotherapy arm had reached 48 weeks, eight of them had experienced virological failure. Of these, six underwent successful genotypic testing and three were found to have integrase resistance-associated viral mutations (N155H, R263K and S230R). They all restarted combination ART and were resuppressed to < 50 copies/ml within 12 weeks.

There were no clear risk factors for viral rebound. Among those who experienced virological failure, time on ART ranged from 2 to 14 years, highest-ever viral load ranged from 7420 to 99,270 copies/ml, and they switched from regimens containing dolutegravir, rilpivirine, efavirenz (Sustiva) or nevirapine (Viramune) plus two NRTIs. All of them reported excellent adherence.

[harleymc]

I know there was at least one other dolutgravir monotherapy trial discontinued due to  a high rate of treatments failure.

Why to they keep on trying to invent square wheels?

[Jim Allen]

Yup, i agree.

Not sure why they expected Dolutegravir to fair better in monotherapy, the past has shown that monotherapy generally is a bad idea.

[CaveyUK]

I think it's to do with the resistance profile of DTG.

During trials, DTG was seen as outstanding compared to many of the older drugs in terms of resistance. Indeed, I think they may have been one case recently which was reported at a conference, but since launch there hadn't been a single case of anyone who started with a DTG-containing regimen as first-line treatment, who developed resistance.

It follows that if the resistance barrier is so high theoretically, that it may be a decent candidate for monotherapy and this was mooted during the clinical trial of the drug itself.

Now, we know that it ISN'T a good drug for this purpose, but still glad they tried. The viral suppression as a single drug worked well for a decent length of time, which provides hope that sooner or later they will find a drug which does work for this.

Of course, continued trials are now pointless but I guess if a trial is three quarters of the way through, it may be more cost effective to complete the trial and add to the data discovered, in case it helps future research.

[harleymc]

I'm just puzzled and angry that this trial continued so long when other trials of DTG monotherapy were discontinued, due to failures, some time ago.  The Ethics committee were asleep.

[eric48]

I'm just puzzled and angry that this trial continued so long when other trials of DTG monotherapy were discontinued, due to failures, some time ago.

Are you able to name this other 'trial', because, in my book (clinicaltrials.gov), this was the only one.

Furtheron, more than 90% of patients succeded their DTG monotherapy. We may want to hear from them, as they must be very happy...

As for the infortunate few, they had to get back to standard tritherapy, which was what they had before the trial

Too bad for them, but where is the harm?

[harleymc]

I'd read about the dolutgravir monotherapy trial being cancelled well before May. I'm thinking around January or February.  Maybe it was the same trial, I don't know, maybe they were just slow at doing the media release. 

What's the harm? Let me see 10% of the trial participants now having integrase inhibitor resistance mutations.

[eric48]

What's the harm? Let me see 10% of the trial participants now having integrase inhibitor resistance mutations.

Nope... only 3 (out of 100) had a viral escape with associated mutations (and minor, while you are at it) DTG based tritherapy could remain an option (although they may have changed strategy)

All of the other escape had NO mutation (or could not be detected) they simply resumed the TRI therapy that they had before

You try, bad luck, but where is the harm ?

[Jim Allen]

Are you able to name this other 'trial', because, in my book (clinicaltrials.gov), this was the only one.

On that point, ill just add from a different book a link as people may have seen updates and news in the past on studies previously looking into this.

2011 Reports a number of small scale studies http://i-base.info/htb/29154
2017 http://i-base.info/htb/31289

My own thoughts are, dolutegravir mono-therapy, viral rebounds (thankfully no forward transmission reported), this next to the patients dropping off for other reasons and a few left with drug resistance. As a go to market therapy it did not cut it but i hope something was learned, and the dual therapies seem to have been doing a lot better.

http://www.eatg.org/news/simplifying-hiv-treatment-dual-therapy-works-but-monotherapy-with-either-boosted-pis-or-dolutegravir-doesnt/

 

[eric48]

but i hope something was learned, and the dual therapies seem to have been doing a lot better.

Yep! Tivicay monotherapy may not be for everyone. Neither are other reduction alternatives. How do you know who can do it and who can't if you have no failures and no means to deduct rules.

This is why you need a good doctor if you consider strategies that are other than plain standard, one fit all,  tritherapy . You can only design a selective screening system if you work on analysing failures, not just throw 'failure' to people's face.

It is worth knowing who can and you should refrain from it. With test and treat, more and more patients are treated with strategies, which, on the long run could be simplified.

The upcoming International Aids Society conference has an entire session on discussing who and when can reduce the meds. So this is not a subject out of the blue.

Many of these strategies are slowly, but steadily, entering guidelines. So it does patients a disservice to throw 'failures' at them, whereas those failures are what we (they) learn from. The Spanish team, cited, in you first link, provided a complete analysis of failures at CROI-2017.

The take home message is not that failures occur, but that failures are predectible, hence avoidable.

Any simplification strategy that has zero failure, is simply put, a strategy that is not  simplifying enough.

Whether people like this or not is beyond the point: the debate is on going within the scientific community and for a cause. It will resurface, here or elsewhere, and shying away from it is conterproductive.

[Jim Allen]

People have different view points, but I don't think that equals to anyone shying away from the idea or discussion of it, i will say talk in the scientific community is just the same as anywhere else, its talk and talk is cheap and i'm not seeing any guideline changes as of yet other than a few tests and trials.

I will say that who knows with better screening and understanding of the parameters we could be in a very different place with regards to treatment in 10 or 15 years from now, but in it current format its clear to me at least, and the current manner that patients are cared for and monitored its not ready for any wide usage.

Jim

[eric48]

the current manner that patients are cared for and monitored its not ready for any wide usage.

This is at he same time right and wrong.

The WHO has already endorsed one of the proposed reduction scheme.

It is therefore being implemented in 'poor' countries, but not in 'rich' countries (where the economic powers that be are against promoting it actively). As a result, 'poor' country folks are, at this moment, benefiting from these improved guidelines, whereas, the 'rich' guys are still under guidelines that are inconsistent with the recent moves by WHO and are, unkowingly, being over-medicated, at their expense.

[Jim Allen]

I think we will just have to agree to disagree.  I've not seen any change endorsed outside of trials or where standard treatment is available.

Jim

[eric48]

This correct, changes in guidelines are reflective of trials.

Following to the MONARK trial (Spain) the Spanish guidelines have authorized PI monotherapy (with a screening process)

Following the ENCORE-1 trial, the WHO guidelines have endorse the reduction of EFV from 600 mg to 400 mg. (blanket authorization, no screening)

None of this was translated in other guidelines, but, these alternative stragetegies do exist nonetheless.

Interestingly enough, the MONARK trial results (before a screening rule was designed) where far worse than the DOLUMONO results. Yet it has been approved, after a satisfactory screening rule has been established.

Therefore, it can be expected that the DOLUMONO strategy will help design eligibility rules.

It is also expected that deboosting of PIs or dose reduction may enter guidelines in the near future.

So better that saying : na... this does not exists, better have a look at what, in fact, exists, why they do , and why they do not percolate into some of the guidelines (especially US), and keep an eye on what might be in some of the guidelines, in the near future.

 

[Jim Allen]

The encore reduction in strength is still in a combination with triple therapy.
Nobody is denying that dosing is getting better, even if you look at the upgraded Truvada its a lower dosage as example as its more effective.

However there are no wide endorsed changes to guidelines for mono or bi therapy where standard therapy is available. Who knows where medication will take us in years to come and with better clinical settings but we are not there today. As for Spain its only 1 small locations and we will see what happens with that in time

Jim     

[eric48]

We though you  could do better than that conventional thinking

[CaveyUK]

I guess everyone is different. I personally value my life enough to not be fucking around by experimenting and risking meds failure, until there is conclusive scientific evidence and agreement that an alternative approach is valid and safe.

Anecdotal evidence or the presence of doctors who - rightly or wrongly - are willing to step outside the guidelines, isn't enough to convince me.

Personally, I'd love to find out that simplification really works across the board and I am grateful for the studies that are looking into this. I'm not about to pre-empt the conclusions of these studies though and risk damaging myself (or others).

[OneTampa]

Regarding reduced Dosage, have been on 400 mg Sustiva for over 15 years.

Research finally caught up with my forward thinking Doctor.

Link:

https://www.poz.com/article/Sustiva-dose-24228-5320

[eric48]

Research finally caught up with my forward thinking Doctor.

research did, and so did the WHO guidelines... Some guielines in Europe are starting to reflect these more mordern guidelines. Eventually this will surface into the US ones. But when ?

This kind of monotherapies do work on some people (as show by the 90% success rate) and not on others; So hopefully they will be able to figure out who is a good candidate and who is not (actually there was a presentation at last CROI exactly on that). If a proper screening process can be designed, then some how the strategy will be adopted by some doctors; And it does not matter so much that it is adopted by all doctors

[Jim Allen]

That's a lot of if's and maybe's. Who knows maybe one day guidelines will change and they will have systems and tools, protocols but that would not be anytime soon.

Jim

[Jim Allen]

 

https://www.poz.com/article/treating-hiv-just-tivicay-good-idea
November 10, 2017

Treating HIV With Just Tivicay Is Not a Good Idea After All

Publishing their findings in The Lancet HIV, researchers from the open-label Phase II noninferiority DOMONO study recruited 104 people on stable combination ARV treatment, switching 51 of them to once-daily Tivicay monotherapy immediately and then switching the remaining 53 people to Tivicay monotherapy (as single-drug regimens are called) after a 24-week deferral period during which they continued on their previous combination ARV regimen.

At the end of the initial 24-week period, 2 percent of those in the group that switched to Tivicay immediately had a viral load of 200 or higher, compared with none of those in the group that remained on combination therapy during this period. At the 48-week mark, 8 percent of the 95 percent who were still on Tivicay monotherapy at that point had a virologic failure, including six of those in the immediate-switch group and two in the deferred-switch group. Three of these participants developed viral mutations associated with resistance to integrase inhibitors, the ARV class to which Tivicay belongs.

As a result of these negative outcomes, the researchers terminated the study early and ultimately concluded that Tivicay monotherapy should not be recommended.

[zach]

Jim, what is the status of the dual therapy studies of 3TC/DTG? I know some smaller pilot studies showed promise. I know there was at least one larger study, but I forget the name and am on a phone so Google research is a little difficult.

[Jim Allen]

Gemini is still in Phase 3 testing after a very promising phase 2 results. Phase 3 started in late 2016.

Study Comparing Dolutegravir (DTG) Plus Lamivudine (3TC) With Dolutegravir Plus Tenofovir/Emtricitabine

https://www.clinicaltrials.gov/ct2/show/NCT02831764?term=GEMINI&recrs=deghim&cond=HIV%2FAIDS&rank=2

https://www.clinicaltrials.gov/ct2/show/NCT02831673?term=GEMINI&recrs=deghim&cond=HIV%2FAIDS&rank=3

https://forums.poz.com/index.php?topic=63655.msg716013#msg716013