September 8th, 2019

The Curious Case of M184V, Part 2 — and More!

The inspiration for today’s post comes from two recent emails from ID/HIV colleagues — thank you.

Here’s the first, from Dr. Mehri McKellar from Duke:

Hi Paul,

When are you going to do part 2 of The Curious Case of M184V, Part 1?

I am waiting patiently. 🙂

Mehri

Mehri, wait no more, because here it is! And thank you for the reminder, which is quite timely since there’s now greater clarity than ever about M184V, and what to do with that next regimen.

That first post summarized why we even care about this mutation, and what makes it so special — and so curious. Specifically:

  1. It’s the most common NRTI mutation observed with treatment failure. HIV docs averse to memorizing mutations should definitely put this one on their short list anyway — sorry, some you just have to know.
  2. Despite finding it frequently in people on treatment with viremia, we rarely see it transmitted in newly diagnosed patients. Latest data had it at  < 1% in the United States.
  3. M184V is selected by 3TC (lamivudine) or FTC (emtricitabine), leading to high-level phenotypic resistance. Despite this resistance, 3TC and FTC retain some antiviral activity.
  4. It impairs viral fitness. Viruses with M184V just don’t grow as well in vitro.
  5. It improves susceptibility to tenofovir, zidovudine, stavudine. By contrast, it worsens susceptibility to abacavir and didanosine.

Part 1 also mentioned that, despite how common this mutation was in clinical practice, we still didn’t have clarity about the best treatment option with this mutation. The date of that post was May 21st, 2017, and here’s the good news — there’s been quite a bit of progress on this front.

The most important data come from the DAWNING study, which evaluated people who had failed first-line treatment with two NRTIs and an NNRTI, then randomized them to receive either dolutegravir or lopinavir/ritonavir, plus at least one active NRTI as measured by baseline genotype testing.

The study was an overwhelming win for the dolutegravir strategy (84% vs. 70% viral suppression in the DTG vs. LPV/r arms, respectively), prompting early termination of the trial. The results certainly made us much more comfortable using dolutegravir plus NRTIs as a second-line treatment option, even in patients harboring some NRTI resistance.

Not surprisingly, most participants (84% in DTG arm, 81% in LPV/r arm) had M184V at baseline, which if present did not alter the primary study results favoring DTG. Most of the subsequent NRTI regimens chosen included either TDF or ZDV.

(Time for a complex, kind of geeky, digression. DAWNING let the investigators choose what NRTIs they used to combine with DTG or LPV/r. In the WHO guidelines, which assumed no genotypes available, and hence possible K65R, people previously receiving TDF were advised to go on ZDV, and the converse. As a result, it is likely that in DAWNING some of the participants who had M184V alone went on ZDV, even though they didn’t “need” to — tenofovir would have been active. And we hate to use ZDV these days, don’t we? Plus, two people in the study did have subsequent treatment failure with integrase resistance — but none of them had M184V alone.)

So, DAWNING takes care of people who are failing therapy with isolated M184V — the best approach is to give them DTG with at least one active NRTI, with tenofovir the ideal choice, given its enhanced activity (see Point #5, above). Often we’ll keep the FTC (or 3TC) along for the ride, since it’s so nontoxic and, as noted in Point #3, still has some activity.

But what about suppressed patients? What if they have M184V, and you’re interested in switching?

Here we can get some information from the 4030 study, presented this year at IAS. (I was the presenting investigator.) People with viral suppression on DTG plus TAF or TDF/FTC were randomized to TAF/FTC + DTG or to switch to the single pill BIC/FTC/TAF. Unlike most switch studies, prior failure with resistance was permitted, and participants were stratified by NRTI resistance into three groups:

  1. Tenofovir resistance (either K65R or 3 or more TAMS)
  2. Any other NRTI pattern (which includes M184V, either alone or with others)
  3. No NRTI resistance

The overall results demonstrated noninferiority of BIC/FTC/TAF to DTG plus TAF/FTC. These results held up regardless of the baseline resistance category.

Ah, but what about those challenging patients with both tenofovir resistance plus M184v? (This is the and More! part of the title.)

Time for another email, this time from another ID/HIV specialist — Dr. Risa Hoffman, from UCLA!

Hi Paul,

In the study you presented at IAS – did any people have both K65R and M184 (or in other words, resistance to both TAF and FTC/3TC?). We are doing a journal club on the ever-favorite topic of using bictegravir/FTC/TAF or a similar regimen in the presence of NRTI resistance…. I’m still looking for the answer about using this regimen when someone has mutations to both the TAF/TDF and FTC (I think you posed this question to the DAWNING study team at CROI…). Seems risky.

Thanks!

Risa

This is the kind of detail one can’t put in a 10-minute conference presentation, so here it is:

Of the 30 participants in that first category (which is resistance to tenofovir by either K65R or lots of TAMS), 21 also had M184V/I (13 BIC, 8 DTG). Of these 21 participants, 4 had K65R with M184V (3 BIC, 1 DTG), and the rest (17) had TAMs with M184V (10 BIC, 7 DTG).

And none in either arm had treatment failure at week 48.

So where does that leave us?

In the setting of treatment failure, I’m quite comfortable that patients with M184V alone can be successfully treated with tenofovir (TAF or TDF)/FTC plus DTG. BIC/FTC/TAF would probably work too, though it hasn’t been tested.

For people who are already suppressed on an integrase-based or NNRTI-based regimen, they can be successfully managed with either DTG plus tenofovir/FTC or BIC/FTC/TAF, even if they have more than just M184V for NRTI resistance. There is enough residual activity of the NRTIs to let the high resistance barrier integrase inhibitors (DTG or BIC) do most of the work.

Two key remaining questions:

  • For treatment failure with K65R plus M184V, what is the best approach? ZDV is highly active against these viruses, but who wants to use it? Should it be DTG plus DRV/r? Something else?
  • For suppressed patients on NRTIs plus a boosted PI (and there are a lot of them in the world), can they be switched to DTG plus TAF/FTC or BIC/FTC/TAF? Even if we don’t know their resistance history?

When clinical research answers those questions, it will be time for The Curious Case of M184V, Part 3.

Hey, it’s still officially summer, at least until September 23 — let’s go swimming!

3 Responses to “The Curious Case of M184V, Part 2 — and More!”

  1. Dr Srinivssan Ramesh says:

    Dear Dr Sax thank you for clarifying the cART regimen to be used in patients with an M 184 V mutation.You have made a boring task of memorising names of mutations interesting

  2. Oge Alozie says:

    Dear Dr Sax…

    So speaking of M184V, what are your thoughts about it when used with 3TC/DTG? Is DTG carrying the load even with the reduced fitness of M184V and 3TC along for the ride? Or is it too soon to tell and just stick to the FDA label of not using that combo if virus carries that mutation?

    Thank you

  3. Serena Koenig says:

    Thanks Paul,

    This is a fantastic blog post. The information you have presented here is extremely useful for clinicians in resource-poor settings, who are struggling to make the best decision about which patients to place on the new TDF-3TC-DTG regimen, without the benefit of resistance testing.

    I have already forwarded this to colleagues in several countries.

    Thank you for so elegantly summarizing a very challenging topic.

    Serena Koenig

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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