An ongoing dialogue on HIV/AIDS, infectious diseases,
May 21st, 2017
The Curious Case of M184V, Part 1
Thanks to our sophisticated research team here at NEJM Journal Watch, we have an excellent idea who reads this thing for its scintillating ID/HIV content.
Most of you are clinicians — doctors, nurses, PAs, PharmDs. A smaller proportion are researchers, lab-oriented types who wandered over here unexpectedly after an errant search, expecting the latest in CRISPR-Cas9 gene editing and instead getting an ID Link-o-Rama, a rumination on vintage medical photos, and a mysteriosis about listeriosis.
But another divider is whether you consider yourself an HIV specialist or not. A grab bag of ID (mostly), primary care, and other subspecialty clinicians, HIV specialists know and ruminate over lots of the same stuff even though there’s no formally designated HIV specialty by the American Board of Internal Medicine.
And today’s topic is most definitely an HIV-focused one, triggered by an email I received last week from one of my colleagues:
Subject: M184V
Paul,
What’s your go-to regimen in the setting of a solo M184V?
Jon
For the non-HIV specialist readers, allow me to decipher the code in the above question. “M184V” is the shorthand for methionine replacing valine at position 184 in reverse transcriptase. It is by far the most commonly encountered nucleoside reverse transcriptase inhibitor (NRTI) mutation after failure with regimens containing lamivudine (3TC) or emtricitabine (FTC).
And with that single paragraph, I’ve hinted why HIV drug resistance — and genotypes in particular — baffle some of even the most astute and brilliant ID clinicians. It’s like reading about the coagulation cascade or the complement system. You have to work with this stuff frequently to understand the lingo.
But for those seeing HIV patients on a regular basis (especially as outpatients), this question — what should be done after M184V? — is both quite relevant clinically and, surprisingly, not readily answerable from the literature.
Remember, M184V is a special mutation — it does some very weird things:
- Viruses that harbor M184V don’t replicate well. In virology parlance, they’re “less fit.”
- M184V causes marked phenotypic resistance to 3TC/FTC, but this doesn’t translate clinically. Or, to cite the invaluable Stanford HIV Drug Resistance Database, “M184V/I are selected by 3TC/FTC and reduce susceptibility to these drugs >100-fold.” For an analogy, think of high-level gentamicin resistance in an enterococcus isolate — but then ignore it and use gentamicin anyway. Because unlike these enterococci, where gentamicin would be useless, studies show that 3TC still exerts significant antiviral activity despite this loss of phenotypic activity. I’ve cited these studies before, but they deserve emphasis: Virologic rebound occurred after stopping 3TC in patients who already had developed M184V; and 3TC alone slowed CD4 decline more than no treatment despite M184V being present in all patients.
- M184V influences the in vitro susceptibility of certain other NRTIs in a favorable way. Yes, with M184V, susceptibility to tenofovir, zidovudine, and stavudine improves. In other words, an M184V containing virus is more susceptible to tenofovir than a wild-type virus, a phenomenon referred to as hypersusceptibility. Someone much smarter than I can explain the molecular mechanism of this phenomenon (it certainly won’t be me).
Because of these odd effects, and because both 3TC and FTC are so well tolerated, there’s a practice (not universally observed) of continuing 3TC or FTC even after M184V has been selected. But should this be done?
And with that background, let’s get back to the question in Jon’s email — what to do after M184V?
Imagine this case — a patient who failed a regimen of dual NRTIs plus an NNRTI (let’s say TDF/FTC/EFV) some time in the past. He had a genotype then showing M184V and K103N (conferring resistance to efavirenz), and then was lost to follow-up for a few years.
He now shows up saying he wants to start treatment again. Let’s give him a CD4 cell count of 250 and a viral load of 50,000. He of course wants as few side effects, and as few pills, as possible.
What would you choose as his antiretroviral regimen?
23 Responses to “The Curious Case of M184V, Part 1”
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
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The strongest data support a boosted PI-based regimen, such as DRV/c + FTC/TAF. The assumption is that with respect to resistance, what applies to a boosted PI also applies to DTG. The combination of DTG + FTC/TAF would probably do well, though we have less data supporting that choice. I’d be less enthusiastic about DTG/ABC/3TC because M184V is better for tenofovir than for abacavir. Gilead is attempting to study EVG/c/FTC/TAF in patients with M184V, but until we see that data, I would stick with a boosted PI or DTG.
In 2017 maybe the best combination is TAF/FTC and DOLUTEGRAVIR ,In alternative I chose TAF/FTC and DARUNAVIR ou even GENVOYA.Since in Portugal we still dont have TAF I had to prescribe the products with TDF.
I ment of course boosted Darunavir
I would use in our resource limited setting boosted ATZ+truvada. We do this routinely and so far have had good virological response. Doultegravir which I agree would be a good option is left to 3rd line in our setting.
TAF-FTC-EVG/c with DRV. 2 pills once daily. http://www.natap.org/2015/IDSA/IDSA_12.htm
The patients in that study all had 2 or more resistance mutations, not just the 184.
Yes
And they were DRV experienced patients with undetectable viral load for months.
I think this regimen would work fine, no doubt.
But in the case presented above, there are options with less components or less drug interaction and also 2 pills once daily (ex; DTG+TAF/FTC, DRV/c + TAF/FTC)
I prefer to keep EVG/c/TAF/FTC + DRV for DRV experienced patients with 2 or more class resistance like the study above
(* Exclusions were Q151M, T69Ins, signature DRV-R, INSTI-R, >/= 4 TAMs)
Do you think the second point is due to the first and third points (clinical effectiveness in spite of phenotypic resistance is due to reduced fitness and/or hypersensitivity)? I would agree with Joel’s selected regimens of boosted Darunavir or Dolutegravir + FTC/TAF. I’ll be curious about the data with elvitegravir or cabotegravir
I would use DTG + TAF/FTC
Data form «subanalysis» of SAILING study are reassuring… but I agree that the strongest data is with DRV/r(c).
I would be less enthusiastic about DTG/ABC/3TC or EVG/c/TAF/FTC for the same reasons as above (Joel Gallant)
* I know some clinicians who would first start DRV/r(c) + TAF/FTC until undetectable viral load x months, then switch to DTG.
I agree with Joel but would strengthen the “less enthusiastic” part about avoiding DTG/ABC/3TC to say I’d avoid it altogether. Rather than the hypersusceptibility that M184V/I lends TDF, it actually weakens ABC a bit, leaving DTG with not much support.
I will put him on TDF/FTC and DTG. DTG is well tolerated and has shown superiority to LPV/r. The fact that it is once daily regimen will an advantage for someone will adherence issues in the past. The only diasadvantage is here in Botsana we dont have DTG in co-formulations.
I would first order a resistance test in order to make sure that K65R doesn´t come up “unexpectedly” (perhaps this is where part 2 will kick in). Meanwhile, i think that Dr. Gallant has said it perfectly: a boosted PI (DRV/r) plus TDF/3TC or FTC has the strongest evidence in this scenario. In Argentina, we don´t have neither DRV/c nor TAF so we still have to stick with RTV as a booster (except for EVG/c/FTC/TDF) and with TDF. ATV/c has been approved recently but we are still in the process of incorporating it.
In a resource unlimited world, one could use the STR rilpivirine FTC TDF (odefsey) and dolutegravir so there would be 3 drugs to which the hiv were S. two smallish pills. I would repeat the geno and would expect the 184 to have disappeared and the 103 to have persisted.
DTG+FTC/TAF will likely work, but the data behind it in this situation is still fairly sparse (the SAILING subgroup analysis only had 13 patients with the M184V mutation and that analysis was never published). A more conservative approach might be an initial regimen of DTG+FTC/TAF+DRV/c until suppressed and then to peel off the DRV/c at that point to maintain the patient on DTG+FTC/TAF.
From what I am reading, most people are fine with essentially a two drug regimen as long as it includes TAF/TDF and/or DRV/r or DTG because of the possible hypersusceptibility and the impact of DRV/r or DTG. It has been hard for me to let go of the 3 drug mantra drilled into us in the early days. What are the series of long-term studies that give everyone the confidence to do this?
In my practice, I have used Odefesy and Tivicay and have had good results (4 patients at 48 weeks and longer with undetectable viral load)
Is a frequent question. Few data exist in general but are supportive of PI based therapy. Remembered a study conducted with ETV (former TMC125) in combination with 2 NUC compared with PI which was discontinued because an early high viral failure on ETV arm. Certainly patients not also harboured 184V but also NNRTI mutations and some patients on an extensive form.
I do think that we may know on alternatives to PI very soon since an ongoing study in 2nd failure comparing LPV/r and DTG plus 2 Nucs in NNRTI 1st line failure was early discontinued because significantly higher therapy failure on PI arm. So it may be possible that quite soon DTG would be largely consider in this scenario.
Besides a post hoc analysis of a study in HTE patients rescue either with RAL or DTG plus OBT showed that in puts harbouring NRTI mutations no patients failed when received DTG plus 2 NUC ( no PI) compared with few failure on RAL arm ( combined only with NUC). Indirect data but encouraging. Thx Paul
Very interesting! I was not aware of this study result, certainly does sound promising for DTG.
Paul
Could Emilio or Paul point us toward the RCT mentioned examining 2 different regimens for virological failure please ?
It looks very much like this study, which is ongoing (i.e. not terminated):
https://clinicaltrials.gov/ct2/show/NCT02227238
Tx, Mark
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M184V influences the in vitro susceptibility of certain other NRTIs in a favorable way. Yes, with M184V, susceptibility to tenofovir, zidovudine, and stavudine improves. In other words, an M184V containing virus is more susceptible to tenofovir than a wild-type virus, a phenomenon referred to as hypersusceptibility……interesting phenomenon…
So am I jumping the gun if I go straight to a nuke-sparing regimen (DTG + DRV/c) in a newly infected patient with an isolated M184V (immune to Hep B)? Thanks!
Probably would work fine, though no prospective clinical trials data. Alternatively, TAF/FTC + DTG or TAF/FTC + DRV/c would work too. Note that the former was tested in a second line study called DAWNING that is about to be presented at the IAS meeting in Paris. Here’s the title: “Superior efficacy of dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/RTV) plus 2 NRTIs in second-line treatment: interim data from the DAWNING study.”
Paul