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


What's your go-to regimen in the setting of a solo M184V?


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?