New HIV Treatment Guidelines, and the End of an Era

The new Department of Health and Human Services (DHHS) HIV treatment guidelines are out, and thanks to skillful direction by Alice Pau, it's as usual a must-read document -- all 288 pages, of course!

There are several major changes, so a good place to start is the all-important "What's New in the Guidelines" summary page. Some of the biggest modifications come in the "What to Start" section:

  • There's now a more focused list of "Recommended regimens" -- it's down to just 5. Specifically, TDF/FTC plus DTG or EVG/c or RAL (that's 3), ABC/3TC/DTG (4), and TDF/FTC plus DRV/r (5).
  • The regimens that are limited to patients with low HIV RNA are now classified either as "Alternative" -- TDF/FTC/RPV -- or "Other" (ABC/3TC plus EFV, ABC/3TC plus ATV/r).
  • TDF/FTC plus ATV/r is now an "Alternative" regimen, largely due to the results of ACTG 5257.
  • TDF/FTC/EFV is now an "Alternative" regimen, largely due to issues of tolerability.

With the caveat that as a member of the Guidelines panel, I can only give you my personal perspective (not that of the committee), here are a few comments on this last one -- the demotion of efavirenz from "Recommended" to "Alternative" -- which seems to me a pretty big deal.

First the good stuff about EFV, which was approved by the FDA way back in 1998:

  1. In clinical trials, efavirenz has been better or as good virologically than all its comparators for years and years. I still remember the shock when we learned that EFV creamed indinavir -- a potent protease inhibitor, who would have predicted that? -- and subsequently it won or tied in numerous head-to-head studies. That success continued until the drug was compared to integrase inhibitors (in particular dolutegravir), but note that rates of virologic failure were still just as low with EFV even in this comparison. And is there any agent that so consistently does well in patients with high baseline HIV RNA and/or low CD4?
  2. Efavirenz has such a long half life that regimens with the drug are remarkably forgiving, even if people forget to take it every day. It's so forgiving, in fact, that studies suggest you can do fine taking it only 5 days a week, or at a reduced daily dose. Not that we recommend these strategies, but still -- we all have patients on EFV-based regimens who admit that they skip it periodically (usually because of side effects, but that's a different story), yet they maintain virologic control.
  3. Although no HIV treatment is cheap, TDF/FTC/EFV is less expensive than most of the other initial regimens we use today.
  4. Efavirenz (with TDF/FTC or TDF/3TC) is the default initial treatment globally, where it is widely available as a single pill taken once a day. That counts for a lot -- obviously the vast majority of people with HIV in the world don't live here.

So what's the issue? Why then is it now an "Alternative" rather than a "Recommended" option? In my opinion, it comes down to progress we've made in improving side effects. Many choices are available now that are simply easier for patients -- and clinicians, who can skip the time on pre-treatment education and management of tricky side effects. Specifically:

  1. All the clinical trials comparing EFV with integrase-based options demonstrate significantly lower rates of central nervous system (CNS) side effects with the latter. As already noted, in the head-to-head study against dolutegravir, drug discontinuations due to adverse events led to a superior result for DTG. The same thing happened when EFV was compared to RPV – in the low viral load stratum, RPV was superior because it was better tolerated.
  2. Virtually everyone who starts EFV gets some sort of CNS side effect of varying severity in the first week or two. Not a good idea to start the day (or even a week) before a big presentation, or travel, or some other major life event. In most patients, these CNS side effects diminish rapidly over the first few weeks of therapy. However, a minority still have some residual weirdness going on long term -- dizziness, abnormal dreams, morning grogginess. Some learn to live with it and are fine, but others don't realize how off they've been feeling until they stop the drug. (Brief aside -- what's up with the small fraction of patients who choose to take EFV during the day? That always perplexed me.)
  3. More serious CNS side effects can rarely occur, in particular depression. In this retrospective analysis of four randomized clinical trials, patients randomized to EFV-based regimens had a more than two-fold increased risk of suicide or suicidal ideation compared with those not receiving EFV. And while the absolute risk was overall low, this is a severe enough adverse effect that one should be very cautious about using the drug in anyone with a history of depression. Although observational cohort and claims data have not shown this association, remember that this is a tricky thing to find in such data, and that in clinical practice we avoid prescribing EFV to patients with psychiatric disease.
  4. Every ID/HIV doctor has had patients who just can't take this drug, and it's not from depression. OK, anecdote time -- here are a few of mine: The guy who drives for a living who knew immediately he wasn't as alert on the road taking EFV. The person whose dreams were so vivid that they were essentially indistinguishable from hallucinations (and not pleasant ones). The high-functioning scientist who simply couldn't concentrate at work. The person (actually a few) with severe rash and fevers. Of course some of the vivid dream stories were pretty funny -- my favorite was someone who dreamt that her kitchen had been extensively renovated, including specific selections of cabinets and appliances. Imagine her disappointment when she came downstairs to find the scruffy old kitchen unchanged!

Yes, I still have patients on EFV-based treatment who are doing great, and they don't want to switch -- that's fine, no reason to do so. But the bottom line is that I haven't prescribed TDF/FTC/EFV to a patient starting HIV therapy in nearly three years. Too many other good options out there now.

Hey, progress is a good thing!

I did this poll before -- now let's try it again, a year and a half later:

I still frequently use efavirenz-based regimens as initial therapy.

  1. True — still the gold standard.
  2. False — plenty of better options out there now.

[Editor's note: You can vote on this poll and view results by visiting the original blog post.]

Paul Sax is Clinical Director of Infectious Diseases at Brigham and Women's Hospital. His blog HIV and ID Observations is part of Journal Watch, where he is Editor-in-Chief of Journal Watch AIDS Clinical Care.