An ongoing dialogue on HIV/AIDS, infectious diseases,
April 8th, 2015
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:
- 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?
- 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.
- Although no HIV treatment is cheap, TDF/FTC/EFV is less expensive than most of the other initial regimens we use today.
- 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:
- 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.
- 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.)
- 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.
- 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:
14 Responses to “New HIV Treatment Guidelines, and the End of an Era”
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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As an HIV doctor practicing in a middle income country I suddenly found yesterday that most of the ARV treatment regimens prescribed in my country now correspond to the “alternative” category in the American Guidelines. An unintended consequence of this update in DHHS guidelines is that different standards are being established for HIV treatment in rich countries and the rest of the world which has happened before, but this time I suspect closing the gap will be harder.
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As a medical student, I just wanted to say thanks for your recent post; having an experienced person distill that huge amount of information is incredibly helpful.
I just have one question regarding your point on the long half-life of EFV and compliance issues. As a student on the ID floor, I was taught that one downside of Atripla is the low threshold of EFV resistance developing, which would affect NNRTI efficacy as a whole. Do you find this to be an issue with semi-compliant patients?
Yes, high-level resistance to efavirenz occurs with just one mutation — when it happens. The good news is that the regimen is so potent, and the half life so long, that you really need to have bad non-compliance to get resistance.
Paul
I am a Doctor In Brazil and, beleieve me, atripla has just arrived here as first line treatment in the NNRTI arm. The PI recommended for initial treatment is lopinavir/r. The problem is that we don’t have guidelines as in other countries. What we have here are strict recommendations. In other words, you are not free to make a choice of first line regimen. Unless your patient have adverse effects (rash, SNC side effects, etc) you can not chance the first choice!
To answer your “brief aside”: as a patient, I am more alert during the day taking EFV in the morning, because of the sleep disturbances that occur to me if I take it at bedtime. Just my personal experience.
I agree with Juan Sierra- Madero. In my country de initial HIV Treatment is EFV-based and I think it will be for longer time because the cost of DGV. I am from Argentina.
Paul,
Thanks for another great distillation of what I agree are some pretty sweeping changes to the guidelines. I have some very experienced HIV clinician-colleagues who are tried and true ‘Sustiva believers’ and actually kept prescribing it until the bitter end. I think the suicide risk was a big turning point for me.
And to Juan g’s comment:
“I suddenly found yesterday that most of the ARV treatment regimens prescribed in my country now correspond to the “alternative” category in the American Guidelines.”
I also have decidedly uncomfortable feelings whenever we enjoy great therapeutic advances in the US and Europe when so many of those with HIV on this planet have AZT/3TC/NVP, FTC/TDF/EFV or second-line LPV/r. I look to the effervescent excitement about TAF in the same way: How long after the approval of TAF will we allow TDF-based backbones to continue in Africa & Asia?
Thanks Paul for a great summary of the new guidelines. Like you, outside of a clinical trial, I haven’t started a patient on EFV in many years. The other point I think that is worth mentioning is the lipid effect. In spite of what we wanted, EFV was never a truly lipid friendly drug. CROI this year really reinforced the importance of addressing CV risk in HIV patients. I’ve had many patients over the years where a switch from EFV to a more lipid friendly agent had a very positive effect on the lipid profile. Ah… the end of an era. Now we just need some new young HIV providers!! Present company excluded of course.
Right on cue. Just in time before Sustiva goes generic? In the limited resources environment (s), I.E. county – state government health systems, efavirenz will continue to be utilized or at least tried in appropriate, individualized HIV therapy – for many patients, just like generic tenofovir disproxil fumarate will be (unless they quit making it or rather, never make it..tick tock, tick tock)…because of “the good stuff” above, albeit care teams in this setting will have to continue to keep in mind – monitor and individualize care because of the “not so good ADR potential”.
I too am a Physician in Brazil, and we have just in 2014 moved from inicially giving everybody AZT/3TC/EVZ to the better TDF/3TC/EVZ.
True that EVZ is hard on our population with comorbid psychiatric conditions (including drug and alcohol abuse).
But … in the populational level … and remember in Brazil we have universal TOTALLY FREE coverage of ART … it seems the TDF/3TC/EVZ is not a bad combo to start with, even more now that it is a single dose, once a day, pill.
We can change EVZ easily if psych comorbities show up or in the case of drug/alcohol abusers or in the case of adolescents.
The ratio: pill cost / (safety / harm / ease of use / viral supression / CD4 elevation)… will be for most low to high income patients (and countries) skewed to EVZ for a long time.
I ve just know my status and tried ARV for 3 weeks. In Vietnam TDF/3TC/EFV is first recommened. I got very very bad experience with my mood now. Everyday, when i take a nap at noon, there are alot lot images, strange throught it also inscrease my heart speed. But i have no choice. I dont know how long i have to wait for those friendly drugs come. there are 2 type of HIV treatment here in Vietnam. One is free (CD4<350), another is paid by patient (but its not expensive as in US because using generic one). Currenty, i cant take a nap at all always being despressed.
Hi ,
Long term effectiveness of Integrase inhibitors could become a major problem .
Ogata et al had shown that HIV mutants lacking Integrase were able to complete replication cycle and give rise to productive infection using HERV K 10 integrase .
This finding seriously challenges the long term viability of Integrase inhibitor based therapy. More research is required to evaluate activity of Integrase inhibitors against HERV K family of endogenous retroviruses and possibility of Transcomplementation between HERV K 10 and HIV -1 leading to eventual failure of Integrase inhibitor based therapy . HERV K viremia in patients with HIV/AIDS patients is a well known phenomenon .
DHHS may have gone overboard to recommend Integrase inhibitor based regimens especially Raltegravir and Elvitegravir based ones as they have low genetic barrier for development of resistance .
Besides short term efficacy long term durability of ARV regimens should be a prime consideration in designing ARV regimen for patients . Because first regimen is the best regimen and it should last as long as possible …
and on that accont PI based regimens outscore NNRTI or Integrase inhibitor based regimens .
Thanks .
[…] in Atripla was moved off the recommended list—a move he called, “a pretty big deal.” In an editorial posted to the New England Journal of Medicine’s Journal Watch, Sax says that, “it comes down to progress we’ve made in improving side […]
EFV will probably be used more in the future because of price difference between it and DVG.