HIV and ID Observations

In today’s New England Journal of Medicine, the SINGLE study finally makes its appearance “in print.”  (The study results were first presented over a year ago.) The highlights:

• SINGLE was a double-blind, randomized clinical trial comparing abacavir/lamivudine plus dolutegravir to tenofovir/FTC/efavirenz in 833 treatment-naive study subjects. That’s right, three different drugs in each arm — you don’t see that much in HIV clinical trials these days. 
• At 48 weeks, 88% of the dolutegravir group and 81% of the efavirenz group had HIV RNA < 50, making the dolutegravir arm superior. CD4 response also significantly better.
• The difference between the two arms was driven by more study drug discontinuations in those receiving the EFV regimen; virologic responses were similar.
• There was no resistance detected among those with virologic failure on dolutegravir.

Setting aside the NRTIs for now, we must again note that this is the very first time anything has beaten an EFV-based regimen, and it’s not for lack of trying.  Starting with its surprising defeat of indinavir way back in the 1990s, efavirenz has subsequently bested fosamprenavir, lopinavir/r, nevirapine, nelfinavir, and abacavir.

(And let’s not forget once-daily soft-gel saquinavir/r. That’s nine pills/day just for the saquinavir/ritonavir, yikes.)

The most any challenger could do was tie — see atazanavir/r, raltegravir, elvitegravir/cobicistat — or, in the case of rilpivirine, offset lesser antiviral activity with a better tolerability profile. In short, up until the SINGLE study, one could argue that EFV-based treatments — especially TDF/FTC/EFV — represented the gold standard against which all other regimens must compete.

Has that now changed?  I think it has.

Note that these SINGLE study results come out just as other data and clinical experiences have less forcefully nudged efavirenz off its perch on top of the HIV treatment world. Want a single pill for HIV treatment? There are now two other options, TDF/FTC/rilpivirine and TDF/FTC/elvitegravir/cobicistat, both of which have significantly lower rates of CNS side effects and rash; abacavir/lamivudine/dolutegravir is on its way as another option.

Furthermore, those efavirenz CNS side effects may not be so benign —  a study presented at this year’s IDWeek (disclosure: I’m a co-investigator) found that those randomized to efavirenz had twice as high a rate of suicidal ideation as in the non-efavirenz treatments. Yes, the absolute risk was low, but this is a much more serious adverse effect than the famous “vivid dreams” reported so frequently by those receiving efavirenz.

So what about the rest of the world? The World Health Organization Guidelines, updated just this summer, have this to say about initial regimens:

Once-daily regimens comprising a non-thymidine NRTI backbone (TDF + FTC or TDF + 3TC) and one NNRTI (EFV) are maintained as the preferred choices in adults, adolescents and children older than three years … TDF + 3TC (or FTC) + EFV as a fixed-dose combination is recommended as the preferred option to initiate ART

Which means we are far from seeing the end of the efavirenz era globally, where the drug is widely (and accurately) viewed as effective, inexpensive, and relatively well-tolerated. All good things.

Just not quite good enough anymore, given what’s out there as competition.

Your thoughts?