On Nov. 3, 2008, the U.S. government updated its Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. These guidelines were last updated on Jan. 29, 2008. We asked Joel Gallant, M.D., M.P.H., to provide a summary of the changes. Dr. Gallant is not only one of the top clinicians and researchers in the United States, he's also a guidelines panel member.
Can you walk us through the most important updates to the guidelines?¹
Probably the most important updates had to do with what to start treatment-naive patients on. There were several major changes. One is that once-daily ritonavir [Norvir]-boosted darunavir [TMC114, Prezista] was added as a preferred PI [protease inhibitor] component based on the published results of the ARTEMIS data.² Also, once-daily boosted lopinavir [Kaletra] was moved from an alternative to a preferred PI component based on the recent Abbott trial comparing once- versus twice-daily lopinavir.³ The only exception in this change is in pregnant women, where there's concern about lower lopinavir levels in the third trimester of pregnancy.
The other big change was that the dual nucleoside combination of abacavir and lamivudine [Epzicom, Kivexa] was demoted from a preferred to an alternative nucleoside component because of data from both the SMART⁴ and D:A:D studies⁵ suggesting an increased risk of myocardial infarction [MI] in patients with a lot of cardiac risk factors, and also because of ACTG 5202,⁶ which suggested that there was a lower efficacy in patients with a baseline viral load greater than 100,000 [copies/mL].
Those would be the most important ones, but there were a few other changes that are worth noting.
About the abacavir/lamivudine change, was that the fastest entry and exit of an agent from the preferred guidelines?
Yes. That was pretty amazing, because the guidelines had promoted it to a preferred component⁷ just as the data from D:A:D⁸ came out and just as the press release about the 5202 study had come out.⁹ All of those happened in the same month or so. As soon as those data came out, the guidelines panel had to begin reviewing the data and it really became consolidated in Mexico City at the International AIDS Conference when the actual 5202 data were presented⁶ and then we heard about the SMART data recapitulating the data from D:A:D.¹⁰ It had a brief presence in the preferred list; it didn't last very long.
Can you talk a little bit about why this change was made? There must have been a lot of discussion about removing abacavir/lamivudine from the preferred list. Was the change made more because people starting treatment with a viral load greater than 100,000 copies/mL failed on abacavir [Ziagen]-containing regimens in the 5202 study or because of the results from D:A:D and SMART that found more heart attacks in people taking abacavir?
It's really a combination of all of those things. The view is that each one of those studies is a little red flag. When we get three red flags like that, it's something we have to take seriously, even if we don't completely understand the results.
ACTG 5202 was a very large study comparing efavirenz [Sustiva, Stocrin] versus boosted atazanavir [Reyataz] and the combinations of abacavir/3TC versus tenofovir/FTC [Truvada].⁶ The data safety monitoring board stopped the study in the group of patients who started treatment with a viral load greater than 100,000 [copies/mL] because they were significantly more likely to fail on abacavir/3TC than tenofovir/FTC.⁹
The results were quite significant. Although we haven't seen this in any other studies, we haven't ever had a study this large with this many people who have a high baseline viral load.
This is obviously concerning. We don't have the final results of ACTG 5202 yet. We don't know what's going to happen in the group that started treatment with a viral load less than 100,000 [copies/mL]. But in the past, drugs that have performed less well at high viral loads have generally turned out to be less effective overall. It's too early to say whether that will be true in the case of abacavir/3TC.
Then there were the D:A:D⁵ and SMART results.⁴ These results are more complicated and less clear-cut because these are not results from a randomized controlled trial, but from observational data. Still, when you have two different studies show a significant increase in risk of heart attack with a drug, you have to pay attention. We don't have a mechanism for this. It's unexpected. We don't understand it. But it seemed pretty clear that -- especially in patients who started out with risk factors for heart disease -- there was an association with a higher risk for MI with abacavir use.
Taken together, all three of these studies raise concerns. They certainly don't mean that abacavir/3TC shouldn't be used. In many patients, this would be the preferred regimen even though it's not listed as preferred in the guidelines.
For example, somebody who had some renal insufficiency but did not have cardiac risk factors would be, probably, much better off on abacavir/3TC than on tenofovir/FTC. It's very important to stress the fact that "alternative" doesn't mean "bad." This is not being put into the category of drugs like d4T [stavudine, Zerit] that you really shouldn't use. It just means that if all else is equal and there's nothing stopping you from using tenofovir/FTC, then you would use that. If you have a reason not to use tenofovir/FTC, then you could certainly use abacavir/3TC.
I think people think there's a bigger chasm between "preferred" and "alternative" than there is.
Alternative regimens are perfectly acceptable regimens. They're regimens where we have a reasonable degree of confidence in their efficacy and safety. They're just not the first things you go for.
I look at it like this: If I had a patient sitting in front of me who had absolutely no contraindication to using tenofovir/FTC, why would I pick abacavir/3TC? I wouldn't. I would use tenofovir/FTC.
In contrast, the reverse is not true. If I had a patient who had no contraindications to abacavir/3TC or tenofovir/FTC, given what we know now, I would always pick tenofovir/FTC. If you think that way -- and I think it's appropriate to think that way -- then it's logical that tenofovir/FTC becomes the preferred regimen.
But, like I said, in many patients, abacavir/3TC is preferred over tenofovir/FTC because of patient characteristics, primarily concerns about kidney function. It's not at all to say that it's inappropriate or wrong to use abacavir/3TC, but I just think that the default nucleoside backbone at this point is tenofovir/FTC. You would use abacavir/3TC in people who are not appropriate candidates for tenofovir/FTC and who don't have multiple cardiac risk factors.
There are certainly people who are not good candidates for either of those two nucleoside backbones because, in fact, many cardiac risk factors are also kidney risk factors and vice versa. We don't really have good guidelines on what to do with those people. One option might be to consider a regimen that did not include any nucleoside analogs.
That's not even on any list.
Right. It isn't, because there's not a lot of data right now. But we do have some data about nuke-sparing regimens, and with the recent approval of raltegravir [Isentress],¹¹ the number of nuke-sparing regimens has increased. We'll just have to see what happens with the data that are being collected now.
Was there a lot of discussion about this change? Was it one of the most debated issues regarding these new guidelines?
I can't speak for the panel, because what goes on in the panel is not for public consumption. I can say that there have been plenty of comments coming to the panel during the open comment period about this choice -- certainly, there are people and drug companies who've disagreed with that decision.
Most of the disagreement, I think, has come because of this misunderstanding of what the term "alternative" means. Many people have said, "How can you leave us with just one nucleoside option?" The point we're making is: We're not leaving people with one nucleoside option. There are several nucleoside options, just one happens to be preferred.
I guess there is a lack of clarity regarding the terminology.
Yes. I think so. Remember, there is a category in the guidelines of regimens not to be used and drugs not to be used. This is certainly not in that category.
I can't remember if it's still there, but there used to be a category of alternatives to the alternatives. Trizivir [zidovudine/lamivudine/abacavir] used to be in that. You can do a lot worse than being an alternative regimen.
You should change the wording to "best," "better," "good" and "fair."
[Laughs.] It could be like a Starbucks thing. Everything's at least big if not more so.
Now that we have discussed a deletion from the list of preferred antiretrovirals, let's discuss an addition -- the spanking new protease inhibitor darunavir.
It was approved recently¹² and the 400-mg formulation came out based on the 48-week data from ARTEMIS,² which have been published now, showing non-inferiority compared to lopinavir/ritonavir and actual superiority when you looked at those with a baseline viral load greater than 100,000 [copies/mL].
We've recently heard the 96-week data,¹³ which confirmed the 48-week data. Those data were presented at ICAAC [48th Annual ICAAC/IDSA 46th Annual Meeting], but those data were not being considered in this version of the guidelines.
Could you talk a little bit about the regimen simplification section? It's the only meaty section that was added.
It's a nice section. It talks about how you might simplify therapy in a variety of patient populations. It is based on all of the new data that we have about newer, simpler regimens -- nowadays most treatment-naive patients really should be on a simple once-a-day combination with very few pills, and even treatment-experienced patients with drug resistance often can be treated with fairly simple regimens.
We have a lot of people out there who are on these older regimens that were in vogue in the past, but are probably no longer necessary. For example, somebody without any drug resistance could be switched over to a once-a-day regimen. Single drug switches or switches within classes can often make a lot of sense. The guidelines also talk about patients who do have suspected drug resistance and what considerations you might give for those patients.
I think the bottom line from that section is to convince people that the notion "if it ain't broke, don't fix it" should not be a motivator for how we practice.
There's nothing wrong with improving the simplicity, convenience or tolerability of a regimen, even if the original one is working virologically. Patients who are doing well virologically can still expect to be changing therapy as we get new data about better, more convenient, better-tolerated or less toxic regimens.
But don't you think that a lot of clinicians are reluctant to open that can of worms? Many providers are already managing too many patients. Many may worry that they'll see their patients experience a whole new set of side effects and other problems.
It may be a little more work in one visit, but ultimately it's often better for the patient. Personally, I would find my practice extremely boring if all I did was just keep people on the same regimens year after year. The thing that is interesting to me is trying to figure out how I can optimize a regimen for a patient. If all I do is write a prescription and that's the end of it and I never have to rethink my decision, I'd get pretty bored.
What's interesting about this simplification section is that it finally gives permission to health care providers to change people's regimens even if they are working -- focusing not on viral control but on quality-of-life issues. It also acknowledges that the new HIV regimens are much easier to take than the older regimens.
Yes, exactly. It's very discouraging to me when I see somebody who's still on a thymidine analog and developing worsening lipoatrophy that could have been completely prevented had the clinician been willing to make a simple switch to a preferred option. There's no reason for that. That's an example of an iatrogenic complication that's completely unnecessary.
Is there anything new in the guidelines that people who follow all the HIV meeting news would not have expected or heard about?
No, probably not. If you were really up to date, you would probably have anticipated that these changes would have been made. There were a few changes that might have escaped people's notice because the studies were smaller.
For example, it's no longer recommended that the combination of unboosted atazanavir, ddI [didanosine, Videx] and FTC [emtricitabine, Emtriva] or 3TC [lamivudine, Epivir] be used, because of concerns in a large ACTG study.¹⁴ Of course, that's probably not a regimen people were using much of anyway.
Then there were three very small studies looking at the combination of nevirapine [Viramune], tenofovir [Viread] and either FTC or 3TC that showed concerning high rates of virologic failure and resistance.¹⁵⁻¹⁷ Because those studies were so small, the current change in the guidelines says not that the combination shouldn't be used, but that it should be used with caution until we have the results of an ongoing trial that's looking at that combination.
But I think that most people could have anticipated the changes made with respect to darunavir, once-daily lopinavir and abacavir/3TC. Although there's still some controversy, I think the decision to make those three changes was correct.
I noticed there were some tweaks in the HIV monitoring recommendations with respect to things like resistance testing for people with low viral loads.
We've usually said that you should do resistance testing when someone's viral load is greater than 1,000 [copies/mL]. The problem with that is it requires leaving people on failing regimens for quite a long time before doing the resistance test. During that time while you're waiting, they may be developing new resistance mutations.
The new guidelines say that you could consider resistance testing if a patient's viral load is 500 to 1,000 [copies/mL]. That's because we can often get resistance tests at that level. In fact, the Monogram assays actually list 500 as their cutoff. There is the risk that you won't get a result. But at the same time, you may get a result that could be helpful and could allow you to intervene before more resistance has time to occur.
I noticed there was also a note about the enhanced tropism assay.
Yes. The new tropism assay, which is the one you would get if you ordered the tropism assay now from Monogram, has a much higher sensitivity for detecting dual/mixed or X4 virus than the previous version.¹⁸ The sensitivity is now 99.7%. As a result, you can be much more confident that if the assay comes back showing R5 virus, that's indeed what the patient has. There was a concern with the earlier assay that you could be falsely reassured by the results and then the patient could fail maraviroc [Selzentry, Celsentri] due to the selection of pre-existing dual/mixed virus.¹⁹ While that could still happen, it's much less likely to happen now.
Didn't we just hear some important news from ICAAC about when to start therapy²⁰ as well as interesting data about raltegravir [MK-0518, Isentress]?²¹ How soon will that information make it into the guidelines?
It's a good question. It's important to point out that even though this revision of the guidelines came out after ICAAC, people shouldn't be confused and think that they reflect the data from ICAAC. It takes much longer than that to revise guidelines based on new data. All these changes reflect data that came out up until Mexico City and the International AIDS Conference. Of course, the guidelines really wait for published data rather than just looking at presented data.
The data we heard from ICAAC specifically about the use of raltegravir in treatment-naive patients will certainly be considered by the guidelines panel, but I doubt that we'll see any changes until the panel has had a chance to review the publication that comes out based on that study.²¹ The same is true for things like the NA-ACCORD observational study [looking at the risks and benefits of initiating antiretroviral therapy at a CD4+ cell count between 350 cells/mm³ and 500 cells/mm³ instead of at 350 cells/mm³], which could potentially affect the "When to Start" section of the guidelines but, again, we'd have to wait for publication of those data.²⁰
Do you think the guidelines have become a little bit more responsive to HIV research in the Internet age? For many years, it seemed the guidelines were a little bit behind the savviest HIV specialists.
Yes. I think they're very responsive. I've only been on the panel for a short time and I've been impressed at how quickly they can turn things around. But keep in mind that the guidelines have worked this way for a long time. They don't just come out once a year or once every couple of years. They're constantly evolving based on monthly meetings of the panel. Because the guidelines are not being released in journals or publications -- they're being published on the web -- we don't have that publication lag. You could argue that somebody who's really keeping up with things might be a step ahead of the guidelines, but not too far ahead. I think that this is a pretty up-to-date document.
I noticed in the newest guidelines a note stating that for two weeks after an update to the guidelines -- so two weeks after November 3, which was the date of the release -- the public can submit comments to the panel. Do you get a lot of comments?
They don't come to me, of course, they come to the guidelines committee. But we certainly are told about comments that are relevant that we need to consider in deciding whether we've made the right decisions or not. That's always been the case. That opportunity for public comment has been the case for as long as I can remember. The comments are certainly taken seriously.
Do you think that there are health care providers who still do not refer to the guidelines and use outdated treatment regimens? Do you have any ideas on how these guidelines can be better utilized?
Well, boy, we sure try to make it easy! Granted, it's a big document. But the good thing about any updated treatment guideline is that there's always a summary of the changes, so you don't have to go through the whole document to find out what's been changed. If you want to take a short cut, you can go directly to the tables. For example, the "When to Start" or "What to Start With" table. I believe that the document is an incredibly useful summary of treatment and of the current data. But for those of you who are too busy, you can go straight to the tables.
I get concerned when I hear that people are still prescribing things like AZT/3TC [zidovudine/lamivudine, Combivir] and nelfinavir [Viracept], which has not been preferred now for quite some time. There is clearly an inertia, especially among less experienced clinicians. I think those are exactly the types of clinicians who need to use guidelines because they're not able to keep up with the primary sources of data and really need somebody to help distill this down for them.
Isn't there still the recommendation that if you're not an HIV specialist you should consult with one?
It's certainly my recommendation. I think that everybody with HIV should have some connection with an HIV expert, even if they're being managed by a primary care physician. There should be some sort of consultation, at the very least.
One problem is that there simply aren't enough HIV experts out there to provide regular care for everybody with HIV. So we may have to come up with new models of how that might work. I don't think that it's necessary, for example, that everybody with HIV be seen every three months by an HIV expert. But I do think that when primary care clinicians are managing people with HIV, they need to have someone they can go to and, preferably, someone who's actually met and evaluated the patient.
We've come to the end of our time. Thank you so much, Dr. Gallant, for taking the time to talk with me.
This transcript has been lightly edited for clarity.
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