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Research Alert: Study Casts Doubt on "Shock and Kill" Cure Strategy

A Closer Look at the New U.S. DHHS HIV Treatment Guidelines for Adults and Adolescents (Part 2)

An Interview With Joel Gallant, M.D., M.P.H.

February 13, 2008

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This is part 2 of an update of the U.S. DHHS HIV Treatment Guidelines for Adults and Adolescents. For part 1, please click here.

On January 29, 2008, the U.S. government released the second part of its new HIV treatment guidelines. This second section contains antiretroviral recommendations. The guidelines have become the HIV treatment bible for U.S. health care providers and savvy people living with HIV. The guidelines contain a wide range of recommendations, including when HIV meds should be started, what regimens are preferred and what to do when someone has developed a lot of drug resistance.

The guidelines are updated about once or twice a year by a panel of 35 experts. The panel consists of HIV doctors and researchers, and even a few people living with HIV. Dr. Joel Gallant is not only one of the top clinicians and researchers in the United States, he's a guidelines panel member. Dr. Gallant is a professor of medicine and epidemiology at the Johns Hopkins University School of Medicine in Baltimore.

Joel Gallant, M.D., M.P.H.
Welcome, Dr. Gallant. Part 2 of the U.S. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents has been released.1 Can you walk us through the most important updates?

Sure. The most important part was the change in the what-to-start section for initial combinations for treatment-naïve patients. Perhaps one of the most important changes was that abacavir/3TC [lamivudine], or Epzicom, got promoted to a preferred regimen. It had previously been an alternative. Meanwhile, AZT/3TC [zidovudine/lamivudine], or Combivir, got demoted, if you will, from a preferred to an alternative regimen.

To Construct an Antiretroviral Regimen, Select 1 Component from Box A + 1 Component from Box B
This chart has been adapted from a similar chart from the U.S. DHHS HIV Treatment Guidelines for Adults and Adolescents. To view the complete guidelines, click here. (Large PDF)
So now the two preferred nucleoside backbones are: tenofovir/FTC [emtricitabine], or Truvada; and abacavir/3TC, or Epzicom. The reasons for this change are pretty obvious. I think the AZT/3TC got downgraded to alternative primarily because of the Gilead 934 study that demonstrated that tenofovir/FTC was superior, and also better tolerated, with less lipoatrophy, less anemia, less GI toxicity, and probably better lipid profiles than AZT/3TC.2

For reasons mainly of long-term toxicity and twice-daily dosing, AZT/3TC is no longer a preferred regimen. Which is really kind of an historic thing, when you think about it, given how AZT was the first antiretroviral drug available, and Combivir has been such an important backbone for so many years.

Sorry to interrupt, but would you clarify the ramification of these revised guidelines: Do the revised guidelines state that people who are currently taking an AZT/3TC-containing regimen should be taken off of it?

No, it doesn't say that at all. There are certainly reasons why you might consider that, given that the Gilead 934 study2 and other studies3 did show progressive loss of subcutaneous fat with continued use of AZT. The story is somewhat similar to what we saw with d4T [stavudine, Zerit], but perhaps not as rapidly progressive. You could certainly make a case for switching, not to mention the benefits of switching from a twice-a-day dose to a once-a-day regimen. That makes sense for a lot of people. But the guidelines certainly don't come out and say that you should switch. This section is talking about how to choose treatment options for a person who has never been on therapy before.

So, what about the promotion of abacavir/3TC, from an alternative to a preferred regimen? We knew, in previous versions of the guidelines, that Epzicom, or Kivexa, as it's called in some countries, was an alternative regimen, not because it wasn't effective, but because of the issue of abacavir hypersensitivity. Now that we can test for HLA-B*5701 that issue has subsided significantly.4,5 So, if you can test for HLA-B*5701, and use abacavir only in those patients who test negative, then the risk of hypersensitivity is low enough that it makes sense to consider this another preferred combination. The guidelines specifically state that abacavir/3TC is now preferred in those patients who have tested negative for HLA-B*5701.

People suspected that it would happen. You can never know for sure, of course, because the workings of the guidelines panel are not public until they become public. But everybody kind of assumed, I think, that this would happen, especially after the Sydney conference last year, where the data on HLA-B*5701 testing became so convincing that it really left very little room for doubt anymore about the utility of that test.4,5

Let me just point out that there were a few other changes. Ritonavir [Norvir]-boosted saquinavir got moved up on the basis of the GEMINI study.6,7 It was in a category that doesn't really exist anymore; that is, a category called "acceptable, but inferior to preferred or alternative components." On the basis of the GEMINI study it's now an alternative PI.

Then, in terms of options that are no longer recommended for initial therapy:

  • nelfinavir [Viracept]-based regimens;
  • d4T/3TC as a dual nucleoside component; and
  • the triple-nucleoside combination -- abacavir/3TC and AZT, [known by the brand name of] Trizivir.

Trizivir was kept on that list for a long time after it was shown to be virologically inferior.

It was. It was always considered kind of ... In the last set of guidelines, it was sort of an alternative to the alternatives. It was kind of in a funny category that really doesn't exist anymore; that is to say, it would be acceptable to use it if you couldn't use the preferred regimen, and you couldn't use the alternative, which didn't leave a very big place for it. But now it's completely off, altogether.

Before we move on, let me just point out some things that weren't discussed in the guidelines. That is, some of the newer drugs. So, darunavir [Prezista] is not listed there. Yet we do know that there are some emerging data on darunavir for treatment-naïve patients from the ARTEMIS study, where it looked very good at the dose of 800 mg plus 100 mg of ritonavir.8 But the ARTEMIS study is not mature; it hasn't been published yet. The numbers are still relatively small. So although I think a lot of us feel that darunavir will eventually have a place for treatment-naïve patients, it didn't seem like it was ready for primetime yet.

Similarly, raltegravir [MK-0518, Isentress], while there are data looking very good comparing raltegravir to efavirenz [Sustiva, Stocrin], that's still preliminary, unpublished data.9 So no recommendation was made regarding using raltegravir in treatment-naïve patients.

Then regarding maraviroc [Selzentry, Celsentri]: I don't think there's much enthusiasm for using that drug in naives because of the need for tropism testing and the somewhat lackluster results when it was compared to efavirenz.10 So, just to be aware that the guidelines committee is aware of these drugs. It's not that they are ignoring them, but they really need more solid data before they can make recommendations.

Reasons for Not Recommeding as Initial Therapy
This chart has been adapted from a similar chart from the U.S. DHHS HIV Treatment Guidelines for Adults and Adolescents. To view the complete guidelines, click here. (Large PDF)
OK. So, on to treatment interruption. What are the new recommendations? Or are they the same recommendations?

They've come out a little more strongly against treatment interruptions. Basically they say that, with the exception of interruption because the patient's too sick, or needs surgery, or something like that, they do not recommend treatment interruption for any reason, unless it's part of a clinical trial. Clearly, this comes from the SMART study, which just showed that people who interrupted therapy had all sorts of problems, in comparison with people who continued on therapy11 -- and not only in terms of loss of CD4 cells, but even in the development of conditions that we would have thought were toxicities of treatment, but in fact were things that happened to people off therapy. So the treatment interruption section is pretty definitive about saying that there's no place for a plan to treatment interruption, especially long-term treatment interruption, in people with HIV.

I notice there's a little bit of a new discussion regarding the selection of an NNRTI-based regimen versus a PI-based regimen for first-line therapy. Do we know yet which one is better, or more powerful? I know there are different studies that have shown different things.

I don't have that section in front of me to quote, so I'll just speak from my own opinion. First of all, I think it's hard to lump these categories together. So, for example, it's hard to just talk about NNRTIs, because basically you're talking about efavirenz and nevirapine [Viramune], and the data for efavirenz are much, much stronger than for nevirapine, in terms of just the quantity of studies and the results. So when we talk about NNRTIs here, we're really talking about efavirenz. Then, with boosted PIs, or with PIs, there are also differences.

We know from the 5142 trial that efavirenz outperformed lopinavir/ritonavir, or Kaletra, in most ways, at least in terms of virologic efficacy.12 It seemed to also reduce viral load more rapidly, to suppress viral load more rapidly.

On the other hand, there were advantages to the use of lopinavir/ritonavir, in terms of CD4 response. There are other data from other studies suggesting that people on boosted PIs may have somewhat better CD4 response than people on efavirenz.

Also, in terms of the consequences of failure: Patients in 5142 were less likely to have failed efavirenz, but if they did fail it, they had greater resistance consequences than if they failed lopinavir/ritonavir.

To me, it makes it kind of a toss-up. If I had to say -- from a purely virologic perspective -- what the best drug is to use right now, I'd say it's efavirenz. But there are some real-world considerations that might cause you to choose a boosted PI. One would be in patients, where you're worried about their adherence, and it seems like a treatment interruption is likely to occur in their future; those people might be better off on a boosted PI because of the issue of resistance.

Then there are people who start out with zero T cells. Some of them do great with efavirenz and have very good CD4 responses. But we also see people who sort of get stuck at low CD4 counts. I think there's some data suggesting that they may have better CD4 responses with a boosted PI.12

The question, I guess, is: Should that influence your decision of which drug to use, or should you just go ahead and use what should be used, i.e., efavirenz, if that's the one you want to use, and then see what happens? Then, if the patient doesn't have a good CD4 response, consider switching. We don't have a lot of data on that approach. But some data suggest that that approach may work. I think it's impossible to say that one is better than the other. You really have to individualize based on the patient.

One thing I think we can say for sure -- and I hope we can put to rest this idea that I still hear people saying, that if you have a patient with advanced disease, a high viral load or a low CD4, then you must use a PI -- that is an antiquated notion that has been put to rest by studies like 509513 and 5142.12 Certainly, the height of the viral load should not influence your decision in that sense.

I see that the guidelines mention the question of whether there are benefits to treat someone during acute infection. Can you talk about that?

Yes. I don't have that section right in front of me. I don't remember there being a lot of new information, or a lot of big changes, in terms of that discussion. It's still an open question. It's why there are clinical trials, trying to decide whether there is a benefit to early treatment. There's certainly plenty of hypothetical evidence to suggest there might be a benefit. But we don't have the clinical data to say that this is helpful.

Then, the other question, of course, is if you do decide to start treatment in early infection, how long do you continue it? In the light of the SMART data,11 we are now nervous about discontinuing therapy. Yet, it seems kind of funny to commit somebody to life-long treatment, just because they started very early.

We desperately need clinical data. That's why I strongly encourage people who identify patients at that stage to refer them to clinical trials when they are available.

One of the things that the guidelines panel mentioned was that because a newly infected person is much more likely to be resistant to NNRTIs than PIs, if you're starting somebody on therapy with acute retroviral syndrome and you've ordered a genotype that will take a few weeks to get back, you're probably better off starting someone like this on a PI-based regimen, at least until you get the genotype results back. Putting patients on an efavirenz-based regimen could be risky, if they turned out to have been infected with a non-nuke-resistant virus. The reason for this is that it only takes one mutation to be resistant to non-nukes, whereas you'd have to have multiple mutations to be resistant to a PI.

You're actually quoting from the guidelines now.

That last thing I said is definitely from the guidelines.

I wanted to make sure people understood what was in the guidelines and what was not. I noticed there was a whole new section updated about tuberculosis. How common is that in the United States right now?

Well, certainly not as common as in the developing world. But we do see a lot of TB, especially in inner city populations and immigrant communities.14 So it's definitely something that people need to be aware of.

What are the new recommendations?

One recommendation regards skin testing. The guidelines point out that because a TB skin test can be falsely negative in people with low CD4 counts, they recommend that if you did a test with a CD4 below 200, and then they've responded to therapy, that you repeat the test after the response. That would give you a more accurate result.

Then, the guidelines discuss the issues of when to start antiretroviral therapy in people with active TB. I don't think they come out with a solid recommendation. There are a lot of issues here. Certainly one of them is drug interactions between rifampin and antiretrovirals. The other is the real potential for immune reconstitution inflammatory syndrome, or IRIS, in people who start antiretroviral therapy during active TB. So, in many cases, it's felt better to wait, start TB therapy first, and then wait to start antiretroviral therapy until you've reduced the disease burden from TB and minimized the risk of virus.

On the other hand, studies from Africa have shown that in people who wait too long, especially if their CD4s are very low, there's a higher mortality.15,16 Now, that mortality may not apply here, in places like the United States, but it is something to consider, especially if somebody is diagnosed with TB at a very low CD4 count. So the discussion goes into the risks and benefits of early, versus delayed, antiretroviral therapy in that setting.

Have the recommendations changed at all, regarding coinfection with hepatitis B or C?

I don't believe there's been a big change. Of course, with hepatitis C, there have really never been any specific issues about which antiretrovirals you choose. With hepatitis B, of course, there are, because you want to be using hopefully two drugs that have activity against both HIV and hepatitis B. Usually, that would be tenofovir plus FTC, or perhaps tenofovir [Viread] and 3TC [lamivudine, Epivir].

The guidelines point out the risk of discontinuing that HBV active therapy because of the risk of a flare-up of hepatitis. So that's the main thing. That's not particularly new, but I think it's just worth remembering that we need to try to be using two drugs and remembering also that entecavir [Baraclude] has now been shown to have anti-HIV activity, as well. So you don't want to be using entecavir without a fully suppressive HAART regimen in somebody who's coinfected.

I guess we've covered all the most important new things in the guidelines.

I think so, yes. Because in the last conversation, we talked about the other updates to the guidelines, which were about when to start therapy.

When do you think there will be another revision in the guidelines?

Boy, I don't know. It depends on how rapidly the data come out. I think there are still some sections of the guidelines that are being worked on. You know, this is always a work in progress. Rather than coming out with one, final version all at once, they come out with the new sections as they are developed. But of course, you know, the when-to-start and what-to-start-with sections of the guidelines have always probably been the ones that get quoted the most widely, and that are referred to most frequently. So I think we're in a situation now where those two sections are pretty up to date.

But of course, over the course of this year I'm sure we'll see more data about raltegravir in naives and darunavir in naives. So by later in the year, these recommendations may already be dated and we'll have to update them again.

Dr. Gallant, thank you so much for taking the time to talk to me!

You're welcome. It's great to talk to you, Bonnie.

This is part 2 of an update of the U.S. DHHS HIV Treatment Guidelines for Adults and Adolescents. For part 1, please click here.


References

  1. The DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Office of AIDS Research Advisory Council, US Dept of Health and Human Services; January 29, 2008.
  2. Pozniak AL, Gallant JE, DeJesus E, et al, for the Study 934 Group. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes -- a 96-week analysis. J Acquir Immune Defic Syndr. December 15, 2006;43(5):535-540.
  3. Haubrich RH, Riddler S, DiRienzo G, et al, and the AIDS Clinical Trials Group 5142 Study Team. Metabolic outcomes of ACTG 5142: a prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 38.
  4. Mallal S, Phillips E, Carosi G, et al. PREDICT-1: a novel randomised prospective study to determine the clinical utility of HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects (study CNA106030). In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS101.
  5. Saag M, Balu R, Brachman P, et al. High sensitivity of HLA-B*5701 in Whites and Blacks in immunologically-confirmed cases of abacavir hypersensitivity (ABC HSR). In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEAB305.
  6. Walmsley S, et al. Saquinavir/r (SQV/r) BID versus lopinavir/r (LPV/r) BID, plus emtricitabine/tenofovir (FTC/TDF) QD as initial therapy in HIV-1 infected patients: The GEMINI study. In: Program and abstracts of the 11th European AIDS Conference; October 24-27, 2007; Madrid, Spain. Abstract PS1/4.
  7. Slim J, Avihingsanon A, Ruxrungtham K, Schutz M, Walmsley S. Saquinavir/r (SQV/r) BID vs lopinavir/r (LPV/r) BID plus emtricitabine/tenofovir (FTC/TDF) QD in ARV-naive HIV-1 infected patients: GEMINI Study. In: Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, United Kingdom. Abstract PL2.5.
    View slides: Download PowerPoint
  8. DeJesus E, Ortiz R, Khanlou H, et al. Efficacy and safety of darunavir/ritonavir versus lopinavir/ritonavir in ARV treatment-naive HIV-1-infected patients at week 48: ARTEMIS. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, Ill. Abstract H-718b.
    View slides: Download PowerPoint
  9. Markowitz M, Nguyen B-Y, Gotuzzo E, et al, and the Protocol 004 Part II Study Team. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment HIV-1 infected patients: 48-week data. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB104.
    View slides: Download PowerPoint
  10. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: week 48 results of the MERIT study. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS104.
    View slides: Download PowerPoint
  11. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. November 30, 2006;355(22):2283-2296.
  12. Riddler SA, Haubrich R, DiRienzo G, et al, for the AIDS Clinical Trials Group 5142 Study Team. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection -- ACTG 5142. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0204.
    View slides: Download PowerPoint
  13. Gulick RM, Ribaudo HJ, Shikuma CM, et al, for the AIDS Clinical Trials Group Study A5095 Team. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. April 29, 2004;350(18):1850-1861.
  14. Albalak R, O'Brien RJ, Kammerer JS, et al. Trends in tuberculosis/human immunodeficiency virus comorbidity, United States, 1993-2004. Arch Intern Med. December 10, 2007;167(22):2443-52.
  15. Fairall LR, Bachmann MO, Louwagie GM, et al. Effectiveness of antiretroviral treatment in a South African program: A cohort study. Arch Intern Med. January 14, 2008;168(1):86-93.
  16. Moh R, Danel C, Messou E, et al. Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIV-infected adults in West Africa. AIDS. November 30, 2007;21(18):2483-2491.



This article was provided by TheBodyPRO.com.
 
See Also
Read the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (PDF)

 

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