July 18, 2012
HIV therapy is a rapidly changing field. One might hope that more than 30 years of intimate experience with a virus might leave us with a firm sense of precisely how to treat it. But HIV has largely eluded easy answers, and antiretroviral therapy continues to evolve dramatically almost from year to year.
As a result, seemingly simple questions -- such as "When do I start my patient on antiretroviral therapy?" -- don't have simple answers. In this interview, I was honored to discuss this most fundamental of HIV treatment questions, along with other related issues, with two of the world's leading HIV specialists: Joel Gallant, M.D., M.P.H., a professor of medicine and epidemiology at the Johns Hopkins University School of Medicine and the associate director of the Johns Hopkins AIDS Service; and Paul Sax, M.D., the clinical director of the HIV Program and the Division of Infectious Diseases at Brigham and Women's Hospital, as well as the editor-in-chief of Journal Watch HIV/AIDS Clinical Care.
Both men are currently members of the panel of experts that periodically revises the bible of HIV treatment in the U.S.: the Department of Health and Human Services (HHS) antiretroviral therapy guidelines for HIV-infected adults and adolescents.
Table of Contents
Myles Helfand: It has not been a ridiculous number of years since U.S. HHS HIV treatment guidelines set 200 CD4+ cells as the threshold for starting treatment. And now, here we are: As of March of 2012, the guidelines have been updated to include a recommendation that people start treatment when their CD4+ cell count is above 500. What has led us to where we are now, in terms of the aggressiveness of when to start antiretroviral therapy?
Joel Gallant: Part of it is that the regimens and medications we have are so much better than the ones we had when the cutoff was 200. We used to expect inevitable toxicity with our antiretrovirals. That's no longer the case. We can usually treat with a single, daily dose of medications that are very well tolerated and have pretty minimal long-term toxicity.
In addition, I think we've come a long way from the days when we thought that the only bad thing that happened to you with HIV was that you had a low CD4 count, and that you got opportunistic infections and malignancies. We now know that HIV is a disease of inflammation; of immune activation that, over the long term, can cause medical consequences beyond those of the traditional list of opportunistic infections. These things are more independent of CD4 counts -- and more, perhaps, driven by viral replication. So there's a benefit to suppressing viral replication, regardless of what your CD4 count is.
And then, finally -- and maybe what tipped the scales over to this approach -- has been the results of HPTN 052, showing that antiretroviral therapy for positive patients is the most effective form of prevention that we have. And so when you combine the benefits to the individual who is infected, and the benefits to that person's sexual partners -- and to society, as a whole -- it seems like sort of a slam dunk.
Myles Helfand: Dr. Sax, anything you want to add to that?
Paul Sax: I'd just like to reinforce the last point that Joel said, and mention that it's had an interesting effect in the clinic: Even though it's a public health benefit, this prevention transmission, it turns out to be very motivating for your patients, also.
It's really unusual these days to have someone, once they hear that information, say, "Still, treatment's not for me." Because I guess, deep down, people understandably don't want to be contagious to others. They want to be less contagious. And so 052 -- even though it's kind of new, and we knew it was going to work -- still, having those results out there really changed things a lot.
One other factor is that there's a long-standing belief that, if you use your treatment now, when you're healthy, you're not going to have anything left when you're sick -- because of the idea that eventually everybody fails. But it really turns out that's not the case.
We now know that, over the long-term, people who are successfully treated can remain successfully treated, probably indefinitely, provided they continue their medications. The development of multi-class resistance is a thing of the past, and more linked to the inadequate therapies we had in the '90s than anything about treating HIV.
Joel Gallant: Yeah. In fact, there are some studies now that are showing that people who start with higher CD4 counts are less likely to develop resistance, and less likely to develop toxicity, than people who start with lower CD4 counts. So that just emphasizes the point that Paul made.
Myles Helfand: To what extent is that related to an increase in the potency of the regimens that we have, versus, say, increased levels of adherence, thanks in part to the proliferation of single-pill, once-daily regimens?
Joel Gallant: I think it's both. I think the regimens clearly are more potent; but they're also much easier to adhere to, because of their simplicity and greater tolerability.
In the past, people could do well with combinations of indinavir [Crixivan] and stavudine [d4T, Zerit] and lamivudine [3TC, Epivir], but it was really challenging. And the toxicity was really significant. So even the most adherent patients were going to have problems with those regimens.
Now, we're typically in clinical trials seeing efficacy rates of 90% or above, which is just unprecedented, compared to earlier regimens. It's a combination of the better drugs and easier adherence.
Paul Sax: The other factor is that the use of boosted protease inhibitors [PIs] had almost eliminated the whole issue of new onset protease inhibitor resistance. It's really remarkable, when you think about your clinic population and who the patients are in your clinic who have triple-class failure -- the old-fashioned, triple-class failure [i.e., to PIs, NRTIs and NNRTIs] -- and have high-level PI resistance. Really, none of them started treatment after 2001 or so, when lopinavir/ritonavir [Kaletra] became the standard PI.
So it's really uncommon to see any new cases like that. They do happen, but they're not happening frequently.