An Interview With Joel Gallant, M.D., M.P.H., and Paul Sax, M.D.
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The U.S. vs. Great Britain (and the World)
Myles Helfand: You mentioned HPTN 052 and this increasing awareness that "treatment as prevention" is a real, actual thing -- it's a viable strategy for helping prevent the further spread of HIV. The British HIV Association relatively recently updated its own treatment guidelines, and specifically avoided a recommendation that people start HIV treatment at greater than 500 CD4+ cells.
Dr. Sax, why are the U.S. guidelines more aggressive than the British guidelines in that sense?
Paul Sax: I think it's a matter of degree. First of all, there is unanimity among HIV specialists that, if you have limited resources for paying or covering antiretroviral therapy, you get much more benefit per person if you delay treatment. That's excluding the transmission piece. So if that's the case, then actually recommending therapy only for people with lower CD4s makes sense.
But if you look at it differently -- if you say, "Well, we do have the resources to pay for these treatments (and I would argue we do), then there is benefit accrued along the entire CD4 spectrum. The one that's most obvious are people with AIDS; but then, of course, there are these other benefits at higher CD4s that Joel has alluded to.
So I think it has a lot to do with resources. We have problems with our health care system in the United States. No one needs to go through them. But one of the problems we don't have -- at least right now, knock on wood -- is paying for HIV treatment among those who are in care.
Myles Helfand: I don't know if the people on ADAP [AIDS Drug Assistance Program] waiting lists would necessarily agree with that, though.
Paul Sax: Well, let's take a look at that. I think it's reasonable to drill down and say: How many people in the United States who are in care are actually denied HIV therapy?
And the number is actually very small, even in the worst-case states -- you know, the southeastern United States. I would argue it's much lower than people who are denied care for other health care conditions than it is for HIV. So, by contrast, if you talk about some of the very expensive biologics to treat rheumatoid arthritis, or you're talking about neurologic conditions that have very expensive treatments, that's much less likely to be covered than HIV therapy.
One reason why we've been so good at having a system for treating HIV is because treatment is so darn effective. It's very hard to argue against it.
So, yes: There are individual cases and individual states where there are waiting lists. But those are relatively small numbers, given the size of this country.
Joel Gallant: One of the issues is that some of the benefits that we accrue by treating very early may be benefits that you wouldn't notice in the short term. It's not that you're going to prevent people from developing pneumocystis, but that you may be lowering a long-term risk of things like cardiovascular disease or bone disease. We may not see those benefits for several decades. And, of course, when people who control the purse strings make decisions, they're not really interested in those long-term benefits.
But there's also the financial benefit of preventing transmission, since it's obviously much cheaper to prevent a new case of HIV infection than to treat it for life. Paul has more experience with cost effectiveness analyses than I do, but there have certainly been people who have looked at the cost effectiveness of treating to prevent HIV and it's generally come out to be very favorable.
Myles Helfand: Yet then we look at WHO [World Health Organization] guidelines, which are about as conservative, relatively speaking, as you can get when it comes to HIV treatment guidelines globally. There's been a lot of discussion over this, seen over the past few years, regarding the nature of WHO guidelines, and to what extent they should be capitulating to public health and policy realities, versus just saying, "This is what people need."
You had mentioned just a little bit earlier, Dr. Sax, that if we have the resources to be able to pay for treatment that we should do it. Why wouldn't treatment guidelines be irrespective of the ability to pay?
Paul Sax: Well, that's a very interesting debate -- whether guidelines should include issues of cost and resource allocation. I'm of the opinion that introducing that topic is important.
But we do live in that finite world, as far as resources are concerned -- don't get me wrong. For example, the use of tesamorelin [Egrifta] for visceral adiposity is not generally covered in AIDS Drug Assistance Programs. But at least here we have a fairly good system, as fragile as it might be, to pay for treatment for everyone.
If you don't have that -- and internationally they don't, and they have to prioritize -- you really do get much more bang for the buck by treating people with more advanced disease.
Interestingly, there's this paradox: In resource-limited settings there are more aggressive opportunistic infections that occur at higher CD4 cell counts, [and thus] the benefit, as far as preventing AIDS complications, is greater in those settings than it is in the United States. Which is one reason why, even after HPTN 052 showed a clinical benefit for people with CD4s greater than 350, some people have said, "Well, that's only because those are mostly cases of tuberculosis. How can you show that same benefit in Western Europe and in the United States, where there's much less TB?" And that is a fair argument.
Joel Gallant: On the other hand, there's also greater risk in toxicity to early treatment in a developing country setting than there is here. For example, in most of the countries that the WHO guidelines are written for, typical starting regimens involve d4T or AZT [zidovudine, Retrovir], which we don't use much. If they're monitoring viral load at all, it's very infrequently, so patients often have pretty extensive resistance by the time they've moved to second-line therapy.
So, in that setting, under those conditions, it probably wouldn't make sense to treat at very high CD4 counts. Because you're putting patients at great risk for relatively small benefit.
In contrast, here in the U.S., where the regimens are very safe and we have good monitoring, there is a benefit that outweighs the risk.
Paul Sax: Yeah. There's a really nice paper that was just published in AIDS, looking at the response to ART [antiretroviral therapy] in sub-Saharan Africa, and looking at how a CD4 greater than 500 appears to confer an even greater benefit there than it does in the U.S.
When Not to Start Therapy
Myles Helfand: OK. So, here in the U.S., the guidelines now unanimously recommend that therapy be initiated at any CD4+ cell count, which is a pretty ubiquitous recommendation. But what are the exceptions to that rule?
Are there cases in which a clinician, on a case-by-case basis, should be second-guessing that? Or should they think, "As soon as somebody comes into my clinic" -- or my hospital, or my practice -- "and is either diagnosed with HIV or just presents with HIV, I need to start them on treatment"?
Joel Gallant: Well, remember, it's not a rule, it's a guideline, a recommendation. And I think one of the most obvious exceptions would be somebody who is simply not ready to start -- who either doesn't want to start or who is going to have problems adhering to therapy.
In patients with very high CD4 counts, this is never an emergency. So you have time to prepare the patient and to make sure that everything's set up to maximize adherence. We shouldn't look at this as something that has to be done on the first visit. Patients need to buy into this, and be ready to do it.
The other exception for me would be the elite controller who has a high CD4 count -- the person whose viral load is already undetectable and the CD4 is stable and normal. It's possible there could be some benefit to treatment for those people, but it sure is going to be hard to prove it.
Myles Helfand: How can a clinician know whether a person is going to be an elite controller? Is it necessarily an indication if they present with a high CD4+ cell count -- say, above 600 -- and an undetectable, or very low, viral load? That doesn't necessarily mean they are an elite controller, right?
Paul Sax: No. Absolutely right. We all have had experiences -- in particular, people with recently acquired HIV, where they start out with very favorable-looking prognostic numbers, both by clinical experience and cohort analyses, and they get virologic escape from the immune control. That can occur over time. There's no easy way to tell whether someone's going to end up having that phenotype permanently.
There are some correlates, like the HLA-B*5701 -- ironically, the same one that goes along with abacavir [Ziagen hypersensitivity] -- and the CCR5 heterozygotes. But nothing absolute.
Joel Gallant: Of course, you don't need to be able to predict the future. You can simply say, "I'll treat when there's either CD4 progression or viral escape."
Myles Helfand: Well, how do you balance? Is there a checklist that a clinician can go down, where he or she begins to say, "The CD4+ cell count is 350; now I begin pressuring the patient and talk to the case manager about getting the patient more effective support"? How do you begin to make that differential between "OK, this person is fine; I don't need to push too much" and "This person really needs to get into treatment"? Dr. Sax, let's go with you.
Paul Sax: This is going to sound perhaps overly obvious. But there are people that you really have to twist their arms, because you have to remind them that even though they feel well, HIV is still potentially a fatal condition, and AIDS is a fatal condition; and that, in order to avoid that, they'd have to go on antiviral therapy.
Most of the time, you can make the case very persuasively and get people to buy into treatment. I like the way Joel phrased it before: It's for those people where the urgency of starting is considerably greater.
You can either use, if they're very scientifically oriented, all the science; or you could use pictures. You could use all kinds of analogies, like saying, "Look. This is like treatment of very severe high blood pressure. You may feel totally fine, but what we're trying to prevent is a devastating stroke." And getting people on treatment, most of the time, works.
I will say that there is a subset of people who simply won't take antivirals. Based on cohort studies, based on our own clinic, and based on Ryan White reports, they're probably 10% of most practices. A lot of them don't show up [for their appointments] -- or, when they do show up, they are sick. It's very hard.
I think one reason it's very hard to manage them is because the causes of that kind of behavior are so diverse -- not just one thing. It's usually multiple things.
Joel Gallant: I think also, patients sometimes come in and are surprised when we recommend treatment. Or I hear other clinicians say, "Well, my patients, when I tell them they should start treatment, they balk at that."
Well, of course! They've been taught the lessons that we've taught them over the years: That you don't need treatment till you're sick, or you don't need treatment till your CD4 falls. When we tell them we're now recommending treatment for everyone, it comes as a surprise.
But we can easily re-teach them. They have an infectious disease; we have a treatment for it. It doesn't take a big leap to understand that you should be treating this infectious disease. It's just a matter of undoing the lessons that we've been teaching them over the years. And I think that can be done.
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