Can Antiretrovirals Help Those Who Control HIV Naturally?

It has become increasingly clear over the past few years that the long and winding road to an HIV cure will consist of many pathways. Although substantial research resources are being put toward a renewed push to finally find a viable HIV vaccine, explorations are also expanding into the possible value of gene therapy, stem-cell transplantation and even broad-spectrum antivirals, among other areas.

Alongside all of these potential paths to a cure lay the one we've already been on for the past two decades: the use of antiretroviral agents. Despite all we've learned about HIV pathogenesis and treatment, we still don't fully understand either the ultimate potential or the final limits of what antiretroviral therapy can achieve. And given that effective HIV treatment remains, for the moment, the closest alternative we have to a widely available cure, it is justly still receiving a great amount of attention from some of our brightest research minds.

Which is where our interviewee for this episode of HIV Management in Depth comes in. Jonathan Li, M.D., an instructor in medicine at Harvard Medical School's Brigham and Women's Hospital, is a highly respected HIV research veteran who has teamed up with his equally respected Brigham colleague Paul Sax, M.D., to conduct a new study on the effect of single-pill, once-daily antiretroviral therapy on HIV-positive people who, until recently, we didn't think needed to be on treatment at all: HIV controllers.

But why don't I let him explain it?

Dr. Li and I spoke by phone to discuss the details of his new endeavor, an AIDS Clinical Trials Group study known as A5308. The currently ongoing study has thus far enrolled 20 of its target of 57 patients, and is actively seeking additional volunteers.

Why don't we start with a little bit of background leading into why this study exists?

HIV controllers, as you are well aware, is this really remarkable group of patients who can suppress their HIV to very low levels without the need for antiretroviral therapy.

Historically, it's been thought that these patients are in a privileged position, and at little risk of HIV disease progression or clinical disease. But it's become clearer over the past couple years that this assumption is just not entirely true.

We found that HIV controllers generally have active viral replication, just very low levels of it. And they have higher levels of chronic inflammation, which we're concerned may lead to increased risk of early aging and HIV disease progression, especially since a subset of these patients do have eventual CD4 decline over time. There have been some recent studies showing that HIV controllers may have higher cardiovascular disease, as well.

So the primary goal of this study is to determine whether antiretroviral treatment can lower inflammation and normalize the immune function for the HIV controllers.

A low percentage of people are identified as HIV controllers, so we're talking about a small group of people that you can possibly pluck from, right?

Correct.

What's the percentage estimated of people with HIV who are controllers?

It's tough to estimate. But the elite controllers, those individuals with viral loads less than 50 copies, it's far less than 1%. With controllers, we're looking at a viral load of less than 500: Those are probably still less than 5%, I would say.

What kind of research has been done so far in this area? By which I mean the potential effects of initiating antiretroviral therapy in people who are controllers, and the additional benefits that come from that?

There's been very little research in this area. One study was published just last year by Steve Deeks' group, and Hiroyu Hatano. They published a study of 16 participants. Interestingly, they found that treating HIV controllers -- and they had a slightly different definition; they used, I think, viral load less than 1,000 in their study, a little bit of a looser term for HIV controllers -- but they found that it decreased HIV viral load. Even at very low levels, they could see a decrease. Also, there appears to be a decrease in markers of T-cell activation.

Now, that study, as I mentioned, is a smaller pilot study: 16 participants. They didn't have the sample size to really fully explore some of the important effects that they found. They found, for example, trends in various other markers, [such as] soluble inflammatory markers, that they just didn't have the sample size for.

In addition, our study has a viral dynamics component, where intentionally studying how the virus decays with the use of antiretroviral therapy. That will give us some insight on the various reservoirs that are harboring HIV in these patients.

The upside of having their study is that it reassures us on a couple of different fronts: First, that being treated with antiretroviral therapy, there is risk of various side effects. But their study, as well as some of the participants that we've enrolled so far [in A5308], have generally found it to be very well tolerated.

In addition, a hypothetical concern that we had when designing the study is that when patients are put on therapy, generally because their immune system is -- how do I put it: less revved up; not as activated all the time as when they see active viral replication -- what happens when these patients stop therapy? Can their immune system still control the virus?

In Steve's study, they had a number of patients who stopped therapy, and they returned to their controller status -- which, to us, is also reassuring, as well.

Do you guys have a hypothesis going in that led you to use Complera as your drug of choice? Is there anything in particular you're expecting?

Yeah. One of the reasons we chose Complera is that it's better tolerated than efavirenz, which is the most commonly used antiretroviral therapy today -- Atripla; efavirenz-based or containing regimens. But rilpivirine (Edurant) has been shown to be better tolerated. Now, in a head-to-head trial against efavirenz, rilpivirine did worse in the group of patients with the highest viral load -- those patients with viral load over 100,000. [But our] patients are the exact opposite of that; these are patients with the lowest viral loads. Those patients did really well in that study.

That is one of the reasons why Complera was chosen. But our hypothesis is that antiretroviral therapy will decrease not just T-cell inflammation, but also a lot of these soluble markers of inflammation that you've been hearing about that have been linked to various other chronic, long-term effects of aging and non-AIDS-defining conditions -- cardiovascular disease, cognitive dysfunction and things like that.

I think that another important point is that I've been asked: What does this mean for the cure agenda?

HIV controllers have always thought to be an ideal, natural model for what a successful functional cure would resemble. If you can get someone who is not a controller to a controller status by stimulating their immune system, or somehow giving them some therapeutic vaccine, that would be as good as a cure.

But if this is really our goal, then I think that we have to have a complete understanding of what it means for our patients. Will further suppression of this already low-level viral load have any additional benefits for our patients, for this population -- and for our patients in the future? What is the cost of not achieving complete suppression of the virus?

And by "complete," in this case you're talking about, what? Sub-10 viral load? Sub-5?

You can't give a number to it. Because even when patients are on a fully suppressive antiretroviral therapy regimen, if they're a hundred percent adherent, you can still find some HIV in their bloodstream. How much HIV is in there will depend on how long they've been on treatment, and probably depend on kind of the size of their viral reservoir, things like that.

But that HIV is not likely to be causing new rounds of replication. Some of that is just some HIV that will come out because they've got this reservoir where HIV is constantly being produced.

But HIV controllers -- elite controllers and controllers -- will have higher levels. It's hard to quantify the difference. But it's been shown that HIV -- even elite controllers have these detectable viremia episodes, and controllers have even higher viral loads than that. These are definitely higher viral loads than what you would normally see, I think, in patients on long-term suppressive antiretroviral therapy.

The question is, does getting them from an already-low level to fully suppressing them to an even lower level: How much does that help? And do we think that that amount of benefit, in terms of inflammation, is enough to affect any downstream long-term health of these patients?

Also, I think the immunology and virology components of the study will give us a lot of important insight on the pathogenesis of HIV within this population, and really give us a deeper understanding of where HIV is hiding, and how the immune system maintains control. When we're studying elite controllers, and we say, "OK; so controllers have some amount of viral replications. And we know that controllers have higher amounts of chronic inflammation." Well, are these two related? If you don't treat, you can never 100 percent tell how much these things are related, or whether they are two completely different processes.

Those are some of the reasons behind doing this study -- in addition to just helping the patients themselves.

What other subanalyses are you guys planning? Are you planning to look into specific tissues or compartments?

We are not doing any tissue biopsies in this particular study.

So, not a horribly invasive study for the volunteers.

Exactly. It's already a little bit difficult to -- involvement has been a little bit slower than we had hoped. We knew that that would be a concern: These patients had been told for years and years and years that they don't need treatment, ever. And to try to change their thinking a little bit, or to make them aware that therapy might be beneficial, takes some education and some convincing.

Not only that, but you clearly are an empathetic human, and it is not unrealistic to think that not everybody is going to be like Timothy Brown, and be willing to be poked and prodded to the ends of the Earth. So it's understandable.

Absolutely. I completely agree. But we are going to be doing everything we can with the blood, in terms of looking at T-cell activation, various cellular activation, markers of systemic inflammation. We're going to try to look through all these different cell populations to see where HIV might be hiding, and whether or not it will enhance the regeneration of T cells, the use of alternative therapy.

We'll be looking at quality of life in patients, as well.

Can you be more specific about what you mean by quality of life?

Patients are getting a questionnaire to see whether they have side effects. Sometimes, for non-controllers, when they take treatment there will be some side effects associated with that. That's part of what we're trying to figure out: How bad the side effects affect them.

But also, some of my patients, at least, feel better on treatment. It's not that necessarily they weren't feeling -- you know, that they had this baseline of health that they were used to that they didn't realize was necessarily abnormal. But on treatment, these patients actually felt a little more energy, a little bit better.

We want to look at how difficult is it for these patients to take [treatment]. Are there any side effects that are really affecting their life? Or are they not having any problems with these medications?

How are you going to be measuring adherence?

During the initial part of the study, there's a viral decay component for a subset of patients. But for those patients, they'll be getting an adherence journal to be taken home to fill out what time of day that they're taking the medications. Otherwise, when they're coming in for their visits there's a questionnaire to ask them about adherence.

OK. But no intensive pill bottle counting or electronic tracking?

No.

Why 57 patients for target enrollment? What makes 57 a magic number?

It's a balance between the numbers that we think that we can realistically enroll, as well as a statistical analysis of what makes sense, in terms of powering the study for being able to see a difference in the T-cell activation.

Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.

Follow Myles on Twitter: @MylesatTheBody.

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