An Interview With Jonathan Li, M.D.
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.
Jonathan Li, M.D.
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?
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.