New Paradigms of First-Line HIV Therapy: Determining When (and With What) to Start

A Podcast Discussion With Eric Daar, M.D., and Trevor Hawkins, M.D.

November 11, 2009

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Table of Contents



Bonnie Goldman: Hello and welcome to HIV Management Today -- a new, clinical management series from The debut podcast in the series is entitled: "New Paradigms of First-Line HIV Therapy: Determining When (and With What) to Start." I'm Bonnie Goldman, editorial director of

Joining us are two of the top HIV clinician/researchers in the United States. Dr. Eric Daar, is chief of HIV medicine at Harbor-UCLA Medical Center in Los Angeles, Calif., and a professor of medicine at the UCLA's David Geffen School of Medicine. Dr. Trevor Hawkins is founder and medical director of Southwest CARE Center in Santa Fe, and associate clinical professor at the University of New Mexico.

When to Initiate HIV Therapy

Let's begin with the question of when to start HIV therapy. During the past year or so there have been a flurry of new studies that have called into question when is the optimal time to initiate antiretroviral therapy. Dr. Daar, can you share with us your thoughts?

Eric Daar: I think this continues to be an area for which there has been a lot of discussion and, almost, controversy, because of the limited data to answer the specific question. Clinicians would like to have a randomized control trial to definitely address this issue, and we've never had that. So we've relied heavily upon cohort data, recognizing all the limitations of it. As a result of the cohort data, the bar has shifted. What we've always incorporated -- along with the data supporting a potential role for earlier therapy that would translate into some better outcomes -- is the cost of therapy in, particularly, not dollars, but the toxicity and the risk of selecting for resistance.

I think what we've seen over the last several years is more and more cohort data supporting earlier therapy. We now have a randomized control trial from Haiti that actually demonstrated that people who started antiretroviral therapy with a CD4 count of between 200 and 350 T cells did better than those who started at less than 200.1

We have two cohorts that have demonstrated potentially better outcomes amongst those who start therapy between 350 and 4502,3 or 500, and one cohort that even shows better outcomes amongst those who started with CD4s of greater than 500, versus less than 500.4

The cohorts alone probably wouldn't be sufficient to drive dramatic changes in clinical practice, but it's coming along with the fact that we have so many antiretroviral treatment options that are currently very well tolerated, with extremely high levels of efficacy, relatively low levels of toxicity and low levels of resistance, and many other options. So even if resistance were to develop, we'd still be able to successfully treat patients.

We took the small, randomized control trial, dramatic changes in the types of therapies that are available for our patients and then built on top of that.

One other major observation has come out over the last several years with respect to this relationship between ongoing viremia and high levels of immune activation and inflammation, and how this might affect other end organs -- other than things like the immune system -- such as endothelial function, which can have an impact on cardiovascular disease and renal disease.

And that is that, with all of this, there's an increasing case being built, even in the absence of a large, randomized control trial, for perhaps recommending antiretroviral therapy to virtually every HIV-infected patient who, importantly, is ready, willing and able to commit to treatment.

Bonnie Goldman: Dr. Hawkins, do you agree or disagree?

Trevor Hawkins: I do agree. I agree with Eric particularly in the sense that, if the evidence came from just the cohort studies, then I think we would be more nervous. Because cohort studies have inbuilt potential bias -- both lead time bias and confounding issues that can affect which groups do what. But there's such a body of evidence that replicating virus is just not a good thing in almost any infection, particularly one as widespread as HIV, which affects so many different body compartments.

As Eric said, we clearly have evidence that ongoing viremia leads to high levels of immune activation. You can measure that by measuring immune activation markers. This, in turn, drives inflammation. And inflammation is a big buzzword these days. It clearly affects organs; it affects blood vessels; it affects endothelial function.

We have a lot of data, too, on CD4 counts and how important they are. A lot of cohorts have suggested that non-AIDS events, non-AIDS malignancies, cardiovascular disease, renal disease and liver disease are related to nadir CD4 count. A study from France, from Charlotte Lewden, M.D., Ph.D., looked at 2,300 patients from the boosted-PI [protease inhibitor] era in a couple of French hospital cohorts, along with a well-matched HIV-negative cohort.5 And although the mortality rate was seven times higher in the HIV cohort, those patients who reached a CD4 count of 500 and above had the same mortality rate as the HIV-negative cohort.

So, it's not a definitive study, but more grist to the mill. There's this growing sense that HIV replication, if left unchecked, is just not a good thing.

Neurocognitive Performance in CHARTER Cohort (n = 1555)

Adapted from Robert Heaton et al. CROI 2009; abstract 154.

One thing we haven't mentioned is neurocognitive function. There was some recent data this year from the CHARTER cohort, suggesting that neurocognitive function is significantly impaired in up to half of that particular cohort, and that function is directly correlated with nadir CD4.6

There's a growing body of evidence that I think a lot of us -- and I'm one of them -- believe is sufficient reason to offer antiretroviral treatment to anybody, again, as Eric said, and very importantly, when patients are ready to start therapy.

One further point I would make is that, I know in my neck of the woods, in New Mexico, 60% of newly diagnosed patients here have a concurrent diagnosis of AIDS. They are presenting late. So, to some extent, you could argue that the argument around the data is somewhat academic, although it's still important.

However, we have data from D.C. that suggests that as opt-out testing is made more available, the CD4 count at the time of diagnosis does, in fact, go up -- theirs went from around 200 in 2002 up to around 300 in 2007, largely linked, we think, to newer testing.7 So I do think that if widespread opt-out testing becomes more accepted, this argument on this issue will become more and more relevant.

Eric Daar: I agree with Trevor. I think that there are a lot of other issues that we need to sort out that may be very important in this question about when to start.

The neurocognitive issues are extremely important, and I agree, there are several studies that seem to suggest that it is the CD4 nadir, or how advanced someone's disease was, that defines the level of neurocognitive dysfunction, more than their current CD4 or viral load. So there may be ongoing neurologic damage -- almost certainly is -- during the course of the disease that may be only partially, or maybe not at all, reversible.

I think other comorbidities are also important to consider. Even though people with relatively high T cells probably have a relatively low absolute risk of things like death and progression to clinical AIDS, at the very least, serious consideration of other comorbid conditions might influence the decision. We know that ongoing viral replication may predispose people to things such as renal, liver and cardiovascular disease. So patients who have underlying organ dysfunction, for any one of a number of reasons, in these areas might use that as an additional excuse to consider starting therapy earlier than they might have otherwise.

I think both the U.S.8 and European guidelines9 have increasingly -- over the last several years -- taken these comorbid conditions into consideration, and suggest that they be part of the discussion with an individual patient about when therapy should be optimally started.

Trevor Hawkins: I know hepatitis B is clearly indicated in our guidelines. Hepatitis C, I think, is mentioned in the European guidelines. It would be interesting to see if the new U.S. guidelines, which are due fairly soon, will mention hepatitis C. Because clearly HIV accelerates the progression of hepatitis C where that's a comorbidity.

I might also mention bone disease, which seems to be more common. Both osteopenia and osteoporosis are more common in patients with HIV disease.

One thing we haven't mentioned, though it is clearly as important, is that there's very strong data to suggest that an undetectable viral load very significantly diminishes the risk of transmission.10 Since the CDC [U.S. Centers for Disease Control and Prevention] estimates that half of all new infections are derived from people who don't know they are HIV positive, testing those people and treating them will hopefully reduce the incidence rate.

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This article was provided by It is a part of the publication HIV Management in Depth.


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