HAART at 10: an interview with Joseph Gathe.

Joseph Gathe, Jr, MD, is an HIV-treating physician and clinical researcher. He is the Medical Director of the Donald R. Watkins Memorial Foundation Houston.

RITA: Highly active antiretroviral therapy (HAART) is almost 10 years old. What do you think has been the greatest lesson we've learned about HIV treatment in the last 10 years?

JG: We've learned several lessons. First, we've learned that an orchestrated, scientific response can lead to control of a critical disease when great minds come together. But this is a two-edged sword. We cannot rest on any laurels, and this is a learning process that cannot end. The great boon for HAART has been the ability to keep people alive, but there have been evolving side effects and other aspects of therapy that we could not foresee. We must he circumspect and cautious in the future for the sake of patients. Smart people can make a difference, hut we could never have anticipated the ramifications of the drugs once they were being used in the real world.

RITA: Do you think HAART has taken the spotlight from, or possibly even derailed, other promising research or treatment advances?

JG: Not really, but there has been some complacency among scientists and activists alike resulting in a reduced urgency for finding other ways to approach the treatment paradigm. HAART has bought us time; we are sitting in the oasis and can take a drink for a moment. But we need vaccines (both preventive and therapeutic). We need better ways to achieve immune reconstitution in the setting on HIV infection. It's disheartening that there is not more dialogue between virologists and immunologists. This may or may not he on account of the success of HAART. What we have achieved with HAART is reaching its maximum efficiency. Our approach to really improve patient outcomes has to be different (immune approaches, vaccines, etc.) People are dying in different ways, not from the typical opportunistic infections seen more frequently in the earlier clays of AIDS. I see cancers, heart attacks, organ failure and other manifestations-even in younger patients--that I attribute to a "premature aging" of patients and incomplete immune restoration.

RITA: What has HAART not delivered?

JG: HAART has delivered time, but it has not delivered a cure. Also, it has not delivered the ability to effect long-term management of HIV-positive patients with the current treatment paradigm. In diabetes, insulin can be given over a long period of time without adverse side effects or toxicities. HAART over a long time can be toxic, not to mention expensive. If we do not achieve a cure, then we need long-term and affordable solutions to HIV disease.

RITA: Many people characterize HIV (at least where HAART is available) as a "chronic, manageable" condition--what's your take on this?

JG: I think it is chronic and manageable. When a new patient comes in, that's what I say--mainly because the patients I see think this is a death sentence. They need to understand that if they take care of themselves and play this correctly, then an extended life expectancy is possible. HIV today is more like diabetes than, say, cancer, but it must be closely monitored. Most of all, we need to instill hope in patients.

RITA: What about the less pretty side of HAART (side effects, toxicities, drug interactions, lipodystrophy, etc.)? How does this affect your ability as a clinician to treat this disease?

JG: This impacts my practice greatly. A patient's T cells and viral load may be fine, but mentally, this person can be in bad shape. With something like lipodystrophy, patients may avoid being out in public, for example. This is something that must be overcome in a physician-patient relationship. One thing that can be done is working to prevent this from happening in the first place by carefully selecting antiretroviral agents. But some big questions still exist. Is this caused by the treatments, or the disease, or both? The pendulum of thought for early versus latex treatment is still moving. You can't wait too long before treatment, otherwise damage from HIV could predispose patients to a variety of risks even in the setting of HAART. We need more studies looking at the "new endpoints" of HIV: liver disease, kidney failure, lipodystrophy/metabolic effects. This is not about opportunistic infections or AIDS anymore. And, these are the issues that patients care about.

RITA: Where do you think HIV treatment will be in another 10 years?

JG: I hope we will be able to use treatment for short periods of time, and then use immune-based therapy such as a therapeutic vaccine to control the virus over longer periods of time. But here's my greatest fear. In my practice, I see 3 or 4 newly diagnosed patients each week. This is during a time when healthcare resources in general are being cut, and HIV care is not being supported in the same ways as in the past. Not only will quality of care decline, but I feel that there are no new generations of researchers, and especially clinicians, coming forward in this field. People are moving to industry and other more profitable areas. When the group that's in their mid-to late 40s moves on, there may not be people to replace them. This could further relegate the disease to the backburner. We need more manpower I'm very disturbed by this trend.

RITA: Some people view the entry inhibitors in development as the next great hope in HIV treatments, possibly replacing some classes of antiretroviral agents as first-line treatments: a second-generation HAART, if you will. How do you view the possibility of "HAART II"?

JG: I view it as a mixed bag. I have great hope because we need new classes of drugs, and these entry inhibitors may have fewer toxicities overall. However, my greatest concern is that these agents may not be able to stand alone and may have to be combined with agents that act within the cell anyway. I have concerns about patients whose virus is not purely CCR5-tropic, even though agents like TNX355, enfuvirtide (Fuzeon), and CCR5 antagonists may all be combinable. Also, there are concerns about pre-existing resistance to various agents when trying to construct viable regimens.

RITA: Speaking of drug resistance, it's a problem. But indications of drug-resistant HIV with decreased viral "fitness" and "replicative capacity" are showing a different side of drug resistance. Do you think we can reach a time when achieving certain HIV mutations would actually be a therapeutic strategy?

JG: No question about it. With new patients, I have 5 goals:

1. To control viral load

2. To improve CD4 T cell count

3. To try to prevent the development of resistance if possible

4. To direct any resistance that does develop down the "path" that I prefer

5. To pick the most logical partner medications (those with proven efficacy and durability) and not just combine any drugs. HIV resistance can be a friend or a toe. I believe in making it a friend, for example trying to induce hypersensitivity to non-nucleoside reverse transcriptase inhibitors (NNRTIs) by capitalizing on the maintenance of resistance to nucleoside agents. This can result in improved virologic responses to an NNRTI-based regimen. We have enough evidence to start using such approaches in the clinic.

RITA: Finally, do you ever think there will ever be a cure for HIV?

JG: No. (But I still hope there will he!) First of all, viral illnesses do not typically get "cured." We may develop vaccines to prevent them, they may run their course and be cleared by the immune system, or they may establish a chronic latency that persists through the host's lifetime. What I hope can one day happen (as was demonstrated in work presented at the Conference on Retroviruses and Opportunistic Infections a few years ago, where monkeys with SIV remained healthy despite having high viral loads) is that we can exploit how to down-regulate the ability of the immune system to react to HIV. If we could somehow turn off immune hyperstimulation that results in chronic cytokine dysfunction, tissue damage, etc., then perhaps the virus would be more latent, such as in cytomegalovirus or Epstein-Barr virus infections. If we do not find a cure, then establishing a long-term, "symbiotic" relationship that minimizes immune damage would be desirable.