HAART at 10: an interview with Cal Cohen.

Cal Cohen, MD, is an HIV-treating physician and clinical researcher. He is Research Director of the Community Research Initiative of New England and the HIV Clinical Management Consultant at Harvard Vanguard Medical Associates in Boston.

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?

CC: Probably the realization that HIV can (but not always will) be controlled potentially for a normal lifespan--at least much closer than what we had imagined before HAART.

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

CC: No, actually I do not. It's fair to say that the work that went into antiretrovirals made HAART successful--it earned the spotlight. We went from having dramatic success with HAART in the 1990s, to dealing with the challenges of HAART, to developing more safe and durable success in HIV-positive patients today. Sure, other potential therapeutic approaches have not gone ahead as fast, but this is not because of HAART being in the spotlight.

RITA: What has HAART not delivered?

CC: HAART is lacking in that we need more confidence in its safety. There are cosmetic issues, organ toxicities, etc. and these vary between individuals. We certainly don't want people looking sicker than they are because of issues like fat wasting; that is a tough price to pay. The promise of newer medications--if they are less toxic--is that people will look as good as their numbers.

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

CC: It's basically true, but, of course, not for everyone. At this point, we know what it takes to control virus (plus, whatever immune-based therapies may eventually be able to offer). Even though some research is showing, for example, a 17% increase in the relative risk of a heart attack in patients taking HAART, this is not as bad as the days when much higher percentages of patients suffered from other issues, like peripheral neuropathy. Clearly, progress is being made, but HAART is still not as good as it needs to be.

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?

CC: What do you mean?

RITA: In other words, compared to other diseases, how does the HAART paradigm measure up?

CC: The field of HIV has had tremendous advancement on a continuous basis (at least, when compared with other fields). But we are still learning the rules of the game. Other diseases have had decades of work behind them and are therefore more "mature." In the field of HIV, we are less confident of our decisions at this point. In cancel we know to treat periodically. In diabetes, we know to treat every day. But in HIV, there is an uncertainty that simply won't be answered for years to come. In the meantime, we need drugs that stay up to date with the challenges of this epidemic, whether that is adherence difficulties or toxicity. Studies like the CPCRA's SMART Trial (Strategies for the Management of Anti-Retroviral Therapy) may eventually provide us with more answers. In HIV, there is still room for creativity at this point.

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

CC: There are a number of things happening right now to help answer that question.

1. Continued development of medications that are simpler, safer, and more effective. In several cases, we are down to regimens comprising 2 pills once a day, and we are looking to do even better. What about not taking medications every day? Maybe 5 out of 7 days is good enough. Smaller or longer "breaks" may be possible. Research will bear this out. In the area of initial therapy, we can continue to be proud of our progress, in light of what starting therapy was like even just 5 years ago. However, there are still ambiguities as to when treatment should be started.

2. Continued interest in other ways to simplify therapy. An example of this would be the induction/maintenance scenario. Perhaps with newer, more potent drugs, we can start with 3 medications to achieve viral control and then maintain control with fewer drugs.

3. Ongoing lessons of how not to create resistant virus. Resistant virus is being spread, and there will still be patients dealing with the damaging effects of resistant virus because of limited treatment options. I hope that immune-based therapies will one day be able to compensate for the limitations of antiretroviral medications when it comes to viral resistance--not to replace HAART, but to be used together in combination to achieve better and more balanced control of infection.

4. Efforts to treat the world, rather than the rich of the world. AIDS is an international issue, and the US is not exempt. If we are not capable of treating our own citizens, then how can we contribute to the global crisis? HIV must be a priority. Tax cuts must be balanced with public health; initiatives for smaller government involvement must be balanced with the collective good.

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"?

CC: HAART is a goal and cannot be defined in terms of classes or medications or specific agents. As we have seen over the past 10 years, HAART evolves. Newer agents tend to be better than earlier ones. The same things may happen with newer classes. What we want is a safe, durable way to curb the damage caused by uncontrolled HIV infection. While the actual principle of HAART may not change, how it's accomplished will change. Certainly for the next 5 years, we will be expanding the repertoire and therefore expanding ways to accomplish the goals of therapy in terms of what combinations to use, when to use them, how we might rotate drugs, etc.

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

CC: In some ways, this already is a therapeutic strategy, but it's not completely reliable. HIV often pays a price to mutate. Resistance sometimes weakens the virus, but sometimes the virus can compensate and overcome this effect. Capitalizing on viral resistance is not always a reliable strategy. If there was a reliable way to control the virus tiffs way, then we'd have a much easier time with treatment. However, while we know resistance can slow this virus down--we all know resistant virus can win; look at what happened in the era of treating with just nucleoside reverse transcriptase inhibitors (NRTIs) and the ongoing deaths from uncontrolled HIV. We are getting smarter about resistance, though. We know that resistant virus with reduced replication capacity is better than stopping medications entirely. We can preserve CD4 T cells to some degree using resistance as a tool--until better options come along. To me, this is a second-best strategy, but I am certainly not trying to minimize its importance when it is the best we can do.

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

CC: Sure. I'm willing to think so. I don't know who will develop it, how it will come to be, or what it will involve. But it is important for everyone involved in this field to imagine that a cure is possible. I am not even convinced it will happen in my lifetime, but I can maintain that it's at least plausible. If not, then we just close the door on this epidemic. Two years ago, Bill Clinton spoke at the annual Conference on Retroviruses and Opportunistic Infections and said that if researchers do their job in terms of science, and politicians do their job in terms of access, then perhaps HIV will one day flow from our blood into the history books where it belongs.