High Bar

Have we limited cure research by approaching it through a treatment paradigm?

by Jeannie Wraight

high bar[dropcap]W[/dropcap]orking in HIV cure research, developing potential HIV therapeutics and eradication strategies focused on ABOBEC3g, Dr. Harold Smith of the University of Rochester had some interesting insight into whether a cure for HIV is possible and how current and past HIV research and perspectives may be affecting our ability to develop a cure, or cures, for HIV.

In the first part of this two-part series, which ran in the October edition, Dr. Smith discussed his groundbreaking research on ABOBEC3G and its relationship to cure research. Here, he delves into how we define “cure,” the limitations of comparing HIV treatment regimens and HIV cures, and how our knowledge base might be expanded.

Jeannie Wraight: Recently, Nobel Prize Laureate Françoise Barré-Sinoussi stated that she did not feel a cure for HIV is possible. What are your thoughts on that?
Dr. Harold Smith:
“Cure” as a word is being used as an absolute and that’s a problem. We need to explore what a cure could be and how to define it.
What if you could treat someone with a new therapy and afterwards they don’t need treatment again for the next ten years. Or what if you could only cure one particular clade? Are those cures? For those people, yes.

So, when we use the word “cure,” we’re going into a dangerous realm because it’s a convenient term for a complicated scenario. If you look at the past twenty-five to thirty years of therapeutic development, we’ve had great success in buying people time and reducing illness. That’s the positive outlook. The negative outlook, from the cure perspective, is that those thirty years represent complete failure to cure. It was determined early that if you’re going to be successful then you should set the bar a little lower, maybe first just reducing viremia and that’s what the pharmaceutical industry did.

We haven’t been able to get to a cure and that may lead some to say that a cure is not possible. We have to be open to the possibility that we may have missed something. I think not rigorously pursuing Vif [a protein of HIV and a potential drug/cure target] has been an opportunity lost. Each time industry develops something new, like integrase inhibitors, that’s more effective, more broadly neutralizing, has more tolerable side effects, it raises the bar for anything that might come after. It has to at least satisfy this bar and integrase set a whole new bar with low cytotoxicity, once a day dosing, etc. The industry is saying that a cure, whatever you come up with, can’t even sit at the table until you show low toxicity, low side effects in a laboratory, and that you can generate drug-resistant strains, because every form of HIV therapy and every drug target has always had the quality that in the laboratory people expect the virus will work around it and drug resistance will develop.

But think about a cure. A cure can’t be something HIV works around. What if cure is something in between Timothy Ray Brown and integrase inhibitors? What if it’s like a shock from hell where you’re hospitalized for six months but after that you have a lifelong cure. Would people take it?

I would.
So, why does a cure have the same rubric as long-term life treatments? We’re almost shooting ourselves in the foot by having what we know doesn’t work for a cure serve as the standard for bringing a cure forward.

Most people would say, if you keep doing something and it’s not working, maybe you should do something else. I’m saying that there are other essential parts of HIV like vif that remain completely unexplored even when the evidence is there. If someone’s really upset that there’s no cure, they should evaluate if we’ve exhausted all our possibilities and if we haven’t-why? Why are we not spending our resources testing diverse and divergent hypotheses, not just those coming from a few key opinion leaders and industry?

Right, so is it a scientific issue, or is it a political and financial issue?
I’d say it’s both. There’s not enough money to go around. I’d say the most devastating thing to a field is KOL [key opinion leaders] because nonscientists, scientists, and peer reviewers tend to listen to and popularize these opinions instead of thinking for themselves. A cure is likely to have many different dimensions requiring many people thinking about it.


Jeannie Wraight is the former editor-in-chief and co-founder of HIV and HCV Haven (www.hivhaven.com) and a blogger and writer for TheBody.com. She is a member of the Board of Directors of Health People, a community-based organization in the South Bronx and an advisor to TRW (Teach me to Read and Write), a community-based organization in Kampala, Uganda. She lives with her husband in New York City.