麻豆传媒

AMSTERDAM -- What would a cure for HIV look like?

It would be low-risk. It would be easy to use on a broad scale. It would be cheap. And it would be better than the best current therapy.

That's a high bar. When you add in the technical, ethical, and commercial obstacles, it's easy to see why cure researchers might be daunted and -- sometimes -- hard to see why most of them aren't.

"It's really, really tough to eradicate the virus," said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases. And it's almost equally difficult to reach the next best thing -- durable remissions, of whatever length, that allow people to rely on their own immune systems and avoid daily anti-HIV drugs.

The first, Fauci said here at the , would be an elegant result, but it would be "very difficult, problematic, and might be unattainable." And it's unlikely that even a successful eradication process would be inexpensive, risk-free, and scalable.

On the other hand, he held out more hope for the second option.

HIV is unusual among pathogens in that it does not cause the human immune system to produce broadly neutralizing antibodies, at least not until late in the course of the infection. But researchers have now isolated and cloned about 90 such antibodies and early work in animals is promising.

The hope is, Fauci said, that a cocktail of three or more such antibodies, engineered to make them long lasting, might turn the trick, allowing patients to go off antiretroviral medications for months at a time.

"We haven't done that yet, but I think it's entirely feasible," he said.

But Fauci noted that current medications -- when people with HIV have access to them -- are very good indeed, yielding complete control of viral replication with very limited side effects. As a bonus, study after study (including a new one at this meeting) has shown that successful treatment renders HIV transmission almost impossible.

This yields the mantra "U equals U": undetectable equals un-transmissible.

What's not clear is whether that would continue to be true during antibody-driven remissions. Is there a level of viral load at which the risk of transmission suddenly is no longer zero and could the antibodies keep HIV below that benchmark?

What is clear is that many of the tools needed to end the HIV/AIDS pandemic already exist. If it were only possible to identify everyone with HIV and get them all on successful treatment, rendering their virus undetectable, the pandemic would end.

Mind you, the same can be said about condoms. If every sex act in the world involved proper use of condoms, the pandemic would be crippled, although presumably transmission associated with injection drug use would continue to add some fuel to the fire.

And the argument can also be made about simple abstinence.

In practice, though, it seems likely that more tools will be better than fewer -- and it's going to take time to develop them.

Take one of the most promising approaches to viral eradication -- what's called kick and kill.

After infection, HIV, as is well known, establishes a "reservoir" in which quiescent virus can lie hidden from treatment. Stop treatment and the virus roars back from its latent state, infecting and destroying immune cells.

So, why not use drugs to kick the HIV out of the reservoir and then use other drugs to kill the newly visible virus?

That was the premise behind the RIVER randomized controlled trial reported here, according to Sarah Fidler, MBBS, PhD, of Imperial College London. She and colleagues conducted the first large proof-of-concept trial of a kick and kill strategy.

It didn't work.

Or rather both components of the strategy did exactly what was expected of them but there was no evidence of a benefit, Fidler said:

• The kick drug -- vorinostat (Zolinza) -- is a histone deacetylase (HDAC) inhibitor and patients who got it saw significantly increased histone deacetylation.
• The kill component, a prime boost vaccine aimed stimulating the immune system, generated increased numbers of HIV-specific CD4 and CD8 T cells.

The 60 participants were given standard antiretroviral therapy, with or without the kick/kill drugs. But when investigators looked at the primary endpoint -- total HIV DNA in CD4 cells -- they found no difference between the arms of the study.

Part of the problem is that the endpoint is a surrogate marker -- no one actually knows how to measure the size of the HIV reservoir or can even pin down exactly which cells are involved.

"We don't even know what the reservoir is," Fauci said, so the investigators might have been measuring the wrong thing.

It might also be simply that vorinostat is the wrong drug; it's thought of as a first-generation HDAC inhibitor and newer medications might do better at reversing latency.

And it might be that the intervention worked as planned, but the investigators can't know that because all the patients remain on therapy; the study was never designed for what is called an analytic treatment interruption.

Such treatment interruptions remain an area of controversy, commented Sharon Lewin, MD, PhD, of the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia.

On one hand, there is currently no way to predict a remission, so stopping therapy is the only way to see if cure attempt has worked. It is, Fauci, said, the "absolute sine qua non" to determine if a treatment is effective.

On the other hand, stopping treatment can be risky and there are no agreed guidelines on how to manage that risk and when to put patients back on therapy.

Fidler said her result is "definitive but disappointing" but Lewin noted that it's just a first cut at the problem. Newer agents, different combinations, and more fundamental research on the nature and extent of the HIV reservoir are all needed.

Fidler, though, said her study raised some more general issues if, as seems likely, combinations of drugs will be needed to move forward. "We definitely are going to need a combination approach to even get to a remission type of model," she told 麻豆传媒.

That means all the elements will have to be tested for safety alone and in combination before investigators can begin testing for efficacy.

And something that often escapes notice is that most drugs are owned by commercial enterprises; getting permission to use them in clinical trials, Fidler said, can be a drawn-out and painstaking process that delays the testing.

But despite the slowness of progress, researchers are not cast down. "I think we really face some serious challenges," Fauci told 麻豆传媒, but the science of cure is past the early stages.

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