The Cure: Why, Whether, How and When
More than three years ago, Project Inform kicked off a campaign to refocus the attention of the patient, activist and research communities on the need for a true cure for HIV disease. The success of combination therapy and treatment simplification seemed to have created a wave of complacency and a sense that, except for side effects, HIV treatment was finally "good enough." Project Inform has challenged this view ever since. Though the effort was sometimes ridiculed as naïve, a number of influential groups and researchers have now joined the campaign.
Today more people than ever agree that the current standard of lifetime maintenance therapy is not an adequate solution to the HIV epidemic. Several factors made this conclusion more obvious than ever. This article examines four issues about the notion of curing HIV disease: (1) why the goal of curing HIV disease has become so critically important; (2) whether a cure is feasible given current and near future technology; (3) what "cure" means and how it might be achieved; and, (4) when this might be possible. The article also closes with new information about efforts now underway toward reaching this goal.
1. Why Is a Cure so Important?
This may seem obvious to just about anyone with HIV disease, but it has not always been so. Today's regimens offer dramatically better outcomes than what people typically faced earlier in the epidemic. It might be easy for some to think that the problem of HIV has largely been solved. Not quite. Not even close.
Thankfully, the days of a short-term death sentence are well behind us. With good care and treatment, it's fair for people with HIV to expect to live out a relatively normal lifespan. Missing from the greatly improved picture are the ways in which HIV disease still complicates the lives of those affected as well as its costs to both the individual and the public.
Today, HIV treatment means a lifetime of using multiple, expensive medications whose long-term side effects can't be known until they have actually been used long-term. Today's drugs are easier to use and appear far less toxic, but only a few have been used for 10 or more years. We have yet to learn what the consequences will be of 20 or 50 years of use.
Another thing typically overlooked is the lifetime cost of treatment which currently averages between $12,000-$25,000 a year for relatively healthy people with HIV, and much more for those in advanced stages of disease. While these costs have been met in the short-term, we're only beginning to look at the lifetime costs of being on regimens for up to 50 years. It's simple: do the math! And what about the developing world, where roughly 90% of the world's cases of HIV occur? Despite massive infusions of money, and despite reducing the costs of drugs to virtually that of their raw materials, efforts still only reach a modest percentage of the people worldwide who need treatment.
The US committed more than $15 billion to HIV treatment in developing countries over the last five years through the PEPFAR program. The World Health Organization, Global AIDS Fund, Clinton Foundation and many smaller groups along with support programs from the pharmaceutical industry have made enormous additional contributions. The reach is still too small and the amount of money needed must be increased many times over to reach even the most vulnerable parts of the infected population.
It has long been hoped that this would only be temporary; that we would have a vaccine and the numbers of people infected each year would finally begin to drop. Sad to say, but the search for a vaccine hit a wall in the last year. In many ways, we may now be no closer to a vaccine than we were 20 years ago. Some of the most prominent scientists in the world are warning us that a vaccine may never be possible due to HIV's unique properties.
At the very least, if there is to be an HIV vaccine, we currently have no idea how to make one. Similarly, great hope was invested in using microbicides -- gel-like compounds applied to the areas of sexual contact that hopefully block HIV infection. But so far these have proven about as effective as vaccines, which is to say "not at all."
Thus, when we take a sober look at the fight against HIV in the developing world, the prospects of lifetime therapy don't look so good either. First, the expenditures by wealthier nations will have to drastically increase, and then these sums must be sustained for the next 50-100 years, assuming there's no vaccine in the near future. We must ask: how likely will developed nations continue this level of support for as long as it's needed?
Sadly, the answer is not very likely. For one, there's little precedent for sustained medical effort in developing nations, let alone one as expensive, difficult and lasting as fighting HIV is. Secondly, the costs are so large they may not be sustainable at all. Even the great private funds like taht of Warren Buffet will be bankrupted over time by this fight.
In short, lifetime therapy is not a realistic solution for HIV disease even in the US and Europe let alone the developing world. The situation can only worsen if unexpected long-term side effects appear over time.
It should be abundantly clear: the only way to effectively conquer the epidemic is to cure the disease. We cannot coddle the virus with a lifetime of drugs. People with HIV should be enormously grateful to all those who have contributed to developing the drugs we have today. Millions more would have died without them. But their utility is limited and they're not a true long-term solution. The goal of fighting HIV for the first 25 years was to create and distribute effective anti-HIV drugs. The goal of the coming years must be to get people OFF the drugs and back to a state of normal health.
2. Is a Cure Feasible?
It is one thing to conclude that a cure is needed, and perhaps it's the best and only real solution to the epidemic. It is quite another to say that it's possible to create one.
Many scientists argue a cure is unrealistic with any conceivable technology. They quickly insist that a cure requires the complete eradication of HIV. Every copy of it must be prevented from infecting a cell, and every cell that already contains HIV must die off or be destroyed. Otherwise, they believe, the infection will just start up all over again.
While this sounds reasonable at first, is it necessarily so? It is important to ask scientists, "Just what data support this? What study or observation concludes that you have to eliminate every last copy of HIV or infected cell to reach a point where it's no longer a problem?" There are no such data, no such studies. It is a belief, not a scientific fact.
The hints we have from data largely suggest that the opposite may be true. Many viruses peacefully co-exist in the human body, though in some cases they can be highly destructive. Two good examples are CMV and JCV. CMV can cause blindness and death; JCV can cause a horrible form of dementia that leads to death. Yet each is quietly present at low levels in most people and does little or no harm except in rare circumstances.
What about HIV? In primates, the equivalent of HIV is called SIV, and it often replicates freely yet does not cause harm or become AIDS. It's how the immune system reacts to it that causes the harm. Moreover, we know there are literally thousands of humans with HIV who, due to a combination of factors, either maintain only low levels of HIV or simply don't get sick from it. They may be a small minority, but they prove the point: HIV, even in the absence of treatment, is not always destructive.
The data simply do not support the notion that the only way to survive HIV is either through lifetime therapy or by complete eradication of virus. It would be ideal to rid the body of HIV, but an effective cure may NOT require this. If anything, the data suggests the opposite.
We see people repeatedly exposed to HIV who never become productively infected. We see that reducing, though not eliminating, virus in a pregnant woman almost completely eliminates the risk of her passing the infection onto her child. We know that true long-term non-progressors, or elite controllers, sustain some level of HIV infection but show little evidence of clinical illness.
Perhaps a harmful case of HIV requires a certain level of virus before it becomes destructive. Maybe treatment can push the level of virus low enough that it no longer matters. Possibly some of the new properties shown by drugs like CCR5 antagonists and integrase inhibitors may change the underlying conditions that make harmful HIV replication happen.
Dr. Steven Deeks, a key researcher from the University of California, summed it well at a recent Project Inform Update Town Meeting when he said, "Beware of grey haired scientists who tell you something is impossible." He is hardly alone.
There's a growing cadre of young investigators at universities, the NIH and drug companies who believe a cure is indeed feasible, and perhaps sooner than many think. It is instructive to remember that shortly after HIV was found to be the cause of AIDS, some researchers claimed, "It will be impossible to treat this disease at all." Within 21 months, the first drug was approved by the FDA. Little more than 20 years later, scientists claim that people with HIV and access to treatment could expect to live a normal life span. A cure is not only possible; it is the next step in HIV research.
3. How Can HIV Be Cured?
It is admittedly premature to pronounce that one approach or another is the most likely avenue to curing HIV. Instead, there are a number of possibilities. What we need are some serious programs to develop and test them. So far, the most widely tested approach has used just antivirals, alone or together with another kind of drug to try to eradicate HIV.
Scientists back in 1996 thought it would be enough to simply give people the strongest antivirals for several years in a row and this would gradually eliminate even the last copies of HIV. They were wrong, but this led to the discovery that HIV was being sustained, in relatively small amounts, in "reservoirs." These were generally inactive cells, like memory T-cells, which the immune system only rarely activates and uses. They're largely unaffected by HIV drugs and the immune system. For some reason they can only be reached when they are activated.
This led to a second approach, one that was predicted in the 1980s. It also used the most potent antivirals and added a second type of drug to activate these reservoir cells. This ultimately proved dangerous, as it activated all the cells in the body. Still, some scientists believe we haven't given this approach a fair trial. They argue that perhaps we need to use this approach more slowly, but repeatedly, in hopes of reaching all the cells in the reservoirs, but not all at once.
Although neither approach succeeded, they showed that when patients were treated in this way, they would sometimes remain free of active replication for a month or longer without therapy. A similar early attempt used the immune modulator IL-2, which is T cell stimulator, to achieve this goal. This too seemed to delay the return of viral replication in people whose antiviral treatment was interrupted, but it eventually failed.
Thus, attempts at eradication have neither succeeded, nor completely failed. Several studies are now underway to further test eradication theories by using the new integrase inhibitor drugs. Their different mechanism of action offers some theoretical benefits compared to previous antivirals. Remember, though, that we really don't know whether a "cure" actually requires complete eradication.
A recently reported case study from Germany described what happened when a patient was given a stem cell transplant, for treating cancer, by using cells from a donor who lacked the genes that cause the body to make the CCR5 receptor favored by HIV. This case study is described in more detail on Project Inform's website in our coverage of CROI 2008.
More than 300 days after the transplant and any use of antivirals, the patient still shows no evidence of HIV replication, either by standard viral load testing or a more sensitive test that measures what's called pro-viral DNA. Though the investigators are not calling it a cure, they continue to follow the patient to see whether or when HIV replication might restart.
At the very least, it seems to prove the concept that when viral levels are greatly reduced, even if not eliminated completely, the body seems to keep HIV well in check for long periods without antivirals. It would be difficult to find enough donors who have this very special type of genetic mutation, so this exact procedure is not practical for large numbers of people. A similar goal could be achieved through gene therapy, something which eventually could be applied to large numbers. Other types of gene therapy also offer hope in the pursuit of a cure.
Yet another approach seems to offer hope, even if it proves necessary to go after every cell that has been infected by HIV. A German group revealed a new technology, on a laboratory level, which is able to extract viral genetic sequences that have been integrated into human cells. It's a long way from being a practical therapy, but again, it shows proof of the concept.
Other scientists are working on ways to suppress the inflammatory processes triggered by HIV infection. Some believe that it is inflammation rather than any unique activity of HIV that makes it harmful. They believe it causes harm primarily because it causes cells to release inflammatory proteins, which in turn harm the body. If this is correct, turning down or turning off the inflammation may be enough to change HIV into a harmless virus.
These and other approaches all rely on a simple definition of what curing HIV must mean. Cure, in this way of thinking, may not mean absolute elimination of the virus. Rather, it simply requires reaching a state where either there's no measurable HIV replication despite withdrawing therapy, or where the immune response to HIV is changed in ways that no longer harm the body or immune system.
A cure also cannot be expected to automatically repair any damage done to the immune system when HIV was active. It would be great if that could be achieved, but it's not a standard we demand of other cures. Sometimes a cured disease leaves damaged tissue or cells behind. Sometimes the body fixes them over time; sometimes it doesn't. Antiviral drugs aren't completely fixing the immune system now, so we cannot demand that a cure will do it either.
4. When Can a Cure Happen?
This question is impossible to answer. At best, prediction is a tricky business. However, a number of the more enthusiastic researchers seeking a cure believe that the solution may be closer than most believe. Claims that it won't be possible until far in to the future are based on the false definition of cure, the one that demands absolute eradication. Once we realize that this is not required, the cure doesn't seem so very far away.
It's now routine to reach HIV levels below 50 copies. Studies with new drugs are now using a test that measures down to 5 or 10 copies, and there's evidence that the drugs are succeeding at this level. Researchers will need to retest various eradication approaches using these new therapies. We really don't know what happens when HIV is suppressed this low for long periods. Similarly, a few first generation gene therapy studies are well underway and near completion. These may not be the total solution but could well point us there, as does the German stem cell transplant program. The most optimistic researchers we have spoken to believe we will see the first evidence of a cure in as soon as 5 to 10 years.
A few argue that it has already happened, but our ability to see and measure it lags behind. It is even possible the immune system itself has done the job in some cases, but we just don't know it. Why? Because once a person gets truly well, they are seldom studied. We simply would not know if there have been people all along for whom the natural immune response has been sufficient.
We believe this process can and must be accelerated. It currently receives very little funding -- just a tiny fraction of the amount spent developing new antivirals. We are aware of only two pharmaceutical companies that are actively pursuing cure-based research. Merck has a lab dedicated to studying eradication in the same systematic way they develop a new drug. Tibotec/J&J is already engaged in a very interesting gene therapy study that may help point the way. We'd like to see every drug company invest in this area, if for no other reason than the fact that it might offer the last hope for big profits in the fight against AIDS.
There are now 24 antivirals on the market. Each gets only a modest portion of the revenue generated by only about 10% of people with HIV. If the lure of profits is what it takes to generate interest in the cure, so be it. While a cure would certainly end the drug companies' revenue stream from lifetime therapy, several have argued that there are far more profitable areas of medicine and drug development than HIV. They would make more money working in those areas once their patents in HIV expire.
Given the failure of vaccines and the difficulties faced in microbicide development, along with the prohibitive costs of lifetime therapy, we believe research funding must be redirected toward the kind that can result in a cure. This will require a large change in how research is funded, and it requires new insights from basic science as well as clinical research.
Efforts are underway to make this happen. In December 2007, more than 125 scientists from around the world came together in a meeting dedicated to unraveling the challenge of HIV persistence and eradication. These scientists, along with a few activists and foundation representatives, are committed to this type of research.
amfAR has already issued a series of program grants for work in this area. A collaboration of community groups is also organizing a scientific meeting that will take place in the fall to develop plans and strategies to enhance and support this research. TAG (Treatment Action Group), amfAR, FAIR, The Forum for Collaborative HIV Research and Project Inform have banded together to organize and help fund this meeting, which may be the first of several. amfAR is considering a second round of grants to support such work, and FAIR (the Linda Grinberg Foundation for AIDS and Immune Research) will fund another group of proposals.
Collectively, we hope to further influence the Division of AIDS at the National Institute of Allergy and Infectious Diseases to increase its commitment to this type of research.
As we shift our thinking in pursuit of a cure, we will not abandon interim needs. There is still a need for better and less toxic antivirals. There's a profound need to figure out how to make the best use of the new drugs we've recently gained. Project Inform is pursuing these needs on a separate but parallel track through another scientific conference we're organizing for the fall, called HAART 2.0. This meeting will help develop strategies for testing new paradigms of treatment with current drugs. These include such things as one- and two-drug regimens, eliminating the most toxic agents, and reducing the use of drugs that harm the liver or heart. Some of what we learn through that process will not only benefit patients in the short-term but will also contribute toward the final push for the cure.
A Personal Comment
As many of you know, I (Martin Delaney) officially retired from my programmatic role at Project Inform in January, but I have not left AIDS work. I am committed to making this focus on a cure the core of my work in the final chapters of my life. Like others at Project Inform and many other organizations, I believe that we can and must find a real cure. There is no other real solution on the horizon. This is as true for the US and Europe as it is for the developing world. We won't have a cure unless we believe in it and pursue it as our primary goal. We're going to have a cure, and it will happen in our lifetimes.