THE day Jim Pickett stopped taking his anti-HIV drugs, he thought he was signing his own death warrant. The mix of drugs he had taken for the past three years had kept the virus at bay, but the side effects were ruining his life. Every morning, Pickett would gulp down a dozen pills and wait. Wait for the churning in his stomach to begin. Wait for the excruciating cramps and diarrhoea to set in. Then sit in his Chicago apartment and dread the moment, just a few hours away, when he鈥檇 have to do it all again.
鈥淢y T cells were high and my virus undetectable,鈥� he says. 鈥淚 was getting A鈥檚 on my drug report card but feeling like shit. I wanted my life back.鈥� So one day he packed a suitcase for a weekend trip and left his pills at home. He had decided he鈥檇 rather die young but feel better in the meantime.
But Pickett鈥檚 act of rebellion wasn鈥檛 the beginning of the end for him. Since that day two years ago, his body has shown that it can control the AIDS virus without any help from drugs. If and when the virus regains the upper hand, he will return to his drugs until his immune system bounces back. Then he will stop again. Quite by accident, Pickett has stumbled upon a promising new strategy in the battle against AIDS-a technique called 鈥渟tructured treatment interruptions鈥�.
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STI is an on-again, off-again drug regimen that allows the body鈥檚 immune system to build to the point where it can hold the virus in check. The end result is a steady state with enough virus present to keep the immune system primed, but not enough to cause disease. The idea is to use a patient鈥檚 own immune system as part of the treatment strategy. If it works, not only will patients鈥� quality of life improve dramatically, but many more people worldwide will be able to receive the drugs because patients and governments will only have to pay for a short course of treatment instead of a lifetime supply. It could also mean that patients will benefit from the current drugs for much longer before the virus develops resistance. The approach has already kept monkeys drug and disease-free for more than a year, and early clinical trials in humans look promising.
In the twenty years since AIDS was recognised, scientists have identified the virus, mapped its 10 genes and developed a small but powerful arsenal of drugs that can stop it replicating. Still, HIV remains a formidable opponent. Just a few years ago, many AIDS experts thought they had the upper hand. When they gave patients a combination of drugs known as highly active anti-retroviral therapy (HAART), the number of viruses in most patients鈥� blood fell to levels so low that they were undetectable. And with these drugs, AIDS-related deaths have fallen by more than 70 per cent. For a time, people thought the virus could be eradicated.
Such optimism, however, has gradually given way to today鈥檚 challenge of dealing with the drugs鈥� complications and failures. 鈥淭oday, it鈥檚 the drugs, not the virus, that will kill you,鈥� says Luis Montaner, director of the Laboratory of HIV Immunopathogenesis at the Wistar Institute in Philadelphia. Cholesterol levels soar in many patients, putting them at greater risk of heart disease. Others suffer diabetes or damage to liver, pancreas or kidneys. However, the most common and dreaded side effect-the one that laid Pickett so low-is incessant diarrhoea, which can rapidly lead to life-threatening dehydration.
A lot of people would like to find a way to help the body鈥檚 immune system control HIV with little or no help from drugs. But that seemed like an impossible dream, because HIV attacks the very immune cells the body would use to control the infection. The virus targets two types of immune cells: the CD4 or helper T cells and the CD8 cells, also known as killer T cells. The helper T cells鈥� job is to tell the killer cells that HIV is present in the body. Once the killer cells receive that message, they seek out and destroy HIV-infected cells. But HIV kills the helper cells and without them the killers don鈥檛 know what to do.
A first indication that controlling HIV without drugs might not be a pipe dream after all came about three years ago when Franco Lori, an AIDS specialist at the Research Institute for Genetic and Human Therapy in Washington DC, reported the case of a man who has become known as the Berlin patient. For him, the drugs鈥� side effects were so severe that he had to stop. As soon as he restarted, the meds made him sick again, so he quit for good. He鈥檚 now been off drugs for four years, and although the virus remains in his body, his own immune system seems to keep it at bay. Others have tried this strategy, and while many have not been as fortunate a few, like Pickett, have found freedom from the drugs.
Researchers now think they can achieve deliberately the success these patients achieved by accident-especially if they can catch patients right after they become infected. At that time, the helper T cells begin to proliferate and signal the killer cells to attack the virus. In most viral infections, this T-cell response eventually eradicates the virus. But because HIV kills the helper T cells, it gradually undermines the immune system until there are no longer enough T cells to keep pace with the growing hordes of viruses.
What鈥檚 needed, says Bruce Walker, who directs the Partners AIDS Research Center at Massachusetts General Hospital in Boston, is a way to give the immune system a head start so that it can鈥檛 be overtaken. That鈥檚 where drugs can help. If a patient begins HAART within a few weeks of infection-far earlier than current guidelines recommend-the drugs should knock back the virus after it stimulates the helper and killer T cells to proliferate, but before it can infect too many. When treatment is stopped, the resurgent virus activates more helper cells, which in turn promote the production of more killer cells.
鈥淭he trick is to have enough virus present to stimulate the immune system without overwhelming it,鈥� says Dominik Wodarz, a theoretical biologist at the Institute for Advanced Study in Princeton, New Jersey. Repeated cycles of stopping and starting the drugs can build up the immune system stepwise until it鈥檚 strong enough to control the virus on its own.
Catch them early
To test this idea, Walker, along with Eric Rosenberg of Harvard University, began in 1997 to flag up people coming into the emergency room of Massachusetts General Hospital with mononucleosis or severe flu-like symptoms. The early signs of HIV infection resemble mononucleosis-abnormally high levels of immune cells called monocytes in the blood-so if doctors know what to look for they can catch people just after infection. Rosenberg found that about 1 per cent of patients presenting with mononucleosis had just been infected with HIV. After a year, the two doctors had found 16 patients who were so recently infected that most tested positive with only the most sensitive HIV tests. All these patients started HAART immediately.
Today, their study has grown to 40 newly infected patients in various stages of taking drugs or coming off them. Most of them have taken two or three STIs. So far, the results are promising. Fourteen patients have been off AIDS medication for several months, with two off drugs for more than a year and a half. The other 26 are in the early stages of STIs, so it鈥檚 too early to say how well they are controlling the virus.
Of the 14 who have stopped their drugs, only one patient has failed to meet the study鈥檚 stringent criteria for successfully controlling the virus-and even he has done remarkably well. Without drugs, he has about 7000 viruses per millilitre of blood-a number considered far too low to warrant drug treatment, according to current government guidelines. Pickett鈥檚 virus level, by comparison, climbs as high as 45,000 per millilitre and he is still able to manage the infection without drugs.
Similar results have been found with newly infected monkeys. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease (NIAID) in Bethesda, Maryland, showed that animals that received several STIs, with HAART in between, remained healthy for more than a year after they were taken off the drugs. Animals in the control group, meanwhile, which had continuous HAART and then stopped treatment, could not stay off the drugs without getting sick.
Walker鈥檚 Harvard patients offer great hope for people who become infected with HIV in the future, but what of the 34 million who already have the virus? Is there a way to revive their already ravaged immune systems?
Montaner reckons there is. 鈥淭here鈥檚 nothing special about the time immediately after infection,鈥� he says. Successful HAART should suppress the virus thoroughly enough for the immune system to regenerate a good-sized crop of fresh, uninfected helper T cells, he thinks. When drug treatment stops, these fresh cells can begin to activate killer T cells just as they would immediately after infection. For some patients, like Pickett, one interruption may be enough, while others with less vigorous immune systems may need several STIs to build a stand-alone T-cell response, says Montaner.
So far, clinical trials of the strategy have yielded promising but mixed results. In a study Montaner is conducting, 20 patients have completed a sequence of STIs and have been off their drugs for several months, with none so far needing to restart. He is continuing to recruit volunteers for the study.
Other trials in the US and Europe have been less successful. For example, Mark Dybul, an AIDS expert at the NIAID, found no increase in helper or killer cells after STI in any of the 70 patients he studied. All had to start taking drugs again within months. From dismal results like these, many virologists conclude that the strategy is unlikely to work for patients who have been infected for some time. 鈥淚 would predict that only the patients who are newly infected and still retain an immunological response to HIV will be able to succeed with this therapy,鈥� says Fauci.
But Montaner is more hopeful. The precise timing of the STIs is critical, he thinks. His study uses 鈥済raduated鈥� STIs, in which patients have a two-week STI, then go back on HAART until the viral load is undetectable. This is repeated with a four-week and six-week STI, then patients stop their drugs indefinitely. This approach, he thinks, should be better at priming the immune system compared with the repeated but fixed-time STIs that all other studies have used. Still, he says, no one has perfected the recipe yet. Researchers鈥� varied approaches make the trials difficult to compare. Most other studies have used interruptions as short as one week, for example, whereas Montaner鈥檚 more successful trial is using three graduated intervals.
Time off
Even when STIs work, no one knows how long patients can stay drug-free. But any length of time-even as little as three or four months-would help reduce the drugs鈥� fearsome side effects and may delay the development of drug-resistant viral strains. It would also make treatment more affordable, especially in developing countries. And by keeping virus levels low, the strategy might also help reduce the transmission rate of the virus-a big plus in Africa, where millions of new infections occur each year, and where few have access to continuous drug therapy. Montaner hopes to test this possibility next year in a large trial in South Africa.
Still, with so many uncertainties, many virologists say patients who abandon successful drug treatment are playing with fire. Stopping and starting HIV drugs, they fear, could be as bad as stopping and starting antibiotics in a bacterial infection, increasing the amount of HIV in the blood-and therefore the risk of transmitting the virus-and encouraging the emergence of drug-resistant strains. And there are some unanswered questions, such as what is the best timing for treatment interruptions, and whether certain drugs will work better than others, says Walker. For example, some drugs have a long half-life in the body, which would prevent viruses from kick-starting the immune system when HAART is stopped.
But most HIV researchers are keeping an open mind. 鈥淲e are in the honeymoon period of this idea, where everything is hypothetically possible,鈥� says Montaner. 鈥淭here鈥檚 no indication yet that it doesn鈥檛 work.鈥�
The most promising strategy, though, may be to boost the immune system with a vaccine before beginning STI. Even a vaccine that didn鈥檛 confer total immunity could help prime the immune system and make the STI safer and more likely to succeed, says Walker. David Ho and his colleagues at the Aaron Diamond AIDS Research Center in New York have already tested this idea in four patients, using an experimental vaccine called Alvac 1452. When treatment was interrupted, two of the patients were able to go for more than three months before treatment had to be restarted. The other two went for less than three weeks.
Although the vaccine seemed to have an impact, the study was much too small to draw firm conclusions. But Walker and Montaner are both planning their own trials as soon as a better vaccine becomes available. Meanwhile, Lori鈥檚 team plans a study in which patients will be vaccinated with genetically modified immune cells produced from their own blood that mimic the appearance of HIV-infected cells. In monkeys and HIV-negative human volunteers, the cells provoke a more powerful response than existing vaccines.
If the vaccine booster can be made to work, it might help overcome what is perhaps the biggest obstacle to STI: the reluctance of the patients themselves to take a chance on it. 鈥淚t takes a great leap of faith to stop a drug regimen that鈥檚 working well, even though there are many nasty side effects,鈥� says Montaner. 鈥淧atients are afraid to let the virus go free.鈥�
But for Jim Pickett, who likens his life before he gave up the drugs to non-stop chemotherapy, the decision is already an easy one. Anything is better than the daily cycle of chemical torture.
