Slightly edited reprint from LA Weekly
Full copy available from the WA office
GENEVA -- At least three separate research teams at the 12th World AIDS Conference announced that strains of HIV which are resistant to many drugs, including the powerful protease inhibitors, have been transmitted from one person to another. In the midst of nearly 14,000 conference participants was a couple from New York City, one of whom recently contracted a highly resistant strain of HIV from the other.
One partner took years to become resistant to most HIV drugs, using them one after another as they came on the market, desperate to save his life. But now, his spouse is starting out with his partners' resistant strain. This eliminates most current treatments as an option.
Vigor of the Virus
Such cases re-emphasize the importance of prevention. But they also point to the virulence of HIV, which has killed almost 12 million people, infects another person every five seconds, and now is mutating under the pressure of powerful, but not curative drugs. "It's not surprising at all" that resistant strains have begun to circulate, says Tony Fauci, director of the National Institute of Allergy & Infectious Diseases. Indeed, given the astonishing vigor of this virus, many of the conference's scientific findings were sobering, but not surprising. Among the most important are that HIV continues to replicate even when patients are taking potent medication. In the very first days after the virus enters the body, it infiltrates certain long-lived cells that then harbor it for many years. So, even if a patient has an ordinary strain of HIV that is vulnerable to the drugs -- and even if that patient is among the lucky 10 percent of infected people who live in a First World country, (where the expensive drugs are available), "it will be very difficult to eradicate this virus" from the body.
Yet the AIDS death rate continues to drop all across the developed world.
Many researchers, believe it might not be necessary to eradicate every last virus from a patient's body. There is growing evidence that suggests (much like cancer remission), that the immune system can control HIV under the right circumstances, and that an AIDS-ravaged immune system can be regenerated with therapy.
The Cocktail -- It's No Party
Whether the goal is eradication or remission, the therapy is a cocktail of three or more drugs, often involving a protease inhibitor, that patients must take every day to suppress the virus. The afore mentioned couple is resistant to at least 9 of the 11 approved drugs -- and possibly all of them.
Several studies presented at the conference suggested that some people are relaxing their safer-sex standards because they believe the new treatments have made AIDS manageable. Prevention workers will undoubtedly have to combat this misconception.
In San Francisco, one out of 35 newly infected patients was found to have a virus resistant to all four approved protease inhibitors, and most of the AZT family of drugs.
In Switzerland, two out of 67 recently infected patients were found to be carrying strains highly resistant to protease inhibitors, and several more were resistant to other drugs.
U.S. military researchers found two out of 16 untreated patients with mutations that confer resistance to protease inhibitors.
There are more than 40 percent of U.S. patients being prescribed substandard drug combinations, which greatly increases the risk of resistance (our guess is that most of these 40% are women and/or people of color). Moreover, 30 to 50% of all patients have trouble taking their medicine as directed, which can also induce resistance.
HIV doesn't need to be super-resistant to wreak havoc. Ordinary HIV is virulent enough. In the first days after infection, the virus infiltrates so-called "resting T-cells." Since those cells are long-lived, HIV can lurk in them for years, capable of re-emerging and continuing the progression toward AIDS. If drugs could completely shut off virus replication, then this pool of cells would die off in 3 to five years.
But last year, evidence emerged from Fauci's lab that the drugs don't completely suppress the virus. In Geneva, Dr. David Ho presented proof that HIV keeps replicating, even when the drugs appear to be working to the extent that very sensitive tests cannot detect any virus in the blood. HIV's under-the-radar replication keeps infecting the resting T-cells, foiling attempts to eradicate the virus. Ho's conclusion: "We have overestimated the potency of our [medical] regimens."
Trial results of several promising new drugs were reported, but it remains to be seen if they will have a more powerful effect. Probably the most encouraging was a drug called efavirenz (brand name Sustiva). It was shown to be at least as potent as the strongest protease inhibitor, though its long-term efficacy is not yet known.
The research suggests that even under the most intense drug pressure, HIV not only keeps replicating, it also mutates and evolves.
Slow evolution of resistant mutations has occurred in some patients on seemingly effective drugs. This could explain some cases in which the drugs appear to be working perfectly, yet the virus eventually breaks through, rising back up to dangerous levels.
Whether this ongoing replication maintains HIV in the body or actually leads to drug resistance, some doctors are recommending that their patients take four drugs instead of three. But the drugs often cause side effects. Widely publicized have been fat and cholesterol disturbances, possibly leading to coronary problems in the most severe cases. Other doctors are taking the opposite approach and suggesting that their patients delay starting therapy if they are healthy and have relatively intact immune systems.
One person recounted his personal history of HIV and showed slides of his lymph nodes, a key immune-system site. Just after the last international AIDS conference 2 years ago, HIV had ravaged his lymph nodes. His T-cell count, a common measure of immune function, had plummeted to 152: healthy people typically have more than 1000. But now, following 2 years of effective therapy, he says; "I could be dead if I had listened to those same researchers who now say 'hit hard and hit early'."
But Fauci draws a different conclusion. This man was lucky not because he waited until he lay at death's door to start treatment, but rather because effective drugs were finally developed. Fauci suggests that anyone who has a high degree of virus replication, even those who are very healthy, should start therapy, because suppressing the virus can protect the immune system. The cold fact is that no one knows the optimal moment to start therapy.
Perhaps the best news from Geneva is that most patients who respond well to treatment are slowly regaining their immune systems.
A leading immunologist from France, has studied more than 300 patients who were fairly advanced in HIV disease. Among those who responded well to the drugs and almost never missed a dose, CD4 counts have risen steadily. She looked at many other aspects of the immune system, such as the ability of cells to respond to various bacteria and viruses, and in virtually every test the immune system showed steady improvement.
Immune System Revival
Though she estimates that full recovery will take four to eight years, she thinks "there is no limitation" to the capacity of the immune system to revive itself. That process might be speeded up by special immune-enhancing drugs, such as interleukin 2, or IL2, which showed excellent results in several studies presented at the conference. But even with IL2, the immune responses specific to HIV almost never came back.
The human immune system is exquisitely precise; the cells and antibodies that protect against the flu, for example, do nothing against herpes or TB. The reason HIV is so devastating is that it kills the very immune-system cells that orchestrate the body's counterattack against it. These cells are called HIV-specific helper T-cells, and the virus wipes them out in just three to 18 months after it has entered the body. Unfortunately, the French researcher has seen no revival of HIV-specific helper cells, even after two years of immune recovery.
To control HIV and achieve remission, HIV-specific immune responses are required.
A few patients -- less than 1% -- control the virus on their own, without ever taking drugs. Many of these "long-term nonprogressors" have very strong HIV specific responses.
Furthermore, Harvard's Bruce Walker and the University of Seattle's Julie McElrath, have each found that if patients are treated very early, (within weeks of getting infected), suppressing the virus prevents the destruction of the critical HIV-specific helper cells. Encouraged by anecdotal cases of patients who went off their medication yet have been controlling HIV without drugs. Trials are being designed to see if that experience can be duplicated. In the meantime, doctors strongly warn patients against stopping their drugs, lest HIV come raring back.
The trials will use patients who started therapy soon after becoming infected. However, the vast majority of people with HIV don't know they are infected until long after they have lost their HIV-specific responses. Can anything be done for them? Perhaps.
In a "late-breaker" Fred Valentine of New York showed that an HIV vaccine developed by the late Jonas Salk stimulates strong HIV-specific helper responses in mid-stage patients being treated with combination therapy. Patients who did not get the vaccine but did receive standard treatment showed no such gain.
A Little Ray of Hope
In the future, then, it is very possible that patients will be treated with standard drug cocktails to suppress their virus, with the addition of IL2 to speed the recovery of their immune systems, and an added AIDS vaccine to stimulate their HIV-specific immunity. After all that, maybe, just maybe, some patients would be able to stop taking the toxic and demanding drug cocktails and instead have their immune systems control the virus on its own.
Even if that goal isn't achieved, invigorating the immune system might extend the effectiveness of drugs, buying patients the most valuable thing: time.
The National Institutes of Health has temporarily stopped enrollment of pregnant women into protease inhibitor trials for fear that the drugs may increase the risk of premature delivery. Concerns are very preliminary and pregnant women currently taking drug combinations that include protease inhibitors can continue doing so. However, HIV-infected women who have increased risks of premature birth should be closely watched. The studies were stopped last week due to "an unexpected number" of premature births, based on the finding that 3 of 10 babies studied were born premature and one died in utero.
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