The Washington Blade, Friday, February 12, 1999
Lisa Keen

People acquire the virus, and their immune systems hold onto it. People take medications that can suppress the virus, but then they forget to take a dose or two. Or they skip a dose because it lands right smack in the middle of that big meeting with all the company bigwigs or the first date they've had in a long time. Or they wake up kind of sick and don't feel up to swallowing 12 pills one morning. Or they just can't afford to pick up their prescription this month; there's no money and no insurance to cover it.

And when they don't take their seven pills at 7 on an empty stomach, four pills at 8, three at 3, three more at 5 but on an empty stomach, two at 6, another two at 10, and two more at 11, people allow HIV to mutate.

And when HIV mutates, some of the drugs that they didn't take don't work anymore. Then people need other drugs. But there are only 10 other drugs to choose from and to figure out which drug to drop and which to pick up, people need to pay for two very expensive laboratory tests that their insurance companies probably won't pay for and their doctors probably won't know how to interpret.

As tedious and cumbersome as the whole pill-drill can get, people also have to handle the stress that comes with not being certain how long any drug combination is going to last them. And it is only after patients are biding their pill-taking and enduring the uncertainty that they get to the point where many experts believe HIV infection has become a "chronic, manageable illness" and not a time-bomb. If people with HIV can make it through all this, however, there were some reports at last week's Retrovirus conference in Chicago that might help them understand how doctors hope to "manage" the disease.

Healing thyself

Since last year, most experts have agreed that any hope of managing HIV into a chronic illness will require the strength and cooperation of the individual's immune system. The widely publicized report from the opening day of this year's conference -- about clues suggesting that the AIDS virus originated in chimpanzees and was probably transferred to humans through bites and other wound infections -- could potentially help in this area of research. Since chimpanzees carry the virus but don't get sick from it, noted University of Alabama researcher Beatrice Hahn, scientists might study the chimpanzee immune system to understand why. But more direct research -- on humans -- produced some good news this year.

Two reports presented in Chicago indicated that the thymus gland -- the place where immune "T-cells" are produced -- is still functioning in many adults. Previously, medical experts thought the thymus gland did all its work during a person's very early infancy and childhood years and then shut down. One report this week, from the University of California-San Francisco, indicated that there is "significant production" of T-cells in one's 30s and 40s. The production of T-cells by the thymus does begin to decrease in one's late 30s, and production is essentially halted by 55, but, as one scientist put it, "Immune reconstitution can be achieved in young individuals."

Reports also indicated last week that these T-cells -- CD4s which sound the alarm when such things as viruses enter the body, and CD8s which attack and kill the invaders -- might be able to fend off HIV infection better than originally thought. As Eric Rosenberg of Massachusetts General explained during a presentation Thursday, "We're all infected with viruses that cause latent infections." In fact, 95 percent of people are "infected" with the Epstein-Barr virus (which causes mononucleosis), the herpes virus, and others. But most people's immune systems are strong enough to keep these viruses from causing disease in the body. Rosenberg reported that there is "mounting evidence" that CD8 cells can control HIV, too. The key, scientists are learning, is to stop the virus from decimating so many CD4 "alarm" cells early in infection. Without those alarms, CD8 fails to attack.

Rosenberg and his colleagues at Mass General believe the best way to preserve CD4 cells is to administer strong antiviral treatment to a person as soon after infection as possible -- even before the body starts producing antibodies. The trick there, of course, is finding a way to tell someone is HIV-infected without waiting the two to four weeks it takes for antibodies to emerge. But Rosenberg said he believes there are ways. One way relies on patients and their doctors to recognize the symptoms of acute HIV infection (fever, fatigue, headache -- which sound a lot like the flu -- as well as skin rashes and oral and genital ulcers). If people have these symptoms, said Rosenberg, and there's any reason to suspect they might have been infected, doctors should do further testing and consider treating the patients. The danger here is that recent reports have also indicated that using tests that can detect HIV in the blood to make a diagnosis of HIV infection result in a large number of "false positives." But Rosenberg's team was able to identify 20 patients prior to their producing antibodies. Five of those patients who were treated right away have, one year later, "highly significant" T-cell responses against HIV that are characteristic of long-term non-progressors. He compared his group to a group of patients from Italy who were identified very early on but not given treatment and have developed "no significant" response against HIV.

If Rosenberg's theory proves true, the next question, he said, is whether a patient, "if treated early enough," can eventually discontinue taking antiviral drugs. As noted in last week's article on the conference, one patient at Mass General who received treatment prior to testing positive for HIV antibodies stopped taking therapy (after being on it for 17 months) but saw his virus begin to creep back up after only six weeks off drugs. But on the optimistic side, noted Rosenberg, this patient's viral load came back slowly after several weeks; patients who begin therapy later and then stop it typically see their viral loads rebound quite rapidly and within days.

Hurting thyself

One of the hard parts about starting drug therapy, no matter when one starts it, is that some of the drugs patients must rely on cause health complications which can, in and of themselves, be quite worrisome. There were more reports last week about the especially troublesome complications associated with the use of protease inhibitors -- heart disease, fat accumulation, and problems with sugar in the blood. But the reports were also contradictory, complicated, and almost constantly changing. One poster from Germany suggested patients on protease inhibitors have a "five-fold increase in risk" of having a heart attack, but two posters right next to it, both from the United States, said there is no significant difference in the incidence rate of cardiovascular heart disease or heart attacks. A researcher at one of the U.S. posters faulted the German poster for failing to separate patients by CD4 count. He noted that a report late last year indicated the risk of heart disease to people on protease inhibitors seems more related to the patient's CD4 count than it is to the protease inhibitor.

Australian researcher Andrew Carr said the loss of fat from a patient's arms and legs while on protease inhibitors is "irreversible." But posters from New York University and St. Vincent's Hospital in New York said they found the aggressive use of testosterone and other drugs have helped resolve the so-called wasting in the extremities as well as fatty deposits such as buffalo humps.

Carl Grunfeld of the University of California-San Francisco said Monday he believes the "benefits of protease inhibitors outweigh the risks." By his calculation, protease inhibitor therapy increases the incidence of cardiovascular "events" by 0.14 percent per year or 3.56 new cases per 100 person years every 10 years. He pointed to studies suggesting that the dramatic increases in cholesterol in the blood and the development of fat deposits in some parts of the body and wasting in other parts might be associated with pre-existing conditions in the patient. Genetics, he noted, plays a role in why some people in general suffer from high cholesterol or are vulnerable to heart disease, while others aren't. Grunfeld suggested doctors take into account a patient's coronary risk before prescribing protease inhibitors.

Surprisingly, while doctors still seem concerned about the side effects showing up since the use of protease inhibitors, there was a new and consistent call last week for "intensification" of drug therapy. From the opening "overview" by Italian researcher StefanoVella to L. Zhang at the Aaron Diamond AIDS Research Center in New York, the solution offered for most "failures" of current regimens was "intensify."

D. Descamps of France studied 116 patients on the commonly prescribed regimen of AZT-3TC-indinavir and said that those who began to see their viral loads go up did show the virus had mutated around 3TC but that "failure was not associated with resistance."

"Failure was due to the low potency of the drugs," said Descamps. A researcher from Merck, the maker of the non-nucleoside efavirenz and the protease inhibitor indinavir, said a study of patients who failed on regimens involving these drugs indicated that "failure does not require a change in all drugs."

"One option [for responding to such failures], said the researcher, "is intensification of any agent to which the virus is still susceptible. And replacing those [drugs] which the virus has resistance to."

But the advice comes, of course, at the same time scientists are actively contemplating the possibility that "intermittent" therapy -- to give the immune system a chance to build up its own strength against HIV -- might be the answer, too.

Whatever "the answer" turns out to be, it is likely to be a combination of "intensification" and "intermittent." Bruce Walker of Massachusetts General noted, at a press conference Wednesday, that it often takes three to four years for cancer patients on chemotherapy to reconstitute their immune systems to the point where they are strong enough to fight off disease again. And that is likely to be the scenario for HIV patients, too.

"People on [triple-drug combinations]," said Walker, "are just now reaching those stages."
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