The Washington Blade - February 4, 2000
Lisa Keen

After years of growing consensus around the strategy of "hit early, hit hard," many experts now appear to be backing off the "early." After assuming the development of certain fat deposits were linked to the use of protease inhibitors, researchers now say the phenomenon also occurs in patients who have never taken the drugs. For the past few years, doctors warned patients never to miss a dose; now some are talking about the possibility that deliberate interruption of therapy might be beneficial. And after calculating that the risk of transmitting HIV through oral sex was extremely low, a study emerged this week indicating it is actually "significant."

Thus was the nature of the news at the Seventh Conference on Retroviruses and Opportunistic Infections, held in San Francisco Jan. 30 through Feb. 2. One of the most startling turnabouts in the news at this week's conference rated only one poster presentation -- the news that oral sex is responsible for a much greater percentage of infections than originally thought. [See separate story in this issue.] The poster came from researchers at the U.S. Centers for Disease Control and Prevention in collaboration with researchers at the University of California-San Francisco. After investigating the mode of transmission for 102 Gay and bisexual men, the study concluded that eight men had most "likely" been infected through oral sex. Previously, only a handful of cases out of thousands had been attributed to oral sex.

In the area of missing doses, the conventional wisdom has been -- and still is -- that any interruption of a combination therapy gives the AIDS virus an opportunity to replicate and mutate. But now, there is growing belief that a "strategic interruption" of therapy might actually be beneficial.

Strategic skipping

The notion has been around for a couple of years. That is when news first emerged that a patient in Berlin had started and stopped his therapy twice and then was able to stay off the therapy and yet have his viral load remain under control. His viral load has remained under control for more than three years now without medication. At the Retrovirus conference this year, a number of researchers reported on their preliminary studies in using the strategy -- called "structured intermittent treatment" or "structured treatment interruptions." The theory behind the strategy is that stopping the drugs allows just enough HIV to emerge that the patient's immune system can handle it and can learn how to fight off HIV itself.

A group of researchers led by scientists in Switzerland used the strategy on a group of 43 patients who had kept their viral loads below 50 for at least six months on a triple-drug protease inhibitor combination. The Swiss researchers stopped treatment for two weeks, resumed it for two months, and then repeated this cycle four times. At the end of that fourth cycle (10 months later), the patients went off therapy until or unless their viral loads climbed back up above 5,000.

According to the researcher presenting the results of this study Tuesday, 28 had viral rebound when they first stopped therapy. Of 16 patients who continued to the point of the second interruption, 12 experienced viral rebound. Of the four patients who made it to the third interruption, three kept their viral loads below 5,000, a result the Swiss characterized as "modestly encouraging."

"Structured treatment interruption will induce remission in only a minority of patients," said Swiss researcher Bernard Hirschel, who presented the study. Several other posters and presentations gave a mixed assessment of the strategy's prospects. A poster from Spain reported similar results, while a study of three patients in Paris was less successful. A poster presentation from the National Institute of Allergy and Infectious Diseases Monday indicated that 12 patients who stopped triple-drug therapy had their viral loads rebound to levels they were before beginning therapy. Yet a poster from Canada found 13 patients who stopped therapy and kept their viral loads very low for at least 90 days, as did a smaller study from New York and Pennsylvania.

A poster from Massachusetts General Hospital, a pioneer in this strategy, tried the therapy on seven patients who had begun triple-drug therapy prior to having developed HIV antibodies, and all had viral rebound within one to eight weeks of having stopped therapy. But all showed signs of a strengthening immune system and the researchers concluded: "Structured treatment interruptions results in a persistent augmentation in the frequency and breadth of [killer T-cell] responses in these subjects, which can be further boosted by additional controlled interruptions in therapy."

The most successful report came from a poster presented by Franco Lori and Julianna Lisziewicz from the Research Institute for Genetic and Human Therapy in Washington, D.C., and Italy. Lori and Lisziewicz took a group of eight patients with HIV who were taking the nucleoside ddI and the cancer drug hydroxyurea who had kept their viral loads below detectability for two years and compared them with a similar group on a standard triple-drug combination. They stopped the treatment for both groups and noticed that the protease inhibitor group rebounded above 10,000 within six weeks, while the hydroxyurea-ddI group went the entire eight-week interruption period without significant rebound.

While they acknowledged that they cannot be sure, Lori and Lisziewicz said they believe hydroxyurea played a role in the success.

In an article in the Jan. 22 edition of the British medical journal The Lancet, Lori and Lisziewicz described having success with two out of three patients who had never taken antiviral drugs before. The three were given a combination of hydroxyurea and ddI for three weeks, then no drugs for one week, then treatment for three months, then no drugs until their viral loads rose above 5,000. At that point, drugs would be restarted again. One patient went six months before his viral load rose above 5,000 following the second interruption. Another went five months following his fifth interruption. The third patient had mixed results. But, the scientists noted, "importantly, anti-retroviral treatment rapidly reduced [viral load] below the limit of detection after each restart."

A number of researchers presenting reports emphasized the risk in the strategic interruption treatment. University of Colorado researcher Constance Benson, chair of the conference's program committee, said the concept had "not yet been proven" and emphasized at a press conference Sunday that it would be a "dangerous message to say this is an appropriate approach à at this point in time."

Lori and Lisziewicz emphasized, in an interview, that these results are all still "very preliminary" and that patients should not attempt to mimic these or other studies on their own.

"There is absolutely not enough for anybody to go out and try it," said Lori. Lori said researchers first must do randomized control studies before they will know whether the success with his group was "an accident à or whether this is the way to go."

In other sobering news, Diane Havlir of NIAID reported Tuesday that patients on triple-drug therapy who added hydroxyurea to their regimen suffered a "disproportionate" incidence of toxicity.

Switching to a regimen with hydroxyurea, said Havlir, "led to a significantly higher rate of failure due to toxicity." Havlir said the hydroxyurea "contributed to two deaths." But she added that doctors should not abandon the drug, noting that there is a "large body of data to attest to the safety and efficacy of hydroxyurea," which has been used for years in the treatment of cancer.

New concerns with old success

A big concern, of course, is that when therapy is stopped, the AIDS virus begins replicating and destroying the immune system. In related news this week, one report revealed that, when the virus re-emerges after drug therapy has been stopped, it is not always coming from the so-called "latent reservoirs" in lymph tissue, as previously believed. Previously, it was assumed that the virus began replicating from within the so-called "latent reservoirs" in the inactivated immune cells that had been stimulated. But a study from the National Institute of Allergy and Infectious Diseases this week indicated that the virus in these so-called "resting" T-cells "does not account entirely for the early rebounding" HIV in blood in patients who have stopped taking their drug combinations. The study, noted its lead author, T.W. Chun, suggests the "possibility" that some "other persistent HIV reservoirs" are responsible. Where are these other reservoirs? No one yet knows.

Meanwhile, some new concerns were raised this week about the highly touted triple-drug protease inhibitor combinations, as well as some new light around old concerns.

A study from Australia, presented Sunday, noted that 54 percent of 1,337 patients with HIV experienced what is now being referred to as "altered fat distribution" -- or the accumulation of fatty deposits in the abdomen and neck and loss of tissue in the face, arms, and legs. Six percent suffered the phenomenon in their abdominal area, 20 percent in their face, arms, and legs, and 28 percent in all four areas. In most patients, noted researcher J.E. Miller, the fat accumulation was mild to moderate in severity. The study found the phenomenon was more likely to develop in patients 40 and older and in patients with more advanced HIV disease.

But Australian researcher David Cooper noted Monday, at a press conference, that there is "circumstantial evidence" now that nucleoside analogs cause toxicity "not just to the liver and muscles but also to fat." While 54 percent of people on protease inhibitors are developing the "altered fat distribution" side effect, so are about 20 percent of people on nucleosides.

What causes the "altered fat distribution"? A study from the University of California-San Francisco suggested that the altered fat distribution is not being caused by the HIV infection itself. The study looked at the phenomenon in six different groups of about three dozen patients each. There was no altered fat distribution in people who were HIV-negative or in people who had HIV but had never taken any antiviral drugs. Only those patients who had been on either nucleoside analogs or a combination of nucleosides and protease inhibitors exhibited the altered fat distribution. The study, said author Kathy Mulligan, suggests that protease inhibitors may account for the phenomenon in some people but not all. Her study found that the phenomenon almost never occurs in a patient without the presence of certain other factors that are not drug-related, such as being over 40 and having been HIV infected for more than seven years.

There was some discussion about the possibility that the phenomenon might be driven, in part, by the natural aging process, as well as the protease inhibitors.

In one of the first studies to see whether a change in drugs can improve the fat accumulation side effect, researchers in Australia reported Sunday that switching to a combination with a non-protease substitute did help. The study included 80 patients on a protease inhibitor combination. Some were kept on that regimen, some were given the nucleoside abacavir, some the non-nucleoside nevirapine, and some were given the nucleoside adefovir plus hydroxyurea. The study found that viral loads could be kept low while fat was reduced. A companion study, in Spain, also found success, testing substitution with nevirapine specifically. That study, too, found some improvement, but "only partial."

A newly emerging worry here this week involved reports that a significant number of patients on protease inhibitors are experiencing significant loss of bone mineral density -- in some cases, a thinning of the bones, in other cases, actual bone loss. One such study, presented by Pablo Tebas of St. Louis, found that 21 percent of 60 patients on protease inhibitors experienced significant bone density loss. By comparison, only 11 percent of 35 patients not taking protease inhibitors suffered such loss, and only 6 percent of a control group that was HIV-negative and matched for age, gender, and race.

"We're potentially looking at a new long-term side effect that could have significant implications for morbidity," said William Powderly of St. Louis. Not surprisingly, the emergence of this latest side effect, coupled with continued concern about the side effects with the fatty tissue and their related metabolic manifestations for the liver and heart, prompted a number of researchers to urge doctors against rushing to start patients on drugs as early as possible.

"There is still so much we do not understand about HIV, for instance, why the [human immune system] doesn't control HIV," said London researcher Robin Weiss at Sunday's plenary.

"Although HIV came from nowhere," said Weiss, "the death rate is dropping" due to new medications. "But is it going to go on dropping or à have we just won a few years?"
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