Partial Eclipse of the HAART
New treatment strategies to overcome roadblocks.
by Richard Jefferys

The complexities of HIV research and treatment are enough to leave anyone's head spinning. That's especially true now, as the limitations of what is know as HAART-highly active antiretroviral therapy-continue to be revealed. Looking back, the 1996 World AIDS Conference in Vancouver will be remembered as the HAART honeymoon, a point at which it looked like triple drug combinations might be able to blast HIV into nonexistence. Overnight, "hit hard, hit early" became a popular mantra for treatment among researchers, with Dr. David Ho of the Aaron Diamond AIDS Research Center filling the role of chief cheerleader. With HAART, Ho and others suggested, the eradication of HIV-a cure-was no longer a fantasy.

"Infectious disease has taught us for years -- especially with severe infections like systemic fungal infections, bacterial, TB -- that you treat it early and you treat it at the outset with everything you've got." Thus spoke Dr. Ho in July of 1996.

Recently however, Ho's own group has published evidence in the New England Journal of Medicine showing that a low-level or "residual replication" of the virus exists in people on HAART, even when the virus is "undetectable" (below the limit of detection in the blood). Similar findings were presented in the same Journal issue by longtime Ho collaborator Alan Perelson and a team of doctors at the Northwestern University Medical School in Chicago. Other reports and an accompanying editorial in the June issue of Nature Medicine by leading HIV researcher Roger Pomerantz suggested that new treatment strategies are needed to tackle residual or latent HIV in the current "post-HAART" era.

Taken together, these reports strike directly at the heart of the HIV eradication theory. Though no one's giving up on a cure, it appears that HAART alone won't do the trick. While these findings received heavy coverage in the mainstream media, they have not come as a surprise to most researchers. Ho and colleagues presented the information about residual, or latent, infection as an argument for stronger anti-HIV drugs. Others support the idea of harnessing the immune system's own ability to control HIV using novel immune boosters or vaccines.

In addition, HIV protease inhibitors, still the backbone of most HAART regimens, have been increasingly associated with abnormally high levels of fats (cholesterol and triglycerides) in the blood and changes in body fat distribution, part of a syndrome referred to as lipodystrophy. These side effects increase the risk of heart attacks and pancreatitis (see "Fat Disorders"). Nonprotease drugs have also been linked with this syndrome.

Finally, drug failure and drug resistance have also made it hard for some people to control the virus. After mixing and matching numerous "salvage" therapies, they're running out of options.

Given this picture, what can we do? Is it time to panic? Not yet, say the experts, who present reassuring evidence that we can overcome the present hurdles.

• Their most important finding is that the immune system is surprisingly resilient and that "hitting hard and early" may not be necessary to prevent the development of AIDS.
• Secondly, continuous use of HAART may not be necessary to preserve health; instead, intermittent use of HAART shows promise and might reduce the risk of drug-related side effects. Nonprotease regimens and emerging drugs may also provide alternatives and reduce drug toxicities.
• Lastly, immune control of HIV-without HAART-may be possible if the immune system is given the right kind of encouragement.

We've known for a long time that long-term survivors with HIV (called nonprogressors) often have low but detectable levels of viral replication, but that their immune T-cell counts stay high and they don't get sick. In this group, HIV-specific immune responses appear critical to keeping the virus in check. But in people with chronic HIV infection, these HIV-specific immune responses are gradually lost. If they can be restored through new vaccines, then remission, or long-term control of the virus, becomes a feasible goal.

So instead of eradication and "hitting hard," frontline scientists are hotly debating such controversial ideas as deferring treatment, "drug holidays," "auto-vaccination," "stop-and-go" therapy, and immune boosters.

Deferring Treatment
There is renewed interest in delaying HIV treatment rather than starting it early. Jay Levy, a renowned San Francisco-based immunologist, started the ball rolling with an article in The Lancet in September 1998 that offered more conservative guidelines for HIV therapy than the current federal recommendations (see "Uncle Sam Says"). These guidelines recommend HAART for individuals whose CD4 T-cell counts fall below 500 and/or whose HIV RNA viral load levels rise above 20,000 copies. Dr. Levy suggested that "current therapeutic regimens should be reserved for those patients who have symptoms or whose CD4 T-cell counts have dropped substantially." He prefers to begin treatment when CD4 T-cell counts are less than 400 and/or HIV RNA levels exceed 30,000 copies on at least two occasions. These lab values, he believes, are "representative of what appears to be evidence of an early demise in the immune response, but one that can be reversed."

Recently released guidelines from the British HIV Association (BHIVA) echo Levy's advice, suggesting that "a CD4 (T-cell) count of around 350 cells is a reasonable level of immunodeficiency at which therapy might be started." Veteran U.S. treatment activist Mark Harrington recently summed up the debate in this way: "The reasons to start early are theoretical; the reasons for starting later are practical."

Drug Holidays
When happens when you stop HAART? How quickly does HIV bounce back? What happens to the immune system? Studies of intermittent HAART are looking into these questions. We already know that completely stopping HAART does not necessarily lead to drug resistance as feared. The first demonstration of this came from a seminal HAART study involving a Crixivan/AZT/3TC regimen. Several individuals in the study developed kidney stones from Crixivan and had to stop therapy for several days. Although their viral loads rebounded during the break, they disappeared again when treatment was restarted. A recent French study of HAART interruptions -- dubbed "drug holidays" -- produced similar results.

There is a very important caveat: these studies have usually involved people taking their first or second treatment regimen. There has been at least one report of an individual on a successful fourth-line or "salvage" combination who did not manage to reduce his viral load to an undetectable level again after a drug holiday. For now, new studies of HAART interruption will probably focus on people with early HIV infection. In this population, it's been observed that CD4 T-cell counts often stay elevated even after HAART is stopped and viral loads rebound. Therefore, periodic use of HAART may preserve health and immune function for extended periods, while minimizing side effects. The other potentially beneficial aspect of this approach is that drug resistance is unlikely to develop when no drugs are being taken. Look for new "drug holiday" studies beginning nationwide through the AIDS Clinical Trials Group (ACTG).

There may be situations in which drug holidays are appropriate for people with late-stage HIV disease. Two studies of "salvage" or rescue HAART combinations, one by Dr. Mike Youle in London, the other by a German researcher, Veronica Miller, have documented better results with people who took a drug holiday before starting a new regimen. Youle gave patients a mega-HAART salvage regimen of six to eight drugs. Most patients also took a drug holiday before embarking on this heavy-duty combination. He found that their chances of reducing their viral load to under 400 copies increased by 15 percent for every month of the drug holiday. The longer the holiday, the better the salvage regimen worked. A drug holiday also seemed to improve the response to a multi-drug salvage regimen, Miller showed. Using resistance testing in her study, she reported that during the drug holidays, more than half the participants saw levels of drug-resistant virus fall below the limit of detection.These individuals also had a far better response to their salvage regimen than people with drug-resistant virus levels that stayed detectable.

Immune Control
The immune system has long been viewed as helpless in the face of the marauding, nasty HIV virus. Ongoing studies are demonstrating, however, that the immune system can be revved up to fight HIV more effectively. A team of scientists at Harvard, led by Dr. Bruce Walker, is testing structured drug holidays in recently-infected individuals to see if their HIV-specific immune responses can be boosted. A colleague of Walker's, Eric Rosenberg, recently reported on one person in this study who, as of June, had taken a second treatment break. This individual's viral load climbed to 67,000 copies over several weeks-which would normally have prompted the researchers to restart HAART. But the patient developed a case of hepatitis A, which forced him to delay HAART until the liver infection improved. While they waited, his HIV viral load level dropped to 490 copies by itself-with no help from HAART. A second test showed a viral load count of around 1,000 copies, at which point HAART was restarted. This patient has started his third planned drug holiday and it will be interesting to see what happens this time around.

A related strategy is being pursued by maverick Italian researcher Franco Lori. Nicknamed "stop-and-go," Lori is testing treatment interruptions in people who've been HIV-positive for some time, using a nonstandard, nonprotease HAART combo of ddI and d4T and an old cancer drug, hydroxyurea. Lori thinks hydroxyurea may have unique immune-boosting qualities and may work against latently infected "memory" T-cells. In January, Lori reported that after a third drug holiday, it took over a month for viral load levels to become detectable in three of his patients. A much larger study is underway.

A number of therapeutic vaccines also aim to boost HIV-specific T-cell immune responses, including cellular immunity (primarily "type-1" antiviral helper T-cells, and cytotoxic T-lymphocyte, or CTL, responses). Furthest along in clinical trials is Dr. Jonas Salk's immunogen, known as Remune. At the University of Alabama at Birmingham, Dr. Mike Saag has an intriguing Remune study in the works. Participants whose viral loads have been undetectable for at least six months on HAART will get three shots of Remune over the course of several months. Then HAART will be stopped for at least six weeks, to see how well Remune-induced immune responses can control HIV.

On the other side of the globe, an enthused team of Australians are beginning human studies with a therapeutic "naked DNA" vaccine called Co-X-Gene that is the precursor of a promising monkey vaccine (see "Monkey Vaccine Renews Hope"). Co-X-Gene is also being studied as a preventive vaccine.

Along with therapeutic vaccines to goose HIV-specific immunity, nonspecific immune boosters are also being studied. The most famous is interleukin-2 (IL-2), which can boost T-cell levels and may stimulate dormant T-cells to become active. IL-2 is also being tested in federal clinical trials as a strategy to flush out virus from dormant cell reservoirs. Earlier this year, Tae-Wook Chun of the National Institutes of Allergy and Infectious Diseases (NIAID) reported that after adding IL-2 to a HAART regimen, six of 14 patients had no signs of infectious virus, whereas patients from another study taking only HAART had latent HIV that was much easier to detect. On the downside, IL-2 may cause severe, flu-like side effects.

NIAID's Dr. Anthony Fauci recently reported that the people from this IL-2 study later stopped their HIV meds and saw the virus rebound back. So even though it was impossible to detect, the virus was still there, hidden inside dormant immune cells. The good news is that one individual "spontaneously" reduced his viral load below 400 copies after the initial rebound. This may be evidence of an HIV-specific immune response similar to what Bruce Walker reported with Remune.

"The goal of immune-mediated containment of HIV is realistic and needs to be pursued with vigor," contends Walker.

Future Steps
As in many relationships, our life with HAART is getting much more complicated now that the honeymoon is over. On the horizon we may face considerable bickering (changing guidelines), extended separations (drug holidays), and maybe even divorce (immune control). But as we stand at the cusp of a new millennium, it's also reassuring to imagine that the immune system may one day develop the strength to go it alone against HIV. That would be a total eclipse of the HAART.

Richard Jefferys is a treatment advocate at AIDS Treatment Data Network (ATDN).