Fast, total suppression called key to treatment

Virus reservoirs persist, but news is not all bad

Pushing viral loads as low as possible and as fast as possible are the most important determinants of sustained success with antiretroviral therapy in 1998. But even that strategy apparently fails to rid the body of small pools of latent virus, and boosting of the immune system or other novel approaches may be required if patients are ever to free themselves of lifelong medication.

Study data presented by a diverse group of researchers at the 12th World AIDS Conference confirm that drug regimens sending a patient's viral load to undetectable levels at a faster rate had a longer duration of suppression. At the same time, those patients who could not reach viral load suppression below 50 copies cannot sustain undetectable levels for a long period, Douglas Richman, MD, a leading AIDS researcher at the University of Southern California in San Diego, reported.

"People who have greater than 50 copies reflect ongoing replication," he said. "In those people who even have a couple hundred copies, contrasted to those who have less than 50, new drug-resistant mutations can appear, albeit very slowly."

As a practical matter, the results question whether less sensitive assays - those that cannot measure virus down to 50 copies - are adequate for good treatment management. "I would argue that the more sensitive assays are the way we want to go in managing patients on antiretroviral therapy," he added.

HIV reservoirs deal setback to therapy

But even in patients who have no detectable virus using the most sensitive assays, scientists have found in the past year that HIV persists in latent form in small reservoirs of resting CD4+ T cells. The finding is a setback for earlier speculation that highly active antiretroviral therapy (HAART) could eventually eradicate the virus and treatment could be stopped.

"Despite situations where plasma viremia is completely suppressed, even using the most sensitive assays repeatedly, there is residual virus replication," said David Ho, MD, director of Aaron Diamond AIDS Institute in New York City.

Researchers at the National Institute of Allergy and Infectious Diseases had more bad news to share. The latent pools of infected cells are established extremely early in the course of infection and are not significantly diminished with HAART.

"We have shown that initiating HAART as soon as 10 days after the onset of the symptoms of acute HIV infection does not prevent the formation of latent reservoirs of virus," said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases in Bethesda, MD. "By the time high levels of HIV are detectable in the blood, the virus probably has spread to the lymphoid organs and established a pool of latently infected cells."

Fauci presented evidence from nearly a dozen patients showing that treatment had little or no impact on reducing the level of latent virus. The institute's findings, however, contradict studies at the Aaron Diamond AIDS Institute. In a similar number of patients treated soon after infection, researchers there were able to show a slow decay of the reservoirs.

Antiretroviral potency overestimated

Ho could not explain the reasons for the different findings, except that his patients were treated earlier in the course of infection. The fact that virus is still replicating in the face of HAART underscores a point driven home at the conference: The potency of antiretroviral regimens has been overestimated.

"In looking at the hurdles to viral eradication, I would rather have less of this latency problem and more of the drug potency problem, because this we know how to do better," he explained. "With the new agents coming along, it is easier for us to deal with than regulating the immune system."

Even on the immune side of the equation, there is conflicting evidence regarding how successfully HAART can restore immune function. Some researchers have enough confidence in the completeness of restoration that they are taking patients off preventive therapy for opportunistic infections. Bernard Hirschel, MD, conference chairman, noted that he takes his patients off prophylaxis if their viral loads are stable and CD4 counts have risen and stabilized between 200 and 400.

However, as shown in a U.S. study of 27 patients on HAART therapy, immune function in lymph nodes may not complete for many patients. Nearly all the patients had immune dysfunction (hypergammaglobulinemia) even after more than two years of therapy, reported researchers at SUNY Stony Brook. Their study also found reservoirs in the lymph nodes despite virus in the blood at levels lower than 20 copies.

Diminishing those latent pools of HIV is a new field of study, but researchers at NIAID already are looking at the possibility of "flushing out" the virus by stimulating infected CD4+ T cells with antibodies or with combinations of cytokines, such as interleukin-2.

"In our in vitro studies, we have shown that it is indeed possible to decrease the number of latently infected cells, but a single round of purging doesn't completely eliminate the virus," Fauci said.

As researchers continue to search out ways to kill the virus, others are looking at enhancing white blood cells to restore immune system function. Researchers at the University of California at San Francisco, for example, are looking at stimulation of macrophages with WF10, a drug manufactured by Oxo Chemie Inc. in San Francisco, that may augment their effectiveness.

Novel immune-based therapies targeting HIV reservoirs also are being explored. Cell Genesys Inc. reported on Phase II trial data of its AIDS gene therapy showing that it decreased HIV levels in gastrointestinal lymphoid tissue in four out of five patients. The company is initiating a Phase II trial in patients who have undetectable virus in the blood following antiretroviral therapy. Patients will receive three infusions of the gene therapy and will be followed for at least six months.

In addition, Glaxo Wellcome's new second- generation protease inhibitor, amprenavir, may support immune reconstitution. In one small study both CD4 and CD8 cells returned to normal ratios in lymph nodes in eight patients, the company reported.

An approach at the other end of the spectrum is being pursued by researchers at Hoffmann - La Roche. With the identification two years ago of two cellular co-receptors as essential for HIV to bind or fuse to cell membranes, there exists the potential of blocking HIV before it infects cells.

"While the benefits of today's protease inhibitors in treating HIV are clear, the potential for blocking infection of cells in the first place holds tremendous hope," says Nick Cammack, PhD, researcher at Roche Discovery in the United Kingdom.

Yet another approach may be the use of therapeutic vaccines in patients with chronic HIV infection. Such a strategy may "compensate for the early loss of certain components of the virus-specific immune system," said Guiseppe Panteleo, MD, director of infectious diseases at Beaumont Hospital in Lausanne, Switzerland.

"The strategy of complementing HAART with immune-based intervention may lead over time to a new steady state where viral replication may be effectively controlled even in the absence of antiviral therapy, and ultimately to eradication of HIV," he explained.