Optimism Over Anti-HIV Cocktails Tempered by Concerns

SAN FRANCISCO—Preliminary results of a prospective Centers for Disease Control and Prevention study of nearly 45,000 US patients show a dose-response relationship between anti-HIV regimens incorporating protease inhibitors (highly active antiretroviral therapy or HAART) and decreased HIV-related mortality.

“At this moment, we are in a period of incredible optimism with the use of protease inhibitors to treat HIV disease,” Paul A. Volberding, MD, of the University of California, San Francisco, said at a conference on globally emerging viral infections.

Dr. Volberding warned, however, that drug resistance to the new agents may loom on the horizon, and that such regimens are generally unavailable “in countries that lack the infrastructure and resources of the West.”

Specific changes in the AIDS epi-demiologic profile since the advent of protease inhibitors include the virtual disappearance of some opportunistic infections, Dr. Volberding said, including Kaposi’s sarcoma, cytomegalovirus (CMV) retinitis, and mycobacterium avium (MAC), a hallmark manifestation of late-phase AIDS. On the other hand, the prevalence of non-Hodgkin’s lymphoma has not changed, and that of warts—oral, cutaneous, and genital—has increased.

“This raises concern,” Dr. Volberding said, “because in connection with cervical warts, we might see an acceleration in the rate of cervical cancer, which hasn’t been that common in HIV.”

Concerns about the economic impact of the new, expensive therapies are overblown, Dr. Volberding said. A randomized sampling of the whole country by the Rand Corporation found that outpatient visits and hospitalizations related to HIV represent less than 1% of US health care expenditures. “So while it’s an expensive epidemic,” he said, “the expense is exaggerated by some groups for political reasons and is not dominating the health care system.”

Other studies have shown that the increased treatment cost incurred by using protease inhibitors is offset by reductions in hospitalization and other treatment costs. “So the net effect of using these new expensive therapies is, in fact, cost reduction as well as improvement in patients’ disease and survival,” Dr. Volberding said.

For this reason, he noted, countries with second-tier economies, such as Brazil, Argentina, and the Philippines, are finding that it makes economic sense to offer the new HIV treatments to their populations.

On the scientific front, pressing unanswered questions about the new regimens include:

How effectively does the immune system repair itself following anti-retroviral therapy?

When should treatment be started?

What are the mechanisms of pathogenesis of the disease?

Recent reports show that without continuous aggressive therapy, the virus rebounds, so reservoirs and eradication (as opposed to suppression) are important research targets.

“We’ve known for a long time,” Dr. Volberding said, “that interaction between HIV gp120 and the CD4 receptor on the cell’s surface is required for infection, but recently we’ve learned that infection also requires interaction with a chemokine receptor. The actual trigger for the cell-viral fusion appears to be the uncoiling of the external part of gp41, which then penetrates the cell membrane, triggering viral fusion.”

T20 Blocks Virus-Cell Fusion

T20, a new drug that has been very promising in small-scale trials, is the first specific blocker of the fusion of the virus with the cell, he said. The agent works by binding to the external part of gp41 to prevent it from uncoiling.

When to start therapy is controversial, but Dr. Volberding’s view is to “start before the patient is at risk for serious complications or morbid or mortal opportunistic infections, which happens at CD4 cell counts of 200 or 250 cells/mm³.” Currently in the United States and Europe, a CD4 count of 500 cells/mm³ is a common starting point for treatment.

The issue is complex because counting CD4 cells does not fully define the quality of immune response, he said. There is also some danger that the virus will evolve to a more virulent form if therapy is delayed or is not aggressive enough, and the patient must be ready to meet the demands of a rigorous treatment schedule if antiretroviral therapy is to succeed.

Studies Only Go to 48 Weeks

Furthermore, Dr. Volberding commented, “it is not hard to bring the viral load under control with an appropriately aggressive regimen in previously untreated patient, but studies only go to 48 weeks, and we need therapies that can be used for 20 to 30 years as AIDS converts to a chronic disease.”

Very-long-term treatment with the present agents used in HAART may also be compromised by toxicities that have become apparent in some patients after only 1 or 2 years.

The problem of viral resistance is a pressing concern, he said, compounded because new drugs tend to be in the same family as existing ones, increasing the probability of cross-resistance to classes of drugs.

“It is not likely that any of the drugs now in advanced development will offer a meaningful chance for our failing patients to achieve control again,” Dr. Volberding commented. “So while the epidemic is now under amazing control, it is predictable that this will not remain the case.”