Currently approved anti-HIV drug combinations are remarkably effective at reducing the amount of HIV in many patients to undetectable blood levels. For most, the clinical benefits add up to a healthier, longer life. Yet two studies in this week's New England Journal of Medicine demonstrate that, as good as these drugs are at suppressing HIV, other approaches likely will be needed to knock out the last vestiges of the virus.
"These findings are not unexpected," comments Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which provided major support for both studies. "The data add to other recent findings indicating that it may be impossible to eradicate HIV from the body with currently approved antiretroviral therapy. What all these studies underscore is the pressing need to develop more effective, less toxic medications that can be used over the long term to suppress HIV, as well as novel strategies to then purge residual virus from the body and boost the immune system. In this regard, many important leads are being pursued by investigators in government, academia and industry."
The era of highly active antiretroviral therapy, or HAART, began about three years ago when the first protease inhibitors were incorporated into multi-drug HIV treatment regimens that included older anti-HIV drugs such as AZT. Hopes that the drugs could "cure" AIDS were raised when some patients experienced dramatic drops in the level of HIV in their plasma. More sophisticated studies, however, subsequently turned up evidence that some virus survived the therapy by hiding in certain cells and tissues.
The NEJM studies were conducted by separate groups of investigators from the Aaron Diamond AIDS Research Center in New York, led by Linqui Zhang, Ph.D., and David Ho, M.D., and from Northwestern University Medical School in Chicago, led by Manohar Furtado, Ph.D., and Steven Wolinsky, M.D. Both groups focused attention on the reservoir of HIV found within circulating blood cells of patients who had successfully suppressed HIV in their plasma with HAART. The patients were taking various combinations of three to four anti-HIV drugs, including protease inhibitors. With strict adherence to HAART, all had kept HIV below detectable levels for approximately two to three years.
Although evidence has been accumulating that HAART may not wipe out all traces of the virus, it has been unclear what feeds the low-level residual infection. One unanswered question, for example, was whether HAART completely stops viral replication. If not, evidence of viral replication could mean a small but unending source of replicating HIV exists to replenish the reservoir.
To look for evidence of ongoing viral replication, Dr. Zhang and his colleagues studied four sequential cell samples taken from each of eight patients. They examined latently infected cells for changes in the genetic makeup of HIV from sample to sample, which could indicate ongoing replication of HIV. The cells from six patients showed few if any such changes. Over time, however, significant variations in the genetic makeup of HIV's coat protein appeared in cells taken from the other two patients. The changes, the researchers note in their paper, are "likely due to ongoing residual replication, albeit at an exceedingly low level." Studies of various tissue samples and body fluids from one of the two patients confirmed residual HIV replication in cells taken from his lymph nodes, tonsils and gastrointestinal tract.
The Northwestern University group examined at least five sequential blood samples taken from each of five men who also had used HAART to keep HIV below measurable levels for 20 months or more. To investigate the characteristics of the HIV reservoir in these men, they measured changes in the concentrations of HIV DNA and viral RNA in cells over time. They observed that after an initial rapid decline, the levels stabilized, indicating that viral replication persisted. This plateau, they say, suggests that the rate at which cells become infected with newly made virus is approximately equal to the rate at which older infected cells die.
"Unless this quasi-steady state eventually disappears with longer periods of therapy or can be overcome by the use of more potent therapies or alternative approaches that block the potential spread of virus within tissues, HIV-1 may never be eradicated," they write. "...it is sobering to realize," note Dr. Zhang and his colleagues, "that the so-called highly active antiretroviral therapy is actually not always active enough. As we strive to eradicate HIV-1 infection or induce a remission, we must focus on the possibility of further intensifying antiretroviral treatment, even though current therapies are already toxic, costly and complex."
One bright spot in this picture, says Carl Dieffenbach, Ph.D., associate director of the Basic Sciences Program in NIAID's Division of AIDS, is that the technologies developed by these investigators provide "new tools, so that if we ever have a patient in whom it appears the virus has been eradicated, we'll be able to verify that." This ability will become increasingly important, he says, as new and improved drugs shrink the latent reservoir of HIV even further.
The two studies received additional support from two other components of the National Institutes of Health (NIH): the National Center for Research Resources, and the National Heart, Lung and Blood Institute.
NIAID is a component of the NIH. NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov
1. L Zhang, et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. The New England Journal of Medicine 340(21):1605-13 (1999).
2. M Furtado, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. The New England Journal of Medicine 340(21):1614-22 (1999).
3. R Pomerantz. Residual HIV-1 disease in the era of highly active antiretroviral therapy. The New England Journal of Medicine 340(21):1672-74.