Current AIDS drugs may never eradicate HIV from infected individuals, according to a new model of the decline in HIV levels during treatment. Rather, antiretroviral treatment drives HIV down to stable levels, which vary with the efficacy of the drug regimen. One implication of the new model could be a more favorable interpretation of some treatment outcomes once described as failures, according to a report in the October issue of Nature Medicine.
"Our interpretation is fundamentally different than the currently accepted one," says William E. Paul, M.D., chief of the Laboratory of Immunology at the National Institute of Allergy and Infectious Diseases (NIAID) and senior author of the report. "We explain the observed decline in HIV levels largely in terms of changes in the numbers of cells infected after the introduction of drugs, not before."
"These are compelling ideas to consider in our ongoing effort to improve treatment for HIV-infected individuals," says NIAID Director Anthony S. Fauci, M.D.
Current theories hold that intensive treatment with anti-HIV drugs substantially block the virus from infecting healthy CD4+ T cells. The drop in HIV levels following the initiation of treatment reflects the life spans of cells that were infected before treatment was started. The initial rapid decline in HIV levels is due to the death of short-lived populations of HIV-infected cells. This is followed by a much more gradual decline in HIV levels, reflecting the death of cells with much longer life spans. Based on this theory, some scientists have tried to estimate how long it would take to completely eradicate HIV-infected cells from a person's body.
Dr. Paul, Zvi Grossman, Ph.D., of the National Institutes of Health Office of AIDS Research and Tel Aviv University, and their colleagues suggest, however, that significant numbers of CD4+ T cells continue to become infected with HIV after treatment has started. They assert that HIV is continuously transmitted from infected to uninfected CD4+ T cells in multiple localized bursts in lymphoid tissue. The rapid decline in HIV levels that occurs within the first two weeks of the initiation of antiretroviral therapy, they propose, is due to the rapid but incomplete inhibition of viral replication by anti-HIV drugs. Over time, the rate of HIV decline decreases substantially for a variety of reasons. These include a progressively increasing proportion of drug-resistant HIV particles as the overall viral load decreases, and a non-uniform distribution of anti-HIV drugs in infected lymphoid tissue.
According to the new model, the authors predict that the initial rate of HIV reduction during treatment should correspond with the treatment's ability to block infection of new CD4+ T cells. They present data showing that the average rate of HIV decline increased progressively among groups of HIV-infected individuals treated with one, three or five antiretroviral drugs, respectively.
"If, as current theories hold, the rate of HIV reduction reflected the rate at which previously infected cells were killed," says Dr. Paul, "there is no obvious reason why it should be related to treatment regimen."
Drs. Paul, Grossman and their colleagues predict that anti-HIV treatment eventually leads to stable, steady state levels of HIV, even when HIV levels are reduced to undetectable levels. "HIV viral load may stabilize below the level of detection in many individuals receiving highly active antiretroviral therapy (HAART)," explains Dr. Paul. "In individuals on less intensive regimens, viral load may stabilize at higher levels."
"A crucial insight into this issue is provided by studies of 'maintenance therapy,'" says Dr. Grossman. In one such study, researchers in Europe treated HIV-infected individuals with a four-drug HAART regimen for 26 weeks, at which time all participants had undetectable HIV levels. Half of the individuals were then put on a two-drug "maintenance" regimen. Ten weeks later, nine of the 14 patients in the maintenance group had detectable levels of HIV, compared with only one of 11 patients in the HAART group.
"Our interpretation," says Dr. Paul, "is that in most of the maintenance 'failure' cases, the rise from below detectability is toward a new low-level steady state of viral load, and is simply a consequence of the relationship between the steady-state level and the potency of treatment. We suggest that, had these patients been on the two-drug regimen from the outset, they would have reached a detectable steady-state level without first going below detectability."
NIAID is a component of the National Institutes of Health (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.
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Reference: Z Grossman, et al. Ongoing HIV dissemination during HAART. Nature Medicine 5(10):1099-1104 (1999).