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
"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.
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
"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 detectibility 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
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conducts and supports research to prevent, diagnose and treat illnesses such
as HIV disease and other sexually transmitted diseases, tuberculosis,
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