THE BIG QUESTION NOW IN
ANTI-HIV THERAPY - WHEN?
By Jay A. Levy
San Francisco Chronicle 23 February 2001
ANTI-HIV therapies that dramatically reduce AIDS deaths were the center
of controversy at the eighth annual Retrovirus Conference this month in
New federal guidelines recommend a delay before starting antiviral
therapy. At the same time, researchers from the University of California
at San Diego announced that strains resistant to the anti-HIV drugs were
being found in 14 percent of individuals newly infected with the virus.
A heightened sense of caution in starting treatment with these potent
therapies is now apparent. But has this question really been answered?
Time will tell. In the meantime, we have three reasons to question the
administration of combination therapy (also known as highly activated
antiviral therapy, or HAART:
-- The drugs do not eliminate virus-infected cells and thus cannot
-- Long-term use of antiviral therapy, which can be toxic, may also lead
to the emergence of resistant viruses.
-- There is no evidence that early treatment has made a difference in
overall disease progression.
The new recommendations consider evidence that delay does not compromise
the patient's health. On the contrary, delay could improve the long-term
quality of life -- and keep treatment options open.
My concern is not about treatment within the first weeks of infection.
Some studies suggest that antiviral therapy, received before antibodies
develop, delivers some long-term benefits. Unfortunately, few
individuals are aware so quickly that they are infected.
My concern is about treatment months to years after infection. With
other infectious diseases, the microbe either replicates outside a host
cell, or enters the cell, destroying it in the process. Therefore,
treatment is beneficial once the infection is detected.
HIV infection is not like other infectious diseases. HIV incorporates
its genetic material into the chromosome of cells and remains there,
able to reproduce itself and spread to other cells in the body.
The virus creates cellular reservoirs in the immune system and in organs
such as the kidney, heart, testes and brain.
Thus, while some of my colleagues initially thought HIV could be
eradicated with these powerful anti-HIV drugs, the basic biology of HIV
says no. Since this virus becomes part of the cell it infects, without
necessarily killing the cell, the virus can be eradicated only if all
infected cells are eliminated.
While antiviral therapy prevents the spread of HIV to new cells, none of
the current anti-HIV drugs kills previously infected cells. HIV remains
in infected people even after four to five years of antiviral therapy.
Unfortunately, with long-term treatment needed to contain HIV, drug
toxicity and/or viral resistance defeats the effectiveness of the
One reason for early treatment had been to stop HIV from irreversibly
destroying the immune system. This concern does not take into account
the immune systems' flexibility. Even when the essential
disease-fighting cells attacked by HIV are reduced by 25 percent, and
immune system structures such as lymph nodes are completely disrupted,
the immune system can recover with antiviral therapy.
A physician treating an HIV-infected individual must consider the
options. The persistence of HIV in cells argues for a delay in
initiating antiviral treatments. Unless the infected person is sick, the
very real problems of long- term treatment must be considered: toxicity
which may lead to damage of the pancreas, heart, kidney or brain),
emergence of resistant viruses and suppression of the body's natural
anti-HIV immune responses.
The increased prevalence of resistant viruses in newly infected people
reflects the widespread use of HAART (highly activated viral therapy),
and the misconception that this treatment will prevent HIV transmission.
Antiviral therapies are powerful, but their use must be saved for the
most effective moment.
Perhaps in the future, therapies will be discovered that will (1) have
some direct effect on HIV-infected cells and (2) can be given long-term
without toxicity. We can hope for development of innovative approaches
that restore and augment the body's natural ability to resist HIV. This
would reduce the need for toxic drugs.
Until then, clinicians should heed the new recommendations and save
antivirals for the time when they can be of best use. I foresee, in
fact, future recommendations that will raise the threshold even higher
before beginning current anti-HIV therapies.
Jay A. Levy is Director of the Laboratory for Tumor and AIDS Virus Research at the
University of California at San Francisco.