SAN FRANCISCOPreliminary 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 Kaposis
sarcoma, cytomegalovirus (CMV) retinitis, and mycobacterium avium
(MAC), a hallmark manifestation of late-phase AIDS. On the other
hand, the prevalence of non-Hodgkins lymphoma has not changed,
and that of wartsoral, cutaneous, and genitalhas
This raises concern, Dr. Volberding said, because
in connection with cervical warts, we might see an acceleration in
the rate of cervical cancer, which hasnt 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 its an expensive
epidemic, he said, the expense is exaggerated by some
groups for political reasons and is not dominating the health care
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.
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
How effectively does the immune system repair itself following
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.
Weve known for a long time, Dr. Volberding said,
that interaction between HIV gp120 and the CD4 receptor on the
cells surface is required for infection, but recently weve
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. Volberdings
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.