Expert Opinion From Barcelona
Edited by Enid Vázquez
For
experienced folks
Dr. Julio Montaner
of the B.C. Center for Excellence in HIV/AIDS at St. Paul’s
Hospital in Vancouver, gave a talk on “new challenges and
perspectives” regarding treatment of people with HIV who’ve
already been on therapy. He focused on three topics: treatment
failure, therapeutic drug monitoring and inhibitory quotient
(IQ), and new drugs on the horizon.
He said his clinic does not
favor the idea of keeping people on partially suppressive
regimens, where the viral load is at detectable levels. Some
researchers have found that such therapy still provides health
benefits to people with HIV. Rather, Montaner prefers to switch
people to a new regimen to aim for undetectable viral load.
He said people can always go back on their old therapy if
the new one doesn’t work out. One problem of staying on a
partially suppressive regimen is that the drug resistance
that builds up may cut off access to new drugs down the road.
However, in one analysis
conducted by his clinic, even the experienced people on a
partially suppressive regimen had survival similar to those
people new to therapy (called treatment “naïve”). Naïve people
generally respond better to therapy (e.g., they may achieve
undetectable viral load).
Montaner said his clinic
is building on the good response people are having with Kaletra.
The drug does well for people with single or multiple protease
inhibitor (PI) failure. The problem, he said, is complex interactions
with other medications. Nevertheless, some research shows
benefits with Kaletra despite its negative pharmacokinetic
profile. He’s waiting for more data.
In dual protease inhibitor
combinations, when combined with a mini-dose of Norvir (100
or 200 mg), he said that with Agenerase, pharmacokinetic problems
may not prevent a beneficial response. However, with Crixivan,
look for renal (kidney) toxicity.
The movement towards therapeutic
drug monitoring (TDM) and inhibitory quotient (IQ) tries to
measure an individual’s blood level of drug. This adds to
the understanding of a person’s response to therapy. It goes
above and beyond the question of drug resistance, for example.
“We no longer see resistance as a black-and-white issue,”
Montaner said.
On the Viread/Videx interaction,
Montaner said the increased blood level of Videx was greater
than had been thought. Higher blood levels may increase the
risk of side effects, including serious ones. He says prescribers
should reduce the level of Videx EC from 400 mg a day to 250
when taken with Viread and food. That’s the preference of
his clinic, although he said clinical trials are needed. “But,
until we have clinical trials,” he said, “this is what we’re
doing. We have to go forward.”
T-20, an experimental drug
taken as a twice-a-day injection, shows significant viral
load drops in experienced patients after 24 weeks of adding
it to stable HIV therapy. [However, T-20 has been showing
this power for years. Other doctors at the conference said
the question is durability.]
Preliminary results with
tipranavir, an experimental once-daily protease inhibitor,
show a very favorable drug resistance profile in multiple
PI failures, Montaner said. He said tipranavir looks like
a good secondary (second regimen) PI to use.
Overall, Montaner said doctors
should think carefully about starting their patients on HIV
therapy, should identify and correct reasons for treatment
failure quickly and should switch failing regimens early.
Adding an active new drug—one the patient is not resistant
to—is not a clear measure for success as once hoped. Instead,
the patient’s entire HIV drug background is important, as
is their clinical history (diseases) and resistance profile.
Resistance:
What have we learned?
That was the title of a talk
by Dr. John Mellors, of the University of Pittsburgh. Resistance
is the ability of HIV to mutate (change) in order to successfully
fight drugs. Some of Dr. Mellors’s remarks follow here.
“No antiviral is resistance
proof, and it’s very unlikely that one will be found. Incomplete
suppression [a viral load that’s still detectable] leads to
resistance and resistance is common in the United States.
“Resistance limits
treatment options and may lead to disease and death. Suppressing
viral load to less than 50 copies can prevent resistance.
Extensive evidence shows that resistance testing improves
suppression when changing therapy.
“Resistance is not
inevitable. Be careful when selecting drugs and follow suppression
carefully. In patients who have never been on therapy, single
and double mutations [changes in the virus that help it beat
the meds] are likely to pre-exist. A 10-fold reduced susceptibility
to therapy has been seen in acute [new] infection [because
of infection with resistant virus]. Also, time to first treatment
failure [usually defined as detectable viral load] is shortened
in those with resistance.
“Incomplete suppression
occurs because of limited drug potency or PK [pharmacokinetics,
how a drug interacts with other substances], incomplete adherence—which
most likely occurs because of intolerance (side effects)—or
prior drug resistance. Even modest evolution [low but detectable
viral load] evolves into resistance.
“In a HCSUS study (HIV
Cost and Services Utilization Study), 63% of people after
their first two years of HAART (highly active antiretroviral
therapy) had greater than 500 copies viral load. Risk factors
for resistance included having advanced AIDS or inexperienced
doctors, and low CD4 count when starting treatment. Greater
access to treatment was the greatest risk for resistance.
[HIV mutates most when antivirals are thrown at it.]
“Treatment failure
that occurs within weeks or months limits future options.
Progression should be anticipated if there is persistent viremia
[detectable viral load]! Avoid blind switches. Test for resistance
in people with more than 1,000 copies viral load. [You cannot
run a resistance test with less than 1,000 copies.] Avoid
impotent regimens or those that have a high pill burden and
frequent dosing.”
Vaccines
Dr. Robert Gallo, one of
the first people to isolate HIV, talked about the search for
a vaccine. Finding the body’s reservoirs of HIV (its hiding
spots) identify targets that are important to vaccine development,
he said.
“Targeting extracellular
[outside of the cell] factors which promote HIV replication
or a diminished immune response is crucial,” Gallo said. He
said dysregulative cytokines, a type of protein in the body,
are an example of this. “We have to identify and find mechanisms
of action for each HIV suppressive factor and exploit this
information,” he said. In poor countries, a TAT vaccine such
as the one his lab is looking at would be welcome because
it can be taken as a shot two or three times a year.
Gallo criticized the idea
that ethics demands triple therapy for the Third World. Instead,
he believes that something is better than nothing. Therapeutic
vaccines can help control disease progression in people living
with HIV.
He said that when looking
at reports on vaccines, look for the words “neutralizing antibodies,”
not just “antibodies.” Antibodies are one of the targets of
vaccines. [They help fight HIV and other invaders in the human
body.]
Gallo said the discovery
of the CCR5 co-receptor in 1995 was an important finding.
CCR5 helps HIV enter the body. People without this gene, or
with a defective one, have higher immunity to HIV infection.
They also have higher resistance to disease if they do get
infected. “Targeting CCR5 is major today. CCR5 is dispensible,
so it’s an important target [for vaccines and medications].
People can be born without it and do fine.” In other words,
toxicity to the targeted CCR5 co-receptor is less of a concern.
Discovery of the gp120 receptor
for HIV, which allows the virus to target the CD4 T-cells,
was another important discovery. All together, there’s a “triple
complex” of membrane fusion (entering the cell), virus-cell
infection or cell-cell infection.
Another target is gp140,
and peptides that can block this HIV co-receptor have been
discovered. Overall, Gallo said a vaccine is critical, especially
to counter the toxicity of current therapies and overcome
the problems of drug resistance. (See “An
AIDS Vaccine” in this issue.)
Current
controversies
That was the title of a talk
by Dr. Michael S. Saag of the University of Alabama at Birmingham.
Saag talked about when to start HIV therapy, what to start
with, when and how to change therapy, Strategic Treatment
Interruptions (STIs) and the benefits of therapy.
Appropriately enough, the
Journal of the American Medical Association (JAMA) had that
day published the new HIV treatment guidelines of the International
AIDS Society-USA (IAS-USA), of which Saag was an author. [See
“New
Treatment Guidelines” in this issue.] Saag called CD4
cells “a moving target.”
The latently infected CD4+
lymphocytes—those that are not yet activated—lay around until
one day they are activated, and then they too infect cells.
It is these cells, which do not die off in two days as previously
thought, but instead take six months to decay, that create
the 60-plus years of treatment estimated for HIV eradication.
In Saag’s clinic, half of
the patients looked at in one report did not stay on their
first therapy for more than two years. For people with greater
T-cell counts, toxicity was the biggest issue. For those with
less T-cells, viral load rebound (increases) was the primary
problem.
When and how to change, he
said, depends on the definition of treatment failure. Generally,
viral load rebound to detectable levels within 16 to 24 weeks
of treatment is considered failure. Something should be done
quickly to prevent the development of drug resistance. However,
in subsequent regimens, the prevention of T-cell decline is
more important than the concern for drug resistance. Nevertheless,
he said, the definition of treatment failure needs to be individualized,
as stated in the IAS-USA guidelines.
With STIs, research has shown
a conversion to wildtype virus—which is good, but there’s
also concern about a steep drop in CD4 cell count. The guidelines
say more data is needed. Study 506 designed to look at STIs
is “now up and running.”
As for benefits, Saag said
the question is, How have benefits been derived? In New York
City, there was a more rapid progression to death between
1990 and 1995 than there was in the HAART era post-1995. Moreover,
New Yorkers were able to survive five years after PCP (pneumocystis
carinii pneumonia, formerly the biggest killer of people with
AIDS, and a quick killer at that).
A cost-benefit analysis from
Saag’s clinic showed an average cost of $18,000 a year to
treat a patient with HIV. However, the figure was $34,000
for people with advanced disease, and $14,000 for the people
with more than 350 T-cells. “There’s a direct cost benefit
to keeping people healthy,” he said.
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