Being Alive 1997 Apr 5: 8
Over the last year, more and more evidence has emerged to
support the proposition that viral load is the single most
important factor in the progression of hiv disease. All things
being equal, we can say that the higher the viral load, the
faster the progression of the disease.
A recent report at the National Conference on Retroviruses
presented additional data on the correlation between viral load
and the suppression of the immune system. Researchers reviewed
data on 1604 hiv+ men in the ongoing MACS study (or Multicenter
aids Cohort Study). They measured the initial viral load of the
study participants and then plotted their annual decline in
T-cells over an average 7.7 years. Those with an initial viral
load of less than 500 had an average CD4 decline of 36 a year,
while those with a starting viral load of greater than 30,000
showed an average yearly decline of 76 T-cells.
With our new understanding of the importance of suppressing
viral load in effectively treating hiv disease comes some new
answers on when to start and when to change antiviral therapy.
Our purpose here is to review what we know today, as well as
outline some questions still to be answered.
The Goal of Antiviral Therapy
At the recent Conference on Retroviruses, Dutch physician Joep
Lange put it best: "The minimal goal of antiviral therapy
should be to suppress hiv replication as much as possible for
as long as possible." Simply put, the purpose of any antiviral
therapy is to get the viral load down as low as possible and
keep it down. The ultimate goal is to achieve aviremia, i.e.
undetectable levels of hiv in the blood.
Some experts would argue that there is an exception to the goal
of undetectable virus. If an individual has "low" viral load,
"decent" CD4 count, and has been infected a "long time," then
some would argue that the person's own immune system is keeping
hiv in check. In such a case, they would recommend frequent
monitoring of viral load and CD4 count, but no antiviral
treatment. The problem, of course, is that there is little
consensus on what is a "low" viral load (less than 5000?), what
is a "decent" CD4 count (greater than 500?), and what is a
"long time" for hiv infection (10 years? 15 years?).
Starting Antiviral Therapy
With the greater use of viral load testing, medical providers
have new data with which to determine when to start an
individual on antiviral therapy. Only a year ago, most
physicians would have agreed that a viral load of less than
10,000 was probably acceptable. In the absence of falling
T-cells and/or opportunistic infections, antiviral treatment
was probably not necessary. Today, that thinking has changed.
If the goal is to reduce the viral load as low as possible for
as long as possible, then anyone with a detectable viral load
should be considered a candidate for antiviral therapy. Most
experts are advocating treatment for anyone with detectable
viral load; they believe that if the viral load is brought
down, this is better for the individual in the long run. This
is a big change in treatment approach over just the last year.
If we have greater consensus today on when to start therapy, we
still don't know which drug regimen is "best" to start with.
Certainly, we now know that monotherapy (treatment with only
one antiviral) is not the way to go. Most physicians recommend
two reverse transcriptase inhibitors. Some would add a protease
inhibitor as well, especially if the individual has a long
standing infection with viral load above a certain threshold or
CD4 below a certain threshold. Defining that threshold,
however, varies from physician to physician.
For the last couple of years, AZT plus 3TC has been the most
common initial combination antiviral regimen. Today, we are
seeing more use of the d4T/3TC combination. This latter
combination has the advantage of twice a day dosing (AZT is
still usually taken on a three times a day schedule). Also,
recent studies have shown that both d4T and AZT penetrate the
cerebral spinal fluid (CSF) equally well. Previous thinking was
that AZT had the advantage here.
Some experts are questioning whether 3TC is the best drug to
start with. They assert that using 3TC up front may induce a
resistance pattern that will limit an individual's future
antiviral choices. These experts recommend ddI as an
alternative, although no trial data on effectiveness is
Changing Antiviral Therapy
With the widespread use of viral load testing has come the
ability to closely monitor the effectiveness of an antiviral
regimen. Medical providers had been judging a regimen as a
failure if it did not suppress an individual's viral load
greater than .5 log (or about one third of the initial viral
load). Now, they are more likely to call a particular drug
combination a failure if it is not able to suppress the virus
to undetectable levels.
In the recent past, if the individual was using a combination
of two reverse transcriptase inhibitors and began to "fail," a
third drug, most likely a protease inhibitor, was added to the
antiviral regimen. Evidence is suggesting, however, that such
an approach is akin to monotherapy with the protease inhibitor.
The two RT inhibitors were not sufficient to suppress the virus
and thus the virus may no longer be sensitive to these two
drugs. Today, the tendency is to change one or both of the RT
inhibitors, as well as to add a protease inhibitor.
Combining Protease Inhibitors
We are also noting today an increasing use of protease
inhibitor combinations. The drug company Abbott recently
reported on a trial that combined ritonavir and saquinavir. The
trial included 141 hiv+ individuals with T-cell counts between
100 and 500 and with no prior therapy with a protease
inhibitor. After 22 weeks of the protease inhibitor
combination, viral load was suppressed an average 2.5 logs.
Aviremia (a viral load of less than 200) was achieved in
three-fourths of the study participants. Four hundred mg twice
a day of each drug proved to be effective and the least toxic
Other trials of two protease inhibitor regimens are being
planned. These trials will include the use of nelfinavir
(Viracept), a fourth protease inhibitor that received FDA
approval in March. We should soon have more data on this new
approach to antiviral therapy.
As one of the participants at the Conference on Retroviruses
noted, "There is nothing magic about the number three." We are
seeing study data emerging on the use of four-drug regimens,
i.e. quadruple combination therapy. Early studies suggest that
this may be an approach that is particularly effective for
those with advanced aids.
One study involved 18 PWAs who had been diagnosed with aids an
average of 4.1 years at the start of the study. The mean viral
load for the group was over 100,000. Some of the group added
one protease inhibitor to their regimen of two reverse
transcriptase inhibitors; this group saw about a one-log drop
in viral load. Those who added two protease inhibitors to their
regimen experienced closer to a two-log reduction in virus in
the blood. Another study of 32 individuals with T-cells less
than 250 showed similar results when a combination of ritonavir
and saquinavir was added to their antiviral regimen. These are
small studies and additional data are needed. However, it may
be that in the future protease inhibitors will be combined,
just as RT inhibitors are today. Indeed, the magic may be in
four (or more) antiviral drugs.
With all we do know today about effective antiviral therapy,
there is still much that we do not know. When should we add a
third drug? At the very start of therapy or when failure on two
drugs is determined? And how do we gauge failure? How low is
low when it comes to viral load? Is an undetectable level
possible for every individual with hiv? Which protease
inhibitor is the best? Should we start with two, rather than
one? And what about sanctuaries for hiv? Is it enough to lower
the viral load in the blood stream? These and many other
questions remain to be definitively answered.
We have come a long way in the last couple of years in treating
hiv disease; let no one doubt, however, that we still have a
way to go.