More Good News on Combination
Therapy Using Protease Inhibitor Drugs
by Ron Baker, PhD
More and more HIV positive individuals are showing up at doctors' offices
seeking drug treatment, as reports regarding the success of combination
regimens continue to proliferate in the press and through word of mouth.
Physicians in New York, San Francisco and Cleveland have reported 50%
reductions in hospitalizations and even higher reductions in death rates
among their patients with AIDS over the past 6-12 months. These encouraging
reports, although anecdotal, appear to represent a significant trend toward
reduced disease progression among individuals using the new protease inhibitor
drugs in combination with nucleoside analogs.
Why are these regimens working? Most virologists believe it is because
they effectively delay the development of drug-resistant HIV. The regimens
work if patients using them are compliant, but HIV load rebounds 2 weeks
or less after therapy is stopped, if too many doses are skipped or if
dosing is suboptimal. The primary objective of anti-HIV therapy is to
completely suppress HIV replication, as indicated by viral load measurements
below the limit of detection of the Roche and Chiron tests (less than
200-500 copies/mL).
Which Combinations are Most Promising?
According to the available data, the most promising combinations are
AZT/3TC/indinavir, AZT/3TC/ritonavir, d4T/ddI/ritonavir, AZT/ddI/nevirapine,
d4T/nelfinavir and ritonavir/saquinavir (600 mg ritonavir plus 400 mg
saquinavir twice daily appears to be the best dose and schedule for this
double protease inhibitor combination).
Preliminary data on 15 people taking AZT/3TC/ritonavir for 6 months show
no detectable HIV in their blood or in tonsil tissue. These encouraging
results suggest that 3-drug therapy can dramatically reduce or eliminate
HIV replication not only in the bloodstream, but also in lymph tissue.
The triple combinations will be most effective when used by individuals
with no prior experience using the drugs or by treatment-experienced individuals
who have not yet developed high-level resistance to any of the 3 drugs
employed.
Resistance to the 2 double combination regimens might be further delayed
by the addition of a nucleoside analog and/or a non-nucleoside reverse
transcriptase inhibitor (NNRTI) not previously used by the individual.
Results of a recent government-sponsored study of d4T plus AZT suggest
that this combination may be ineffective. Preliminary data showed
that people on the d4T/AZT combination did worse than those taking d4T
or ddI alone or ddI /AZT. CD4 cell counts actually declined in the d4T/AZT
group! Information on viral load results in this study is not yet available.
Does Everyone Benefit from Using Protease Inhibitor Drugs?
Unfortunately, not everyone will experience a sustained benefit from
combination regimens that include protease inhibitors. Some individuals
with advanced HIV disease may improve temporarily, then continue to experience
disease progression. In addition, for people who are not compliant (regardless
of their disease stage), resistance will develop quickly and the effectiveness
of therapy will disappear. Some individuals will have serious problems
with the adverse side effects produced by these drugs, and therefore may
not benefit from them. Fortunately, the adverse side effects of the 3
available protease inhibitors differ and most people should be able to
tolerate at least one of them. Within the next 12 months, 2 new protease
inhibitor drugs should become available, creating more options for finding
a tolerable regimen.
When to Start Therapy?
Researchers and clinicians increasingly recommend starting anti-HIV therapy
early in the course of disease, as soon as possible after seroconversion,
if the HIV viral load is above the level of detection by the available
HIV RNA tests or if the CD4 cell count is below 300 cells/mm3.
For some individuals, this could mean very early treatment during acute
(primary) infection, within a few days of initial infection with the virus.
The hope for very early intervention with 3-drug therapy is that, if treated
aggressively, HIV might be eradicated before the virus has time to ÒseedÓ
itself in the lymphoid tissues.
Another advantage of early treatment relates to the fact that less HIV
genetic variation is present in the body during early stages of infection.
This significantly reduces the amount of resistant virus present. In this
situation, a 3-drug combination regimen that contains a potent protease
inhibitor will have a greater chance of completely suppressing HIV replication
for a sustained period. The later the disease stage, the more HIV genetic
variation and the higher the amount of drug-resistant mutant HIV in the
body. In this situation, successful drug therapy becomes difficult to
achieve.
What is the Role for Tests of HIV Viral Load and CD4 Cell Counts?
The best indicator or "trigger" for starting therapy is the
individual's HIV viral load level. Some clinicians will recommend triple
combination with 2 nucleoside analogs and a protease inhibitor if the
viral load is at all detectable by the first-generation Roche PCR assay
(with a detection limit of 400 copies/mL) or by the second-generation
Chiron bDNA assay (with a detection limit of 500 copies/mL). Other clinicians
recommend starting therapy only if the viral load is above 3,000-5,000
copies/mL as measured by one of these tests. Almost everyone agrees that
therapy should be started if the viral load is greater than 20,000-30,000
copies/mL.
CD4 cell counts still help to determine the appropriate time to begin
therapy. Many clinicians recommend starting therapy if the CD4 count falls
below 300 cells/mm3, regardless of viral load level. CD4 cell
counts are perhaps most useful in determining the appropriate timing for
initiating preventive therapy for opportunistic infections.
Tests to Detect HIV Resistance to Anti-HIV Drugs
Treatment for HIV infection must be highly individualized in order to
work successfully. While certain generalities hold true for many people,
the individual needs of each patient are paramount in finding an effective
regimen for sustained viral suppression. Deciding on the best drug combination
will be easiest for those individuals without prior treatment experience.
For treatment-experienced individuals, especially those treated longer
than 1-2 years, the decision will be more difficult. The objective for
both groups is similar: to find a 3-drug combination that suppresses viral
replication to low levels, preferably to below the limit of detection
by the Roche or Chiron HIV RNA tests.
To achieve very low or undetectable HIV levels, the combination regimen
must be comprised of 2 or more drugs to which the individual is not already
resistant. How will patients know if they are resistant to a particular
drug or drug combination? One strong indicator is failure of the regimen
in question, with a significant increase in viral load and possibly a
significant decline in CD4 cell counts. But such failure does not reveal
to which particular drug(s) in the regimen the virus has developed resistance.
In the future, simple blood tests may be available that can detect genotypic
and phenotypic changes in the virus that indicate resistance to the various
classes of anti-HIV drugs.
Certain resistance tests are now available, but they are expensive and
do not work for all classes of drugs. For over a year, San Francisco clinician
and researcher Marcus Conant, MD, has been using the reverse transcriptase
antivirogram test (developed in Belgium) for phenotypic resistance testing
of the nucleoside analogs and the NNRTI drugs (nevirapine and delavirdine).
Specialty Laboratories of Santa Monica, CA, offers a test for genotypic
changes in HIV induced by the nucleoside analogs. However, the Belgian
test does not work with the protease inhibitors, and the Speciality test
cannot detect changes affecting the usefulness of protease inhibitors
or NNRTI. Both tests are experimental, and until more research determines
their reliability and sensitivity, third-party payers probably will not
reimburse for their high cost (the Belgian test costs about $600 and the
test from Specialty Laboratories costs about $300).
Summary
The good news about the availability of effective new drug regimens for
the treatment of HIV infection must be tempered by the realization that
these new drugs are expensive, do not work well for everyone, cause adverse
side effects and will not work properly if not used according to a strict
dosing schedule. In addition, the new combination regimens must be regularly
monitored by HIV viral load testing, which is expensive and not universally
available. These complications place considerable burden on patients,
caregivers, educators and service providers.
Despite these disadvantages and complexities, new combination treatment
regimens show great promise toward reaching the goal of making HIV disease
a chronic, manageable illness. It will take concerted effort by private
industry, government, patient advocates and service providers to assure
that the early promise of these potent new therapies is fully realized
by all people living with HIV infection and AIDS.
Ronald Baker is Editor-in-Chief of BETA and Director of Treatment
Education and Advocacy at the San Francisco AIDS Foundation.
Page last updated 20 December 1996
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