Update from the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication
AIDS INFORMATION NEWSLETTER
AIDS Information Center
VA Medical Center, San Francisco
Viral Load and Genotypic Resistance Assays
Validation of HIV-1 RNA and CD4 count as surrogate markers in the
The CEASAR trial examined the effect of adding lamivudine
(3TC), loviride (an experimental non-nucleoside reverse
transcriptase inhibitor), 3TC plus loviride or placebo to a
zidovudine (AZT) containing regimen. The addition of a 3TC
containing regimen to AZT had a dramatic effect in delaying disease
In this analysis, Montaner and colleagues studied the value
of a change in viral load and/or CD4 cell count in predicting
clinical outcomes. This sub-study analyzed 794 patients.
Surprisingly, the treatment induced effects on CD4 and HIV-1 RNA
levels at weeks 8 to 28 predicted most, if not all, of the eventual
clinical outcome (predictive value 100%, lower 95% confidence
interval 56%) [Montaner, abstract 61].
Comment: Until recently, "body count" studies, in which survival
was the only relevant outcome, was the gold standard in large scale
clinical trials. The results from this analysis indicate that
studies designed to analyze surrogate endpoints only are probably
sufficient, and that large, expensive clinical endpoint studies are
no longer necessary. Licensure of new drugs by the Food and Drug
Administration need not bdepend on evidence that the drug delays
disease progression or prolongs life.
Detection of HIV-1 RNA in the plasma of patients in whom HIV-1 RNA
is undetectable using commercial assays
Current standard of care is to treat HIV aggressively, with
an explicit goal of attaining "undetectabe" levels of plasma HIV
1 RNA (typically defined as a viral load less than 200 to 500
copies/ml). The natural history of patients who achieved
undetectable levels remains unclear.
In a study reported by Natarjan and colleagues, an
ultrasensitive viral load assay (RT-PCR, lower level of detection
50 copies/ml) was used to better characterized patients with 5
months of documented viral load levels less than 500 copies/ml
(Chiron, bDNA assay) or 400 copies/ml (Roche, RT-PCR assay). Most
patients were receiving aggressive combination therapy. Of the 72
patients studied with the ultrasensitive assay, 50 had detectable
levels (>50 copies/ml) [Natrajan et al, abstract 51].
Comment: Plasma HIV-1 RNA can be readily detected in the majority
of patients with so-called "undetectable levels" using current
assays. This suggests that many patients have persistent low level
viral replication, despite the use of combination therapy. Whether
these patients are more likely to eventually fail a given regimen
remains to be determined. Biologically, one can assume that a
patient with a viral load < 50 copies/ml is more likely to achieve
long-term viral suppression than a patient with a viral load of 50
to 500 copies/mL. Once these ultrasensitive assays are commercially
available, clinicians should be able to identify patients at high
risk for failing a given regimen, and therefore be able to
intervene before high level resistance develops.
The durability of response to protease inhibitor therapy is
predicted by viral load
Clinicians clearly need tests which will allow them to predict
who will fail a protease inhibitor, so modifications can be made
before high level resistance develops. Kempf and his colleagues
from Abbott reviewed clinical data from several ritonavir studies
to determine which virological markers predict a durable response
to protease inhibitor therapy.
To be eligible for their initial analysis, patients must have
reached a documented viral load "nadir" (i.e., their lowest viral
load), and then rebounded with a virus containing at least two
resistance mutations. Of the 29 patients studied, 6 received
ritonavir monotherapy, 16 received zidovudine (AZT) plus ritonavir,
and seven received the combination of ritonavir and saquinavir.
Baseline RNA did not predict how long the patient would respond to
a given therapy. The absolute value of the viral load nadir was
highly predictive of the durability of viral suppression
(R2=0.885): the lower the nadir, the longer the response. Patients
who achieved levels below the level of quantification (< 200
copies/ml) had the longest response.
To confirm this observation, Kempf and colleagues looked at
202 subjects who received at least 30 days of ritonavir or
ritonavir plus AZT, and who had at least a 0.5 log decrease in
viral load. Subjects who discontinued therapy were excluded form
the analysis. Of the 152 patients eligible for analysis, baseline
viral load at the time ritonavir was initiated did not predict
duration of maximal response. Once again, subjects who achieved a
viral RNA < 200 copies/ml had a durable response, while those who
never went below 1000 copies/ml rebounded back toward baseline
quickly. Most subjects reached their nadir by week 12.
Notably, many patients who went below 200 copies did
eventually rebound. It is unclear if more sensitive assays (lower
limit of detection 20 copies/mL) could more accurately predict
outcome [Kempf, abstract 62].
Comment: This data suggest that the viral load at week 12 of
therapy with a protease inhibitor is highly predictive of outcome.
Therefore, clinicians may want to modify or change therapy at week
12 if the viral load remains greater than 200 copies/ml.
Genotypic or phenotypic susceptibility testing may not predict
clinical responses to indinavir
Should genotypic or phenotypic assays be performed routinely
in the clinic? This critical question was another focus of the
meeting. Several very promising assays are in development. Should
they be used? Unfortunately, there is no convincing evidence that
genotypic or phenotypic assays reliably predict response to
Condra and colleagues at Merck presented several case studies
illustrating the limits of genotypic assays. In their experience
with indinavir (Crixivan), subjects often rebound with clear
genotypic changes but a normal phenotype. In each case, genotype
predicted failure to indinavir prior to the development of
detectable phenotypic resistance. Although the presence of
phenotypic resistance likely predicts failure, it is unclear if
"phenotypic susceptibility" predicts success.
Does a lack of genetic information for resistance predict
success? Again, Condra presented case studies of a few subjects who
stopped therapy after failing indinavir. Wild-type virus rebounded
quickly, and the patient's genotype reverted to normal. Later, when
indinavir was restarted, failure occurred rapidly, despite the
absence of genotypic resistance at the time indinavir was started.
Unfortunately, resistant variants often exist at very low levels,
well below the level of detection. These minor "quasi-species" are
selected for rapidly in the presence of a drug [Condra, abstract
47]. Therefore, the patient's prior treatment history may be a
better predictor of outcome than genotype.
Comment: Genotypic and phenotypic assays are undergoing evaluation
in several clinical studies. Until further data is available, viral
load data and the patient's prior antiretroviral history should be
the most important factors in developing therapeutic strategies.
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