At the Resistance
Workshop in June ’99 Felipe Garcia first reported on a group of 10 chronicly
infected individuals who interrupted therapy
twice 6 months apart. Garcia cautioned that therapy interruptions should
only be attempted in controlled studies. In this study, viral load rebounded
after each interruption but following the rebound in the second interruption 4/9
had their viral load spontaneously decline and a proliferative p24 response was
detected in 2 of these 4 only after the second stop. The viral loads for these 4
people declined (0.8 to 2 log) but remained detectable. The viral loads ranged
from above 1,000 to about 40,000 copies/ml. Therapy was re-started and they all
declined to undetectable. No resistance was detected. A third interruption is
planned.
Ten patients were
initially included in the study with CD4 counts >500. They started therapy
with D4T+3TC and either ritonavir or indinavir. After 1 year of treatment
patients had a plasma viral load <20 copies/ml, volunteered to stop therapy,
and had been below 20 copies/ml for at least 8 months. Just prior to the first
stop, plasma viral load was <20 copies in all cases and below 5 copies/ml in
7/10 patients. CSF viral load was <20 copies/ml in all patients. Among the 6
patients with accessible tonsils, tonsillar tissue VL was <40 copies/ml of
tissue in 5 and 485 copies/mg in the other patient. So this was a well
suppressed group of patients. Nine patients reached the time point of the second
stop. At week 28 (2nd stop), plasma VL was <20 copies/ml in all cases and
below 5 copies/ml in 7/9.
A rebound in plasma VL
occurred in all cases. After the first stop, one month after re-starting therapy
VL dropped below 20 copies/ml again in all patients and remained <20
copies/ml after 6 months until the 2nd stop. However, after the second stop 4
patients’ viral load rebounded to similar levels of their baseline level but
then dropped spontaneously (without therapy). The drops ranged from -0.80 log to
-2.09 log. A proliferative p24
response was detected in 2 of these 4 only after the second stop.
Although viral loads
rebounded after both stops they did not detect RT and protease mutations known
to be associated with resistance to RT inhibitors or protease inhibitors. They
used the Visible Genetics System for genotyping. Garcia conducted an
immunological study which showed some immune system decline after first
interruption: the patients’ CD4s, naïve CD4s and CD8s decreased. There was an
increase in CD38+CD8 cells and of both memory CD4s and memory CD8s. Garcia
reported that 6 months after restarting therapy patients regained these losses
in the immune system back to where they were prior to the stop. After the second
stop, which he characterized as lesser immune deterioration, CD4s decreased but
CD38+ CD8 cells did not change and the naïve and memory cells did not change.
Several concerns have been raised about interruptions--what happens over
long-term by allowing virus to re-seed tissues, such as lymph, after significant
reductions due to HAART suppression? Long-term implications of interruptions are
yet unknown. Although several individual reports appear promising it is too soon
to discern who might respond well to STI and who might not. Although so far it
appears that viral load declines back to undetectable after re-starting therapy
research experience with this is limited.
STI
in Chronic Infection.
At Lisbon, Lydia Ruiz
reported on 12 chronically infected individuals who interrupted therapy. They
had viral suppression below 20 copies/ml for at least 24 months. They
interrupted therapy for 30 days or until viral rebound above 3,000 copies/ml.
Individuals had been infected for mean 7.7 years. These results are following 1
interruption as future interruptions are planned. Viral burden increased
exponentially in 10 of the 12 patients during interruption period while 2
persons maintained levels below 20 copies/ml. In 5 of 10 patients, plasma viral
load started to be detectable between 10-15 days, whereas in the 5 remaining
individuals, viral load increase slowed to 18-21 days after interruption. The
slope of viral load increase during interruption was similar in all patients
except the 2. Ruiz said treatment was successfully resumed in all patients. No
drug resistance mutations were found except in one person. Ruiz reported that in
contrast with prior data, Ruiz did not observe flatter viral rebound slopes in
those patients heterozygous for the 32 mutation in CCR5.
STI in Acute
Infection: 1 year follow-up.
At ICAAC, Marty
Markowitz reported on 4 individuals who started HAART between 7 and 90 (median
52 days) days within the onset of symptoms of acute infection and chose to stop
therapy. They were part of 14-person study. Patients were on therapy about 3
years at the time of discontinuation (median days 1049). They now had normal CD4
counts and CD4/CD8 ratios. Their median CD4s increased to 977 from 488 at
baseline and their median CD4/CD8 ratio had improved to 1.25. Levels of
culturable residual virus ranged from 0.03 to 0.25 (median 0.11) IUPM
(infectious units per million) CD4+ T-cells. At discontinuation, all 4 patients
had maintained undetectable viral load and had <50 copies/ml. After stopping
therapy the time to detectable virus (> 50 copies/ml) was 23, 26, 14, and 24
days, respectively). On day 25, the person with 6 million baseline viral load
had their viral load peak at 32,000 and decided to resume therapy. Their viral
load peaked sooner and higher than the other 3 patients. After re-starting
therapy their viral load went back down to <50 copies/ml. In the other 3
persons peak plasma virus reached 21,965, 20,150, and 14,391 copies/ml on days
38, 193, and 77 after stopping therapy. Without resuming therapy these
individuals remain with plasma virus of 2102, 3400, and 4700 copies/ml after
252, 222, 154 days, respectively. All 3 patients had detectable HIV-specific
CTLs at the time of therapy discontinuation. In 2 of 3 patients, the levels of
CTLs appeared to increase suggesting stimulation from virus after stopping
therapy and/or partial virus control. In the third person the CTL levels
decreased and then increased after stopping therapy.
3
Therapy Interruptions: CTL & HIV-Specific CD4 responses.
At IDSA, Eric Rosenberg
reported on 2 individuals who had interruptions. Both individuals experienced
partial but not complete control of HIV replication following interruptions.
Subject one interrupted therapy 3 times. The first interruption was planned and
it took about 3 weeks for virus to begin to replicate, whereupon it went up to
17,000 copies/ml. After restarting therapy (protocol mandated restarting therapy
at 10,000) viral load promptly went back down to undetectable and stayed there.
Due to acute hepatitis A the person had an unplanned second interruption. Again,
it took 2 weeks for virus to return whereupon virus shot up to 37,000. He was
still too ill to restart therapy and within 72 hours fell to 6,000. 48 hours
later his viral load was 400. Over the next 2-3 weeks slowly viral load started
creeping up (it was still below 10,000) and therapy was restarted because it
wasn’t a planned interruption. Viral load rapidly declined to below detection
after restarting therapy. The second person had two interruptions. The first
interruption lasted 2-3 weeks during which he had low viral load but then it
rebounded to 116,000 copies/ml. Therapy was re-started and viral load was kept
below limits of detection. When therapy was discontinued a second time the
person went 4 months consistently with viral load below 5,000 copies/ml. Despite
being below 5,000 the person elected to restart therapy at the 4-month period
"to try for a better result". Both subjects experienced improved CTL
response in breadth and magnitude. As well both experienced improved stimulation
index which measured the HIV-specific CD4 response. Subject one had a SI of 80
prior to first interruption (above 10 is considered significant) which went to
over 800 after second interruption. Subject two had a SI of 20 at baseline that
improved to 120 after first interruption.
Veronica Miller and her
German colleagues gave patients a drug holiday of 2-3months followed by Mega
HAART (>5 drugs) for salvage therapy. These were very treatment experienced
individuals who were failing therapy. After a drug holiday 26/39 had their virus
return to wild-type. Drug resistance was not detectable. This surprised a number
of resistance researchers. In 13/39 they did not revert to wild-type. The
reverters received a Mega HAART regimen of at least 5 drugs or more. Baseline
susceptibility was associated with a virological response (achieving and
maintaining VL<500 c/ml). 67% of responders had viral populations which were
sensitive to at least 4 of the drugs in their regimen; whereas, 70% of patients
of failing regimens (never achieving <500 c/ml) had viral populations which
were sensitive to a maximum of 3 drugs in their regimen. During drug holidays
viral load increased by a median of 0.71 log and CD4s declined by a median of 89
cells. Treatment with drug regimens resulted in a median week 8 VL reduction of
2.9 log for patients with shift to wild-type and 0.78 log in patients without a
shift to wild type. Researchers reported CD4s increased subsequent to restarting
therapy but slowly. 19/24 patients with shift to WT reached <500c/ml within
24 weeks compared to 1/9 without shift to WT. Miller concluded complete
treatment interruptions may lead to shifts in the viral population, with a
change to WT as the dominant variant in some patients. These changes in
susceptibility may be associated with better treatment responses. However, CD4
counts need to be closely monitored during drug holidays. The German group also
said that if a person did not respond to the drug holiday and Mega HAART the
first time they would give them a second drug holiday and try another Mega HAART
regimen. They said this worked for some.
A number of researchers
think that although undetectable resistance to the drugs is present. And that
eventually it will emerge. However, viral load reduction for a period of time
may offer clinical benefit. I personally spoke with the German researchers and
they have an ongoing program utilizing the drug holiday approach, and they have
confidence that the approach works for some individuals. Bare in mind this
approach is used for people who are failing therapy who have resistance to drugs
they are using. Additional studies will explore this question.