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Reported by Jules Levin
http://www.natap.org/2004/CROI/croi.htm
Three studies final 72-week results were presented at the Retrovirus
Conference this week. My reports on APRICOT & the French ANRS study
were emailed & all reports are posted for reading on the NATAP website
in addition to ongoing full coverage of new information reported at
the conference, the most important HIV/AIDS conference each year. Ray
Chung reported the final results from this study for the ACTG 5071
research team at the 11th Annual Retrovirus Conference. Pegylated
interferon plus ribavirin is now the standard of care in HCV
monoinfection, and this study compared Pegasys/RBV to standard IFN/RBV
in coinfected patients. Treatment has been associated with toxicities,
higher in coinfected patients (up to 29% premature discontuainuation
rates have been seen in studies), but the discontinuation rate in this
study was low, 12%. The overall sustained viral response (SVR was 27%
for Pegasys/RBV and 12% for patients taking IFN/RBV) was lower in this
study than seen in the APRICOT study also reported at Retrovirus. This
is probably due to a high percentage of African-Americans & Hispanics
in this study and because ribavirin was started at a lower than
normally used dose. It was dose escalated from 600 mg daily and is
usually used at no less than 800 mg daily, and often at 1000 mg daily
or perhaps more. In APRICOT ribavirin was dosed at 800 mg daily.
An important finding in this study is that 90% of study patients who
achieved a sustained viral response stopped or improved liver disease
progression (liver histology); and perhaps a more important finding
was that 35-38% of viral nonresponders achieved an improvement in
histology. These finding needs further characterization. Was there a
difference between relapsers and non-responders? Is there a certain
viral load reduction associated with improved histology or is
interferon therapy itself without viral load reduction capable of
improving histology?
This study is a multicenter (21 sites) randomized, controlled trial
for 133 patients. Patients were HCV RNA+ with abnormal histology
(biopsy), including compensated cirrhosis (HAI >0), patients had any
ALT score, and were HBeAg negative. They had CD4 >100 and HIV <10,000
copies/ml on stable ART for >12 weeks, or were ART naive with CD4
>300. Patients received biopsy before study and after 48 weeks
treatment. They were randomized to receive Pegasys administered by
subcutaneous injection once per week plus 600 mg RBV daily or IFN a-2a
plus RBV 600 mg daily, and were dose escalated with RBV over a period
of time. This was decided upon when the study was initially designed
several years ago but is not considered an optimal way to treat now.
Preliminary HALT-C study results show that reduced doses of RBV at the
initiation of therapy can reduce sustained response rates. The purpose
of this approach was to try to reduce the side effects of RBV which
can lead to reduced hemoglobin within a few weeks after starting
therapy and this can lead to fatigue. Today, I donÕt think a study or
clinician would normally start RBV dosing with less than 800 mg daily.
In the IFN/RBV arm patients initially received 6 million intl units of
standard IFN subcutaneously injected three times weekly for a period
of time followed by 3 MIU 3x/wk plus dose escalated RBV. Previously
conducted studies have shown mixed results with use of higher than 3
MIU of IFN 3x/wk; there is no clear opinion that higher doses of
standard IFN are more effective. This point is moot now that we have
pegylated interferon. But preliminary study results suggest that
higher dosing of pegylated interferon may be more effective in
clearing HCV RNA than the currently approved doses: 180 mcg per week
for Pegasys and 1.5 ug/kg/week for PegIntron. This may be helpful for
prior non-responders who are willing & able to put up with increased
side effects likely to result from higher doses of pegIFN.
The original primary endpoint of this study is week 24 safety and
efficacy. The final analysis aims are to compare end of treatment and
sustained viral responses between IFN a-a/RBV and Pegasys/RBV in
HCV/HIV coinfection; to assess predictors of SVR, and to assess
histologic response.
BASELINE CHARACTERISTICS
79-85% male
33% African-American, 12-15% Hispanic
Age- 44 yrs
Karnofsky score: 90
CD4, median: 444-492
HIV RNA <50 copies/ml: 60%
On ART: 85-87%
Log10 HCV RNA IU/mL: 6.2
Log10 HCV RNA >6.0: 82%
HCV genotype 1: 77-78%
Abnormal ALT: 86-88%
Median HAI score (out of 18 points): 5.0
Median fibrosis score (out of 6 points): 2.0
Cirrhosis (fibrosis 5-6): 9-11%
VIRAL RESPONSES (ITT)
This is a small study (133 patients) compared to APRICOT (800
patients). The overall sustained viral response rate is 27% for
patients taking Pegasys/RBV vs 12% for patients taking IFN/RBV. For
patients with genotype 1, the SVR was 14% vs 6% for patients taking
Pegasys/RBV vs IFN/RBV; for patients with non-1 genotype, SVR was 33%
for patients taking IFN/RBV and 73% for patients taking Pegasys/RBV.
SVR 72 WEEKS (sustained viral response; 48 weeks treatment, 24 week
followup):
--Pegasys/RBV: 27% (n=66)
--IFN/RBV: 12% (n=67)
(p value 0.03)
GENOTYPE 1
--IFN/RBV: 6% (3/52)
--Pegasys/RBV: 14% (7/51)
NS
NON-1 GENOTYPE
IFN/RBV: 33% (5/15)
Pegasys/RBV: 73% (11/15)
P value 0.07; genotype 1 vs non-1, p<0.001
WEEK 24 VR
IFN/RBV: 15% (10/67)
Pegasys/RBV: 44% (29/66)
P<0.001
GT 1
IFN/RBV: 7% (4/52)
Peg/RBV: 33% (17/51)
P 0.001
NON-1 GT
IFN/RBV: 40% (6/15)
Peg/RBV: 80% (12/15)
NS
ETVR (48 weeks)
IFN/RBV: 12% (8/67)
Peg/RBV: 41% (27/66)
P<0.001
GT 1
IFN/RBV: 6% (3/52)
Peg/RBV: 29%
NS; GT 1 vs non-1 GT, p<0.001
NON-1 GT
IFN/RBV: 33% (5/15)
Peg/RBV: 80% (12/15)
P 0.03; GT 1 vs GT non-1 p<0.001
PREDICTORS OF SUSAINED VIRAL RESPONSE (multivariate analysis)
Taking Peg/RBV, having genotype non-1, not being a previous IDU, and
having a low baseline HCV RNA were all predictors of achieving a
better response, SVR.
These were not predictors of SVR: age, race, use of ART, use of PI,
baseline HIV RNA, CD4, liver histology, use of growth factors.
EARLY VIRAL RESPONSE (EVR)
Studies in HCV monoinfection show that an early responseÑ2 log
reduction in HCV RNA or undetectable HCV RNA by week 12Ñis predictive
of an SVR. Patients without EVR usually do not achieve SVR. The
applicability of this concept has not been established in treating
coinfection, but this small study did find that 100% of patients that
did not achieve EVR by week 12 did not achieve SVR. For patients with
an EVR, 51% had an SVR and 49% did not have an SVR. So the Positive
Predictive Value was not that great, in other words if you had an EVR
that was not greatly predictive that you would achieve SVRÑonly 51%
did so. But, if you did not achieve EVR 100% did not achieve SVR. This
suggests that by week 12 or if you want to wait longer, say by week 16
or so, if you donÕt see viral response you can consider stopping
therapy because you are not likely to achieve SVR. This rule does not
necessarily apply to individuals with advanced liver disease, stage 3
or 4 on biopsy. Studies show interferon may slow liver disease
progression. If you have late stage disease many doctors consider
keeping you on what iscalled Maintenance Therapy, which is usually
half dose interferon in the hopes that this can slow disease
progression. So you may be able to remain healthy to benefit for new
drugs in development which may take several years from now.
PREMATURE DISCONTINUATIONS
Only 12% of patients discontinued prematurely similarly for each arm,
which is lower than expected and has the effect of improving the
overall SVR.
Common side effects and lab abnormalities were similar in frequency
for both groups: flulike symptoms, depression, anemia, neutropenia,
thrombocytopenia (reduced platelets), increased glucose, ALT, lipasr,
lactate. There were no reported opportunistic infections.
No loss of HIV disease control was observed.
SUBSTANTIAL PORTION OF VIRAL NON-RESPONDERS EXPERIENCED HISTOLOGIC
RESPONSE
Week 24 biopsies were obtained in 45 patients receiving IFN/RBV and 26
receiving Peg/RBV. 38% (16) taking IFN/RBV were found to have
histologic response, and 35% (9) taking Peg/RBV were found to have
histologic response. For histologic responders the median HCV RNA
reduction from week 0 to 24 was -0.61 log, and -1.01 log for patients
taking Peg/RBV. For histologic non-responders, the median HCV RNA
change (wk 0-24) was 0.58 log for patients taking IFN/RBV and -0.71
for patients taking Peg/RBV.
HISTOLOGIC RESPONSE WAS OBSERVED IN MOST VIRAL RESPONDERS
Week 48 change from week 0. HAI improvement defined as decrease by 2
or more points. This data shows that 90% of viral responders either
stop or improve disease progression.
HAI Improved in 56% (20): 62% for IFN/RBV, 52% for Peg/RBV HAI
unchanged in 44% (16): 38% for IFN/RBV, 48% (11) for Peg/RBV
CD4 DID NOT FALL FURTHER FROM WEEK 24 TO WEEK 48 AMONG VR/HRs CD4
counts and CD4% did not fall after week 24 on treatment, and CD4 count
increased after treatment was stopped.
Chung summarized: Pegasys/RBV was superior to IFN/RBV in achieving SVR
in coinfection. SVR rates for genotype 1 are lower than seen in
monoinfection.
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