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New HIV Drugs / Hep C: quicker HCV progression nin coinfection; sumptomatic
hyperlactatemia in coinfected patients taking RBV; PegIntron/RBV in coinfected
Report by Jules Levin
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I just came from a 4pm oral session where various entry inhibitors, the Merck
integrase inhibitor, and other new drugs were discussed. Researchers from
the manufacturers reported the latest updates much of which you are familiar
with. the Merck integrase info was reported at the Resistance Wksp & I
reported it to you. Its available on my website. The T-20 data I reported to
you. More T-20 data will be reported Friday at the Late breaker Oral session
here. Roche/Trimeris has T-1249 which is a more potent fusion inhibitor than
T-20 and appears to be effective aginst T-20 resistant HIV. Unfortunately
these two drugs are administered by subutaneousl injection and are associated
with injection site reaction. Progenics Pharmaceuticals reported here on
their two attachment (entry) inhibitors in development - PRO542 and PRO140.
SCH-C and SHC-D are two entry inhibitors in development by Schering Plough
and these were discussed at this session. Rob Murphy reviewed new protease,
NNRTI, and NRTI drugs in clinical development and there are a bunch that look
effective against HIV resistant to the currently available drugs. Due to the
development of new entry and integrase inhibitors we are, as I've been
telling you for a while, I think entering a new era of treating HIV. T-20 is
expected to be on the market in early 2003; and hopefully the other drugs
described will make it through the development process. I am hopeful that in
several years we will have enough new entry inhibitors and integrase
inhibitors to form an entire regimen. These drugs should not be
cross-resistant with currently available classes of drugs. It's like starting
over, in a way. 83% of patients were taking HAART
HCV/HIV Coinfected Patients Progress More Quickly Than Monoinfected Patients
In this afternoon's oral session on HCV/HIV coinfection at 2pm there were
several interesting presentations. This report will be relatively brief as I
have a meeting at 7pm. AH Mohsen from Guys Kings' and St Thomas School of
Medicine in London, UK reported on his study comparing the progression of
hepatic fibrosis in HCV/HIV coinfected and HCV monoinfected patients. 120 HCV
and 50 coinfected patients were studied, if the researchers knew how long
their duration of HCV infection was and if they had not received HCV therapy.
The known duration of HCV-infection was estimated by the year of first IVD
use or transfusion. Plus, they had to have a liver biopsy. Liver biopsies
were assessed by one person: Ishak Score- fibrosis stage 1-4; inflammatory
grade 0-18. They also reported on the fibrosis progression rate. 80% were
IVDUs. 95% caucasian. Average age at infection: 22. Average duration of HCV
15-16 years. Current alcohol intake >0 units/week at biopsy: 55% in HCV
group, 24% in coinfected group. ALT at biopsy: 83 in HCV group, 74 in
coinfected group. Genotype 1: 56% in HCV group and 53% in coinfected group.
Coinfected patients were reported to progress more quickly than monoinfected
patients. The estimated time to cirrhosis from infection was 22 years in the
coinfected patients vs 33 years in the monoinfected patients. The rate of
progression was faster in the coinfected patients: 0.181 units/year vs 0.121
units/year. Repeat biopsies were performed in 6 coinfected patients: median
interval between biopsies 3.5 years (range: 2.1-6 years). the average
fibrosis progression rate was 0.29 unit/year and time to cirrhosis was 13.8
years.Patients with coinfection had significantly higher inflammation despite
having lower alcohol intake and had higher rates of more advanced fibrosis.
The researchers found being HIV+ was significantly associated with
development of fibrosis bt 4.38 times (using a multivariate analysis). The
duration of HCV-infection was also associated with developing fibrosis:
having HCV for >15 years increased risk of developing fibrosis by 3.7 times.
Having an ALT >80 was also a risk for faster fibrosis progression by 2.86
times. Having a CD4 count <250 increased risk of progression to stage 3 & 4
fibrosis by 3.75 times (p=0.03). In summary Mohsen reported that coinfected
patients had a 1.5 fold increase in fibrosis progression rate.
Symptomatic Hyperlactemia in Patients Receiving Interferon+Ribavirin & on HIV
Therapy and PegIntron plus Ribavirin in Coinfected Patients
DH Smith (UCSD) reported on patients taking d4T and ddI and were also
receiving Pegasys plus ribavirin in the Apricot Study. Symptomatic
hyperlactemia (SHL) has been seen uncommonly in patients on nukes,
specifically on d4T or ddI. SHL has also been seen in coinfected patients
treated with ddI and ribavirin. SHL is defined here as symptoms consistent
with elevated lactate, fatigue, abdominal pain, bloating, shortness of
breath, nausea, vomiting & parsasthesis (numbness). Elevated lactate is >2.0
mM/l. Smith reviewed cases of SHL in the 853 patients in APRICOT, which is a
large study of Pegasys alone, Pegasys plus ribavirin, or interferon plus
ribavirin in coinfected patients. Ribavirin was administered at dose of 400
mg twice a day. There were 8 SHL cases: before starting this study 5/8 were
on d4T plus ddI; 2/8 on d4T, 1/8 on AZT; 4/8 on PI; 4/8 on NNRTI. Patients
were on HAART an average on 18 months, had cd4s of 560, and 75 copies of
viral load; ALT was 101; fibrosis stage was 1.8 (0-6), necroinflammatory
Score (0-18) 6.3. On average these patients were 41 years old, 3/8 were
female, on HCV treatment for average 8 months, had an HCV viral load
reduction of 5.5 log, and 3/8 had <600 copies of HCV RNA. Their average peak
lactate level was 5.4 mMol/l.
2 patients required hospitalization, and 1 died from complications of
pnuemonia. Both were male on d4T and ddI. Peak lactate were the highest among
the cases at 15 and 19 mMol/l. At presentation with SHL, 7/8 stopped HAART
and 4/8 stopped HCV therapy. Upon resolution of SHL symptoms, one patient
restarted HAART, while 2 of 4 restarted HCV therapy. Patients on d4T were 2.2
times more likely to develop SHL (p=0.04). Patients on ddI were 8 times more
likely to get SHL (p<0.01). 88% of patients getting SHL were on d4T and 50%
not getting SHL were on d4T. 63% getting SHL were on ddI and 18% not getting
SHL were on ddI. Smith reported the rate of SHL in the Apricot Study was not
different than the rate for patients on HAART, 8/725 patient-years vs 7/516
patient-years. But the implication from this study taken with results
presented with another study presented in this session suggested a potential
association between d4T, ddI and ribavirin. In Apricot SHL developed within
17-104 days. While the overall trial incidence was 1% for SHL, at one site
out of 1001 sites the rate was 21% (5/26 patients (p<0.01). Smith summarized
during combination HCV/HIV therapy SHL is a rare but potentially fatal
disease. Symptoms are non-specific and vague, and require a high degree of
suspicion. d4T and ddI use are risk factors for the development of SHL.
Female gender may also be a risk factor. Smith said since the rate was
similar in the Apricot study to those receiving HAART alone this complication
could be due to HCV treatment or an unmasking of subclinical multifactorial
hepatic mitochondrial injury by HCV treatment.
Rafael Esteban reported preliminary results from a study of coinfected
patients receiving standard interferon plus ribavirin vs PegIntron plus
ribavirin, plus HAART. Patients received interferon 3 MIU/3x/wk plus 800 mg
RBV daily or PegIntron 1.5ug/kg plus 800 mg RBV daily. In the IFN/RBV group
(n=34) ALT was 149, 24/34 had genotype 1 or 4, HCV RNA was 6 million, HIV RNA
was <80 in 21/34, CD4 was 526. In the PegIntron group (n=30) ALT was 109,
18/34 had genotype 1, HCV RNA was 6.4 million, 22/34 had <80 copies HIV RNA,
and cd4s were 580. 42% receiving Peg/RBV had sustained response (ITT) vs 33%
getting IFN/RBV. This difference may not be significant. 31% with genotype 1
or 4 receiving Peg/RBV had SR vs 13% receiving IFN/RBV. This was I think
reported to be significant but they did not report how patients with high vs
low viral load before therapy performed. Plus I don't think they reported
what level of HCV RNA was undetectable. There was no difference in response
between IFN/RBV & Peg/RBV for genotype 2/3 patients: 67% for IFN/RBV vs 55%
for Peg/RBV. CD4s went down from 550 to 412 but CD4% did not decline. HIV RNA
did not increase. hemoglobin went down significantly from 15 to 13.2,
platelets went down just a little, neutrophils decreased from 3020 to 1990. 4
patients (14%) reduced PegIntron dose mostly due to neutropenia, 10% on
Peg/Rbv and 13% on IFN/RBV reduced RBV dose. Esteban reported significant
hyperlactatemia requiring reduction or discontinuation of RBV can occur - I
think he reported 8% incidence- and is more frequent in patients with
established cirrhosis and those with a prior history of antiviral
hepatoxicity. Esteban talked about an assay he developed, a test for mtDNA
copy number in PBMC, which may be more useful than blood lactate levels in
monitoring patients to prevent mitochondrial DNA depletion. He reported its
use in this study and that it appeared effective in detecting mtDNA damage.
This test should be validated in studies. Although this complication appears
to be uncommon, the potential development of this and the report of SHL above
raise an important concern about the development of this problem in HCV+
patients.
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