.jpg)
http://natap.org/
_______________________________________________
>From Jules: I am at the HCV Drug Resistance Workshop in Bosyon where Mark Sulkowski is delivering the opening talk and discussing IL28b genetic disposition. This gene predicts response to peg/rbv and we know the cc mutation predicts a favorable response to peg/rbv. In fact a recently published japanese study which I distributed found 95% of treatment naive patients who received telaprevir plus peg/rbv achieved SVR. The test will be available commercially soon and will play a very important role in deciding if a patient should begin therapy when the new HCV protease inhibitors are expected to be available in 2011 around September.
Friday, July 2, 2010
Gregg Allman undergoes successful liver transplant
Gregg Allman undergoes successful liver transplant
By CHRIS TALBOTT (AP) – 2 hours ago
NASHVILLE, Tenn. — Rock 'n' roll Hall of Famer Gregg Allman underwent a successful liver transplant surgery Wednesday morning at the Mayo Clinic in Jacksonville, Fla.
Allman's manager Michael Lehman told The Associated Press in a phone interview that Allman was groggy but awake Wednesday morning and that the co-founder of the seminal Southern rock group The Allman Brothers Band could be sitting up and on his feet by nightfall.
"He's psyched to put this time of his life behind him and have a chance again to feel really healthy and good, and hopefully live for many more years to come," Lehman said.
Allman began treatment for Hepatitis C in 2007 but chronic damage to his liver led to the transplant. He had been on the waiting list until doctors found a suitable liver.
Lehman said Allman got the call late Tuesday afternoon and drove to Jacksonville from his home near Savannah, Ga., for the early morning surgery.
Doctors told him to expect to be in the hospital for up to a week, stay in the Jacksonville area for up to three weeks and possibly be back on the road by November, Lehman said. Doctors said he should be able to participate in the wedding of his daughter, Island, on July 26, he added.
"It's his dream to be able to walk her down the aisle," Lehman said.
Allman battled addiction over the years and has been suffering side effects from the hepatitis, though he still managed a robust touring schedule. He had been on the transplant list longer than average, Lehman said, but his schedule was kept mostly clear in anticipation of a possible transplant this summer.
Lehman says he's planning a late fall tour that could begin in November and a new Gregg Allman Band album, the T Bone Burnett-produced "Low Country Blues," is due in January.
"I changed my ways years ago, but we can't turn back time," Allman said in a news release. "Every day is a gift, and I can't wait to get back on the road making music with my friends."
Online: http://www.greggallman.com and http://www.allmanbrothersband.com
By CHRIS TALBOTT (AP) – 2 hours ago
NASHVILLE, Tenn. — Rock 'n' roll Hall of Famer Gregg Allman underwent a successful liver transplant surgery Wednesday morning at the Mayo Clinic in Jacksonville, Fla.
Allman's manager Michael Lehman told The Associated Press in a phone interview that Allman was groggy but awake Wednesday morning and that the co-founder of the seminal Southern rock group The Allman Brothers Band could be sitting up and on his feet by nightfall.
"He's psyched to put this time of his life behind him and have a chance again to feel really healthy and good, and hopefully live for many more years to come," Lehman said.
Allman began treatment for Hepatitis C in 2007 but chronic damage to his liver led to the transplant. He had been on the waiting list until doctors found a suitable liver.
Lehman said Allman got the call late Tuesday afternoon and drove to Jacksonville from his home near Savannah, Ga., for the early morning surgery.
Doctors told him to expect to be in the hospital for up to a week, stay in the Jacksonville area for up to three weeks and possibly be back on the road by November, Lehman said. Doctors said he should be able to participate in the wedding of his daughter, Island, on July 26, he added.
"It's his dream to be able to walk her down the aisle," Lehman said.
Allman battled addiction over the years and has been suffering side effects from the hepatitis, though he still managed a robust touring schedule. He had been on the transplant list longer than average, Lehman said, but his schedule was kept mostly clear in anticipation of a possible transplant this summer.
Lehman says he's planning a late fall tour that could begin in November and a new Gregg Allman Band album, the T Bone Burnett-produced "Low Country Blues," is due in January.
"I changed my ways years ago, but we can't turn back time," Allman said in a news release. "Every day is a gift, and I can't wait to get back on the road making music with my friends."
Online: http://www.greggallman.com and http://www.allmanbrothersband.com
New HCV Antiviral in the Pipeline
New HCV Antiviral in the Pipeline
excertped from new Hepatology textbook recently published
Table 1. Antivirals in the pipeline.
Screen shot 2010-06-22 at 9.01.45 AM.png
HCV life cycle and targets for STAT-C
HCV is a positive-sense single-stranded RNA virus of approximately 9600 nucleotides.
The HCV genome contains a single large open reading frame encoding for
a polyprotein of about 3100 amino acids. From this initially translated polyprotein,
the structural HCV protein core (C) and envelope 1 and 2 (E1, E2); p7; and the
six non-structural HCV proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, are
processed by both viral and host proteases. The core protein forms the viral nucleocapsid
carrying E1 and E2, which are receptors for viral attachment and host cell
entry. The non-structural proteins are mainly enzymes essential for the HCV life
cycle (Bartenschlager 2004; Pawlotsky 2007). P7 is a small hydrophobic protein
that oligomerises into a circular hexamer, most likely serving as an ion channel
through the viral lipid membrane (Carrere-Kremer 2002; Clarke 2006). The large
translated section of the HCV genome is flanked by the strongly conserved HCV
3´ and 5´ untranslated regions (UTR). The 5´ UTR is comprised of four highly
structured domains forming the internal ribosome entry site (IRES), which plays an
important role in HCV replication (Figure 2).
Figure 2. Genomic organisation of HCV.
Screen shot 2010-06-22 at 9.03.43 AM.png
Figure 9. Antiviral activity of NS3/4A protease inhibitors.
Screen shot 2010-06-22 at 9.05.22 AM.png
Resistance to NS3/4A inhibitors
Because of the high replication rate of HCV and the poor fidelity of its RNA-dependent
RNA polymerase, numerous variants (quasispecies) are continuously produced
during HCV replication. Among them, variants carrying mutations altering the conformation
of the binding sites of STAT-C compounds can develop. During treatment
with specific antivirals, these drug-resistant variants have a fitness advantage and
can be selected to become the dominant viral quasispecies. Many of these resistant
mutants exhibit an attenuated replication with the result that, after stopping exposure
to specific antivirals, the wild type may displace the resistant variants (Tong
2006; Sarrazin 2007). Nevertheless, HCV quasispecies resistant to NS3/4A protease
inhibitors or non-nucleoside polymerase inhibitors can be detected at low levels in
some patients who were never treated with specific antivirals before (Gaudieri 2009;
Kuntzen 2008; Rodriguez-Frias 2009; Le Pogam 2008). The clinical relevance of
these pre-existing mutants is not completely understood, although there is evidence
that they may reduce the chance of achieving an SVR after treatment with STAT-C
compounds.
Table 5. Resistance mutations to HCV NS3 protease inhibitors.
Screen shot 2010-06-22 at 9.07.49 AM.png
* mutations associated with resistance in vitro but not described in patients.
Telaprevir
To date, mutations conferring telaprevir-resistance have been identified at four positions,
V36A/M/L, T54A, R155K/M/S/T and A156S//T (Lin 2005; Lin 2007; Sarrazin
2007; Welsch 2008; Zhou 2008) (Table 5). The A156 mutation was revealed
by in vitro analyses in the replicon while the other mutations were detected in vivo
by a clonal sequencing approach during telaprevir administration in patients with
chronic hepatitis C. A detailed kinetic analysis of telaprevir-resistant variants was
performed in genotype 1 patients during 14 days of telaprevir monotherapy and
combination therapy with PEG-IFN a-2a (Sarrazin 2007). Telaprevir monotherapy
initially led to a rapid HCV RNA decline in all patients due to a strong reduction in
wild type virus. In patients who developed a viral rebound during telaprevir monotherapy,
mainly the single mutation variants R155K/T and A156T were uncovered
by wild type reduction and became dominant after day 8. These single mutant
variants were selected from preexisting quasispecies. During the viral rebound
phase these variants typically were replaced by highly resistant double-mutation
variants (e.g., V36M/A +R155K/T). The combination of telaprevir and PEG-IFN
a-2a was sufficient to inhibit the breakthrough of resistant mutations in a 14-day
study (Forestier 2007). It is important to note that after up to 3 years of telaprevir
treatment low to medium levels of V36 and R155 variants were observed in single
patients (Forestier 2008).
As shown also for other NS3/4A protease inhibitors (e.g., ITMN-191), the genetic
barrier to telaprevir resistance differs significantly between HCV subtypes. In all clinical
studies of telaprevir alone or in combination with PEG-IFN a and ribavirin, viral
resistance and breakthrough occurred much more frequently in patients infected with
HCV genotype 1a compared to genotype 1b. This difference was shown to result from
nucleotide differences at position 155 in HCV subtype 1a (aga, encodes R) versus
1b (cga, also encodes R). The mutation most frequently associated with resistance to
telaprevir is R155K; changing R to K at position 155 requires 1 nucleotide change in
HCV subtype 1a and 2 nucleotide changes in subtype 1b isolates (McCown 2009).
Boceprevir
In the replicon system, mutations have been seen at three positions that confer boceprevir
resistance (Table 5). T54A, A156S and V170A confer low level resistance to
boceprevir whereas A156T, which also confers telaprevir and ciluprevir resistance,
exhibits greater levels of resistance (Tong 2006). In patients with chronic hepatitis
C three additional mutations were detected during boceprevir monotherapy (V36G/
M/A, V55A, R155K) (Susser 2009). In a number of these patients at one year and in
single patients at even 4 years after stopping boceprevir treatment resistant variants
could still be detected in the HCV quasispecies by clonal sequence analysis (Susser
2009). However, another study revealed that the antiviral activity of boceprevir was
not different in people whether they had or had not been previously treated with
PEG-IFN a (Vermehren 2009).
Compounds targeting HCV replication
NS5B polymerase inhibitors
NS5B RNA polymerase inhibitors can be divided into two distinct categories. Nucleoside
analogue inhibitors (NIs) like valopicitabine (NM283), R7128, R1626, PSI-7851
or IDX184 mimic the natural substrates of the polymerase and are incorporated into
the growing RNA chain, thus causing direct chain termination by blocking the active
site of NS5B (Koch 2006; Koch 2007). Because the active centre of NS5B is a highly
conserved region of the HCV genome, NIs are potentially effective against different
genotypes. Single amino acid substitutions in every position of the active centre may
result in loss of function. Thus, there is a relatively high genetic barrier in the development
of resistances to NIs.
In contrast to NIs, the heterogeneous class of non-nucleoside inhibitors (NNIs)
achieves NS5B inhibition by binding to different allosteric enzyme sites, which results
in conformational protein change before the elongation complex is formed (Beaulieu
2007). For allosteric NS5B inhibition high chemical affinity is required. NS5B is
structurally organized in a characteristic “right hand motif”, containing finger, palm
and thumb domains, and offers at least four NNI binding sites, a benzimidazole-
(thumb 1)-, thiophene-(thumb 2)-, benzothiadiazine-(palm 1)- and benzofuran-(palm
2)-binding site (Lesburg 1999; Beaulieu 2007) (Figure 12). Because of their distinct
binding sites, different polymerase inhibitors can theoretically be used in combination
or in sequence to manage the development of resistance. Because NNIs bind distantly
to the active centre of NS5B, their application may rapidly lead to the development of
resistant mutants in vitro and in vivo. Moreover, mutations at the NNI binding sites do
not necessarily lead to impaired function of the enzyme.
Figure 13. Antiviral activity of nucleoside analogue NS5B polymerase inhibitors.
Screen shot 2010-06-22 at 9.14.08 AM.png
Non-nucleoside analogs
At least 4 different allosteric binding sites have been identified for the inhibition of the
NS5B polymerase by non-nucleoside inhibitors. An overview of the antiviral activities of
non-nucleoside polymerase inhibitors in monotherapy studies is shown in Figure 14.
NNI site 1 inhibitors (thumb 1 / benzimidazole site)
BILB1941, BI207127 and MK-3281 are NNI site 1 inhibitors investigated in phase
I clinical trials and have shown little to modest antiviral activity (Erhard 2009; Shi
2009; Sarrazin 2009). No viral breakthrough via selection of resistant variants was
seen after 5 days of treatment with BILB1941 or BI207127.
NNI site 2 inhibitors (thumb 2 / thiophene site)
Filibuvir (PF-00868554) is a NNI site 2 inhibitor with modest antiviral activity in a
phase I study. In a subsequent triple therapy trial with filibuvir, pegylated interferon
a-2a and ribavirin for 4 weeks viral breakthrough was observed in 5/26 patients.
VCH-759, VCH-916 and VCH-222 are three other NNI site 2 inhibitors with
antiviral activity in monotherapy studies (Cooper 2009; Sarrazin 2009). For VCH-
759 as well as VCH-916 viral breakthroughs via selection of resistant variants
were observed.
NNI site 3 inhibitors (palm 1 / benzothiadiazine site)
ANA598 is a NNI site 3 inhibitor that displayed antiviral activity during treatment of
genotype 1 infected patients. Viral breakthrough was not observed during this short
monotherapy trial.
NNI site 4 inhibitors (palm 2 / benzofuran site)
Monotherapy with the NNI site 4 inhibitor HCV-796 showed low antiviral activity
in genotype 1 infected patients (Kneteman 2009; Villano 2007). Viral breakthrough
was associated with selection of resistant variants conferring a medium to high level
of phenotypic resistance. For GS-9190 low antiviral activity was observed in a clinical
study and variants conferring resistance were identified in the beta-hairpin of the
polymerase. ABT-333, another palm site inhibitor, demonstrated antiviral activity in
patients with genotype 1 infection and from in vitro replicon as well as clinical studies
specific variants were observed as main resistance mutations.
Figure 14. Antiviral activity of non-nucleoside analogue NS5B polymerase inhibitors.
Screen shot 2010-06-22 at 9.18.27 AM.png
NS5A inhibitor
In a single ascending dose study it was shown that inhibition of the NS5A protein with
BMS-790052 leads to a sharp initial decline of HCV RNA concentrations (Nettles
2008). BMS-790052 is the first NS5A inhibitor binding to domain I of the NS5A protein,
which was shown to be important for regulation of HCV replication. No clinical
data on resistance to this class of drugs have been presented yet and results of multiple
dose studies are eagerly anticipated. (from Jules: clinical data, in patients was presented at the EASL meeting in April 2010 and previously at AASLD 2 years ago)
Once-daily NS5A Inhibitor (BMS-790052) Plus Peginterferon-alpha-2a And Ribavirin Produces High Rates Of Extended Rapid Virologic Response In Treatment-naïve HCV-genotype 1 Subjects: Phase 2a Trial - Bristol-Myers Squibb Study AI444014 - (04/20/10)
BMS-790052 is a First-in-class Potent Hepatitis C Virus (HCV) NS5A ...
Nov 1, 2008 ... This new class of drug, the BMS NS5A inhibitor, attracted quite a lot of discussion because of it potent viral load reduction of -3.6 logs, ...
www.natap.org/2008/AASLD/AASLD_06.htm
The Most recent data updates on new HCV antivirals and new interferons were reported at the recent EASL:
EASL 45th Annual Meeting
(European Association for the Study of the Liver)
April 14-18, 2010
Vienna, Austria
excertped from new Hepatology textbook recently published
Table 1. Antivirals in the pipeline.
Screen shot 2010-06-22 at 9.01.45 AM.png
HCV life cycle and targets for STAT-C
HCV is a positive-sense single-stranded RNA virus of approximately 9600 nucleotides.
The HCV genome contains a single large open reading frame encoding for
a polyprotein of about 3100 amino acids. From this initially translated polyprotein,
the structural HCV protein core (C) and envelope 1 and 2 (E1, E2); p7; and the
six non-structural HCV proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, are
processed by both viral and host proteases. The core protein forms the viral nucleocapsid
carrying E1 and E2, which are receptors for viral attachment and host cell
entry. The non-structural proteins are mainly enzymes essential for the HCV life
cycle (Bartenschlager 2004; Pawlotsky 2007). P7 is a small hydrophobic protein
that oligomerises into a circular hexamer, most likely serving as an ion channel
through the viral lipid membrane (Carrere-Kremer 2002; Clarke 2006). The large
translated section of the HCV genome is flanked by the strongly conserved HCV
3´ and 5´ untranslated regions (UTR). The 5´ UTR is comprised of four highly
structured domains forming the internal ribosome entry site (IRES), which plays an
important role in HCV replication (Figure 2).
Figure 2. Genomic organisation of HCV.
Screen shot 2010-06-22 at 9.03.43 AM.png
Figure 9. Antiviral activity of NS3/4A protease inhibitors.
Screen shot 2010-06-22 at 9.05.22 AM.png
Resistance to NS3/4A inhibitors
Because of the high replication rate of HCV and the poor fidelity of its RNA-dependent
RNA polymerase, numerous variants (quasispecies) are continuously produced
during HCV replication. Among them, variants carrying mutations altering the conformation
of the binding sites of STAT-C compounds can develop. During treatment
with specific antivirals, these drug-resistant variants have a fitness advantage and
can be selected to become the dominant viral quasispecies. Many of these resistant
mutants exhibit an attenuated replication with the result that, after stopping exposure
to specific antivirals, the wild type may displace the resistant variants (Tong
2006; Sarrazin 2007). Nevertheless, HCV quasispecies resistant to NS3/4A protease
inhibitors or non-nucleoside polymerase inhibitors can be detected at low levels in
some patients who were never treated with specific antivirals before (Gaudieri 2009;
Kuntzen 2008; Rodriguez-Frias 2009; Le Pogam 2008). The clinical relevance of
these pre-existing mutants is not completely understood, although there is evidence
that they may reduce the chance of achieving an SVR after treatment with STAT-C
compounds.
Table 5. Resistance mutations to HCV NS3 protease inhibitors.
Screen shot 2010-06-22 at 9.07.49 AM.png
* mutations associated with resistance in vitro but not described in patients.
Telaprevir
To date, mutations conferring telaprevir-resistance have been identified at four positions,
V36A/M/L, T54A, R155K/M/S/T and A156S//T (Lin 2005; Lin 2007; Sarrazin
2007; Welsch 2008; Zhou 2008) (Table 5). The A156 mutation was revealed
by in vitro analyses in the replicon while the other mutations were detected in vivo
by a clonal sequencing approach during telaprevir administration in patients with
chronic hepatitis C. A detailed kinetic analysis of telaprevir-resistant variants was
performed in genotype 1 patients during 14 days of telaprevir monotherapy and
combination therapy with PEG-IFN a-2a (Sarrazin 2007). Telaprevir monotherapy
initially led to a rapid HCV RNA decline in all patients due to a strong reduction in
wild type virus. In patients who developed a viral rebound during telaprevir monotherapy,
mainly the single mutation variants R155K/T and A156T were uncovered
by wild type reduction and became dominant after day 8. These single mutant
variants were selected from preexisting quasispecies. During the viral rebound
phase these variants typically were replaced by highly resistant double-mutation
variants (e.g., V36M/A +R155K/T). The combination of telaprevir and PEG-IFN
a-2a was sufficient to inhibit the breakthrough of resistant mutations in a 14-day
study (Forestier 2007). It is important to note that after up to 3 years of telaprevir
treatment low to medium levels of V36 and R155 variants were observed in single
patients (Forestier 2008).
As shown also for other NS3/4A protease inhibitors (e.g., ITMN-191), the genetic
barrier to telaprevir resistance differs significantly between HCV subtypes. In all clinical
studies of telaprevir alone or in combination with PEG-IFN a and ribavirin, viral
resistance and breakthrough occurred much more frequently in patients infected with
HCV genotype 1a compared to genotype 1b. This difference was shown to result from
nucleotide differences at position 155 in HCV subtype 1a (aga, encodes R) versus
1b (cga, also encodes R). The mutation most frequently associated with resistance to
telaprevir is R155K; changing R to K at position 155 requires 1 nucleotide change in
HCV subtype 1a and 2 nucleotide changes in subtype 1b isolates (McCown 2009).
Boceprevir
In the replicon system, mutations have been seen at three positions that confer boceprevir
resistance (Table 5). T54A, A156S and V170A confer low level resistance to
boceprevir whereas A156T, which also confers telaprevir and ciluprevir resistance,
exhibits greater levels of resistance (Tong 2006). In patients with chronic hepatitis
C three additional mutations were detected during boceprevir monotherapy (V36G/
M/A, V55A, R155K) (Susser 2009). In a number of these patients at one year and in
single patients at even 4 years after stopping boceprevir treatment resistant variants
could still be detected in the HCV quasispecies by clonal sequence analysis (Susser
2009). However, another study revealed that the antiviral activity of boceprevir was
not different in people whether they had or had not been previously treated with
PEG-IFN a (Vermehren 2009).
Compounds targeting HCV replication
NS5B polymerase inhibitors
NS5B RNA polymerase inhibitors can be divided into two distinct categories. Nucleoside
analogue inhibitors (NIs) like valopicitabine (NM283), R7128, R1626, PSI-7851
or IDX184 mimic the natural substrates of the polymerase and are incorporated into
the growing RNA chain, thus causing direct chain termination by blocking the active
site of NS5B (Koch 2006; Koch 2007). Because the active centre of NS5B is a highly
conserved region of the HCV genome, NIs are potentially effective against different
genotypes. Single amino acid substitutions in every position of the active centre may
result in loss of function. Thus, there is a relatively high genetic barrier in the development
of resistances to NIs.
In contrast to NIs, the heterogeneous class of non-nucleoside inhibitors (NNIs)
achieves NS5B inhibition by binding to different allosteric enzyme sites, which results
in conformational protein change before the elongation complex is formed (Beaulieu
2007). For allosteric NS5B inhibition high chemical affinity is required. NS5B is
structurally organized in a characteristic “right hand motif”, containing finger, palm
and thumb domains, and offers at least four NNI binding sites, a benzimidazole-
(thumb 1)-, thiophene-(thumb 2)-, benzothiadiazine-(palm 1)- and benzofuran-(palm
2)-binding site (Lesburg 1999; Beaulieu 2007) (Figure 12). Because of their distinct
binding sites, different polymerase inhibitors can theoretically be used in combination
or in sequence to manage the development of resistance. Because NNIs bind distantly
to the active centre of NS5B, their application may rapidly lead to the development of
resistant mutants in vitro and in vivo. Moreover, mutations at the NNI binding sites do
not necessarily lead to impaired function of the enzyme.
Figure 13. Antiviral activity of nucleoside analogue NS5B polymerase inhibitors.
Screen shot 2010-06-22 at 9.14.08 AM.png
Non-nucleoside analogs
At least 4 different allosteric binding sites have been identified for the inhibition of the
NS5B polymerase by non-nucleoside inhibitors. An overview of the antiviral activities of
non-nucleoside polymerase inhibitors in monotherapy studies is shown in Figure 14.
NNI site 1 inhibitors (thumb 1 / benzimidazole site)
BILB1941, BI207127 and MK-3281 are NNI site 1 inhibitors investigated in phase
I clinical trials and have shown little to modest antiviral activity (Erhard 2009; Shi
2009; Sarrazin 2009). No viral breakthrough via selection of resistant variants was
seen after 5 days of treatment with BILB1941 or BI207127.
NNI site 2 inhibitors (thumb 2 / thiophene site)
Filibuvir (PF-00868554) is a NNI site 2 inhibitor with modest antiviral activity in a
phase I study. In a subsequent triple therapy trial with filibuvir, pegylated interferon
a-2a and ribavirin for 4 weeks viral breakthrough was observed in 5/26 patients.
VCH-759, VCH-916 and VCH-222 are three other NNI site 2 inhibitors with
antiviral activity in monotherapy studies (Cooper 2009; Sarrazin 2009). For VCH-
759 as well as VCH-916 viral breakthroughs via selection of resistant variants
were observed.
NNI site 3 inhibitors (palm 1 / benzothiadiazine site)
ANA598 is a NNI site 3 inhibitor that displayed antiviral activity during treatment of
genotype 1 infected patients. Viral breakthrough was not observed during this short
monotherapy trial.
NNI site 4 inhibitors (palm 2 / benzofuran site)
Monotherapy with the NNI site 4 inhibitor HCV-796 showed low antiviral activity
in genotype 1 infected patients (Kneteman 2009; Villano 2007). Viral breakthrough
was associated with selection of resistant variants conferring a medium to high level
of phenotypic resistance. For GS-9190 low antiviral activity was observed in a clinical
study and variants conferring resistance were identified in the beta-hairpin of the
polymerase. ABT-333, another palm site inhibitor, demonstrated antiviral activity in
patients with genotype 1 infection and from in vitro replicon as well as clinical studies
specific variants were observed as main resistance mutations.
Figure 14. Antiviral activity of non-nucleoside analogue NS5B polymerase inhibitors.
Screen shot 2010-06-22 at 9.18.27 AM.png
NS5A inhibitor
In a single ascending dose study it was shown that inhibition of the NS5A protein with
BMS-790052 leads to a sharp initial decline of HCV RNA concentrations (Nettles
2008). BMS-790052 is the first NS5A inhibitor binding to domain I of the NS5A protein,
which was shown to be important for regulation of HCV replication. No clinical
data on resistance to this class of drugs have been presented yet and results of multiple
dose studies are eagerly anticipated. (from Jules: clinical data, in patients was presented at the EASL meeting in April 2010 and previously at AASLD 2 years ago)
Once-daily NS5A Inhibitor (BMS-790052) Plus Peginterferon-alpha-2a And Ribavirin Produces High Rates Of Extended Rapid Virologic Response In Treatment-naïve HCV-genotype 1 Subjects: Phase 2a Trial - Bristol-Myers Squibb Study AI444014 - (04/20/10)
BMS-790052 is a First-in-class Potent Hepatitis C Virus (HCV) NS5A ...
Nov 1, 2008 ... This new class of drug, the BMS NS5A inhibitor, attracted quite a lot of discussion because of it potent viral load reduction of -3.6 logs, ...
www.natap.org/2008/AASLD/AASLD_06.htm
The Most recent data updates on new HCV antivirals and new interferons were reported at the recent EASL:
EASL 45th Annual Meeting
(European Association for the Study of the Liver)
April 14-18, 2010
Vienna, Austria
Harlem Hepatitis C Task Force Meeting
Harlem Hepatitis C Task Force Meeting
Wednesday July 28th (3-5 PM)
North General Hospital - 1879 Madison Avenue , New York , NY 10035 – 5th Floor Conference Rooms 2 & 3
* RSVP would be appreciated. Refreshments will be provided.
Agenda
* “A Comparison of HIV and HCV Health Beliefs in an Inner-City Community” Presentation - Katie Krauskopf, MD, Mount Sinai
* HCV Treatment Readiness Tool (HCV–PRT) Project Update – Caroline Licht, PhD , Harlem Hospital
* NYC HCV Advocacy Committee Update
o Advocacy Training
o Adopt a Representative Initiative
o Open advocacy issues & How to get involved
* HCV Services Referral Pathway Map – Update
o Getting patients from testing into medical care: Overcoming insurance obstacles & HCV Coaching Program Project
* NYC Hepatitis C Task Force Website Update
o Job, Volunteer & Clinical Trial boards
* Community Announcements
o If you would like to add an announcement to the agenda, reply to this email.
Immediate Action Alert!
* Call Assembly Speaker Sheldon Silver (518-455-3791) and ask him to take leadership in order to pass Gottfried’s Syringe Bill, 8396, through the Assembly. Greater access to new syringes and less re-use of syringes = less hepatitis c transmission. See HCV Task Force website for More info & Call Script.
* Viral Hepatitis and Liver Cancer Control and Prevention Act of 2009 (HR 3974). Contact your U.S. House Representative’s office in Washington , DC and ask for support. See www.nvhr.org and or the HCV Task Force website for More info & Call Script.
Upcoming Events
* Heroin Stamp Project, an exhibition. Opening: Wednesday June 23rd from 7-10 PM. Viewing Hours: June 23rd – June 39th Weekdays: 11am - 7pm, Saturday & Sunday: 12 - 6pm. Location: White Box 329 Broome Street (@ Bowery) New York , NY 10002 . Free and open to the public. The Social Art Collective is proud to present Heroin Stamp Project, an exhibition focusing on the branding of heroin in New York City . At once beautiful and unsettling, the images in the exhibit illustrate a complex narrative around public health and preventable consequences of injection drug use. For more info see http://nycstamps.tumblr.com and on FaceBook
Nirah Johnson , LMSW, Community Projects Specialist
Office of Viral Hepatitis Coordination - NYC Department of Health & Mental Hygiene
125 Worth Street, Room 326. New York , NY 10013
(212) 341-0432 - njohnso2@health.nyc.gov
Office of Viral Hepatitis Coordination Website
NYC Hepatitis B Coalition Website
NYC Hepatitis C Task Force Website
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Forwarded Message: Harlem Hepatitis C Task Force Meeting
Harlem Hepatitis C Task Force Meeting
Friday, June 18, 2010 12:38 PM
From:
"Nirah Johnson"
To:
undisclosed-recipients
Harlem Hepatitis C Task Force Meeting
Wednesday July 28th (3-5 PM)
North General Hospital - 1879 Madison Avenue, New York, NY 10035 – 5th Floor Conference Rooms 2 & 3
* RSVP would be appreciated. Refreshments will be provided.
Agenda
· “A Comparison of HIV and HCV Health Beliefs in an Inner-city Community” Presentation - Katie Krauskopf, MD, Mount Sinai
1 HCV Treatment Readiness Tool (HCV–PRT) Project Update – Caroline Licht, PhD, Harlem Hospital
2 NYC Hepatitis C Task Force Website Update
· Job, Volunteer & Clinical Trial boards
· NYC HCV Advocacy Committee Update
· Advocacy Training
1 Adopt a Representative Initiative – Regional team leaders
2 Open advocacy issues
3 How to get involved
· Community Announcements
Nirah Johnson, LMSW, Community Projects Specialist
Office of Viral Hepatitis Coordination - NYC Department of Health & Mental Hygiene
125 Worth Street, Room 326. New York, NY 10013
(212) 341-0432 - njohnso2@health.nyc.gov
Office of Viral Hepatitis Coordination Website
NYC Hepatitis B Coalition Website
NYC Hepatitis C Task Force Website
Wednesday July 28th (3-5 PM)
North General Hospital - 1879 Madison Avenue , New York , NY 10035 – 5th Floor Conference Rooms 2 & 3
* RSVP would be appreciated. Refreshments will be provided.
Agenda
* “A Comparison of HIV and HCV Health Beliefs in an Inner-City Community” Presentation - Katie Krauskopf, MD, Mount Sinai
* HCV Treatment Readiness Tool (HCV–PRT) Project Update – Caroline Licht, PhD , Harlem Hospital
* NYC HCV Advocacy Committee Update
o Advocacy Training
o Adopt a Representative Initiative
o Open advocacy issues & How to get involved
* HCV Services Referral Pathway Map – Update
o Getting patients from testing into medical care: Overcoming insurance obstacles & HCV Coaching Program Project
* NYC Hepatitis C Task Force Website Update
o Job, Volunteer & Clinical Trial boards
* Community Announcements
o If you would like to add an announcement to the agenda, reply to this email.
Immediate Action Alert!
* Call Assembly Speaker Sheldon Silver (518-455-3791) and ask him to take leadership in order to pass Gottfried’s Syringe Bill, 8396, through the Assembly. Greater access to new syringes and less re-use of syringes = less hepatitis c transmission. See HCV Task Force website for More info & Call Script.
* Viral Hepatitis and Liver Cancer Control and Prevention Act of 2009 (HR 3974). Contact your U.S. House Representative’s office in Washington , DC and ask for support. See www.nvhr.org and or the HCV Task Force website for More info & Call Script.
Upcoming Events
* Heroin Stamp Project, an exhibition. Opening: Wednesday June 23rd from 7-10 PM. Viewing Hours: June 23rd – June 39th Weekdays: 11am - 7pm, Saturday & Sunday: 12 - 6pm. Location: White Box 329 Broome Street (@ Bowery) New York , NY 10002 . Free and open to the public. The Social Art Collective is proud to present Heroin Stamp Project, an exhibition focusing on the branding of heroin in New York City . At once beautiful and unsettling, the images in the exhibit illustrate a complex narrative around public health and preventable consequences of injection drug use. For more info see http://nycstamps.tumblr.com and on FaceBook
Nirah Johnson , LMSW, Community Projects Specialist
Office of Viral Hepatitis Coordination - NYC Department of Health & Mental Hygiene
125 Worth Street, Room 326. New York , NY 10013
(212) 341-0432 - njohnso2@health.nyc.gov
Office of Viral Hepatitis Coordination Website
NYC Hepatitis B Coalition Website
NYC Hepatitis C Task Force Website
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Forwarded Message: Harlem Hepatitis C Task Force Meeting
Harlem Hepatitis C Task Force Meeting
Friday, June 18, 2010 12:38 PM
From:
"Nirah Johnson"
To:
undisclosed-recipients
Harlem Hepatitis C Task Force Meeting
Wednesday July 28th (3-5 PM)
North General Hospital - 1879 Madison Avenue, New York, NY 10035 – 5th Floor Conference Rooms 2 & 3
* RSVP would be appreciated. Refreshments will be provided.
Agenda
· “A Comparison of HIV and HCV Health Beliefs in an Inner-city Community” Presentation - Katie Krauskopf, MD, Mount Sinai
1 HCV Treatment Readiness Tool (HCV–PRT) Project Update – Caroline Licht, PhD, Harlem Hospital
2 NYC Hepatitis C Task Force Website Update
· Job, Volunteer & Clinical Trial boards
· NYC HCV Advocacy Committee Update
· Advocacy Training
1 Adopt a Representative Initiative – Regional team leaders
2 Open advocacy issues
3 How to get involved
· Community Announcements
Nirah Johnson, LMSW, Community Projects Specialist
Office of Viral Hepatitis Coordination - NYC Department of Health & Mental Hygiene
125 Worth Street, Room 326. New York, NY 10013
(212) 341-0432 - njohnso2@health.nyc.gov
Office of Viral Hepatitis Coordination Website
NYC Hepatitis B Coalition Website
NYC Hepatitis C Task Force Website
Hearing by the Committee on Oversight and Government Reform
Hearing by the Committee on Oversight and Government Reform,
United States House of Representatives
In response to the Institute of Medicine (IOM) report last January -- Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C –- and AASLD’s collaboration with the Trust for America’s Health (TFAH) to bring attention to the burden of liver disease created by viral hepatitis, the House Oversight and Government Reform Committee held a hearing on Thursday, June 17th, entitled Viral Hepatitis: The Secret Epidemic. During the hearing, the Committee urged Congress to pass legislation to boost the diagnosis and treatment of viral hepatitis. Witnesses included Representatives Hank Johnson, Bill Cassidy and Mike Honda as well as Dr. Howard Koh, Assistant Secretary for Health at the Department of Health and Human Services, Mr. Randy Mayer, Chief of the Bureau of HIV, STD and Hepatitis at the Iowa Department of Public Health, Mr. Michael Ninburg, Executive Director of the Hepatitis Education Project, Dr. Jeffrey Levi, TFAH, and Mr. Rolf Benirschke, Spokesperson for Hepatitis C Awareness.
Representative Cassidy did an excellent job articulating the impact of viral hepatitis should it go unchecked. He raised the point that it costs $50 to vaccinate a child against HBV, but costs over $1 million to treat a HBV patient over their lifetime should they receive a liver transplant. He cited the effectiveness of the vaccines for children program authorized by Congress during the Clinton administration and urged Congress to act again to fight viral hepatitis. He stressed that the most important thing that can be done is to educate providers, patients, and their families. In his testimony, Representative Honda advocated for the support and passage of his bill, HR 3974.
Assistant Secretary Koh -- accompanied by Dr. John Ward -- said that the interagency report would be completed this fall. He cited the need for more research for a HCV vaccine, to improve awareness of infection, reduce the spread of hepatitis in health care settings, and raise awareness within and testing of high risk populations. When asked by Chairman Towns (D-NY) whether hepatitis could be eliminated, Koh responded that it could be with the right resources. Koh also touched on screening guidelines and cited the US Preventive Services Taskforce (USPSTF) as just one of the groups that releases screening guidelines. Representative Bilbray (R-CA) asked about the target population for screening, saying he believes that the population should be viewed multi-dimensionally. Koh and Ward responded that risk based screening models have created barriers to screening and given the segment of the population most likely to be developing symptoms, an age based strategy could be more effective.
While both Democrats and Republicans on the committee agreed that something must be done to
United States House of Representatives
In response to the Institute of Medicine (IOM) report last January -- Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C –- and AASLD’s collaboration with the Trust for America’s Health (TFAH) to bring attention to the burden of liver disease created by viral hepatitis, the House Oversight and Government Reform Committee held a hearing on Thursday, June 17th, entitled Viral Hepatitis: The Secret Epidemic. During the hearing, the Committee urged Congress to pass legislation to boost the diagnosis and treatment of viral hepatitis. Witnesses included Representatives Hank Johnson, Bill Cassidy and Mike Honda as well as Dr. Howard Koh, Assistant Secretary for Health at the Department of Health and Human Services, Mr. Randy Mayer, Chief of the Bureau of HIV, STD and Hepatitis at the Iowa Department of Public Health, Mr. Michael Ninburg, Executive Director of the Hepatitis Education Project, Dr. Jeffrey Levi, TFAH, and Mr. Rolf Benirschke, Spokesperson for Hepatitis C Awareness.
Representative Cassidy did an excellent job articulating the impact of viral hepatitis should it go unchecked. He raised the point that it costs $50 to vaccinate a child against HBV, but costs over $1 million to treat a HBV patient over their lifetime should they receive a liver transplant. He cited the effectiveness of the vaccines for children program authorized by Congress during the Clinton administration and urged Congress to act again to fight viral hepatitis. He stressed that the most important thing that can be done is to educate providers, patients, and their families. In his testimony, Representative Honda advocated for the support and passage of his bill, HR 3974.
Assistant Secretary Koh -- accompanied by Dr. John Ward -- said that the interagency report would be completed this fall. He cited the need for more research for a HCV vaccine, to improve awareness of infection, reduce the spread of hepatitis in health care settings, and raise awareness within and testing of high risk populations. When asked by Chairman Towns (D-NY) whether hepatitis could be eliminated, Koh responded that it could be with the right resources. Koh also touched on screening guidelines and cited the US Preventive Services Taskforce (USPSTF) as just one of the groups that releases screening guidelines. Representative Bilbray (R-CA) asked about the target population for screening, saying he believes that the population should be viewed multi-dimensionally. Koh and Ward responded that risk based screening models have created barriers to screening and given the segment of the population most likely to be developing symptoms, an age based strategy could be more effective.
While both Democrats and Republicans on the committee agreed that something must be done to
Sunday, June 20, 2010
the care of HIV–HCV coinfected patients changed significantly in “real life” in France between 2004 and 2009
In conclusion, the care of HIV–HCV coinfected patients changed significantly in “real life” in France between 2004 and 2009. These results underline the importance of continuing efforts to educate physicians and patients about increasing the access of coinfected patients to HCV treatment. Efforts should be made to improve the care of these patients, such as increasing the access to and the number of patients receiving treatment for HCV infection, the possibility of starting HCV treatment earlier (i.e. before the presence of a high liver fibrosis score), the introduction of HCV treatment even in patients with low CD4 cell counts, and earlier referral of patients with cirrhosis to a liver transplant unit.....RESULTS: The rate of liver biopsy decreased (14% vs. 38% vs. 56%), while the use of non-invasive liver damage tests increased (47% vs. 24% vs. ND) in the 2009, 2006, and 2004 surveys, respectively. The rate of patients that had never been treated for HCV infection progressively decreased in the 2009, 2006, and 2004 surveys (37%, 42%, and 54%). The main reasons for HCV non-treatment changed as HCV treatment was deemed less questionable and the lack of liver biopsy became a very rare reason (6%, 18%, and 34%). Among patients treated for HCV infection, the rate of sustained virological response increased (49%, 29%, and 29%). The main factors independently associated with HCV treatment were a liver fibrosis score >F2 (odds ratio=3.5; 95% CI 2.1–5.7), a liver biopsy activity grade A2 (2.7; 1.4–5.3), a CD4 cell count 350ml (2.7; 1.6–4.4), European origin (2.1; 1.3–3.4), daily alcohol consumption<30g (2.1; 1.2–3.8), and male gender (2.0; 1.2–3.3)."
Articles in Press
Care of hepatitis C virus infection in human immunodeficiency virus-infected patients: Modifications in three consecutive large surveys between 2004 and 2009
Journal of Hepatology June 2010
Patrice Cacoub12, Philippe Halfon3, Eric Rosenthal4, François Bailly5, Firouze Bani Sadr6, Yves Benhamou7, Stéphane Chevaliez8, Jean Michel Pawlotsky8, Lionel Piroth9, Yazdan Yazdanpanah10, Stanislas Pol11
Received 30 November 2009; received in revised form 9 February 2010; accepted 15 March 2010. published online 05 May 2010.
Corrected Proof
ABSTRACT
Background & Aims
To analyze the care of HCV infection in HIV–HCV coinfected patients and its progression between 2004 and 2009.
Patients and methods
Three hundred eighty HIV–HCV coinfected patients were prospectively included from November 22 to 29, 2004 (2004 survey), 416 patients from April 3 to 10, 2006 (2006 survey), and 419 patients from June 15 to 22, 2009 (2009 survey).
Results
The rate of liver biopsy decreased (14% vs. 38% vs. 56%), while the use of non-invasive liver damage tests increased (47% vs. 24% vs. ND) in the 2009, 2006, and 2004 surveys, respectively. The rate of patients that had never been treated for HCV infection progressively decreased in the 2009, 2006, and 2004 surveys (37%, 42%, and 54%). The main reasons for HCV non-treatment changed as HCV treatment was deemed less questionable and the lack of liver biopsy became a very rare reason (6%, 18%, and 34%). Among patients treated for HCV infection, the rate of sustained virological response increased (49%, 29%, and 29%). The main factors independently associated with HCV treatment were a liver fibrosis score >F2 (odds ratio=3.5; 95% CI 2.1–5.7), a liver biopsy activity grade A2 (2.7; 1.4–5.3), a CD4 cell count 350ml (2.7; 1.6–4.4), European origin (2.1; 1.3–3.4), daily alcohol consumption<30g (2.1; 1.2–3.8), and male gender (2.0; 1.2–3.3).
Conclusion
Compared to the 2004 and 2006 surveys, the 2009 coinfected patients had liver damage assessment more frequently, more patients had received HCV treatment and more patients had achieved a sustained virological response.
Introduction
Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is a frequent and particularly serious problem [1], [2], [3], [4], [5], [6]. About 30% of HIV-infected patients in France are also infected with HCV, i.e. close to 30,000 patients [1], [2], [5], [6]. Since the widespread use of combined antiretroviral therapy (cART) was begun, AIDS mortality has progressively decreased, while chronic liver disease, linked primarily to HCV, has become one of the leading causes of morbidity and mortality [2], [4], [6].
Considerable therapeutic progress has been achieved in HCV-infected patients due to combination therapy with pegylated interferon and ribavirin, resulting in a 55–60% sustained virological response (SVR) in HCV mono-infected patients (40–50% in HCV genotype 1, the most frequent HCV genotype worldwide) [7]. Results from large therapeutic trials in HIV–HCV coinfected patients have provided important information. A particularly encouraging result was that the pegylated interferon and ribavirin combination achieved an SVR in 27–44% of coinfected patients [8], [9], [10], [11], resulting in histopathological improvement in most of them. Recent results report similar SVR rates in coinfected more than in HCV mono-infected patients [12], [13], [14], [15]. HCV treatment, however, is given to a small number of HIV–HCV coinfected patients for many reasons, e.g., HCV treatment deemed questionable (minimal hepatic lesions, alcohol abuse, active drug use), lack of available liver biopsy, psychiatric contraindication, and physicians’ conviction of poor patient compliance [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. Following the First European Consensus Conference on the treatment of chronic hepatitis B and C in HIV-infected patients in 2005, the coinfection guidelines in HIV medicine from the European AIDS Society in 2008 as well as their recent update at the European AIDS Clinical Society conference, it may be assumed that differences in the guidelines may have had an impact on treatment compliance and management standards [26], [27].
The aim of the present study was to analyze the care of HIV–HCV coinfected patients in France in 2009 (including initial workup, mode of treatment, follow-up modalities, and virological response) through a survey and to compare results with surveys conducted in 2004 and 2006 [17], [22].
Patients and methods
The same methodology was used in the three surveys, and details have been published elsewhere [17], [22]. In brief, physicians involved in the management of HIV-infected patients were recruited from 50 specialized centers from all of metropolitan France. These centers were representative of those providing the standard of care in HIV cART in France. Each physician was asked to prospectively fill out a standardized data collection form for all HIV–HCV coinfected patients seen between November 22 and 29, 2004 (2004 survey), April 3 and 10, 2006 (2006 survey) and June 15 and 22, 2009 (2009 survey). The form included sociodemographic data of the patient and physician, the HIV and HCV virological status, information regarding the pre-therapeutic workup of HCV infection, the type of HCV treatment, and its follow-up. In the 2006 and 2009 surveys, some questions were added to obtain more details on current addiction (alcohol consumption, IVDU, and substitution), liver damage assessment (biopsy or non-invasive tests), modalities of the follow-up of patients with cirrhosis, HCV treatment modalities and their virological results [sustained virologic response (SVR) was defined as an undetectable HCV-RNA (<50IU/ml) sixmonths after the end of HCV treatment], use of erythropoietin, use of anti-depressants, and the type of HIV treatment. This form had been pre-tested by four physician specialists managing HIV–HCV coinfected patients in order to optimize the type and means of data collection.
Discussion
In the last decade, chronic liver disease, linked primarily to HCV, has become one of the leading causes of morbidity and mortality in HIV-infected patients [2], [4], [6]. In the present study we had the opportunity to analyze the care of HIV–HCV coinfected patients in France in 2009 (including initial workup, mode of treatment, follow-up modalities, and virological response) and to compare the results with those obtained in the 2004 and 2006 surveys. We showed that the care of HIV–HCV coinfected patients has changed significantly in “real life”: (1) patients had more liver damage assessment; (2) more patients had received HCV treatment; and (3) more patients achieved a sustained virological response.
The complete workup of HCV infection in coinfected patients has progressed dramatically, mostly due to better liver damage assessment. In the 2009 and 2006 surveys, non-invasive liver tests had been done in 72% vs. 45% of patients using serum biomarkers (52% vs. 67%), transient elastography (63% vs. 11%), or both (25% vs. 22%). Numerous groups in France have been leaders in the development of non-invasive techniques for liver fibrosis assessment and this may partially explain the increased use in our surveys. The absence of liver biopsy was given as one of the main reasons for non-treatment in the 2004 survey, while this reason was given in only a small percentage of patients in the 2006 and 2009 surveys. Fibrometer, Hepascore, and FibroTest were shown to be able to stage liver fibrosis in HIV–HCV coinfected patients with area-under-the receiver operating characteristic curves (AUROCs) of 0.89, 0.84, and 0.78 for the diagnosis of >F2, respectively [28]. In 114 HIV–HCV coinfected patients with liver biopsy performed before and sixmonths after the end of HCV treatment, non-invasive biological scores showed a significant decrease in SVR patients [29]. Evaluations of liver stiffness using transient elastography have shown cut-off values from 4.5 to 7.2kPa for the diagnosis of significant fibrosis, with AUROCs from 0.72 to 0.83; performances were even better for the diagnosis of cirrhosis with AUROCs from 0.95 to 0.97 [30], [31]. The dual combination approach of serum biomarkers and transient elastography for the diagnosis of significant fibrosis could avoid the use of liver biopsy. Other methods have also been developed, including a novel panel of blood markers [32] and a genomics-based approach [33].
The percentage of coinfected patients who had never received HCV treatment decreased from 54% to 37% between 2004 and 2009, while the number of reasons cited by physicians for non-treatment decreased from 2.4 to 1.8 (out of the 11 choices presented on the data collection form). The reasons for non-treatment were numerous and their profile also changed [34], [35], [36], [37], [38], [39]. HCV treatment was deemed less questionable, the absence of liver biopsy no longer seemed to be a major barrier, and the number of contraindications to HCV treatment decreased (mainly due to fewer psychiatric reasons). Barriers to HCV treatment were more frequent in HIV–HCV coinfected than in HCV mono-infected patients, mainly due to depression and ongoing alcohol and injection drug use [19], [24], [40]. Fleming et al. [16] reported a cohort of 149 HIV–HCV coinfected patients, 70% of whom were ineligible for HCV treatment mainly due to non-compliance with medical visits, drug or alcohol use, and active psychiatric disease. Maida et al. [36] reported that only 40.1% of 405 coinfected patients had already been exposed to interferon-based therapies. Other groups found even smaller proportions (<2–33%) of coinfected patients who had undergone HCV treatment [24], [37], [38]. More recent data from the EuroSIDA group however showed results quite similar to those found in the present study. In European countries, the incidence of starting HCV treatment in HIV–HCV coinfected patients increased from 3.9 per 1000 patients prior to 1998 to 32.6 per 1000 patients in the year follow-up after 2004. In multivariate analysis, an estimated 23% annual increase in the incidence of starting HCV treatment was found when adjusting for baseline factors [39]. Programs are successfully integrating hepatitis C care for IVDUs into health-care settings [20]. Studies in methadone maintenance patients showed rates of SVR in 28–94% of patients with excellent completion rates of HCV treatment (72–100%) [41]. Many aspects of the barriers to HCV treatment can be overcome with direct treatment, such as the anti-depressant drugs used in only 20% and 22% of patients in the 2006 and 2009 surveys, respectively [21], [41], [42], [43]. Asthenia may be a consequence of treatment-related anemia during HCV therapy [44], [45]. Erythropoietin treatment should then be considered to maximize SVR in HCV therapy; it had been used in 7% of patients in the 2006 survey and 34% in the 2009 survey. Its use may help to maintain full doses of standard of care treatment, especially ribavirin, by improving the quality of life during the treatment [46], [47].
A dramatic increase in the SVR rates in coinfected patients between 2004 and 2009 was seen in the present study. In the 2004 survey, we did not have specific data available concerning the duration and type of HCV treatment. In the 2009 and 2006 surveys; however, most treated patients (94% vs. 80%, respectively) had received the combination of pegylated interferon and ribavirin. It is striking to note that an SVR was obtained in 29% of patients in the 2004 and 2006 surveys and in 49% of those in the 2009 survey. This figure is very close to that reported (up to 54%) in recently published large randomized trials [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [47]. Based on data from large therapeutic trials and clinical studies (reflecting a more pragmatic attitude) [48], about half of HIV–HCV coinfected patients receiving HCV treatment will have an SVR. In terms of coinfection and its particular seriousness [49], [50], [51], [52], these results seem particularly encouraging [27].
In HIV–HCV coinfected patients with end-stage liver disease, liver transplantation shows promise as a potential therapeutic option. In one study [53], 2- and 5-year survival rates after liver transplantation were 73% and 51%, and 91% and 81% in 35 coinfected and 44 mono-infected patients, respectively. In another study [54], survival at 1, 2, and 3years was 83%, 75%, and 62% in the 12 coinfected vs. 98%, 89%, and 84% in the 59 mono-infected patients, respectively. However, more recent data showed the 5-year survival rate to be significantly lower in coinfected vs. mono-infected subjects, with liver complications secondary to HCV recurrence as the main driver of this poor outcome [55]. Thus, it does not seem that transplantation may be the final solution for most decompensated cirrhotic patients with HIV–HCV. Earlier referral of these patients to a liver transplant unit after the first episode of liver decompensation (which was rarely the case in the two more recent surveys), the use of new drugs that are effective against HCV, and the avoidance of drug toxicity (i.e. cART-related hepatotoxicity) are mandatory for improving the results of this challenging indication for liver transplantation.
In the present study, the immuno-virological control of HIV infection from 2004 to 2009 showed increased rates of undetectable HIV viral load (63–79%) and CD4 level counts >350/ml (49–71%). This control was even better in the sub-group of patients who received HCV treatment [25]. Pegylated interferon and ribavirin responses tended to increase with higher CD4 counts with similar rates of side effects [56], although there are conflicting results [57]. High CD4 cell counts, the lack of markers of severe liver disease and therapy against HCV were factors associated with a better hepatic outcome in HIV–HCV coinfected patients treated with cART [58], [59]. However, more data are needed in order to better define the impact of different cART on SVR rates after HCV treatment in such patients [60], [61].
In conclusion, the care of HIV–HCV coinfected patients changed significantly in “real life” in France between 2004 and 2009. These results underline the importance of continuing efforts to educate physicians and patients about increasing the access of coinfected patients to HCV treatment. Efforts should be made to improve the care of these patients, such as increasing the access to and the number of patients receiving treatment for HCV infection, the possibility of starting HCV treatment earlier (i.e. before the presence of a high liver fibrosis score), the introduction of HCV treatment even in patients with low CD4 cell counts, and earlier referral of patients with cirrhosis to a liver transplant unit.
Results
Sixty-two, 58, and 71 physicians following HIV–HCV coinfected patients participated in the 2009, 2006, and 2004 studies, respectively (two-thirds of physicians participated in all surveys). The profiles of these physicians did not differ in the three surveys, as they practiced in university hospitals (70–74%), general hospitals (22–25%), or other areas (3–7%). They were from departments of infectious disease (52% vs. 47% vs. 39%, respectively), internal medicine (33% vs. 26% vs. 27%), HIV/AIDS information and care (12% vs. 7% vs. 17%), hematology (0% vs. 3% vs. 10%), hepatogastroenterology (3% vs. 7% vs. 6%) or other areas (15% vs. 10% vs. 1%).
During the weeks the studies were carried out, 419, 416, and 380 HIV–HCV coinfected patients were included in the 2009, 2006, and 2004 surveys, respectively (Table 1). Individual patients did not undergo repeated assessments in the different surveys. They were mainly male (about 71% in the three surveys) with a mean age of 45.1±7.3 vs. 43.5±6.3 vs. 41.6±6.6years (36–50years in 80% of patients). Most patients in the three surveys were of European origin (73–82%). Non-European patients were mostly of African origin, i.e. 22% vs. 17% vs. 21% in the 2009, 2006, and 2004 surveys, respectively. In the 2009 and 2006 surveys (data not available in the 2004 survey), 35% of patients had excessive alcohol consumption: 53% vs. 53% with <30g/d, 32% vs. 28% with 30–50g/d, and 15% vs. 13% with >50g/d, respectively; 82/378 (22%) and 70/410 (17%) patients were or had been IVDUs, 72 vs. 56 patients of whom received an opiate substitution treatment.
Patients had been diagnosed with HIV infection for 12.8 vs. 13.7 vs. 12.1years (from 6 to 20years in 68%, 84%, and 77% of patients, respectively). The therapeutic management of HIV infection appeared to be very appropriate as evidenced by high rates of undetectable HIV viral load (<50copies/ml) and CD4 levels >500/ml, and a last measured HIV viral load done an average of 1.8 vs. 2.6 vs. 2.1months before the date when the survey was conducted (87%, 83%, and 91% of patients, respectively, had had an HIV viral load assessment done in the previous threemonths) (Table 1). In 2009 and 2006 (data not available in the 2004 survey), 381/419 (91%) and 377/416 (91%) of the patients received combination anti-retroviral therapy(cART) for HIV, i.e. boosted protease inhibitor based (61% vs. 66%), non-nucleoside based (23% vs. 18%), triple combination of nucleosides (3% vs. 2%), or other regimen (13% vs. 14%).
Patients had been diagnosed with HCV infection for an average of 9.5 vs. 9.6 vs. 8.5years in 2009, 2006, and 2004, respectively (from 1 to 5years in 18%, 13%, and 18%; 6–15years in 52%, 71%, and 70%; and more than 15years in 21%, 12%, and 6%) (Table 1). Patients in 2009 compared to those in 2006 and 2004 had a similar distribution of HCV genotypes (genotype 1 or 4 in 68%, 65%, and 65%, respectively). The extent of the pre-therapeutic HCV workup depended in part on the year of the survey. The liver damage assessment in particular significantly changed over time. The rate of liver biopsy alone decreased 14% vs. 38% vs. 56%, while the assessment of liver damage by means of non-invasive markers only increased (47% vs. 24%, data not available in 2004). There was no correlation between the performance of a liver biopsy and physician specialization. In the 2009 and 2006 surveys (data not available in 2004), non-invasive liver tests had been performed in 72% vs. 45% of patients using serum biomarkers in 172/330 (52%) vs. 124/185 (67%), transient elastography in 224/358 (63%) vs. 20/185 (11%), or both in 100/398 (25.1%) vs. 41/185 (22%) patients. Overall, the proportion of patients who had a liver biopsy or non-invasive markers has increased (86% vs. 82% vs. 56%). A complete workup, including HCV-RNA, HCV genotyping and a liver damage assessment by biopsy or non-invasive tests was performed in 58% vs. 63% vs. 47% in the 2009, 2006, and 2004 surveys, respectively (p<0.001).
The analysis of HCV treatment showed that 165/398 (42%) vs. 199/393 (51%) vs. 100/380 (26%) patients had been previously treated (p<0.01), whereas 21% vs. 16% vs. 17% of patients were receiving ongoing treatment in the 2009, 2006, and 2004 surveys, respectively (Table 2). The main reasons for non-treatment of HCV in 131 (42%) vs. 164 (42%) vs. 205 (54%) patients in the 2009, 2006, and 2004 surveys changed (Table 2), while the number of reasons per patient decreased (1.8 vs. 2.1 vs. 2.4). When HCV treatment was deemed questionable, the reasons given were: minimal hepatic lesions for 53% vs. 47% vs. 32% of patients, chronic excessive alcohol consumption for 35% vs. 29% vs. 31% and active drug use for 20% vs. 6% vs. 12%. The main contraindication to HCV treatment was a psychiatric disorder (83% vs. 67% vs. 73%), while all other contraindications were noted in 5–26% of patients (cardiovascular, poor general condition, neurological, immunological, hematological, etc.). Physician conviction of poor compliance with HCV treatment was centered on the reluctance of the patient (54% vs. 70% vs. 48%) and unfavorable socioeconomic conditions (43% vs. 33% vs. 31%). Patient refusal increased from 16% to 27% of patients. There was no correlation between the number of treated patients and HCV genotype distribution in any of the surveys. Among treated patients, an SVR to HCV treatment was noted in 81/165 (49%) vs. 50/167 (29%) vs. 27/92 (29%) patients; there was an absence of virological response in 40 (24%) vs. 73 (43%) vs. 40 (43%) patients; and a relapse or virological breakthrough in 44 (27%) vs. 44 (26%) vs. 25 (27%) patients, respectively. SVR rates were not significantly correlated to HCV genotypes. Genotype 1, 4, 5 or 6 vs. genotype 2 or 3 showed SVR rates of 53% and 47% vs. 41% and 59% vs. 44% and 56% in the 2009, 2006, and 2004 surveys, respectively. If the optimal duration of HCV treatment in coinfected patients is considered to be about 12months, 31% vs. 53% vs. 58% of patients had stopped their combination therapy prematurely. In the 2009 and 2006 surveys (data not available for the 2004 survey), most treated patients received a combination of pegylated interferon plus ribavirin, 94% vs. 80%. Among these, 22% vs. 20%, were also receiving an anti-depressant drug, and 34% vs. 7% were receiving erythropoietin treatment. In the 2009 and 2006 surveys, cirrhotic patients (128 and 83 patients, respectively) had a follow-up including liver ultrasound exam (mean interval of 7.1 vs. 7.5months) and upper GI endoscopy (mean interval of 13.9 vs. 10.2months), whereas only 10% vs. 8% had been referred to a liver transplant unit.
Compared to non-treated patients in all surveys (Table 3), patients who had received HCV treatment were more likely to be of European origin, had better control of HIV infection (more frequent undetectable HIV viral load, less frequent low CD4 cell count), and were more likely to have had a liver damage assessment. In a multivariate analysis in the 2009 survey (Table 4), the main characteristics that were independently associated with HCV treatment were a liver fibrosis score >F2 (on biopsy, biomarkers or transient elastography), a liver biopsy activity grade >A2, a CD4 cell count >350ml, European origin, daily alcohol consumption <30g, and male gender.
Articles in Press
Care of hepatitis C virus infection in human immunodeficiency virus-infected patients: Modifications in three consecutive large surveys between 2004 and 2009
Journal of Hepatology June 2010
Patrice Cacoub12, Philippe Halfon3, Eric Rosenthal4, François Bailly5, Firouze Bani Sadr6, Yves Benhamou7, Stéphane Chevaliez8, Jean Michel Pawlotsky8, Lionel Piroth9, Yazdan Yazdanpanah10, Stanislas Pol11
Received 30 November 2009; received in revised form 9 February 2010; accepted 15 March 2010. published online 05 May 2010.
Corrected Proof
ABSTRACT
Background & Aims
To analyze the care of HCV infection in HIV–HCV coinfected patients and its progression between 2004 and 2009.
Patients and methods
Three hundred eighty HIV–HCV coinfected patients were prospectively included from November 22 to 29, 2004 (2004 survey), 416 patients from April 3 to 10, 2006 (2006 survey), and 419 patients from June 15 to 22, 2009 (2009 survey).
Results
The rate of liver biopsy decreased (14% vs. 38% vs. 56%), while the use of non-invasive liver damage tests increased (47% vs. 24% vs. ND) in the 2009, 2006, and 2004 surveys, respectively. The rate of patients that had never been treated for HCV infection progressively decreased in the 2009, 2006, and 2004 surveys (37%, 42%, and 54%). The main reasons for HCV non-treatment changed as HCV treatment was deemed less questionable and the lack of liver biopsy became a very rare reason (6%, 18%, and 34%). Among patients treated for HCV infection, the rate of sustained virological response increased (49%, 29%, and 29%). The main factors independently associated with HCV treatment were a liver fibrosis score >F2 (odds ratio=3.5; 95% CI 2.1–5.7), a liver biopsy activity grade A2 (2.7; 1.4–5.3), a CD4 cell count 350ml (2.7; 1.6–4.4), European origin (2.1; 1.3–3.4), daily alcohol consumption<30g (2.1; 1.2–3.8), and male gender (2.0; 1.2–3.3).
Conclusion
Compared to the 2004 and 2006 surveys, the 2009 coinfected patients had liver damage assessment more frequently, more patients had received HCV treatment and more patients had achieved a sustained virological response.
Introduction
Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is a frequent and particularly serious problem [1], [2], [3], [4], [5], [6]. About 30% of HIV-infected patients in France are also infected with HCV, i.e. close to 30,000 patients [1], [2], [5], [6]. Since the widespread use of combined antiretroviral therapy (cART) was begun, AIDS mortality has progressively decreased, while chronic liver disease, linked primarily to HCV, has become one of the leading causes of morbidity and mortality [2], [4], [6].
Considerable therapeutic progress has been achieved in HCV-infected patients due to combination therapy with pegylated interferon and ribavirin, resulting in a 55–60% sustained virological response (SVR) in HCV mono-infected patients (40–50% in HCV genotype 1, the most frequent HCV genotype worldwide) [7]. Results from large therapeutic trials in HIV–HCV coinfected patients have provided important information. A particularly encouraging result was that the pegylated interferon and ribavirin combination achieved an SVR in 27–44% of coinfected patients [8], [9], [10], [11], resulting in histopathological improvement in most of them. Recent results report similar SVR rates in coinfected more than in HCV mono-infected patients [12], [13], [14], [15]. HCV treatment, however, is given to a small number of HIV–HCV coinfected patients for many reasons, e.g., HCV treatment deemed questionable (minimal hepatic lesions, alcohol abuse, active drug use), lack of available liver biopsy, psychiatric contraindication, and physicians’ conviction of poor patient compliance [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. Following the First European Consensus Conference on the treatment of chronic hepatitis B and C in HIV-infected patients in 2005, the coinfection guidelines in HIV medicine from the European AIDS Society in 2008 as well as their recent update at the European AIDS Clinical Society conference, it may be assumed that differences in the guidelines may have had an impact on treatment compliance and management standards [26], [27].
The aim of the present study was to analyze the care of HIV–HCV coinfected patients in France in 2009 (including initial workup, mode of treatment, follow-up modalities, and virological response) through a survey and to compare results with surveys conducted in 2004 and 2006 [17], [22].
Patients and methods
The same methodology was used in the three surveys, and details have been published elsewhere [17], [22]. In brief, physicians involved in the management of HIV-infected patients were recruited from 50 specialized centers from all of metropolitan France. These centers were representative of those providing the standard of care in HIV cART in France. Each physician was asked to prospectively fill out a standardized data collection form for all HIV–HCV coinfected patients seen between November 22 and 29, 2004 (2004 survey), April 3 and 10, 2006 (2006 survey) and June 15 and 22, 2009 (2009 survey). The form included sociodemographic data of the patient and physician, the HIV and HCV virological status, information regarding the pre-therapeutic workup of HCV infection, the type of HCV treatment, and its follow-up. In the 2006 and 2009 surveys, some questions were added to obtain more details on current addiction (alcohol consumption, IVDU, and substitution), liver damage assessment (biopsy or non-invasive tests), modalities of the follow-up of patients with cirrhosis, HCV treatment modalities and their virological results [sustained virologic response (SVR) was defined as an undetectable HCV-RNA (<50IU/ml) sixmonths after the end of HCV treatment], use of erythropoietin, use of anti-depressants, and the type of HIV treatment. This form had been pre-tested by four physician specialists managing HIV–HCV coinfected patients in order to optimize the type and means of data collection.
Discussion
In the last decade, chronic liver disease, linked primarily to HCV, has become one of the leading causes of morbidity and mortality in HIV-infected patients [2], [4], [6]. In the present study we had the opportunity to analyze the care of HIV–HCV coinfected patients in France in 2009 (including initial workup, mode of treatment, follow-up modalities, and virological response) and to compare the results with those obtained in the 2004 and 2006 surveys. We showed that the care of HIV–HCV coinfected patients has changed significantly in “real life”: (1) patients had more liver damage assessment; (2) more patients had received HCV treatment; and (3) more patients achieved a sustained virological response.
The complete workup of HCV infection in coinfected patients has progressed dramatically, mostly due to better liver damage assessment. In the 2009 and 2006 surveys, non-invasive liver tests had been done in 72% vs. 45% of patients using serum biomarkers (52% vs. 67%), transient elastography (63% vs. 11%), or both (25% vs. 22%). Numerous groups in France have been leaders in the development of non-invasive techniques for liver fibrosis assessment and this may partially explain the increased use in our surveys. The absence of liver biopsy was given as one of the main reasons for non-treatment in the 2004 survey, while this reason was given in only a small percentage of patients in the 2006 and 2009 surveys. Fibrometer, Hepascore, and FibroTest were shown to be able to stage liver fibrosis in HIV–HCV coinfected patients with area-under-the receiver operating characteristic curves (AUROCs) of 0.89, 0.84, and 0.78 for the diagnosis of >F2, respectively [28]. In 114 HIV–HCV coinfected patients with liver biopsy performed before and sixmonths after the end of HCV treatment, non-invasive biological scores showed a significant decrease in SVR patients [29]. Evaluations of liver stiffness using transient elastography have shown cut-off values from 4.5 to 7.2kPa for the diagnosis of significant fibrosis, with AUROCs from 0.72 to 0.83; performances were even better for the diagnosis of cirrhosis with AUROCs from 0.95 to 0.97 [30], [31]. The dual combination approach of serum biomarkers and transient elastography for the diagnosis of significant fibrosis could avoid the use of liver biopsy. Other methods have also been developed, including a novel panel of blood markers [32] and a genomics-based approach [33].
The percentage of coinfected patients who had never received HCV treatment decreased from 54% to 37% between 2004 and 2009, while the number of reasons cited by physicians for non-treatment decreased from 2.4 to 1.8 (out of the 11 choices presented on the data collection form). The reasons for non-treatment were numerous and their profile also changed [34], [35], [36], [37], [38], [39]. HCV treatment was deemed less questionable, the absence of liver biopsy no longer seemed to be a major barrier, and the number of contraindications to HCV treatment decreased (mainly due to fewer psychiatric reasons). Barriers to HCV treatment were more frequent in HIV–HCV coinfected than in HCV mono-infected patients, mainly due to depression and ongoing alcohol and injection drug use [19], [24], [40]. Fleming et al. [16] reported a cohort of 149 HIV–HCV coinfected patients, 70% of whom were ineligible for HCV treatment mainly due to non-compliance with medical visits, drug or alcohol use, and active psychiatric disease. Maida et al. [36] reported that only 40.1% of 405 coinfected patients had already been exposed to interferon-based therapies. Other groups found even smaller proportions (<2–33%) of coinfected patients who had undergone HCV treatment [24], [37], [38]. More recent data from the EuroSIDA group however showed results quite similar to those found in the present study. In European countries, the incidence of starting HCV treatment in HIV–HCV coinfected patients increased from 3.9 per 1000 patients prior to 1998 to 32.6 per 1000 patients in the year follow-up after 2004. In multivariate analysis, an estimated 23% annual increase in the incidence of starting HCV treatment was found when adjusting for baseline factors [39]. Programs are successfully integrating hepatitis C care for IVDUs into health-care settings [20]. Studies in methadone maintenance patients showed rates of SVR in 28–94% of patients with excellent completion rates of HCV treatment (72–100%) [41]. Many aspects of the barriers to HCV treatment can be overcome with direct treatment, such as the anti-depressant drugs used in only 20% and 22% of patients in the 2006 and 2009 surveys, respectively [21], [41], [42], [43]. Asthenia may be a consequence of treatment-related anemia during HCV therapy [44], [45]. Erythropoietin treatment should then be considered to maximize SVR in HCV therapy; it had been used in 7% of patients in the 2006 survey and 34% in the 2009 survey. Its use may help to maintain full doses of standard of care treatment, especially ribavirin, by improving the quality of life during the treatment [46], [47].
A dramatic increase in the SVR rates in coinfected patients between 2004 and 2009 was seen in the present study. In the 2004 survey, we did not have specific data available concerning the duration and type of HCV treatment. In the 2009 and 2006 surveys; however, most treated patients (94% vs. 80%, respectively) had received the combination of pegylated interferon and ribavirin. It is striking to note that an SVR was obtained in 29% of patients in the 2004 and 2006 surveys and in 49% of those in the 2009 survey. This figure is very close to that reported (up to 54%) in recently published large randomized trials [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [47]. Based on data from large therapeutic trials and clinical studies (reflecting a more pragmatic attitude) [48], about half of HIV–HCV coinfected patients receiving HCV treatment will have an SVR. In terms of coinfection and its particular seriousness [49], [50], [51], [52], these results seem particularly encouraging [27].
In HIV–HCV coinfected patients with end-stage liver disease, liver transplantation shows promise as a potential therapeutic option. In one study [53], 2- and 5-year survival rates after liver transplantation were 73% and 51%, and 91% and 81% in 35 coinfected and 44 mono-infected patients, respectively. In another study [54], survival at 1, 2, and 3years was 83%, 75%, and 62% in the 12 coinfected vs. 98%, 89%, and 84% in the 59 mono-infected patients, respectively. However, more recent data showed the 5-year survival rate to be significantly lower in coinfected vs. mono-infected subjects, with liver complications secondary to HCV recurrence as the main driver of this poor outcome [55]. Thus, it does not seem that transplantation may be the final solution for most decompensated cirrhotic patients with HIV–HCV. Earlier referral of these patients to a liver transplant unit after the first episode of liver decompensation (which was rarely the case in the two more recent surveys), the use of new drugs that are effective against HCV, and the avoidance of drug toxicity (i.e. cART-related hepatotoxicity) are mandatory for improving the results of this challenging indication for liver transplantation.
In the present study, the immuno-virological control of HIV infection from 2004 to 2009 showed increased rates of undetectable HIV viral load (63–79%) and CD4 level counts >350/ml (49–71%). This control was even better in the sub-group of patients who received HCV treatment [25]. Pegylated interferon and ribavirin responses tended to increase with higher CD4 counts with similar rates of side effects [56], although there are conflicting results [57]. High CD4 cell counts, the lack of markers of severe liver disease and therapy against HCV were factors associated with a better hepatic outcome in HIV–HCV coinfected patients treated with cART [58], [59]. However, more data are needed in order to better define the impact of different cART on SVR rates after HCV treatment in such patients [60], [61].
In conclusion, the care of HIV–HCV coinfected patients changed significantly in “real life” in France between 2004 and 2009. These results underline the importance of continuing efforts to educate physicians and patients about increasing the access of coinfected patients to HCV treatment. Efforts should be made to improve the care of these patients, such as increasing the access to and the number of patients receiving treatment for HCV infection, the possibility of starting HCV treatment earlier (i.e. before the presence of a high liver fibrosis score), the introduction of HCV treatment even in patients with low CD4 cell counts, and earlier referral of patients with cirrhosis to a liver transplant unit.
Results
Sixty-two, 58, and 71 physicians following HIV–HCV coinfected patients participated in the 2009, 2006, and 2004 studies, respectively (two-thirds of physicians participated in all surveys). The profiles of these physicians did not differ in the three surveys, as they practiced in university hospitals (70–74%), general hospitals (22–25%), or other areas (3–7%). They were from departments of infectious disease (52% vs. 47% vs. 39%, respectively), internal medicine (33% vs. 26% vs. 27%), HIV/AIDS information and care (12% vs. 7% vs. 17%), hematology (0% vs. 3% vs. 10%), hepatogastroenterology (3% vs. 7% vs. 6%) or other areas (15% vs. 10% vs. 1%).
During the weeks the studies were carried out, 419, 416, and 380 HIV–HCV coinfected patients were included in the 2009, 2006, and 2004 surveys, respectively (Table 1). Individual patients did not undergo repeated assessments in the different surveys. They were mainly male (about 71% in the three surveys) with a mean age of 45.1±7.3 vs. 43.5±6.3 vs. 41.6±6.6years (36–50years in 80% of patients). Most patients in the three surveys were of European origin (73–82%). Non-European patients were mostly of African origin, i.e. 22% vs. 17% vs. 21% in the 2009, 2006, and 2004 surveys, respectively. In the 2009 and 2006 surveys (data not available in the 2004 survey), 35% of patients had excessive alcohol consumption: 53% vs. 53% with <30g/d, 32% vs. 28% with 30–50g/d, and 15% vs. 13% with >50g/d, respectively; 82/378 (22%) and 70/410 (17%) patients were or had been IVDUs, 72 vs. 56 patients of whom received an opiate substitution treatment.
Patients had been diagnosed with HIV infection for 12.8 vs. 13.7 vs. 12.1years (from 6 to 20years in 68%, 84%, and 77% of patients, respectively). The therapeutic management of HIV infection appeared to be very appropriate as evidenced by high rates of undetectable HIV viral load (<50copies/ml) and CD4 levels >500/ml, and a last measured HIV viral load done an average of 1.8 vs. 2.6 vs. 2.1months before the date when the survey was conducted (87%, 83%, and 91% of patients, respectively, had had an HIV viral load assessment done in the previous threemonths) (Table 1). In 2009 and 2006 (data not available in the 2004 survey), 381/419 (91%) and 377/416 (91%) of the patients received combination anti-retroviral therapy(cART) for HIV, i.e. boosted protease inhibitor based (61% vs. 66%), non-nucleoside based (23% vs. 18%), triple combination of nucleosides (3% vs. 2%), or other regimen (13% vs. 14%).
Patients had been diagnosed with HCV infection for an average of 9.5 vs. 9.6 vs. 8.5years in 2009, 2006, and 2004, respectively (from 1 to 5years in 18%, 13%, and 18%; 6–15years in 52%, 71%, and 70%; and more than 15years in 21%, 12%, and 6%) (Table 1). Patients in 2009 compared to those in 2006 and 2004 had a similar distribution of HCV genotypes (genotype 1 or 4 in 68%, 65%, and 65%, respectively). The extent of the pre-therapeutic HCV workup depended in part on the year of the survey. The liver damage assessment in particular significantly changed over time. The rate of liver biopsy alone decreased 14% vs. 38% vs. 56%, while the assessment of liver damage by means of non-invasive markers only increased (47% vs. 24%, data not available in 2004). There was no correlation between the performance of a liver biopsy and physician specialization. In the 2009 and 2006 surveys (data not available in 2004), non-invasive liver tests had been performed in 72% vs. 45% of patients using serum biomarkers in 172/330 (52%) vs. 124/185 (67%), transient elastography in 224/358 (63%) vs. 20/185 (11%), or both in 100/398 (25.1%) vs. 41/185 (22%) patients. Overall, the proportion of patients who had a liver biopsy or non-invasive markers has increased (86% vs. 82% vs. 56%). A complete workup, including HCV-RNA, HCV genotyping and a liver damage assessment by biopsy or non-invasive tests was performed in 58% vs. 63% vs. 47% in the 2009, 2006, and 2004 surveys, respectively (p<0.001).
The analysis of HCV treatment showed that 165/398 (42%) vs. 199/393 (51%) vs. 100/380 (26%) patients had been previously treated (p<0.01), whereas 21% vs. 16% vs. 17% of patients were receiving ongoing treatment in the 2009, 2006, and 2004 surveys, respectively (Table 2). The main reasons for non-treatment of HCV in 131 (42%) vs. 164 (42%) vs. 205 (54%) patients in the 2009, 2006, and 2004 surveys changed (Table 2), while the number of reasons per patient decreased (1.8 vs. 2.1 vs. 2.4). When HCV treatment was deemed questionable, the reasons given were: minimal hepatic lesions for 53% vs. 47% vs. 32% of patients, chronic excessive alcohol consumption for 35% vs. 29% vs. 31% and active drug use for 20% vs. 6% vs. 12%. The main contraindication to HCV treatment was a psychiatric disorder (83% vs. 67% vs. 73%), while all other contraindications were noted in 5–26% of patients (cardiovascular, poor general condition, neurological, immunological, hematological, etc.). Physician conviction of poor compliance with HCV treatment was centered on the reluctance of the patient (54% vs. 70% vs. 48%) and unfavorable socioeconomic conditions (43% vs. 33% vs. 31%). Patient refusal increased from 16% to 27% of patients. There was no correlation between the number of treated patients and HCV genotype distribution in any of the surveys. Among treated patients, an SVR to HCV treatment was noted in 81/165 (49%) vs. 50/167 (29%) vs. 27/92 (29%) patients; there was an absence of virological response in 40 (24%) vs. 73 (43%) vs. 40 (43%) patients; and a relapse or virological breakthrough in 44 (27%) vs. 44 (26%) vs. 25 (27%) patients, respectively. SVR rates were not significantly correlated to HCV genotypes. Genotype 1, 4, 5 or 6 vs. genotype 2 or 3 showed SVR rates of 53% and 47% vs. 41% and 59% vs. 44% and 56% in the 2009, 2006, and 2004 surveys, respectively. If the optimal duration of HCV treatment in coinfected patients is considered to be about 12months, 31% vs. 53% vs. 58% of patients had stopped their combination therapy prematurely. In the 2009 and 2006 surveys (data not available for the 2004 survey), most treated patients received a combination of pegylated interferon plus ribavirin, 94% vs. 80%. Among these, 22% vs. 20%, were also receiving an anti-depressant drug, and 34% vs. 7% were receiving erythropoietin treatment. In the 2009 and 2006 surveys, cirrhotic patients (128 and 83 patients, respectively) had a follow-up including liver ultrasound exam (mean interval of 7.1 vs. 7.5months) and upper GI endoscopy (mean interval of 13.9 vs. 10.2months), whereas only 10% vs. 8% had been referred to a liver transplant unit.
Compared to non-treated patients in all surveys (Table 3), patients who had received HCV treatment were more likely to be of European origin, had better control of HIV infection (more frequent undetectable HIV viral load, less frequent low CD4 cell count), and were more likely to have had a liver damage assessment. In a multivariate analysis in the 2009 survey (Table 4), the main characteristics that were independently associated with HCV treatment were a liver fibrosis score >F2 (on biopsy, biomarkers or transient elastography), a liver biopsy activity grade >A2, a CD4 cell count >350ml, European origin, daily alcohol consumption <30g, and male gender.
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