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.

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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.
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Figure 9. Antiviral activity of NS3/4A protease inhibitors.

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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.

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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

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

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.

16 Weeks Peg/Rbv vs 24 Weeks: who can be treated for 16 weeks among genotype 2/3

16 Weeks Peg/Rbv vs 24 Weeks: who can be treated for 16 weeks among genotype 2/3
After application of this criterion, the SVR rates were 91% in those randomized to 24 weeks and 82% in those randomized to 16 weeks of treatment (P = 0.0006). Most patients achieved an end-of-treatment response (data not shown); thus, the key factor behind this 9% difference in SVR rates was a higher relapse rate in patients randomized to 16 weeks of treatment (15% versus 6%, P < 0.0001).......In the original intention-to-treat analysis, the overall SVR rates did not differ significantly between treatment groups when only patients with a baseline HCV RNA level 400,000 IU/mL or less were included (82% in those treated for 24 weeks and 81% in those treated for 16 weeks).[7] The results of the current analysis supports this finding that patients achieving an RVR with a baseline serum HCV RNA level of 400,000 IU/mL or less can be treated for 16 weeks without compromising SVR rates because there was no statistically significant difference between those treated for 24 weeks and those treated for 16 weeks (95% versus 91%, P = 0.2012)......

Baseline factors that predicted relapse among genotype 2/3 patients during follow-up were for the most part the opposite of those that predicted SVR: assignment to 16 weeks of treatment (OR 2.96, 95% CI 1.76-4.95; P < 0.0001), presence of advanced fibrosis on liver biopsy (OR 2.42, 95% CI 1.43-4.12; P = 0.0011), higher HCV RNA level (OR 1.96, 95% CI 1.40-2.74; P < 0.0001), and higher body weight (OR 1.03, 95% CI 1.01-1.04; P = 0.0002). Male sex was also a significant predictor of relapse in this analysis (OR 1.79, 95% CI 1.02-3.16; P = 0.0426).......

The results show that for RVR patients with low viral load, low age, or low body weight, rates of SVR in both groups range from 89% to 95%, with differences between the two groups less than 5%. When a patient had at least two of the four positive predictors, low viral load, low age, low body weight, and noncirrhosis, then the SVR rate was 90% in the 16-week group and 93% in the 24-week group, whereas the relapse rates were 6% and 4%, respectively. The difference in SVR rate between the 16-week and 24-week groups remains low (87% versus 88%) in all treated patients (intention-to-treat patients) with RVR and at least two positive predictors.
"

Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin

Hepatology June 2010

Moises Diago 1 *, Mitchell L. Shiffman 2, Jean-Pierre Bronowicki 3, Stefan Zeuzem 4, Maribel Rodriguez-Torres 5, Stephen C. Pappas 6, Andreas Tietz 7, David R. Nelson 8

1Hepatology Section, Hospital General de Valencia, Valencia, Spain

2Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA

3Department of Hepatology and Gastroenterology, INSERM U724, CHU de Nancy, Vandoeuvre-les-Nancy, France

4J.W. Goethe University Hospital, Frankfurt, Germany

5Fundacion de Investigacion de Diego, Santurce, Puerto Rico

6St Luke's Center for Liver Disease, Houston, TX

7Roche, Basel, Switzerland

8University of Florida, Gainsville, FL

email: Moises Diago (mdiagom@meditex.es)


*Correspondence to Moises Diago, Hospital General De Valencia, Av. Tres Cruces 2, 46014 Valencia, Spain

Potential conflict of interest: Dr. Shiffman advises and received grants from Biolex, Conatus, Human Genome Sciences, Romark, Valeant, Vertex, and Zymogenetics. He also advises Anadys, Bristol-Myers Squibb, and Novartis. He received grants from GlaxoSmithKline, Globeimmune, Idenix, Johnson & Johnson, and Wyeth. He is a consultant for Pfizer. He is also a consultant for, advises, is on the speakers' bureau of, and received grants from Roche. He advises, is on the speakers' bureau of, and received grants from Schering-Plough. Dr. Zeuzem is a consultant for, advises, and is on the speakers' bureau of Roche, Schering-Plough, Novartis, and Human Genome Sciences. Dr. Rodriguez-Torres is a consultant for and advises Anadys, Vertex, GlaxoSmithKline, and Pharmasset. She advises Bristol-Myers Squibb, Idera, Human Genome Sciences, Idenix, Intarcia Therapeutics, Novartis, Valeant, Sanofi-Aventis, Virochem, and Gilead. She also advises and is on the speakers' bureau of Roche. Dr. Pappas is a consultant for Orphan Therapeutics and advises Hoffmann-LaRoche. Dr. Nelson is a consultant for, advises, and received grants from Roche.


Funded by:

Roche, Basel, Switzerland


Abstract


The objective of this analysis was to compare sustained virological response (SVR) and relapse rates in patients with a rapid virological response (RVR, HCV RNA <50 IU/mL at week 4) randomized to 24 or 16 weeks of treatment with peginterferon alfa-2a (40KD) 180 g/week plus ribavirin 800 mg/day in the multinational ACCELERATE study. The analysis was restricted to patients who received treatment for 80% or more of the planned duration. Of 1309 eligible patients, 863 individuals (65.9%) achieved an RVR and were included in this analysis (458 assigned to 16 weeks and 405 assigned to 24 weeks). The overall SVR rate was significantly higher in patients randomized to 24 weeks of treatment (91% versus 82%; P = 0.0006) and among patients infected with genotype 2 (92% versus 81%; P = 0.0010) but not genotype 3 (90% versus 84%; P = 0.1308). Relapse rates were significantly lower among all patients randomized to 24 weeks of treatment: overall (6% versus 15%, P < 0.0001); in those infected with genotype 2 (5% versus 17%, P = 0.0001), and genotype 3 (7% versus 14%, P = 0.0489). SVR rates in patients with a viral load of 400,000 IU/mL or less randomized to 24 and 16 weeks of treatment were similar, 95% and 91% (P = 0.2012). Significant pretreatment predictors of SVR included assignment to 24 weeks of treatment (P = 0.0006), absence of advanced fibrosis on liver biopsy (P = 0.0032), lower HCV RNA level (P = 0.0017), and lower body weight (P < 0.0001).
Conclusion: The standard 24-week regimen of peginterferon alfa-2a (40KD) plus ribavirin is significantly more effective than an abbreviated 16-week regimen in genotype 2/3 patients who achieve an RVR. Abbreviated regimens may be considered in patients with a low baseline viral load who achieve an RVR

Article Text


The standard of care for patients with chronic hepatitis C is the combination of pegylated interferon plus ribavirin.[1-4] When treatment-naive patients infected with hepatitis C virus (HCV) genotype 2 or 3 are treated with the standard of care for 24 weeks, sustained virological response (SVR) rates generally exceed 65% and may reach 80% or higher.[5-7] Treatment for longer durations does not increase efficacy in these individuals.[5][6] Given that a consistently high cure rate can be achieved with a 24-week combination regimen in these individuals, several studies have evaluated shorter treatment durations in patients with HCV genotype 2 or 3 infection.[7-10]


The large randomized multinational ACCELERATE trial was designed to test the hypothesis that treatment for 16 weeks in patients with HCV genotype 2 or 3 infection was noninferior to treatment for 24 weeks, as defined by a 6% noninferiority margin. The study demonstrated that 24 weeks of treatment is significantly more effective than 16 weeks of treatment with peginterferon alfa-2a (40KD) 180 ug/week plus ribavirin (800 mg/day). Overall SVR rates in the trial were 70% and 62%, respectively (P < 0.001).[7]


Several smaller trials have selected patients for abbreviated treatment on the basis of the virological response at week 4.[8-10] The results of one of these trials with peginterferon alfa-2b (12KD) 1.0 ug/kg/week plus ribavirin (1000/1200 mg/day) suggested that individuals with a rapid virological response (RVR), defined as HCV RNA less than 50 IU/mL at week 4, achieved an SVR rate after 12 weeks of treatment that was similar to that achieved in patients receiving the standard 24-week regimen (85% versus 91%, respectively).[9] However, a larger trial that randomized patients to peginterferon alfa-2b (12KD) 1.5 ug/kg/week plus ribavirin (800-1400 mg/day) with an RVR to 14 or 24 weeks of treatment concluded that the shorter treatment duration was inferior to the longer duration, with SVR rates of 86% and 93%, respectively.[11] The difference in SVR rates between the two treatment durations in these two studies was attributable to higher relapse rates in patients assigned to the abbreviated treatment regimen.[9][11] The ACCELERATE trial also showed that SVR rates were lower in patients with an RVR who were treated for 16 or 24 weeks (79% versus 85%).[7]


The ACCELERATE trial randomized more than 1400 genotype 2 or 3 patients, 65% of whom achieved an RVR.[7] Based on an intention-to-treat analysis, SVR rates among patients randomized to longer treatment durations may be lower because of higher dropout rates compared with patients randomized to shorter treatment durations. Therefore, a conservative approach to comparing the efficacy of two identical regimens differing only in treatment duration is to restrict analyses to patients who complete the scheduled treatment duration. The large database from this trial provides an opportunity to determine whether a specific subgroup of genotype 2 or 3 patients who achieve an RVR and complete scheduled treatment, for example, those with low baseline HCV RNA levels, can be treated with an abbreviated regimen without compromising SVR rates.

Discussion


The results of this analysis confirm the findings of the intention-to-treat analysis of ACCELERATE in showing that SVR rates are higher in genotype 2/3 patients with an RVR who are treated for 24 weeks than 16 weeks. However, it should be noted that for genotype 3 patients the difference in SVR between 24 and 16 weeks was not statistically significant ( delta= 6%) in contrast to the difference in genotype 2 patients ( = 11%). In the original analysis, SVR rates in patients with an RVR treated for 24 and 16 weeks were 85% and 79%, respectively (P = 0.02).[7] The current analysis included only patients who had an RVR and who completed the planned treatment duration without relevant treatment interruptions (at least 19 doses of peginterferon alfa-2a in the 24-week treatment group and at least 13 doses in the 16-week treatment group). This approach has the advantage of compensating for the difference in withdrawal rates between the two treatment arms. More than twice as many patients withdrew from the 24-week treatment group than from the 16-week treatment group (13% versus 6%), which has the effect of reducing the difference between the two treatment durations in an intention-to-treat analysis. After application of this criterion, the SVR rates were 91% in those randomized to 24 weeks and 82% in those randomized to 16 weeks of treatment (P = 0.0006). Most patients achieved an end-of-treatment response (data not shown); thus, the key factor behind this 9% difference in SVR rates was a higher relapse rate in patients randomized to 16 weeks of treatment (15% versus 6%, P < 0.0001).


Assignment to 24 weeks of treatment was the most important predictor of SVR in the MLR analysis; conversely, assignment to the 16-week regimen was the most important predictor of relapse in the MLR analysis. Other predictors of SVR included the absence of advanced fibrosis on the pretreatment liver biopsy, a lower HCV RNA level, and lower body weight, all of which are well established as predictors of treatment success in patients with chronic hepatitis C.


In the original intention-to-treat analysis, the overall SVR rates did not differ significantly between treatment groups when only patients with a baseline HCV RNA level 400,000 IU/mL or less were included (82% in those treated for 24 weeks and 81% in those treated for 16 weeks).[7] The results of the current analysis supports this finding that patients achieving an RVR with a baseline serum HCV RNA level of 400,000 IU/mL or less can be treated for 16 weeks without compromising SVR rates because there was no statistically significant difference between those treated for 24 weeks and those treated for 16 weeks (95% versus 91%, P = 0.2012).


The authors of other studies of abbreviated regimens for genotype 2 or 3 patients have reported higher relapse rates in patients assigned to the shorter treatment duration.[9][11][12] The increase in the probability of relapse was twofold to threefold greater in patients assigned to abbreviated 12- to 14- week regimens, which is in close agreement with the 2.5-fold higher relapse rate in patients assigned to the 16-week regimen in the current analysis.


In addition to higher voluntary withdrawal rates in patients treated for longer duration, it is possible that differences in treatment exposure may have an effect on SVR rates in patients randomized to different treatment durations. For this reason we included an exposure analysis in the current analysis. Few patients had exposure levels below 80% of the planned dose of ribavirin or peginterferon alfa-2a (40KD); thus, we cannot comment on the impact of large or long-term dose reductions on the probability of achieving an SVR. Most patients had a ribavirin exposure level that was 90% to 100% of the planned amount. Among patients with 80% or greater exposure to ribavirin, the SVR rates were consistently higher in patients assigned to the longer treatment duration. Moreover, there was no trend toward a reduction in SVR rates with decreasing exposure in these individuals.


It is now clear from the results of ACCELERATE and another recently completed large randomized noninferiority study[11] that 24 weeks of treatment produces significantly higher SVR rates than abbreviated regimens and that abbreviated regimens expose patients to a significantly higher probability of virological relapse during follow-up, even in patients with an RVR. In spite of the greater efficacy of the standard treatment duration in their study, Dalgard et al.[11] argued that it would be cost-effective to assign all genotype 2 or 3 patients to abbreviated treatment and to immediately retreat those who relapse. Such a policy assumes that all patients have the same probability of relapse and that all patients will be willing to immediately re-enroll for a longer treatment duration. The results of the current analysis and that reported by Mangia et al.[13] suggest that the first assumption is incorrect; the probability of relapse varies according to several well-established predictors of treatment success. Adopting this approach would require physicians to counsel all patients to prepare themselves for the possibility of undergoing two consecutive courses of treatment, with a total treatment duration of 40 weeks. However, Mangia et al. reported that patients infected with genotype 2 or 3 who achieved an RVR but who relapsed after an abbreviated 12-week course of treatment with peginterferon alfa-2b plus ribavirin could achieve an SVR rate of 70% with a second 24-week course of the same treatment.[13]


The current analysis has shown that several subgroups of patients with an RVR have an acceptable risk:benefit ratio for contemplation of abbreviated therapy in addition to those that have a low baseline serum HCV RNA level. Given that advanced fibrosis was a stronger predictor of relapse in patients with RVR after 16 weeks of treatment (relapse rate of 27%), it is reasonable to exclude all such patients from abbreviated treatment.


Rather than reducing the treatment duration in patients who experience adverse events that must be managed by dose reductions, physicians should encourage continued treatment for the full 24-week duration to maximize the probability of SVR.


Overall, this analysis shows that for patients infected with HCV genotype 2 or 3 and who achieve an RVR at week 4, the standard 24-week treatment duration produces significantly higher SVR rates than an abbreviated 16-week regimen. Shortening the treatment duration should be considered only in patients with a low baseline HCV RNA level and without bridging fibrosis/cirrhosis who achieve an RVR. The difference in SVR rates is attributable to a significantly higher rate of virological relapse in patients treated with the abbreviated regimen.

Results


The per protocol population comprised 1309 individuals, of whom 863 patients (65.9%) achieved an RVR at week 4, completed designated treatment, and were included this analysis. Of the 863 patients included in the analysis, all were considered for the determination of SVR, with patients missing post-treatment HCV RNA values considered as nonresponders. Forty patients were excluded from the analysis of relapse because of missing HCV RNA values at end of treatment (n = 24), breakthrough (n = 5), or missing post-treatment HCV RNA values in patients with response at end of treatment (n = 11).


The baseline characteristics of patients with an RVR who completed treatment were similar, with no significant differences (all P-values > 0.2) by treatment group (Table 1). The mean overall age of patients with an RVR was 45 to 46 years, 60% to 62% were male, 87% were white, and 2% to 3% were black. Approximately 25% to 27% had a low baseline serum HCV RNA levels (
SVR rates exceeded 80% in patients with an RVR regardless of HCV genotype or the assigned treatment duration (Fig. 1A). The SVR rate was significantly lower in patients randomized to 16 than 24 weeks of treatment, overall (82% [377/458] versus 91% [367/405]; OR 0.49, 95% CI 0.32-0.74; P = 0.0006) and in those infected with genotype 2 (81% [196/243] versus 92% [194/212]; OR 0.38, 95% CI 0.21-0.69; P = 0.0010) but not genotype 3 (84% [181/215] versus 90% [173/193]; OR 0.63, 95% CI 0.35-1.15; P = 0.1308).

Virological relapse rates during follow-up were consistently and significantly higher in patients randomized to the shorter treatment duration (Fig. 1B). The relapse rates in patients randomized to 16 and 24 weeks of treatment, respectively, were 15% (67/439) and 6% (23/384) overall (OR 2.77, 95% CI 1.69-4.55; P < 0.0001); 17% (39/233) and 5% (10/204) among patients infected with HCV genotype 2 (OR 3.82, 95% CI 1.85-7.89; P = 0.0001); and 14% (28/206) and 7% (13/180) among those infected with HCV genotype 3 (OR 1.99, 95% CI 1.00-3.99; P = 0.0489).


Among genotype 2/3 patients with a low baseline viral load (HCV RNA level

Predictors of SVR and Relapse by MLR Analysis.


Baseline factors that were identified as significant and independent predictors of SVR among genotype 2/3 patients with an RVR who completed the designated treatment duration included assignment to 24 weeks of treatment (OR 2.12, 95% CI 1.38-3.24; P = 0.0006), absence of advanced fibrosis on liver biopsy (OR 2.06, 95% CI 1.27-3.33; P = 0.0032), lower HCV RNA level (OR 1.52, 95% CI 1.17-1.97; P = 0.0017), and lower body weight (OR 1.03, 95% CI 1.02-1.04; P < 0.0001).


Baseline factors that predicted relapse among genotype 2/3 patients during follow-up were for the most part the opposite of those that predicted SVR: assignment to 16 weeks of treatment (OR 2.96, 95% CI 1.76-4.95; P < 0.0001), presence of advanced fibrosis on liver biopsy (OR 2.42, 95% CI 1.43-4.12; P = 0.0011), higher HCV RNA level (OR 1.96, 95% CI 1.40-2.74; P < 0.0001), and higher body weight (OR 1.03, 95% CI 1.01-1.04; P = 0.0002). Male sex was also a significant predictor of relapse in this analysis (OR 1.79, 95% CI 1.02-3.16; P = 0.0426).


Based on the outcome of the current MLR analysis, rates of SVR and relapse in the two treatment groups were estimated for each baseline covariate shown to be an independent predictor of response (Table 2). Rates for genotype, sex, age, and alanine aminotransferase ratio are also presented for completeness, because they were significant predictors in the intention-to-treat analysis.[7] The results show that for RVR patients with low viral load, low age, or low body weight, rates of SVR in both groups range from 89% to 95%, with differences between the two groups less than 5%. When a patient had at least two of the four positive predictors, low viral load, low age, low body weight, and noncirrhosis, then the SVR rate was 90% in the 16-week group and 93% in the 24-week group, whereas the relapse rates were 6% and 4%, respectively. The difference in SVR rate between the 16-week and 24-week groups remains low (87% versus 88%) in all treated patients (intention-to-treat patients) with RVR and at least two positive predictors.

Impact of Dose Reductions on SVR.


Among patients with an RVR and who completed treatment, SVR rates were consistently higher in those who completed 24 weeks of treatment compared with 16 weeks of treatment regardless of the extent of ribavirin exposure (Fig. 2A). Only a small number of patients had ribavirin exposure that was less than 80% of the planned dose (19/863, 2%); thus, it is not possible to comment on the effect of large or prolonged dose reductions on SVR rates in individuals with an RVR. The results were generally similar when the analysis was restricted to those patients with a baseline HCV RNA level less than 400,000 IU/mL, although most patients had exposure to ribavirin that was 90% or more of the planned dose (Fig. 2B).

Figure 2b. Adherence Matters
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Table 2. Rates of SVR and Relapse Among Subgroups of Patients
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Figure 1. (A) SVR and (B) relapse rates according to treatment duration. Only patients confirmed to be HCV RNA-negative at the end-of-treatment were included in the calculation of relapse rates.


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Patients and Methods



Study Design and Patients.


The inclusion and exclusion criteria, study design, and primary results of ACCELERATE are reported elsewhere.[7] Briefly, treatment-naive patients with chronic HCV genotype 2 or 3 infection were randomized to receive treatment with peginterferon alfa-2a (40KD) (PEGASYS®, Roche, Basel, Switzerland) 180 g/week plus ribavirin (COPEGUS®, Roche) 800 mg/day for either 16 or 24 weeks. Eligible patients had quantifiable HCV RNA (COBAS® AMPLICOR HCV MONITOR Test, v2.0: limit of quantitation 600 IU/mL) and elevated serum alanine aminotransferase levels. All patients were required to have undergone a liver biopsy before enrollment.


Assessment of Virological Response.


Serum HCV RNA levels were measured by qualitative polymerase chain reaction assay (COBAS® AMPLICOR HCV Test, v2.0, limit of detection 50 IU/mL) at weeks 4, 12, at the end of the scheduled treatment period (week 16 or 24), and at weeks 12 and 24 after completion of the scheduled treatment period. The primary efficacy end-point in ACCELERATE was SVR defined as undetectable serum HCV RNA at the end of follow-up (week 40 in patients randomized to 16 weeks of treatment and week 48 in those randomized to 24 weeks of treatment). Virological relapse was defined as detection of HCV RNA in serum during follow-up in a patient that was confirmed to have been HCV RNA-negative at the end of treatment. Patients without an end-of-treatment HCV RNA result or without post-treatment HCV RNA data were not included in relapse rate calculations. The impact of ribavirin exposure on SVR rates was evaluated by calculating the amount of drug received by a patient (percentage of the planned total dose). Physician-initiated dose reductions for adverse events and laboratory abnormalities and patient compliance as recorded in diaries were included in these calculations.


Analysis Populations and Statistics.


The efficacy analysis was conducted in all randomized patients with an RVR that were included in the per-protocol population who completed the scheduled treatment duration of 16 or 24 weeks. Patients were excluded from the per-protocol population when they had (1) major protocol deviations, or (2) treatment interruptions or early discontinuations resulting in less than 13 doses of peginterferon alfa-2a (40KD) or less than 13 weeks of treatment with ribavirin in patients randomized to 16 weeks, and less than 19 doses of peginterferon alfa-2a (40KD) or less than 19 weeks of treatment with ribavirin in patients randomized to 24 weeks of treatment. Use of the standard population rather than the intention-to-treat population ensures that differences in SVR rates or relapse rates are not influenced by a higher dropout rate in patients randomized to the longer treatment duration.


The baseline demographic and disease characteristics in the two treatment groups of the analysis population were compared using the chi-squared test for categorical data and t test for continuous data to verify whether the restriction to the specified analysis population had any relevant impact on the comparability of two treatment groups. SVR and relapse rates in the two treatment groups were compared with the use of the Cochran-Mantel-Haenszel test, stratified according to country of residence and HCV genotype. The common odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. The noninferiority margin specified in the study protocol for the primary analysis[7] was 6%, which was equivalent to an OR of 0.70 when assuming an SVR rate of 80% in the 24-week group. On this basis, the 16-week and 24-week regimens were considered equivalent if the lower limit of the 95% CI for the OR was at least 0.70. Because the current analysis was post hoc, no inferiority margin was assumed, the study results were known, and the subgroups lacked adequate power.


Multiple logistic regression (MLR) models were used to identify baseline factors associated with SVR and relapse in patients who achieved an RVR and who were treated for 16 or 24 weeks. Pretreatment factors considered in the analysis included assigned treatment duration at randomization plus the following baseline factors: age, sex, race (white versus nonwhite), body weight, HCV genotype (3 versus 2), serum alanine aminotransferase quotient, serum HCV RNA level, and the pretreatment liver biopsy result (no bridging fibrosis/cirrhosis versus bridging fibrosis/cirrhosis).


In the current analysis, all statistical tests are exploratory, and thus a significant result (P < 0.05) cannot be considered as formal proof of efficacy. Furthermore, the presence of nonsignificant test results cannot be considered as a formal proof of noninferiority. No adjustment of the significance level of 0.05 was considered necessary because of the exploratory nature of the analysis.

House Panel Calls Attention to Viral Hepatitis Threat

House Panel Calls Attention to Viral Hepatitis Threat

CQ HEALTHBEAT NEWS
June 17, 2010 – 5:43 p.m.
By John Reichard, CQ HealthBeat Editor

Ignorance and neglect are the hallmarks of the viral hepatitis epidemic – not only among the millions of people who are unaware they have the often-lethal condition, but also among policy makers who are more aware of the threat it poses.

That was the message delivered by witnesses and lawmakers at a hearing by the House Oversight and Government Reform Committee Thursday. Their aim: prod Congress and the Obama administration to respond more aggressively to the disease.

The Obama administration witness at the hearing said he gets it. But the signs of a more aggressive government response aren’t entirely reassuring, say groups that have organized to counter the disease.

Some 6 million Americans are living with chronic infection from hepatitis B and C, yet half of those with the B virus and three-quarters of those with the C virus don’t know they have it, the committee said in a notice announcing the hearing.

A major focus was to call attention to the findings of a six-month-old Institute of Medicine (IoM) report on viral hepatitis and the need to implement its recommendations.

Randall Mayer, who testified on behalf of the institute, noted that 150,000 people in the United States are expected to die from liver cancer and other liver diseases associated with the hepatitis B and C viruses.

An estimated 3.5 million to 5.3 million Americans are living with chronic infections from the viruses. Globally the toll of this “secret epidemic” is staggering: one of every 12 people globally has chronic viral hepatitis, about 54,000 of whom immigrate to the United States annually. And about a million deaths occur worldwide from the disease each year.

Greater use of the hepatitis B vaccine has driven down the incidence of that disease in the United States but 43,000 new cases still occur domestically each year. And there is no vaccine for hepatitis C.

The IoM report includes various recommendations to improve surveillance systems to detect viral hepatitis; public health officials around the United States have inadequate systems to monitor the disease. The report also directs publicity campaigns targeting at-risk populations who unknowingly spread the viruses, increase hepatitis B vaccination, develop a hepatitis C vaccine, improve screening for viral hepatitis and give intravenous drug users access to sterile needles to lessen its spread.

Howard K. Koh, assistant secretary for health at HHS, testified that the department “is taking immediate and coordinated steps to reverse” the growing medical and economic burden of viral hepatitis.

As part of its response to the IoM report, HHS has established an interagency working group to better coordinate the responses of the National Institutes of Health, the Centers for Disease Control and Prevention and other federal agencies. A subcommittee of the group is due to produce a “comprehensive strategic action plan” by Oct. 1, Koh said.

But Julie Scofield, executive director of the National Alliance of State and Territorial AIDS Directors, said in a statement that “while there has been recent increased interest in hepatitis within the administration and Congress, this interest has not yet translated into additional funding.”

The group’s statement called the hearing Thursday “the first time Congress has formally examined the federal response to viral hepatitis since December 2004. There has been little progress made in developing a comprehensive prevention and control program in the U.S. due to a lack of funding.”

The National Viral Hepatitis Roundtable, a coalition of some 175 public, private and volunteer groups involved in countering viral hepatitis, announced a new print ad campaign urging swift passage of a bill (HR 3974) to authorize prevention, education and research programs countering viral hepatitis. Sponsors include Rep. Michael M. Honda, D-Calif., and Edolphus Towns, D-N.Y., who chaired Thursday’s hearing.

A tag line of the ad campaign: “If Congress gets on the case now, the leading cause of liver cancer won’t stand a chance.”