October 3, 2013

Provided by NATAP

53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO

HCV at ICAAC:

ICAAC: SVR Tied to Lower Progression, Mortality in HIV/HCV+ With Moderate Fibrosis - the importance of treating coinfected patients -

ICAAC: Lack of Clinically Relevant Drug Interactions Between Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate and Telaprevir - (09/12/13)

ICAAC: Hepatitis C Eradication Reduces Liver Decompensation, HIV progression, and Death in HIV/HCV-coinfected Patients with non-Advanced Liver Fibrosis - (09/12/13)

ICAAC: Acute C hepatitis in Japanese HIV-infected patients in this decade - (09/31/13)

ICAAC: CLINICAL CHARACTERIZATION OF HIV/HCV CO-INFECTED PATIENTS TREATED WITH DIRECT ACTING ANTIVIRAL AGENTS (in Miami)- (09/18/13)

ICAAC: Worse Response to PegIFN/RBV for HCV After Transplant in HIV/HCV+ vs HCV+

ICAAC: HIV Does Not Affect Chance of HCV Genotype 2 or 3 Responding to PegIFN/RBV

Reported by Jules Levin
53rd ICA AC 2013
September 10-13, Denver, CO

Antonio Diaz-Sanchez, Pilar Miralles, Ana Matilla, Teresa Aldamiz-Echevarria, Óscar Nunez, Ana Carrero, Beatriz Merino, Cristina Diez, Rafael Banares, Gerardo Clemente, and Juan Berenguer*
Hospital General Universitario Gregorio Maranón & Instituto de Investigación Sanitaria Gregorio Maranón, Madrid, Spain

ICAAC1

FREQUENT/TIMELY Followup for their HCV is crucial in coinfected patients because they experience accelerated disease progression compared to mono infected HCV patients

from Jules: in this study 94-100% had cirrhosis; 50% had liver decompensation; 40% were diagnosed with HCC, liver cancer; 12-15% had metastasis; , 3-yd survival was 22-28% (SEE SLIDES BELOW). If a patient is found to have cirrhosis surveillance/followup is supposed to occur every 6 months!!!! EVEN if CURED if a patient had cirrhosis before cure they are supposed to do an MRI every 6 months forever to screen for cancer!!! Even if cured if patient had cirrhosis although risk for developing cancer decreases quite a lot if SVR/cure is achieved there still remains a risk for liver cancer. In the slides below you will see before the guidelines treatment after diagnosis was much less likely & more likely after the guidelines, survival was better after guidelines, receiving treatment reduced risk for death although not statistically significant.

STUDY OBJECTIVE: To assess tumor characteristics, surveillance practices, treatment, and survival in PWHIV with HCC before and after 2005, when the new AASLD guidelines for HCC were published. Before & After the guidelines in this study authors reported the same percent of patients diagnosed with HCC, liver cancer (41%) no improvement. very sad, coinfection was neglected here in USA; this is why coinfected patients globally & many in the USA have died, because they were diagnosed late with HCV, did not receive proper followup & surveillance for liver cancer & decompensation, & were not educated properly about starting treatment & the importance of treatment, and all too often received confusing or poor messaging from clinicians - often they were told they were ok, their ALTs were normal, and often these patients did not realize they had serious disease or needed regular followup & they would not return for care & followup in a timely manner......."It is essential thus, to identify cirrhosis using accurate noninvasive methods such as transient elastography; and perform HCC screening with ultrasonography (± AFP) in patients at risk"

Continue here to view posters …..

J Gastroenterol. 2013 Oct 1. [Epub ahead of print]

Sugawara K, Inao M, Nakayama N, Mochida S.

Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.

Abstract

BACKGROUND: The significance of retinopathy during triple therapy with telaprevir is uncertain.

METHODS: Ophthalmologic examination was done prospectively before and every month during the therapy in 95 CHC patients.

RESULTS: Retinopathy was found in 46 (48.4 %), and the specialists recommended discontinuation of the therapy in 9 (9.5 %). Such lesions may develop as adverse effects by telaprevir, since the lesions disappeared following discontinuation of telaprevir in a 65-year-old man, in whom both pegylated-interferon (Peg-IFN) and ribavirin were continued, and reappeared when he took telaprevir again by his decision. Multivariate analysis revealed that interleukin 28B single-nucleotide polymorphism (IL28B SNP) and anemia development during the therapy were independent factors associating retinopathy.

CONCLUSION: Ophthalmologic examinations should be done carefully during triple therapy, since the incidence was higher than that in previous Peg-IFN therapy, and lesions may develop as adverse effects by telaprevir, but not by Peg-IFN, especially in those showing preferable IL28B SNPs allele and/or anemia during the therapy.

PMID: 24081655 [PubMed - as supplied by publisher]

Source

UF researchers report cats may be the key to human HIV vaccine

Published: October 1st, 2013

Category: Health, Research, Veterinary

GAINESVILLE, Fla. — Blood from HIV-infected human subjects shows an immune response against a cat AIDS virus protein, a surprise finding that could help scientists find a way to develop a human AIDS vaccine, report University of Florida and University of California, San Francisco researchers.

Their findings appear in the October issue of the Journal of Virology. This discovery supports further exploration of a human AIDS vaccine derived from regions of the feline AIDS virus.

“One major reason why there has been no successful HIV vaccine to date is that we do not know which parts of HIV to combine to produce the most effective vaccine,” said Janet Yamamoto, a professor of retroviral immunology at the UF College of Veterinary Medicine and the study’s corresponding author.

The researchers are working on a T-cell-based HIV vaccine that activates an immune response in T cells from HIV-positive individuals against the feline AIDS virus. T-cell peptides are small pieces of protein that can prompt the body’s T cells to recognize viral peptides on infected cells and attack them. However, not all HIV peptides can work as vaccine components, Yamamoto said.

“In humans, some peptides stimulate immune responses, which either enhance HIV infection or have no effect at all, while others may have anti-HIV activities that are lost when the virus changes or mutates to avoid such immunity,” she said. “So, we are looking for those viral peptides in the cat AIDS virus that can induce anti-HIV T-cell activities and do not mutate.”

In previous studies, scientists have combined various whole HIV proteins as vaccine components, but none have worked well enough to be used as a commercial vaccine, Yamamoto said.

“Surprisingly, we have found that certain peptides of the feline AIDS virus can work exceptionally well at producing human T cells that fight against HIV,” she said.

The researchers isolated T cells from HIV-positive individuals and incubated these cells with different peptides that are crucial for survival of both human and feline AIDS viruses. They then compared the reactions they got with feline immunodeficiency virus (FIV) peptides to what they found using HIV-1 peptides.

“We found that one particular peptide region on FIV activated the patients’ T cells to kill the HIV,” Yamamoto said.

This feline viral region identified by human cells appears to be evolutionarily conserved — it is present in multiple AIDS-like viruses across animal species, she added.

“That means it must be a region so essential that it cannot mutate for the survival of the virus,” she said.

Yamamoto and her team believe that the feline AIDS virus can be used to identify regions of the human AIDS virus that might be more effectively used in a vaccine-development strategy for HIV.

“We want to stress that our findings do not mean that the feline AIDS virus infects humans, but rather that the cat virus resembles the human virus sufficiently so that this cross-reaction can be observed,” said study collaborator Dr. Jay A. Levy, a professor of medicine at UCSF.

To date, a T-cell-based vaccine has not been used to prevent any viral diseases, Yamamoto said.

“So we are now employing an immune system approach that has not been typically utilized to make a vaccine,” she said. “The possible use of the cat virus for this vaccine is unique.”

Michael Murphey-Corb, a professor in the department of microbiology and molecular genetics at the University of Pittsburgh, has known Yamamoto since she discovered the feline AIDS virus.

“Dr. Yamamoto has identified the immunological Achilles’ heel of HIV,” Murphey-Corb said.

Levy, along with Dr. Mobeen Rathore, director of the UF Center for HIV/AIDS Research, Education and Service in Jacksonville, and the University of South Florida in Tampa provided the blood from HIV-infected subjects. Other collaborators include the UF College of Medicine, the Clinical and Translational Science Institute at UF, and LifeSouth Community Blood Centers of Gainesville.

Research reported on in this news release was supported by the National Institutes of Health under RO1AI65276, RO1AI30904 and RR029890. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Credits

Media Contact: Sarah Carey, careysk@ufl.edu, 352-294-4242

Source

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

1828. Interim Analysis of an Interferon (IFN)- And Ribavirin (RBV)-Free Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 In Treatment-Naive, Hepatitis C Virus Genotype 1-Infected Patients

Session: Oral Abstract Session: Hepatitis C

Saturday, October 5, 2013: 2:45 PM

Room: The Moscone Center: 250-262

Background: The IFN- and RBV-free regimen of DCV (NS5A inhibitor), ASV (protease inhibitor) and BMS-791325 (non-nucleoside NS5B inhibitor, 75mg BID) achieved sustained virologic response (SVR4, SVR12) >90% in treatment-naïve, hepatitis C virus (HCV) genotype (GT) 1 patients. We evaluated this regimen using two BMS-791325 doses (75 vs 150 mg BID).

Methods: HCV GT1, treatment-naïve, non-cirrhotic patients (N=32) were randomized 1:1 to DCV 60mg QD, ASV 200mg BID, and BMS-791325 75mg BID for 24 (Group 1) or 12 (Group 2) weeks. Subsequently, 34 additional patients were randomized to DCV, ASV, and BMS-791325 150mg BID for 24 (Group 3) or 12 (Group 4) weeks. The primary end point was HCV RNA <25 IU/mL at 12 weeks post-treatment (SVR12). Interim results are presented.

Results: Patients were mainly GT1a (74%), white (79%), and IL28Bnon-CC (70%). 64/66 patients had HCV RNA <25 IU/mL by Week 4 (Table). There was no difference in virologic response between 12 and 24 weeks of treatment. Overall, patients achieved SVR4 92% (46/50), SVR12 94% (30/32), and SVR24 94% (15/16). No patient discontinued for adverse events (AEs) related to DCV+ASV+BMS-791325. Most common AEs (≥10% total) were headache, asthenia, and gastrointestinal. Two serious AEs were reported, both unrelated to DCV+ASV+BMS-791325. No hepatotoxicity or Grade 3/4 elevations of ALT/AST or bilirubin were reported.

Conclusion: DCV+ASV+BMS-791325 achieved high rates of SVR4, SVR12, and SVR24 in treatment-naive GT1 patients, characterized by GT1a and IL28Bnon-CC. This regimen was well tolerated with no apparent safety signals. Expansion of the current study is underway to better define the efficacy and safety of this regimen.

Virologic Response During and After Treatment

BMS-791325 Dose

 

75 mg

 

150 mg

Duration

 

24 weeks

 

12 weeks

 

24 weeks

 

12 weeks

Group

 

1 (N=16)

 

2 (N=16)

 

3 (N=16)

 

4 (N=18)

HCV RNA <25IU/mL, n(%)

 

 

 

 

 

 

 

 

     Week 4

 

16(100)

 

16(100)

 

16(100)

 

16(89)a

     EOT/Last on-treatment

 

15(94)b

 

16(100)

 

-

 

17(94)c

     SVR4

 

15(94)b

 

15(94)d

 

-

 

16(89)c,e

     SVR12

 

15(94)b

 

15(94)d

 

-

 

-

     SVR24

 

-

 

15(94)f

 

-

 

-

Virologic breakthrough, n(%)

 

0

 

0

 

1(7)

 

1(6)

Relapse, n(%)

 

0

 

0

 

-

 

1(6)

aOne patient with isolated HCV RNA of 43 IU/mL, one patient missing; b Patient withdrew consent; cOne viral breakthrough; dOne missing; eOne relapse; fA second patient missing.

Gregory T. Everson1, Karen D. Sims2, Maribel Rodriguez-Torres, MD3, Christophe Hézode4, Eric Lawitz5, Marc Bourlière6, Veronique Loustaud-Ratti7, Vinod Rustgi8, Howard Schwartz9, Harvey Tatum10, Patrick Marcellin11, Stanislas Pol12, Paul J. Thuluvath13, Timothy Eley, PhD2, Xiaodong Wang2, Shu-Pang Huang14, Fiona Mcphee15, Megan Wind-Rotolo14, Ellen Chung2, Claudio Pasquinelli2, Dennis M. Grasela2 and David F. Gardiner2, (1)University of Colorado Denver, Aurora, CO, (2)Bristol-Myers Squibb, Hopewell, NJ, (3)Gastroenterology, Fundacion de Investigacion, Rio Piedras, PR, (4)CHU Henri Mondor, Service d’Hépato-Gastroentérologie, Créteil, France, (5)Alamo Medical Research, San Antonio, TX, (6)Hôpital Saint Joseph, Service d’Hépato-Gastroentérologie, Marseille, France, (7)University Hospital of Limoges, Limoges, France, (8)Metropolitan Research, Arlington, VA, (9)Miami Research Associates, South Miami, FL, (10)Options Health Research, Tulsa, OK, (11)Hôpital Beaujon, Clichy, France, (12)Université Paris Descartes, INSERM U1610 and Liver Unit, Hôpital Cochin, Paris, France, (13)Mercy Medical Center, Baltimore, MD, (14)Bristol-Myers Squibb, Princeton, NJ, (15)Bristol-Myers Squibb, Wallingford, CT

Disclosures:

G. T. Everson, Bristol-Myers Squibb: Investigator, Research support

K. D. Sims, Bristol-Myers Squibb: Employee, Salary

M. Rodriguez-Torres, Bristol-Myers Squibb: Investigator, Research support

C. Hézode, Bristol-Myers Squibb: Investigator, Research support

E. Lawitz, Bristol-Myers Squibb: Investigator, Research support

M. Bourlière, Bristol-Myers Squibb: Investigator, Research support

V. Loustaud-Ratti, Bristol-Myers Squibb: Investigator, Research support

V. Rustgi, Bristol-Myers Squibb: Investigator, Research support

H. Schwartz, Bristol-Myers Squibb: Investigator, Research support

H. Tatum, Bristol-Myers Squibb: Investigator, Research support

P. Marcellin, Bristol-Myers Squibb: Investigator, Research support

S. Pol, Bristol-Myers Squibb: Investigator, Research support

P. J. Thuluvath, Bristol-Myers Squibb: Investigator, Research support

T. Eley, Bristol-Myers Squibb: Employee, Salary

X. Wang, Bristol-Myers Squibb: Employee, Salary

S. P. Huang, Shu-Pang Huang: Employee, Salary

F. Mcphee, Bristol-Myers Squibb: Employee, Salary

M. Wind-Rotolo, Bristol-Myers Squibb: Employee, Salary

E. Chung, Bristol-Myers Squibb: Employee, Salary

C. Pasquinelli, Bristol-Myers Squibb: Employee, Salary

D. M. Grasela, Bristol-Myers Squibb: Employee, Salary

D. F. Gardiner, Bristol-Myers Squibb: Employee, Salary

Source

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

715. Optimization of an Interferon-free Hepatitis C Virus Treatment Regimen Containing the NS3/4A Protease Inhibitor Faldaprevir, the Non-nucleoside NS5B Inhibitor BI207127, and Ribavirin for Genotype 1b-infected Patients

Session: Poster Abstract Session: Antimicrobials: Novel Agents

Friday, October 4, 2013

Room: The Moscone Center: Poster Hall C

Posters 715_IFNFree_faldaprevir_deleobuvir.pdf (109.5 kB)

Background: SOUND-C1 demonstrated the potent antiviral activity of faldaprevir (FDV) and BI207127 + ribavirin (RBV) without interferon (IFN) in HCV GT1-infected patients. SOUND-C2 investigated the safety, efficacy, and treatment duration of FDV 120mg QD, BI207127 600mg BID or TID (with an additional induction dose of 1200mg at first intake) ± RBV for 16, 28, or 40 weeks in 362 HCV GT1-infected patients. Dose and treatment duration were optimized in SOUND-C3. Notably, recently completed pivotal phase 3 trials of FDV + PegIFN + RBV (STARTVerso™) have yielded promising results across both GT-1a and 1b patients, including patients with compensated cirrhosis.

Methods: Pharmacokinetic and pharmacodynamic analysis in SOUND-C2 indicated an interaction between FDV and BI207127 that increased plasma concentrations of each drug. Increased plasma concentrations of BI207127 correlated with gastrointestinal adverse events (AEs) and treatment discontinuation in the TID groups. SOUND-C3 eliminated the induction dose and limited treatment duration to 16 weeks in order to optimize therapy.

In SOUND-C3, GT1a patients (n=12) carrying the IL28b CC genotype (rs12979860, GT1a-CC) and GT1b patients (n=20) carrying any IL28b genotype were treated with FDV 120mg QD + BI207127 600mg BID without induction dose + RBV for only 16 weeks. Both studies included cirrhotic patients (9% in SOUND-C2 and 13% in SOUND-C3) and had a primary endpoint of SVR12.

Results: In SOUND-C2, SVR12 rates differed between GT1a- (up to 47%) and GT1b- (up to 85%) infected patients. The presence of cirrhosis had a minor influence on SVR12 rates. Nausea and vomiting were common AEs, especially in the TID arms, but were mainly mild.

In SOUND-C3, 95% (19/20) of GT1b-infected patients achieved SVR12 with the modified 16-week IFN-free regimen compared with 17% (2/12) of GT1a-CC-infected patients.

Conclusion: Modifying the IFN-free regimen of FDV, BI207127, + RBV in SOUND-C3 resulted in an SVR rate of 95% for GT1b-infected patients compared with 85% in SOUND-C2 after 16 weeks of treatment. GT1a-CC infected patients had a clearly lower SVR12 rate with 16-week therapy. The optimized 16-week IFN-free regimen is being investigated in phase 3 studies in GT1b-infected patients.

Parvez Mantry, MD, Hepatobiliary Tumor Program, The Liver Institute at Methodist Dallas Medical Center, Dallas, TX, Marcus Schuchmann, MD, Klinikum Der Johannes Gutenberg, University Hospital Mainz, Mainz, Germany, Ansgar Lohse, MD, Department of Internal Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany, Keikawus Arasteh, MD, EPIMED c/o Auguste-Viktoria-Klinikum, Berlin, Germany, Michael Manns, MD, Hannover Medical School, Hannover, Germany, Thomas Berg, MD, Department of Internal Medicine, University Hospital Leipzig, Leipzig, Germany, Stefan Mauss, MD, Zentrum für HIV und Hepatogastroenterologie, Düsseldorf, Germany, Michael Geissler, MD, Klinik Für Onkologie, Gastroenterologie Und Innere Medizin, Esslingen Hospital, Esslingen, Germany, Wulf Bocher, MD, Boehringer Ingelheim, Biberach, Germany and Stefan Zeuzem, MD, Gastroeneterology, Klinikum der Johann-Wolfgang-Goethe-Universität–Med. Klinik I, Frankfurt, Germany

Disclosures:

P. Mantry, Boehringer Ingelehiem: Investigator, Research grant

M. Schuchmann, Boehringer Ingelehiem: Consultant, Editorial Support and Speaker's Bureau, Consulting fee and Speaker honorarium
Norgine: Consultant, Consulting fee
BMS: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Roche: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Gilead: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Merck: Speaker's Bureau, Speaker honorarium
Falk: Speaker's Bureau, Speaker honorarium
MSD: Speaker's Bureau, Speaker honorarium
DFG: Grant Investigator, Grant recipient

A. Lohse, Boehringer Ingelheim: Editorial Support, None

K. Arasteh, Boehringer Ingelehiem: Board Member, Consultant, Grant Investigator and Speaker's Bureau, Consulting fee, Grant recipient and Speaker honorarium

M. Manns, Roche: Consultant, Grant Investigator and Speaker's Bureau, Grant recipient and Speaker honorarium
Gilead: Grant Investigator and Speaker's Bureau, Grant recipient and Speaker honorarium
Novartis: Grant Investigator, Grant recipient
Boehringer Ingelheim: Grant Investigator, Grant recipient
BMS: Grant Investigator and Speaker's Bureau, Grant recipient and Speaker honorarium
Merck: Grant Investigator and Speaker's Bureau, Grant recipient and Speaker honorarium
Janssen: Grant Investigator and Speaker's Bureau, Grant recipient and Speaker honorarium

T. Berg, BMS: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Essex Pharma: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Gilead: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
GSK: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Novartis: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Roche: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Schering-Plough: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Vertex: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium

S. Mauss, Abbott: Grant Investigator, Scientific Advisor and Speaker's Bureau, Research grant, Research support and Speaker honorarium
BMS: Scientific Advisor and Speaker's Bureau, Speaker honorarium
Tibotec: Scientific Advisor and Speaker's Bureau, Speaker honorarium
Roche: Speaker's Bureau, Research support and Speaker honorarium
GSK: Scientific Advisor, Consulting fee
Gilead: Scientific Advisor, Consulting fee

M. Geissler, Boehringer Ingelehiem: Grant Investigator, Research grant

W. Bocher, Boehringer Ingelheim: Employee, Salary

S. Zeuzem, Abbott: Consultant, Consulting fee
Achillion: Consultant, Consulting fee
AstraZeneca: Consultant, Consulting fee
BMS: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Boehringer Ingelheim: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Gilead: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Janssen: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Merck: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Novartis: Consultant, Consulting fee
Roche: Consultant, Consulting fee and Speaker honorarium
Santaris: Consultant, Consulting fee

Source

Barriers to Hepatitis C Treatment in an HIV-HCV Co-Infected Cohort

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

470. Barriers to Hepatitis C Treatment in an HIV-HCV Co-Infected Cohort

Session: Poster Abstract Session: Prevention and Treatment of Viral Infections

Thursday, October 3, 2013

Room: The Moscone Center: Poster Hall C

Posters IDSA_2013_NU-VHR_txbarriers_final(2).pdf (250.6 kB)

Background: Hepatitis C virus (HCV)-related liver disease has emerged as a leading cause of morbidity and mortality in HIV patients (pts). HCV therapy (HCV-RX) may reduce progression of liver fibrosis and liver related death in these pts.

Methods: Northwestern University Viral Hepatitis Registry (NU-VHR) and HIV Outpatient Study (N-HOPS) are prospective observational cohorts of ambulatory HIV pts recruited from our outpatient HIV Center.  We queried both databases for pts with chronic HCV infection (≥ 1 detectable HCV RNA) in order to define the epidemiology of HCV infection in our center and determine barriers to HCV-RX. 

Results: We identified 102 pts with chronic HCV, 90% had genotype 1. The median age was 52 years. 44 pts (43%) received HCV-RX, 18 (41%) achieved sustained virologic response.  Demographic and clinical characteristics are described in Table 1. Barriers to HCV-RX of untreated pts are listed in Table 2.

Table 1

Never treated (n 59)

Treated*

(n 44)

Characteristic

n

%

n

%

Male

42

71

38

86

Caucasian

20

34

30

68

Risk factor for HCV

     Recreational drug use

31

54

16

42

     MSM

16

28

15

39

     Hemophilia

12

21

9

24

CD4 <200 cells/ml

12

20

1

2

History of heavy alcohol use

13

22

5

11

Positive HBsAg or HBV DNA

2

3

3

7

Liver biopsy done at least once

27

46

34

77

Advanced fibrosis (METAVIR >2)

9

32

10

30

*38 pts received peg-interferon + ribavirin (PEG-IFN/RBV), 6 received PEG-IFN/RBV plus Boceprivir

Table 2

Reason(s) for not initiating HCV-RX*

n

%

Non-adherence with hepatology evaluation

12

20

Treatment not recommended based on absence
of liver fibrosis on clinical assessment
and/or liver biopsy

11

19

Comorbid or medical contraindications Τ

9

15

Active psychiatric illness

8

14

Lost to follow up

6

10

Active substance use

6

10

Patient declined therapy

6

7

Non-adherence with HIV provider visits and/or HAART

2

3

* Some pts have ≥ 1; Τ CD4 count < 200, renal insufficiency, etc.

Conclusion: In this urban HIV-HCV co-infection cohort, only 43% of HIV-HCV infected pts have received HCV-RX, and 82% have ongoing infection. The major barriers to HCV-RX were poor adherence with hepatology evaluation and low uptake of therapy for patients that are eligible for treatment. Infectious Disease centered HCV-TX might provide better opportunities for treatment.

Guajira Thomas, MD1, Claudia Hawkins, MD2, Sudhir Penugonda, MD MPH1, Michael Angarone, DO1, Frank Palella, MD3 and Valentina Stosor, MD1, (1)Northwestern University Feinberg School of Medicine, Chicago, IL, (2)Northwestern University Feinburg School of Medicine, Chicago, IL, (3)Northwestern University, Chicago, IL

Disclosures:

G. Thomas, None

C. Hawkins, None

S. Penugonda, None

M. Angarone, None

F. Palella, Merk: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Gilead Sciences: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Janssen Pharmaceuticals: Consultant and Speaker's Bureau, Consulting fee and Speaker honorarium
Bristol-Myers Squibb: Consultant and Shareholder, Consulting fee and Speaker honorarium

V. Stosor, None

Source

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

462. Telaprevir-based triple therapy for elderly patients with genotype 1 chronic hepatitis C

Session: Poster Abstract Session: Prevention and Treatment of Viral Infections

Thursday, October 3, 2013

Room: The Moscone Center: Poster Hall C

Posters 2013IDweek462.pdf (179.9 kB)

Background: We have reported our experience of treating a cohort of chronic hepatitis C patients using combination with peginterferon-alpha-2b (PEG-IFNα2b) plus ribavirin (RBV) in which over 1,200 patients were analyzed. Significantly lower virological response and higher discontinuation of treatment due to adverse effects were found in elderly patients than the younger. The aim of this study was to evaluate the efficacy and tolerability of triple therapy with telaprevir (TVR), PEG-IFNα2b and RBV in chronic hepatitis C patients aged 65 years and older.

Methods: This prospective multicenter (n=22) study was done in 403 genotype 1 patients with chronic hepatitis C (treatment naïve 33.4%, prior relapsers 43.4%, prior non-responders 18.9% and unknown response 4.2%) who receive 12-week triple therapy of TVR (2250 mg/day), PEG-IFNα2b (60-150 μg/week) and RBV (600-1000 mg/day) followed by 12-week dual therapy of PEG-IFNα2b and RBV. Serum HCV RNA levels were monitored by COBAS TaqMan HCV test. The analysis is restricted to 120 patients (age range of 25-73 years) reaching 12-week follow-up after therapy. Sustained virological response at 24 weeks after therapy (SVR) was done based on intention-treat-analysis.

Results: The rate of undetectable HCV RNA at week 4 was 75% for group A (40 patients aged ≥65) and 77.5% for group B (80 patients aged <65) (P=0.76). No significant difference in SVR rate was found between groups A (72.5%) and B (83.7%) (P=0.14). The SVR rate of interleukin 28B (IL28B) (rs8099917) TT (88.9% and 91.1% for groups A and B, respectively) was significantly higher than IL28B TG/GG (46.2% and 45.8%, respectively) (both P<0.001). The multivariate analysis showed IL28B TT (Odds ratio 8.8, P<0.01) and undetectable HCV RNA at week 4 (OR 13.2, P<0.01) as independent factor associated with SVR. Adverse effects resulted in treatment discontinuation in 12.5% for group A and 10% for group B. No episode of death and hepatic decompensation was observed.

Conclusion: TVR-based triple therapy can be used successfully and safely to treat elderly patients with genotype 1 chronic hepatitis C. IL28B genotyping and early virological response indicate effectiveness in these difficult-to-treat elderly patients. (Co-research group: The Kyushu University Liver Disease Study (KULDS) Group)

Norihiro Furusyo, MD., PhD., Eiichi Ogawa, MD., PhD., Masayuki Murata, MD., PhD., Hiroaki Ikezaki, MD., Satoshi Hiramine, MD. and Jun Hayashi, MD., PhD., Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan

Disclosures:

N. Furusyo, None

E. Ogawa, None

M. Murata, None

H. Ikezaki, None

S. Hiramine, None

J. Hayashi, None

Source

Liver Transplantation

Press Release

October 02, 2013

New research reports that liver transplant recipients who receive substance abuse treatment before and after transplantation have much lower alcohol relapse rates than those untreated or only treated prior to transplantation. A second study determines that continued alcohol abuse following liver transplantation decreases graft survival, further highlighting the importance of preventing alcohol relapse. Both studies are published in Liver Transplantation, a journal of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) estimates that nearly 23% of women and 42% of men, 18 years of age and older in the U.S., drank alcohol at least once a week or more in the previous year. Moreover, the Centers for Disease Control and Prevention (CDC), report that 51.5% of Americans 18 and over were regular drinkers, consuming at least 12 alcoholic beverages in the past year.

Medical evidence shows that alcoholic liver disease (ALD) is the second most common reason for liver transplantation in the U.S. and Europe. Prior research indicates that survival rates following transplantation for ALD are comparable to those for patients without ALD. However, relapse of substance abuse post-transplant is not unusual with rates ranging from 10% to 90%.

A team led by James Rodrigue, Ph.D. with The Transplant Institute at Beth Israel Deaconess Medical Center in Boston, Mass examined 118 liver transplant recipients—52% with a history of alcohol abuse having received substance abuse treatment prior to transplantation. Findings indicate that alcohol relapse was 16% among liver transplant recipients who had substance abuse treatment before and after transplantation. In patients who received pre-transplant or no substance abuse treatment the relapse rates were 45% and 41%, respectively.

“While many transplant centers require candidates with a history of alcohol abuse to attend substance abuse treatment prior to transplantation, our findings emphasize the importance of continued therapy after the transplant to prevent alcohol relapse,” said Dr. Rodrigue.

A related study also published in Liver Transplantation found that excessive drinking—alcohol use without any periods of sobriety—post-transplantation for ALD is associated with decreased graft survival and increased organ scarring (fibrosis). Lead investigator, Dr. John Rice from the University of Wisconsin School of Medicine and Public Health said, “Our study highlights the need for ongoing assessments of alcohol use as part of post-transplant care. Given the shortage of available donor livers, maintaining sobriety is critical to maximizing organ use and patient outcomes following transplantation.”

Source

Full citations: “Substance Abuse Treatment and Its Association with Relapse to Alcohol Use Following Liver Transplantation.” James R. Rodrigue, Douglas W. Hanto and Michael P. Curry. Liver Transplantation; (DOI: 10.1002/lt.23747) Published Online: October 1, 2013.
URL: http://doi.wiley.com/10.1022/lt.23747

Full citation: “Abusive Drinking Post-Liver Transplant is Associated with Allograft Loss and Advanced Allograft Fibrosis.” John P. Rice, Jens Eickhoff, Rashmi Agni, Aiman Ghufran, Rinjal Brahmbhatt and Michael R. Lucey. Liver Transplantation; (DOI: 10.1002/lt.23762) Published Online: October 1, 2013.
URL: http://doi.wiley.com/10.1022/lt.23762

Am J Gastroenterol. 2013 Sep;108(9):1464-72. doi: 10.1038/ajg.2013.205. Epub 2013 Jul 30.

Abe H, Hayes CN, Hiraga N, Imamura M, Tsuge M, Miki D, Takahashi S, Ochi H, Chayama K.

1] Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan [2] Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan [3] Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan [4] Liver Research Project Center, Hiroshima University, Hiroshima, Japan.

Abstract

OBJECTIVES: Direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) have recently been developed and are ultimately hoped to replace interferon-based therapy. However, DAA monotherapy results in rapid emergence of resistant strains and DAAs must be used in combinations that present a high genetic barrier to resistance, although viral kinetics of multidrug-resistant strains remain poorly characterized. The aim of this study is to track the emergence and fitness of resistance using combinations of telaprevir and NS5A or NS5B inhibitors with genotype 1b clones.

METHODS: HCV-infected chimeric mice were treated with DAAs, and resistance was monitored using direct and ultra-deep sequencing.

RESULTS: Combination therapy with telaprevir and BMS-788329 (NS5A inhibitor) reduced serum HCV RNA to undetectable levels. The presence of an NS3-V36A telaprevir resistance mutation resulted in poor response to telaprevir monotherapy but showed significant HCV reduction when telaprevir was combined with BMS-788329. However, a BMS-788329-resistant strain emerged at low frequency. Infection with a BMS-788329-resistant NS5A-L31V mutation rapidly resulted in gain of an additional NS5A-Y93A mutation that conferred telaprevir resistance during combination therapy. Infection with dual NS5AL31V/NS5AY93H mutations resulted in poor response to combination therapy and development of telaprevir resistance. Although HCV RNA became undetectable soon after the beginning of combination therapy with BMS-788329 and BMS-821095 (NS5B inhibitor), rebound with emergence of resistance against all three drugs occurred. Triple resistance also occurred following infection with the NS3V36A/NS5AL31V/NS5AY93H triple mutation.

CONCLUSIONS: Resistant strains easily develop from cloned virus strains. Sequential use of DAAs should be avoided to prevent emergence of multidrug-resistant strains.

PMID: 23896953 [PubMed - in process]

Source

World J Hepatol. 2013 September 27; 5(9): 496–504.

Published online 2013 September 27. doi:  10.4254/wjh.v5.i9.496

PMCID: PMC3782687

Chalermrat Bunchorntavakul, Disaya Chavalitdhamrong, and Tawesak Tanwandee

Abstract

Hepatitis C genotype 6 is endemic in Southeast Asia [prevalence varies between 10%-60% among all hepatitis C virus (HCV) infection], as well as also sporadically reported outside the area among immigrations. The diagnosis of HCV genotype can be inaccurate with earlier methods of genotyping due to identical 5’-UTR between genotype 6 and 1b, hence the newer genotyping methods with core sequencing are preferred. Risk factors and clinical course of HCV genotype 6 do not differ considerably from other genotypes. Treatment outcome of HCV genotype 6 with a combination of pegylated interferon and ribavirin is superior to genotype 1, and nearly comparable to genotype 3, with expected sustained virological response (SVR) rates of 60%-90%. Emerging data suggests that a shorter course 24-wk treatment is equally effective as a standard 48-wk treatment, particularly for those patients who attained undetectable HCV RNA at week 4 (RVR). In addition, baseline and on-treatment predictors of response used for other HCV genotypes appear effective with genotype 6. Although some pan-genotypic direct-acting antivirals have completed phase II/III studies (sofosbuvir and simeprevir) with clinical benefit demonstrated in small number of patients with genotype 6, broad availability of these agents in Southeast Asia may not be expected in the near future. While awaiting the newer therapy, response-guided therapy seems appropriate for patients with HCV genotype 6. Patients with RVR (representing > 70% of patients) are suitable for 24-wk treatment with expected SVR rates > 80%. Patients without RVR and/or those with poor response predictors may benefit from 48 wk of therapy, and a detectable HCV RNA at week 12 (with no early virological response) serves as a stopping rule. This treatment scheme is likely to have a major economic impact on HCV therapy, particularly in Southeast Asia, wherein treatment can be truncated securely in the majority of patients with HCV genotype 6.

Keywords: Hepatitis C, Genotype 6, Epidemiology, Southeast Asia, Treatment, Pegylated interferon, Ribavirin, Response-guided therapy

Core tip: Hepatitis C genotype 6 is endemic in Southeast Asia [prevalence varies between 10%-60% among all hepatitis C virus (HCV) infection], as well as also sporadically reported outside the area among immigrations. The diagnosis of HCV genotype can be inaccurate with earlier methods of genotyping due to identical 5’-UTR between genotype 6 and 1b, hence the newer genotyping methods with core sequencing are preferred. Risk factors and clinical course of HCV genotype 6 do not differ considerably from other genotypes. Treatment outcome of HCV genotype 6 with a combination of pegylated interferon and ribavirin is superior to genotype 1, and nearly comparable to genotype 3. Emerging data suggests that a shorter course 24-wk treatment is equally effective as a standard 48-wk treatment, particularly for those patients who attained undetectable HCV RNA at week 4.

INTRODUCTION

Chronic hepatitis C virus (HCV) infection is a worldwide health problem in that it has a global prevalence rate of approximately 3% and affects over 170 million individuals. It is a leading cause of chronic liver disease and hepatocellular carcinoma worldwide in both industrialized and developing countries[1]. However, geographic differences in the overall prevalence and distribution of HCV genotypes have been well recognized[1]. The majority (87%) of HCV-infected individuals are from Western Pacific countries (62.2 million), Southeast Asia (32.3 million), Africa (31.9 million), and Eastern Mediterranean countries (21.3 million)[2,3]. The prevalence of HCV infection is especially higher in Southeast Asia with an estimate prevalence of 2%-12% among general population in some countries[4], compared to the estimated prevalence of 1.6% in western countries such as the United States[5]. Hepatitis C genotypes 1, 2, and 3 are widely distributed globally and have been the focus of most experimental and clinical studies. Genotypes 4 and 5 are found mainly in the Africa and Middle East. Genotype 6 and its subtypes are found mainly in Southeast Asia[2-4,6]. In some countries in Southeast Asia, such as Thailand, Vietnam, and Myanmar, HCV genotype 6 is one of the most common genotype, detected in 10%-60% of all HCV patients[7-14]. In the past, HCV genotype 6 was believed to be confined to Southeast Asia, but in the changing era of increasing migration of populations, it has been recently reported in nearby areas of Asia, such as China, Taiwan, and Hong Kong (China)[6,15], and as far as western countries, such as United States, Canada[16], and Germany[15]. As globalization (e.g., immigration, travel, and cultural diversity) potentially impacts the epidemiology of HCV, the numbers of patients with HCV genotype 6 seen outside Southeast Asia is expected to increase.

Despite the significant burden of the disease, the creditable data regarding the epidemiology and treatment specifically for HCV genotype 6 are rather limited. This may be largely due to the fact that the majority of the HCV genotype 6-infected population is based in developing countries with limited research facilities and restricted access to publication. This review is aimed to summarize the current available data regarding the epidemiology and treatment of HCV genotype 6, as well as to propose a response-guided algorithm of treatment.

CLASSIFICATION AND DIAGNOSIS

Substantial genetic diversityled to the identification and classification of various genotypes and subtypes of the HCV among different geographical areas. Currently, 6 major genotypes and more than 80 subtypes have been identified from around the world; the previously reported HCV genotypes of 7, 8, and 9 that are endemic in Southeast Asia have been re-classified as subtypes of genotype 6[16,17]. Proper classification of HCV genotypes and subtypes is very important clinically and is dependent on nucleotide sequence disparity[6]. Though the ideal method to accurately identify HCV genotype is by directly sequencing of the entire genome, the current, commercially available methods typically use distinct motifs found within the HCV genome to either indirectly or directly genotype HCV, a more resourceful strategy[6]. Indirect method of HCV genotyping uses genotype-specific antibodies and competitive enzyme immunoassays (e.g., Murex HCV Serotyping Assays, Murex Diagnostics, Dartfort, United Kingdom)[6]. Direct methods of genotyping include direct sequence analysis of 5’-UTR only (e.g., TruGene HCV 5’NC, Visible Genetics, Toronto, Canada), restriction fragment length polymorphism analysis and reverse hybridization line probe assay for the 5’-UTR only (e.g., INNO-LiPA HCV I, Innogenetics, Zwijnaarde, Belgium) or both 5’-UTR and core regions (INNO-LiPA HCV II, Innogenetics, Ghent, Belgium)[6]. Selection of genotyping assay is crucial, especially for genotype 6 variants as genotype 6 shares identical 5′-UTR sequences with genotype 1b, thus making earlier genotyping methods based solely on 5′-UTR sequences alone unreliable and those tests with additional HCV core-sequencing preferable[6,18-21]. Among the newer genotyping methods, INNO-LiPA HCV II assay is one of the most widely used globally. It has been developed on INNO-LiPA HCV I platform with additional sequencing of core regions and demonstrated significant improvement in genotyping accuracy, particularly to differentiate between HCV genotype 1 and genotype 6 variants (about 100% success rate)[6,18-21].

EPIDEMIOLOGY OF HCV GENOTYPE 6

Epidemiologic studies regarding HCV genotype 6 from different parts of the world are summarized in Table ​Table1.1. In brief, HCV genotype 6 is particularly common in Southeast Asia (prevalence among all HCV infections are 9%-31% in Thailand[7-10], 21%-49% in Myanmar[11,12], 32%-46% in Vietnam[13,14], > 90% in Lao PDR[22], and 56% in Cambodia[23]), and is the most common HCV genotype is some of these countries. In addition, geographical differences of HCV prevalence in each individual country were observed in which genotype 6 appears to be more prevalent in the Northern areas of Thailand, Myanmar, and Vietnam, when compared with the central and southern regions[9,10,12-14]. It should be noted that the earlier reports of the prevalence of HCV genotype with previous version of HCV genotypic assays may have underestimated the prevalence of HCV genotype 6 (misclassified with genotype 1). Outside Southeast Asia, HCV genotype 6 is also observed in the nearby areas, particularly Hong Kong and the Southern parts of China[24-26]. Interestingly, HCV genotype 6 is somewhat uncommon in the many countries in Southeast Asia, such as Indonesia, Philippines, and Singapore, as well as in the surrounding countries, such as India, Pakistan, Taiwan, and South Korea[4,18]. Apart from the aforementioned areas, HCV genotype 6 encountered elsewhere (e.g., United States, Canada, and Germany) were mostly immigrants from Southeast Asia[15,16].

Table 1 Prevalence of hepatitis C virus genotype 6 in Asia

Country of origin Population Genotyping method Prevalence of HCV genotype 6 Author
Thailand n = 236; Blood donors throughout the country Reverse hybridization 18.0% Kanisanon et al[7]
n = 58; Volunteers from four hospitals located in the North, North-east, South and Center of the country Core sequencing 8.9% Sunanchaikarn et al[8]
n = 126; Blood donors in the Northern Thailand Core sequencing 31.0% Jutavigittum et al[9]
n = 375; Blood donors in the Central Thailand Core and NS5B sequencing 18.9% Akkarathamrongsin et al[10]
n = 40; Immigrant workers from Cambodia (n = 25) and Myanmar (n = 15) in Thailand Core and NS5B sequencing 56% among Cambodian workers and 26.7% among Myanmar workers Akkarathamrongsin et al[23]
Myanmar n = 110; Blood donors in Yangon and its suburbs NS5B sequencing 20.9% Shinji et al[11]
n = 145; Volunteers from four different border cities of Myanmar Core sequencing 49% (Genotype 6 was mostly found in the Northern cities) Lwin et al[12]
Vietnam n = 308; Patients from urban community-based GI practice in Southern Vietnam Core sequencing 31.5% Nguyen et al[13]
n = 135; Blood donors in Hanoi (Northern Vietnam Core (n = 70) and NS5B (n = 65) sequencing 45.9% Pham et al[14]
Lao PDRHong Kong n = 45; Blood donors in Lao PDR Core and NS5B sequencing 95.6% Hübschen et al[22]
n = 1055; 949 non-IVDU and 106 IVDU from all over Hong Kong Core sequencing 27.1% (23.6% among non-IVDU and 58.5% among IVDU) Zhou et al[26]
n = 212; Blood donors NA 27% Prescott et al[25]
China n = 148; Patients from nine regions in China Core and NS5B sequencing 13% (Genotype 6 was only observed in the South) Lu et al[24]
Source: Ref. [6], with permission. IVDU: Intravenous drug users; NA: Not available; HCV: Hepatitis C virus; GI: Gastrointestinal; PDR: People's Democratic Republic; NA: Not available.

Nowadays in the Western countries, HCV infections are primarily due to intravenous or nasal drug use and, to a lesser degree, to unsafe medical/surgical procedures, tattooing or acupuncture with unsafe materials, and male homosexual activity[27]. This contrasts with the principal routes of HCV transmission prior to 1990’s of blood transfusion and unsafe injection procedures. Despite conflicting published data, several studies have found that many Asian HCV patients have no identifiable risk factor (up to 50%) of HCV acquisition[27]. Intravenous or nasal drug use does not seem to be a major contributing factor to HCV infection. Therefore, inadequately sterilized medical equipment and cultural practices such as acupuncture or cosmetic tattooing are presumably implicated in the transmission of HCV a significant proportion of patients[18]. A cross-sectional study of 308 Southeast Asian Americans with HCV (41% with genotype 6) reported that risk factors for acquisition for HCV genotype 6 are similar to that of other genotypes, with 41% of patients who could not recall any specific exposure risk[28]. Nevertheless, higher prevalence of HCV genotype 6 has been described in some certain populations including intravenous drug users and patients with thalassemia major[10,26,29]. In Hong Kong, HCV genotype 6 was predominantly observed in 58.5%-62.5% among intravenous drug users and 50% among patients with thalassemia major[26,29]. Correspondingly, Seto et al[30] reported that statistically significant larger proportion of patients with HCV genotype 6 were infected through intravenous drug injections when compare to those with genotype 1 (28.2% vs 8.7%, respectively).

CLINICAL FEATURES

There is limited data that specifically addresses the clinical features and natural history of HCV genotype 6. A cross-sectional study performed in 308 Southeast Asians in California found no significant differences in the clinical and virological characteristics (e.g., age, risk factors of HCV acquisition, alcohol consumption, family history of liver disease, liver functions tests, white blood cell and platelet count, HCV RNA viral load, and liver histology) between HCV genotype 6 and other genotypes. Yet, several studies have suggested that Asian patients tend to be older, have lower body mass index (BMI), consume less alcohol and tobacco, and have more advanced liver histology at presentation than non-Asians[18,31]. Late presentation in Asian patients may be secondary to the lack of awareness of appropriate screening and the low proportion of patients presenting with identifiable risk factors[18].

Chronic HCV infection can be associated with various extrahepatic manifestations, including lymphoproliferative (e.g., mixed cryoglubulinemia and lymphoma) and immunological disorders of various organ systems[32]. The prevalence of lymphoproliferative disorders associated with HCV seems to be geographical heterogeneity[32,33]. Without clear reasons, it is more prevalent in Southern Europe (with an increased prevelence in patients infected with HCV genotype 2) than in Northern Europe, North America, and Asia[32,33]. To date, there have been no specific epidemiological and clinical data regarding extrahepatic manifestations of HCV genotype 6. From our experiences, clinically significant extrahepatic manifestations of HCV are rare in Thailand (especially when compared to the relatively high prevalence of HCV in this area).

TREATMENT

Treatment outcomes

A combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) has been the standard treatment for patients with chronic HCV. These drugs are administered for either 48 wk (for HCV genotypes 1, 4, 5, and 6) or for 24 wk (for HCV genotypes 2 and 3), inducing sustained virologic response (SVR) rates of 40%-50% in those with genotype 1, and of > 70-80% in those with genotypes 2 and 3 infections[27,34]. It should be noted that HCV treatment outcome with PEG-IFN/RBV in Asians seems to be superior to that of non-Asian populations, and this may be due to several factors, such as favorable IL28B genotype, low body weight, and HCV genotype misclassification (6 to 1) [18]. More recently, the treatment durations can be modified according to the virological responses (response-guide therapy)[27], and in 2011, direct-acting antiviral (DAA)-based triple combination therapies (boceprevir or telaprevir plus PEG-IFN/RBV) have been approved and shown to improve virological outcomes in HCV genotype 1 patients, with an SVR of up to 65%-75% in treatment-naïve patients[35]. Once achieved, an SVR is associated with long-term clearance of HCV infection, which is regarded as a ‘‘cure,’’ as well as with significant improvement of morbidity and mortality of the patient[27,35]. Among several predictors of SVR to therapy, HCV genotype is considered one of the most robust independent predictors[27]. Compared to other genotypes, data regarding the treatment of HCV genotype 6 are scant and mostly generated retrospectively. The available studies suggest that SVR rates in patients infected with HCV genotype 6 (60%-90%) are superior to those in patients with genotype 1 and comparable to patients infected with genotypes 2 and 3[36-43] (Table ​(Table2).2). The question whether a high treatment response rates in HCV genotype 6 is due to viral factor itself or partialy due to host factor, especially favorable IL28B genotype among Asians, remains unclear.

Table 2 Treatment outcomes of hepatitis C virus genotype 6 (compared to other genotypes)

Ref. Design/treatment Genotype n SVR P value1
Dev et al[36] Retrospective IFN + RBV 52 wk 6 33 82.5% NR
1 17 61.9%
Hui et al[37] Prospective IFN + RBV 52 wk 6 16 62.5% 0.04
1 24 29.2%
Cheng et al[43] Retrospective PEG-IFN + RBV (duration not reported) 6 13 69.2% 0.026
1 61 32.8%
2 18 77.8%
Fung et al[38] Prospective PEG-IFN + RBV 52 wk 6 21 85.7% 0.019
1 21 52.4%
Nguyen et al[40] Retrospective PEG-IFN + RBV (48 wk for genotype 1 and 6; 24 wk for genotype 2/3) 6 34 74.0% 0.016
1 70 49.0%
2/3 63 75.0%
Seto et al[30] Retrospective IFN/PEG-IFN + RBV 52 wkIFN/PEG-IFN + RBV 52 wk 6 26 92.3% NR
1 21 42.9%
Tsang et al[41] Retrospective PEG-IFN + RBV 48 wk 6 70 75.7% NR
1 70 57.1%
Zhou et al[42] Retrospective PEG-IFN + RBV (48 wk for genotype 1b; 24 wk for genotype 2/3 and 6) 6 22 81.8% 0.068
1b 39 59.0%
2/3 42 83.3%
Tangkijvanich et al[48] Prospective PEG-IFN + RBV (RGT2 for genotype 6; 48 wk for genotype 1; 24 wk for genotype 3) 6 34 76.5% 0.309
1 16 62.5%
3 16 81.3%
1P value between genotype 6 vs genotype 1;
2Response-guided therapy (RGT) define as 24 wk for patients with rapid virological response and 48 wk for those without. PEG-IFN: Pegylated interferon; RBV: Ribavirin; SVR: Sustained virological response.

Treatment regimens

The optimal dose and treatment duration of HCV genotype 6 have not been well-established. Most of the earlier studies applied PEG-IFN for 48 wk duration with weight-based RBV dose for HCV genotype 6 reported conflicting results with studies comparing 48-wk vs 24-wk treatment duration (Table ​(Table3).3). In a retrospective cohort of Nguyen et al[44], SVR was significantly higher in patients treated for 48 wk than in those treated for 24 wk (75% vs 39%, respectively; P = 0.044). However, a randomized controlled study from Lam et al[45] (n = 60) found no significant difference in SVR rates in patients treated with PEG-IFN α-2a/RBV for 48 wk vs 24 wk (79% vs 70%, respectively; P = 0.45). Based on this conflicting evidence, differences in treatment duration recommended by the available guidelines are observed. The 2009 American Association of the Study of Liver Disease[34] and the 2012 Asian Pacific Association for the Study of the Liver[46]. Practice Guidelines have recommended 48 wk duration of treatment for patients with HCV genotype 6, as for those with genotype 1, whereas the 2011 European Association for the Study of the Liver Practice Guideline has suggested response-guided therapy for HCV genotype 6 with the same algorithm as genotype 2 and 3[27]. In 2012, the largest randomized controlled trial to date of patients with HCV genotype 6 (n = 105) has been published. This study found no statistically significant difference in SVR rates between the genotype 6 patients treated with 24 and 48 wk of PEG-IFN α-2a/RBV (60% vs 71%, P = 0.24 in the intention-to-treat analysis; 72% vs 79%, P = 0.46 in the per-protocol analysis)[47].

Table 3 Treatment outcomes of hepatitis C virus genotype 6 by the treatment duration

Ref. Design/treatment Duration (wk) n SVR P value
Nguyen et al[44] Retrospective 24 23 39% 0.044
PEG-IFN 2a/2b + WB-RBV 48 12 75%
Lam et al[45] Randomized (1:1) 24 27 70% 0.450
PEG-IFN 2a + WB-RBV 48 33 79%
Thu-Thuy et al[47] Randomized (1:2) 24 35 60% 0.240
PEG-IFN 2a + WB-RBV 48 70 71%
Tangkijvanich et al[48] Prospective 24 if RVR achieved 25 88% NR
PEG-IFN 2a + WB-RBV 48 if no RVR 9 44%
PEG-IFN: Pegylated interferon; RBV: Ribavirin; WB: Weight-based; SVR: Sustained virological response; RVR: Rapid virological response.

Predictors of treatment response and response-guided therapy

For HCV in general, the strongest predictors of SVR are genetic polymorphisms in IL28B, genotype, the stage of fibrosis, and undetectable HCV RNA at week 4 of treatment (defined as rapid virological response; RVR)[27]. Other predictors of response include host factors (e.g., age, BMI, insulin resistance, gender), baseline HCV RNA levels, co-infections, the dose and duration of therapy, virological responses during the treatment, and treatment adherence[27]. These predictors seem to be valuable for all HCV genotypes and may extrapolate to use for patients with HCV genotype 6 as well. With sparse available data, predictors of response in HCV genotype 6 have been observed among studies of HCV genotype 6 include younger age (< 40-50 years)[40,42], low BMI (< 25 kg/m2)[40], treatment adherence[40] and RVR[42,45]. Among these predictors and concordant with observations in other HCV genotypes, RVR was a strong independent predictor of SVR in HCV genotype 6, wherein the positive predictive value (PPV) in achieving SVR in patients with RVR has been 80%-90%[42,45,47,48]. In Thu thuy et al[47] study, RVR was common (in up to 80% of patients) with a high PPV (75%-86%) and negative predictive value (NPV) for the prediction of SVR (0%-8%), regardless of the treatment duration. Thus, none of the patients who did not have undetectable HCV RNA at week 12 of treatment (defined as early virological response; EVR) subsequently achieved SVR[47]. Thus, in those who completed treatment protocol, the importance of RVR in the prediction of SVR has been further substantiated; PPV for SVR was 96% with 48-wk treatment group, and was 91% with 24-wk treatment. In addition, a retrospective analysis by Zhou et al[42] demonstrated that the PPV and NPV of RVR and EVR in patients with HCV genotype 6 are comparable with those in patients with genotype 2/3 infection.

Taken together, it is likely that baseline response predictors together with on-treatment response-guide therapy (RGT) can be utilized for the treatment of HCV genotype 6 in order to optimize treatment outcomes as well as cost-effectiveness (Figure ​(Figure1).1). Based on available data, patients with RVR will benefit with 24 wk of therapy, particularly if they are young, with a BMI < 25 kg/m2, and have a low viral load, whereas patients with older age, non-CC IL28B genotypes, obesity, advanced fibrosis, and high viral loads, would benefit from 48 wk of therapy. The SVR rates among HCV genotype 6 patients with RVR are expected to be at > 80%[42,45,47], and possibly up to > 90% in those who adhere to therapy[47]. Alternatively, patients who do not achieve RVR are expected to have low rates of SVR (0%-30%)[45,47]. If treatment continues, HCV RNA should be checked again at week 12. If HCV RNA is detectable at week 12 then treatment should be discontinued, since SVR rates have shown to be near zero in non-EVR patients[42,45,47]. Correspondingly, a proof-of-concept study (n = 34) utilizing RGT for HCV genotype 6 patients with RVR has been firstly reported by Tangkijvanich et al[48]. In this study, 25 patients who achieved RVR were assigned to receive 24 wk treatment (RGT group) while the remaining 9 patients (no RVR) were assigned for standard 48 wk of PEG-IFN 2a/RBV therapy. SVR rates were significantly higher for RGT group when compared to 48-wk treatment group (88% vs 44%, respectively; P = 0.024)[48]. However, the precise role and protocol of RGT for HCV genotype 6 needs a larger prospective study to address.

WJH-5-496-g001

Figure 1 Response-guided therapy in patients with hepatitis C genotype 6. RVR: Rapid virological response; EVR: Early virological response; BMI: Body mass index; HCV: Hepatitis C virus; IL: Interleukin.

Treatment adverse events

As previously reported in HCV treatment trials, the common side effects of HCV genotype 6 are of general non-specific symptoms and anemia, which are mild and manageable by supportive measures[45,47]. Though the incidence and types of side effects caused by therapy with PEG-IFN/RBV seem to be similar among patients of different HCV genotypes, side effect profiles appear to differ among patients of different ethnicities[6]. Several studies have reported that psychiatric adverse events were less common and ribavirin-induced anemia was more common in Asians than either white or Hispanic patients, and that there were no significant difference between whites and Asians with respect to required ribavirin or PEG-IFN dose reductions[18]. Notably, the lower rates of psychiatric adverse events in Asians may be partly explained from the potential for underreporting psychiatric problems and/or depression in Asian populations due to associated sociocultural stigma[49,50], as well as from the absence of confounders such as alcohol use and drug abuse[51].

Roles of IL28B

Single nucleotide polymorphisms (SNPs) near the IL28B gene responsible for encoding IFN-gamma are strongly associated with spontaneous and treatment-induced clearance of HCV[52,53]. A genome-wide association study of more than 1600 patients infected with HCV genotype 1 found the rate of SVR following PEG-IFN/RBV treatment to be approximately 80%, 40%, and 25% in IL28B genotypes CC, CT, and TT, respectively[52]. Notably, the favorable C allele is frequently found up to 80% in Asians, which is more common than in Caucasians, Hispanics and African Americans, respectively[52,54]. This may be part of the reason that SVR rates for HCV genotype 1 among Asian patients are higher (expected 60%-70%) compared to non-Asian populations[18]. However, the role of IL28B for the prediction of HCV clearance in non-1 genotypes is less clear. Studies from HCV genotypes 2, 3, and 4 yielded somewhat conflicting results, though most studies failed to show a significant association of IL28B variations with SVR[53]. Nevertheless, a preliminary study in Chinese genotype 6 HCV patients (n = 24) has demonstrated a significant association between IL28B polymorphisms (SNPs rs12979860 and rs8099917) and SVR rates[55].

Roles of viral genome mutations

Studies from Japan and Hong Kong have identified assciations between genetic mutations around the interferon sensitivity-determined region (ISDR) of HCV genotype 1b and resistance to IFN-based treatment[56,57]. Accordingly, sequence diversity of HCV genotype 6a within the extended ISDR (covering 192 base-pairs upstream and 201 base-pairs downstream from the ISDR previously defined in genotype 1b) has shown correlation with antiviral treatment outcomes in a report from China[58]. However, it should be noted that this observation was not reproducible among HCV genotype 1b patients in Europe and United States[59,60], which may be partially explained by differences in genetic background, especially the IL28B genotypes.

Roles of DAA

At present, there has been no data on the efficacy of current, FDA-approved DAA, boceprevir and telaprevir, on HCV genotype 6. However, some investigational agents with pan-genotypic antiviral activities (e.g., new generation protease inhibitors, NS5B, and cyclophilin inhibitors) have been shown to suppress HCV replication in HCV genotype 6[61,62]. Recently, sofosbuvir[63] and simeprevir (TMC435)[64] have demonstrated clinical benefit in a small number of patients with HCV genotype 6 in the phase II/III studies. However, further studies with larger number of genotype 6 patients are needed in order to establish the regimens and clinical efficacy in this group of patient. While awaiting clinical trials specifically for genotype 6, one would speculate that the use, or off-label use, of pan-genotypic DAA, especially sofosbuvir and simeprevir, for HCV genotype 6 patients may be seen soon, particularly for those who failed standard treatment with PEG-IFN/RBV. It should also be noted that the availability of DAA is currently very limited in most countries in Southeast Asia due to socio-economic and other barriers.

CONCLUSION

Hepatitis C genotype 6 is endemic in Southeast Asia (prevalence varies between 10%-60% among all HCV infection), as well as also sporadically reported outside the area among immigrations. The diagnosis of HCV genotype can be inaccurate with earlier methods of genotyping due to identical 5’-UTR between genotype 6 and 1b, and the newer genotyping methods with core sequencing are preferable. Risk factors and clinical course of HCV genotype 6 do not considerably differ from the other genotypes. Treatment outcome of HCV genotype 6 with PEG-IFN/RBV is superior to genotype 1, and nearly comparable to genotype 3 (expected SVR rates of 60%-90%). Emerging data suggests that a shorter course 24-wk treatment may be effective as a standard 48-wktreatment, particularly in those patients who attained RVR. In addition, baseline and on-treatment predictors of response used for other HCV genotypes seem to be useful for genotype 6. Although some pan-genotypic direct acting antivirals have completed phase II/IIIstudies (sofosbuvir and simeprevir) with clinical benefit demonstrated in small number of patients with genotype 6, broad availability of these agents in Southeast Asia may not be expected in the near future. While awaiting the newer therapy, response-guided therapy seems to be appropriate for patients with HCV genotype 6. Patients with RVR (representing > 70% of patients) are suitable for 24 wk treatment with expected SVR rates > 80%. Patients without RVR and/or those with poor response predictors may benefit from 48 wk of therapy, and a detectable HCV RNA at week 12 (no EVR) can be served as stopping rule. This treatment scheme is likely to have a major economic impact on HCV therapy, particularly in Asia, wherein treatment can be truncated securely in the majority of patients with HCV genotype 6.

ACKNOWLEDGMENTS

The authors are thankful to Professor K Rajender Reddy at the University of Pennsylvania and the Thai Association of the Study of the Liver for supportive guidance.

Footnotes

P- Reviewers Antonelli A, Rostami-Nejad M, Takaki A, Xu R S- Editor Gou SX L- Editor A E- Editor Liu XM

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