Abbreviations:AE (adverse event), ALT (alanine aminotransferase), BMI (body mass index), BOC (boceprevir), BT (viral breakthrough), CPGs (Clinical Practice Guidelines), CYP3A4 (cytochrome p450 3A4), DAA (direct-acting antiviral), DVR (delayed virological response), EIA (enzyme immunoassays), EPO (erythropoietin), eRVR (extended rapid virological response), EVR (early virological response), G-CSF (granulocyte colony stimulating factor), GRADE (Grading of Recommendations Assessment, Development and Evaluation), HBV (hepatitis B virus), HCC (hepatocellular carcinoma), HCV (hepatitis C virus), IDU (intravenous/injecting drug use), IFN (interferon), IU (international units), LSM (liver stiffness measurement), LT (liver transplant), OST (opiate/opioid substitution treatment/therapy), PegIFN/RBV (pegylated interferon-α and ribavirin), PI (protease inhibitor), PWID (people who inject drugs), RVR (rapid virological response), SCAR (severe cutaneous adverse reaction), SVR (sustained virological response), TSH (thyroid stimulating hormone), TVR (telaprevir)
Blachier M, Leleu H, Peck-Radosavljevic M, Valla D-C, Roudot-Thoraval F. The burden of liver disease in Europe, a review of available epidemiological data. Geneva: European Association for the Study of the, Liver; 2013. www.easl.eu.
Rantala M, van de Laar M. Surveillance and epidemiology of hepatitis B and C in Europe – a review. Eur Surveill 2008;13(21): <http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=18880>.
Smith DB, Bukh J, Kuiken C, Muerhoff AS, Rice CM, Stapleton JT, et al. Expanded classification of hepatitis C Virus into 7 genotypes and 67 Subtypes: updated criteria and assignment web resource. Hepatology 2013. http://dx.doi.org/10.1002/hep.26744 [Epub ahead of print, PubMed PMID: 24115039.].
Natural history and public health burden
The current standard of care and developing therapies
- -How should acute and chronic hepatitis C be diagnosed?
- -What are the goals and endpoints of treatment?
- -What are the results of current therapies and the predictors of response?
- -How should patients be assessed before therapy?
- -What are the contra-indications to therapy?
- -Who should be treated with current licensed drugs?
- -For whom can treatment be deferred?
- -What first-line treatment should be prescribed?
- -How should treatment be managed?
- -How should treatment be tailored to the virological response?
- -How can SVR rates of antiviral treatment be improved?
- -How should patients with SVR be followed?
- -What should be offered to those who fail to achieve SVR?
- -How should patients with severe liver disease be treated?
- -How should special groups of patients be treated?
- -How should patients, infected after substance use, be treated?
- -How should we treat patients with acute hepatitis C?
- -How should untreated patients and non-sustained responders be followed?
- -What are the perspectives of new treatments?
Diagnosis of acute and chronic hepatitis C
Goals and endpoints of HCV therapy
- Martinot-Peignoux M.
- Stern C.
- Maylin S.
- Ripault M.P.
- Boyer N.
- Leclere L.
- et al.
Search for other causes of liver disease
Assessment of liver disease severity
HCV titre and genotype determination
Determination of host genetics
Contra-indications to therapy
IFN-α and ribavirin
Telaprevir or boceprevir based triple therapy
Indications for treatment: Who should be treated?
First-line treatment of chronic hepatitis C: Results of current therapies and predictors of response
Phase III data on telaprevir and boceprevir in treatment-naïve genotype 1 infection
- (1)Patients who are HCV RNA undetectable at week 8 and remain undetectable at week 24 can stop all drugs at week 28.
- (2)Patients with detectable HCV RNA at any time point between week 8 and 24, should continue triple therapy until week 36, then BOC should be stopped and PegIFN/RBV continued until week 48.
- (3)Response-guided therapy should be avoided in the presence of cirrhosis, where the recommended treatment schedule is a 4 week lead-in phase of PegIFN/RBV followed by 44 weeks of PegIFN/RBV plus BOC. This recommendation stems from caution rather than from detailed data in this category of patients.
A potential role for dual therapy in genotype 1 infection
Drug dosing in HCV genotype 1 therapy
Buti M, Agarwal K, Horsmans YJ, Sievert W, Janczewska E, Zeuzem S, et al. OPTIMIZE trial: non-inferiority of twice-daily telaprevir vs. administration every 8 h in treatment-naive, genotype 1 HCV infected patients. In: 63rd annual meeting of the American Association for the Study of Liver Diseases, Boston, MA, November 9–13; 2012 [abstract LB8].
Treatment-naïve patients with genotypes 2, 3, 4, 5, or 6
Monitoring of treatment efficacy
- Vermehren J.
- Kau A.
- Gartner B.C.
- Gobel R.
- Zeuzem S.
- Sarrazin C.
Stopping (futility) rules
Virological response-guided triple therapy
Virological response-guided dual therapy
- (1)The rapid virological response (RVR) is defined as an undetectable HCV RNA at week 4 of therapy.
- (2)The early virological response (EVR) is defined as an HCV RNA, which is undetectable at week 12. In some literature, this is referred to as complete EVR (cEVR).
- (3)The delayed virological response (DVR) is defined as a more than 2 log10 drop with detectable HCV RNA at week 12, and undetectable HCV RNA at week 24. In some literature, this is referred to as partial EVR (pEVR).
- (1)Patients infected with HCV genotype 1, with an RVR can be treated for 24 weeks. A recent meta-analysis suggested that this applies only to those with a low baseline HCV RNA level. As uncertainties remain as to which threshold should be used to distinguish low and high baseline HCV RNA levels, patients infected with HCV genotype 1 (and possibly also those infected with genotype 4) with a baseline viral level <400,000 IU/ml should be treated for 24 weeks, whereas it is reasonable to prolong therapy for a total of 48 weeks in patients with a higher baseline HCV RNA level [41,56,57,59,61,62]. Some suggest a higher threshold.
- (2)Patients infected with HCV genotype 1 (and possibly also those infected with genotype 4) and who achieve an EVR without an RVR should be treated for 48 weeks [61,63,64,65,66,67,68].
- (3)Patients with HCV genotype 1 and a delayed virological response (DVR) can be treated for 72 weeks, provided that their HCV RNA is undetectable at week 24. Insufficient data exist for other genotypes [61,63,64,65,66,67,68]. (Recommendations (2) and (3) clearly refer to patients with genotype 1 infection who are being treated in a setting where PIs are unavailable or contraindicated.)
- (4)In patients infected with HCV genotypes 2 and 3 with an RVR and low baseline viral load (<400,000 IU/ml), shortening of treatment duration to 16 weeks can be considered at the expense of a slightly higher chance of post-treatment relapse [54,69,70,71,72].
- (5)In patients with HCV genotypes 2 and 3 who have advanced fibrosis, cirrhosis or cofactors affecting response (insulin resistance, metabolic syndrome, non-viral steatosis) shortening of treatment duration to 16 weeks should not be considered, even if they have low baseline HCV RNA and RVR. There is insufficient evidence of an equal efficacy [55,73,74,75].
- (6)Patients with genotypes 2 and 3 without RVR and with negative cofactors affecting response could be treated for 48 weeks, provided that their HCV RNA is undetectable at week 24 [41,76].
Monitoring treatment safety
Treatment dose reductions
Measures to improve treatment success rates
Correction of cofactors
- Poordad F.
- Lawitz E.J.
- Reddy K.R.
- Afdhal N.H.
- Hézode C.
- Zeuzem S.
- et al.
Post-treatment follow-up of patients who achieve an SVR
Re-infection following successful HCV treatment
Retreatment of non-sustained virological responders to pegylated IFN- and ribavirin
- (1)Virological relapse: Patients who have undetectable HCV RNA at the end of treatment, but do not achieve an SVR.
- (2)Virological partial response: Patients who have a >2 log10 IU/ml drop in HCV RNA by 12 weeks of treatment, but never achieve undetectable HCV RNA.
- (3)Virological null response: Patients who have a <2 log10 IU/ml drop in HCV RNA by 12 weeks of treatment.
Triple therapy for genotype 1 patients who experienced virological failure during previous dual PegIFN/RBV therapy – results of phase III studies with BOC and TVR
Treatment of patients with severe liver disease
Patients with an indication for liver transplantation
Post-liver transplantation recurrence
Treatment of special groups
Dieterich D, Soriano V, Sherman K, Girard P-M, Rockstroh J, Adiwijaya B, et al. Telaprevir in combination with pegylated interferon-alfa-2a+RBV in HCV/HIV-co-infected patients: a 24-week treatment interim analysis. In: 19th conference on retroviruses and opportunistic infections, seattle, WA, March 5–8; 2012 [abstract 46].
Treatment of patients with co-morbidities
Non-hepatic solid organ transplant recipients
- Orens J.B.
- Estenne M.
- Arcasoy S.
- Conte J.V.
- Corris P.
- Egan J.J.
- et al.
Active drug addicts and patients on stable maintenance substitution
- Marcellin P.
- Chousterman M.
- Fontanges T.
- Ouzan D.
- Rotily M.
- Varastet M.
- et al.