Challenges in the treatment of hepatitis C: Current state and - - PowerPoint PPT Presentation

Challenges in the treatment of hepatitis C: Current state and activities of the German Center for Infection Research (DZIF)

Thomas von Hahn

Klinik für Gastroenterologie, Hepatologie und Endokrinologie Medizinische Hochschule Hannover

Global annual mortality from hepatitis, HIV, tuberculosis and malaria, 2000-2015

WHO Global Hepatitis Report 2017

Viral hepatitis continues to pose a public health challenge…

• Genotype 3
• Pre-treated
• After liver transplant
• Renal failure
• Compensated and

decompensated cirrhosis

• HIV coinfection

… but are there still challenges in treating HCV in individual patients?

?

A Case

History

• 44 y.o. male
• Presents to ER with hematemesis
• RF: (Past?) IVDU and Alcohol Use

Diagnoses

• Variceal bleeding
• Cirrhosis
• HCV Genotype 3 Infection
• HIV Infection under ART

Challenges

• HCV Genotype 3
• ART plus Anti-HCV
• Risik of re-infection in IVDU
• Liver transplant:

− HIV − Possible ALD component − „TX first“ or „Anti-HCV first“

Genotype 3

Genotype 3 Data from the GErman hepatitis C COhort (GECCO)

Christensen et al. AASLD 2017 Abstract #63.

Current Recommendations for HCV Genotype 3

Keine Zirrhose Kompensierte Zirrhose Recommended

• Sofosbuvir/Velpatasvir

/Voxilaprevir (12W)

• Sofosbuvir/Velpatasvir

/Voxilaprevir + Ribavirin (12W)

AASLD/IDSA Empfehlung 2017

Keine Zirrhose Kompensierte Zirrhose Recommended

• Glecaprevir/Pibrentasvir

(8W)

• Sofosbuvir/Velpatasvir

(12W)

• Glecaprevir/Pibrentasvir

(12W)

• Sofosbuvir/Velpatasvir

(12W) Treatment-naive NS5A-experienced

Bourlière et al. NEJM 2017

HCV/HIV Co-Infection

Grazoprevir/Elbasvir in HCV Mono- and HCV/HIV Co-Infection

C-WORTHY Trial. Sulkowski et al. Lancet 2015.

Risk of drug- drug interactions in HCV in real-life

Anti-HCV Regime Höner zu Siederdissen et al. Clin Infect Dis. 2016

DDI between anti- HCV combinations and ART

AASLD/IDSA Empfehlung 2017

Liver Transplantation

DZIF Cohort: DAA following liver TX (MHH/UKE)

Ciesek et al. Transpl. Infect Dis 2016. (LDV/SOF/RBV)

(1) Charlton et al. Gastro 2015 (LDV/SOF/RBV) (2) Manns et al. Lancet ID 2016 (LDV/SOF/RBV) (3) Poordad et al. Hepatol 2016 (DAC/SOF) (4) Ciesek et al. Transpl. Infect Dis 2016. (LDV/SOF/RBV) (5) Kwo et al. NEJM 2014. (DAS/OMB/PAR/RBV)

SVR

All Studies Total: Patients 545 SAE‘s 99 Deaths 12 DZIF Sites:

• Hamburg
• Hannover

Studies on HCV DAA treatment following liver TX

Advanced Cirrhosis

SOLAR-2 Studie: LED/SOF in Advanced Liver Disease

• Pre-TX / Child C Subgroup:
• SVR 81%
• Mortality 12%

Manns et al. Transpl. Lancet ID 2016.

Independent variable

• Strategies „TX before DAA“ vs. „DAA

before TX“ Primary endpoint

• Survival

Secondary endpoints

• Liver function
• HCV status
• TX status

Population

• Retrospective multicenter analysis
• Centers: Frankfurt, Hamburg, Hannover,

Heidelberg, Tübingen Inclusion criteria

• Chronic Hepatitis C
• Advanced Cirrhosis (MELD 15+)

Exclusion criteria

• Contraindication to liver TX
• HCC

DZIF analysis of management strategies in advanced HCV cirrhosis

13 6

Table 1. Baseline Characteristics total cohort DAA pre Tx no DAA pre Tx total 19 13 6 Age (years), mean ± SD 51,95 (±7,4) 52,15 (±7,03) 51,5 (±8,2) male gender, N (%) 15 (78,9) 9 (69,2) 6 (100) BMI (m/kg2), mean ± SD 28,55 (±5,4) 29,41 (±5,98) 26,7 (±3,0) INR, mean ± SD 1,57 (±0,25) 1,56 (±0,21) 1,59 (±0,31) Bilirubin (µmol/L), mean ± SD 78 (±58,3) 65 (±23,5) 104 (±92,2) Creatinine (µmol/L), mean ± SD 119 (±123,6) 92 (±84,7) 179 (±166,3) labMELD, mean ± SD 18,7 (±3,7) 17,5 (±1,7) 21,5 (±5,2) Child-Pugh score, mean ± SD 9,8 (±2,1) 9,2 (±1,99) 10,8 (±1,8)

DZIF analysis of management strategies in advanced HCV cirrhosis

Sandmann et al. Unpublished data.

DZIF analysis of management strategies in advanced HCV cirrhosis

Sandmann et al. Unpublished data.

DAA pre TX No DAA pre TX

What is the current key challenge in HCV?

Glo lobal al Eradic ication ion by 2030 2030 ? ?

• HCV Genotype
• Subgenotype
• Chimäric Genotypes
• Acute vs. Chronic Infection
• Pretreatment
• Resistance
• Fibrosis
• Cirrhosis
• Co-Infections
• Co-Morbidities
• Co-Medications
• Ledipasvir/Sofosbuvir
• Sofosbuvir/Velpatasvir +/-

Voxilaprevir

• Paritaprevir/Ombitasvir/Ritonavir

+/- Dasabuvir

• Glecaprevir/Pibrentasvir
• Elbasvir/Grazoprevir

Ribavirin ? Interferon ? New DAA‘s ? Liver TX ? Vaccine ? Access to Care Resistance testing

What is the current key challenge in HCV?

Reinfections

Summary

• Individual management can be challenging in 2018:

– Very advanced cirrhosis (MELD 15+) – Combinations of unfavorable factors

• Even in „challenging“ patient subgroups „per protocol“ SVR

rates are very high – the challenge often lies in adverse events during therapy and thus „intention to treat“ SVR.

• Key challenge is optimal individualized treatment in face of

– Many available combinations – Many factors impacting optimal choice of regimen – High cost – Risk of resistance development