What is the primary treatment recommendation for a patient with active or chronic Hepatitis C (HCV), as indicated by quantitative Polymerase Chain Reaction (PCR), considering factors such as viral genotype, presence of cirrhosis, and prior treatment experience?

Distinguishing Active vs Chronic Hepatitis C on Quantitative PCR

The presence of detectable HCV RNA on quantitative PCR indicates active hepatitis C infection requiring treatment with direct-acting antivirals (DAAs), regardless of whether the infection is acute or chronic. 1

Understanding the Terminology

The term "active" hepatitis C is somewhat misleading in clinical practice. What matters clinically is:

• Detectable HCV RNA by quantitative PCR = Active viral replication = Indication for treatment 1
• Chronic hepatitis C is defined as persistent HCV RNA positivity for >6 months 2
• All patients with detectable HCV RNA should be treated, as this represents ongoing viral replication with risk of progressive liver disease 2, 1

Pre-Treatment Assessment Required

Before initiating DAA therapy, complete the following essential tests 1:

• HCV RNA quantitative level (viral load) 2, 1
• HCV genotype and subtype determination 2, 1
• Fibrosis staging using noninvasive methods (FibroScan, APRI, FIB-4) 1
• Liver function tests (AST, ALT, bilirubin, albumin, platelet count, INR) 2, 1
• Assessment for cirrhosis presence 2
• Screening for HIV, HBV, and other sexually transmitted infections 2
• Comprehensive drug-drug interaction screening 1

Primary Treatment Recommendations

For treatment-naive patients without cirrhosis (all genotypes): 1

• Sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks (preferred first-line, achieves 98% SVR) 2, 3, 1
• Glecaprevir/pibrentasvir 300mg/120mg once daily with food for 8 weeks (alternative option) 2, 3, 1

For treatment-naive patients with compensated cirrhosis (all genotypes): 1

• Sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks 2, 1
• Glecaprevir/pibrentasvir 300mg/120mg once daily with food for 12 weeks 2, 3, 1

Genotype-Specific Considerations

For HCV Genotype 1a specifically: 3, 1

• Sofosbuvir/velpatasvir for 12 weeks or glecaprevir/pibrentasvir for 8 weeks (without cirrhosis) or 12 weeks (with cirrhosis) 3, 1
• Alternative: Ledipasvir/sofosbuvir 90mg/400mg once daily for 12 weeks 2, 3, 4
• Check for Q80K polymorphism if considering simeprevir-based regimens, as this reduces efficacy 2, 1

For HCV Genotype 1b: 2, 1

• Ledipasvir/sofosbuvir for 12 weeks 2, 4
• Paritaprevir/ritonavir/ombitasvir plus dasabuvir for 12 weeks without ribavirin 2

For HCV Genotype 3 (more difficult to treat): 2

• Treatment-naive without cirrhosis: Sofosbuvir/velpatasvir for 12 weeks 2
• Treatment-naive with cirrhosis or treatment-experienced: Sofosbuvir/velpatasvir for 12 weeks, but consider extending to 24 weeks or adding ribavirin if NS5A RASs present 2

For HCV Genotypes 4,5, or 6: 2, 1

• Sofosbuvir/velpatasvir for 12 weeks 2, 1
• Glecaprevir/pibrentasvir for 8-12 weeks depending on cirrhosis status 2

Treatment Prioritization

Immediate treatment without delay is indicated for: 1

• Advanced fibrosis (≥F3) or any cirrhosis 1
• Pre- and post-liver transplant patients 2, 1
• Severe extrahepatic manifestations 1
• Hepatocellular carcinoma 2, 1

Monitoring During and After Treatment

During treatment: 1

• HCV RNA testing at baseline, weeks 4 and 12, end of treatment, and 12 weeks post-treatment 1
• Liver function tests monitoring 1
• Assessment for hepatic decompensation in cirrhotic patients 1

Definition of cure (SVR12): 1

• Undetectable HCV RNA 12 weeks after treatment completion 1
• Achieved in >99% of patients who reach this endpoint 1

Post-SVR surveillance: 3, 1

• Lifelong HCC surveillance with ultrasound every 6 months for patients with cirrhosis (F4) or advanced fibrosis (F3), even after achieving SVR 3, 1

Special Populations

HIV/HCV coinfected patients: 1

• Use identical HCV treatment regimens as HCV mono-infected patients with identical virological outcomes 1
• Verify antiretroviral drug interactions before prescribing 1

Decompensated cirrhosis (Child-Pugh B or C): 2

• Avoid protease inhibitors 2
• Use sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, or sofosbuvir/daclatasvir with ribavirin 2
• Treatment duration 12-24 weeks depending on genotype and MELD score 2

Pregnancy: 2

• DAA regimens should only be initiated in clinical trials during pregnancy 2
• No DAA therapy is currently approved for use during pregnancy 2

Common Pitfalls and Caveats

Drug-drug interactions are critical: 1

• Comprehensive screening must be performed before initiating DAA therapy 1
• Pay particular attention to antiretrovirals, proton pump inhibitors, statins, and cardiac medications 2

Resistance-associated substitutions (RASs): 3, 1

• Baseline NS5A RASs may reduce efficacy, particularly in genotype 1a and 3 3, 1
• When using elbasvir/grazoprevir, patients with NS5A RASs require 16 weeks plus ribavirin instead of 12 weeks 3

Genotype 3 requires special attention: 2

• Most difficult genotype to treat with available DAAs 2
• Higher relapse rates, particularly in cirrhotic patients with NS5A RASs 2
• Consider extended duration or ribavirin addition in treatment-experienced or cirrhotic patients 2

Post-SVR HCC risk persists: 3, 1

• Achieving SVR does not eliminate HCC risk in patients with cirrhosis or advanced fibrosis 3, 1
• Lifelong surveillance remains mandatory 3, 1