Hepatitis C Infection Treatment Protocol
Primary Treatment Recommendation
All patients with confirmed chronic hepatitis C should be treated with pangenotypic direct-acting antiviral (DAA) regimens, with sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks as the preferred first-line option across all genotypes, achieving sustained virologic response (SVR) rates of 98%. 1, 2, 3
Pre-Treatment Assessment (Mandatory)
Before initiating any DAA therapy, the following tests must be completed 1, 2, 3:
- HCV RNA quantitative testing to confirm active infection 1
- HCV genotype and subtype determination (genotype 1 must be subtyped as 1a vs 1b, as this affects treatment selection) 1, 3
- Hepatitis B testing: HBsAg and anti-HBc to identify HBV coinfection risk 4
- Fibrosis staging using noninvasive methods (FibroScan, APRI, FIB-4) or liver biopsy if uncertainty exists 1, 2
- Comprehensive drug-drug interaction screening before prescribing 1, 3
First-Line Treatment Regimens by Clinical Scenario
Treatment-Naive Patients Without Cirrhosis (All Genotypes)
Option 1 (Preferred): Sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks 1, 2, 3, 4
Option 2 (Alternative): Glecaprevir/pibrentasvir (300mg/120mg total) once daily with food for 8 weeks 1, 2, 3
Treatment-Naive Patients With Compensated Cirrhosis (Child-Pugh A)
Option 1 (Preferred): Sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks 1, 2, 3
Option 2 (Alternative): Glecaprevir/pibrentasvir once daily with food for 12 weeks (extended from 8 weeks) 1, 2, 3
Patients With Decompensated Cirrhosis (Child-Pugh B or C)
Sofosbuvir/velpatasvir 400mg/100mg once daily PLUS weight-based ribavirin for 12 weeks 4, 5
- Ribavirin dosing: 1,000 mg/day if <75 kg; 1,200 mg/day if ≥75 kg, divided twice daily with food 4
- Critical warning: Monitor closely if albumin <3.5 g/dL, platelets <100,000, or MELD >14, as these predict higher risk of further decompensation 1, 5
- SVR rates exceed 80% but are lower than in compensated cirrhosis 5
Genotype-Specific Considerations (2015 Guidelines Context)
While pangenotypic regimens are now preferred, older genotype-specific regimens may still be relevant in resource-limited settings 6:
Genotype 1a (Treatment-Naive)
- Ledipasvir/sofosbuvir 90mg/400mg once daily for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis) 6
- Paritaprevir/ritonavir/ombitasvir plus dasabuvir with weight-based ribavirin for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis) 6
- Avoid simeprevir in genotype 1a with cirrhosis if Q80K polymorphism is present 6
Genotype 1b (Treatment-Naive)
- Ledipasvir/sofosbuvir 90mg/400mg once daily for 12 weeks 6
- Paritaprevir/ritonavir/ombitasvir plus dasabuvir for 12 weeks (no ribavirin needed) 6
Genotype 2 (Treatment-Naive)
- Sofosbuvir 400mg plus weight-based ribavirin for 12 weeks (extend to 16 weeks if cirrhosis) 6
Genotype 3 (Treatment-Naive)
- Sofosbuvir 400mg plus weight-based ribavirin for 24 weeks 6
- Genotype 3 is the most difficult to treat and has higher failure rates 6
Genotype 4 (Treatment-Naive)
- Ledipasvir/sofosbuvir 90mg/400mg once daily for 12 weeks 6
- Paritaprevir/ritonavir/ombitasvir with weight-based ribavirin for 12 weeks 6
Genotypes 5 or 6 (Treatment-Naive)
- Ledipasvir/sofosbuvir 90mg/400mg once daily for 12 weeks 6
Retreatment After DAA Failure
Failed Prior Sofosbuvir-Based Regimen (Without NS5A Inhibitor)
Sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, or sofosbuvir/daclatasvir with ribavirin for 12 weeks (F0-F2) or 24 weeks (F3-F4) 1, 2
Failed Prior NS5A Inhibitor-Containing Regimen
Sofosbuvir with a protease inhibitor (grazoprevir/elbasvir or simeprevir) plus ribavirin for 12 weeks (genotype 1b or 4 without cirrhosis) or 24 weeks (genotype 1a or cirrhosis) 1
Failed Prior Peginterferon/Ribavirin (Without DAA)
Genotype 1 Without Cirrhosis:
- Ledipasvir/sofosbuvir for 12 weeks 6
- Paritaprevir/ritonavir/ombitasvir plus dasabuvir with ribavirin for 12 weeks 6
Genotype 1 With Cirrhosis:
- Ledipasvir/sofosbuvir for 24 weeks (higher SVR than 12 weeks in cirrhosis) 6
Special Populations
HIV/HCV Coinfection
- Use identical HCV treatment regimens as HCV mono-infected patients with identical virological outcomes 1, 7
- Verify antiretroviral drug interactions before prescribing 3
- Monitor CD4+ counts, as median decreases of 84-85 cells/mm³ occur during treatment but recover post-treatment 8
- 100% SVR12 achieved in HIV/AHC patients with DAA regimens 7
Liver Transplant Recipients
- Sofosbuvir/velpatasvir plus ribavirin for 12 weeks (both pre- and post-transplant) 1
- Fewer than one-third of transplant-eligible patients can be delisted after achieving SVR 5
Pediatric Patients (≥3 Years Old)
- Sofosbuvir/velpatasvir dosing per weight-based tables for ages 3-17 years 4
- For genotype 2/3: sofosbuvir plus weight-based ribavirin for 12 weeks (genotype 2) or 24 weeks (genotype 3) 8
- 100% SVR12 in genotype 2 and 97% in genotype 3 pediatric patients 8
Critical Drug-Drug Interactions (Absolute Contraindications)
Do not use DAAs with the following medications, as they significantly decrease DAA concentrations and reduce efficacy 3:
- P-glycoprotein (P-gp) inducers: rifampin, St. John's wort, carbamazepine 3
- Moderate-to-strong CYP3A4 inducers: phenytoin, phenobarbital, efavirenz 3
- Specific interactions with ledipasvir/sofosbuvir: proton pump inhibitors (dose-dependent interaction) 6
- Specific interactions with paritaprevir/ritonavir/ombitasvir: salmeterol and other CYP3A4 substrates 6
Treatment Prioritization (Immediate Treatment Required)
The following patients should receive immediate treatment without delay 1, 2, 3:
- Advanced fibrosis (≥F3) or any cirrhosis 1, 2, 3
- Pre- and post-liver transplant patients 1, 2
- Severe extrahepatic manifestations (symptomatic vasculitis, HCV immune complex nephropathy) 1, 2
- Hepatocellular carcinoma 1, 2
- Individuals at high risk of transmission: active injection drug users, men who have sex with men with high-risk practices, incarcerated persons, hemodialysis patients, HCV-infected women wishing to become pregnant, infected healthcare workers performing exposure-prone procedures 6
Patients with minimal or no fibrosis (F0-F2) should still be scheduled for treatment rather than deferred, though timing may be more flexible 1
Monitoring Protocol
During Treatment
- HCV RNA testing: baseline, weeks 4 and 12 during treatment, end of treatment, and 12 weeks post-treatment 1, 3
- Liver function tests: ALT, AST, GGT decrease during treatment; platelet count increases 9
- For decompensated cirrhosis: monitor albumin, bilirubin, INR, and clinical signs of decompensation 5
Definition of Cure
- SVR12 (undetectable HCV RNA 12 weeks after treatment completion) defines cure, achieved in >99% of patients who reach this endpoint 6, 1, 2
- SVR12 represents viral eradication and is associated with resolution of liver disease in non-cirrhotic patients 1
Post-SVR Follow-Up (Lifelong for Cirrhosis)
Patients With Cirrhosis (F4) or Advanced Fibrosis (F3)
- Lifelong hepatocellular carcinoma (HCC) surveillance with ultrasound every 6 months indefinitely, even after achieving SVR 2, 3
- Continue monitoring for hepatic decompensation, though risk is reduced after SVR 6
All Patients Post-SVR
- Fibrosis reassessment to document regression 2
- Monitor for reinfection in at-risk patients (active injection drug users, men who have sex with men) 2
Expected Clinical Benefits of Achieving SVR
Successful HCV eradication provides 2, 10:
- Prevention of cirrhosis complications, hepatocellular carcinoma, hepatic decompensation, and death 2
- Improvement in liver histology with regression of fibrosis 10
- Resolution of extrahepatic manifestations: mixed cryoglobulinemia (clinical and immunological responses), thrombocytopenia, insulin resistance (improves in 90%), increased glomerular filtration rate, decreased proteinuria and hematuria, reduced articular manifestations 10
- Cardiovascular benefits: significant improvement in atherosclerosis, reduction of major cardiovascular events 10
- Quality of life improvements: improved physical function, reduced fatigue, improved cognitive function, removal of stigma 2, 10
Common Pitfalls to Avoid
- Do not defer treatment in patients with advanced fibrosis (F3-F4), as these patients have the most urgent need and greatest short-term benefit from viral eradication 3
- Do not use genotype 1a-specific regimens without confirming subtype; genotype 1 that cannot be subtyped should be treated as 1a 3
- Do not prescribe DAAs without verifying drug-drug interactions, particularly with antiretrovirals, cardiac medications, and acid-suppressing agents 3
- Do not use protease inhibitor plus NS5A inhibitor combinations in decompensated cirrhosis due to safety concerns, despite efficacy 5
- Do not forget to test for hepatitis B before starting DAAs, as HBV reactivation can occur and has resulted in fulminant hepatitis, hepatic failure, and death 4
Risk Factors for DAA Failure
The following factors predict lower SVR rates 10: