What is the recommended treatment for chronic hepatitis C infection, including first‑line direct‑acting antiviral regimens and considerations for genotype, cirrhosis, prior therapy, and renal function?

Treatment of Hepatitis C

First-Line Treatment: Pangenotypic Direct-Acting Antivirals

All patients with chronic hepatitis C should be treated with interferon-free, pangenotypic direct-acting antiviral (DAA) regimens, with sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks or glecaprevir/pibrentasvir for 8-12 weeks (depending on cirrhosis status) as the preferred first-line options across all genotypes. 1, 2

Recommended First-Line Regimens by Clinical Status

Treatment-Naïve Patients:

• Without cirrhosis: Sofosbuvir/velpatasvir for 12 weeks OR glecaprevir/pibrentasvir for 8 weeks (both achieve ~98% SVR rates) 1, 2
• With compensated cirrhosis (Child-Pugh A): Sofosbuvir/velpatasvir for 12 weeks OR glecaprevir/pibrentasvir for 12 weeks 3, 1

These pangenotypic regimens eliminate the need for genotype testing before treatment initiation, though genotyping remains recommended for treatment planning and retreatment scenarios. 1

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Treatment Selection Based on Renal Function

Patients with severe renal impairment require specific DAA selection to avoid nephrotoxic accumulation:

• GFR ≥30 mL/min/1.73 m² (CKD G1-G3b): Any licensed DAA regimen may be used 3
• GFR <30 mL/min/1.73 m² (CKD G4-G5D, including dialysis): Use ribavirin-free regimens only 3
  • Preferred: Glecaprevir/pibrentasvir (97-98% SVR in EXPEDITION-5 trial with stage 4-5 CKD) 3, 4
  • Alternative: Elbasvir/grazoprevir (94-98% SVR in C-SURFER trial) 3, 5
  • Avoid: Sofosbuvir-based regimens are not FDA-approved for GFR <30 due to renal excretion 3, 6

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Genotype-Specific Considerations for Treatment-Experienced Patients

Genotype 1

Treatment-naïve or PegIFN/RBV-experienced:

• Ledipasvir/sofosbuvir for 12 weeks 3
• Elbasvir/grazoprevir for 12 weeks 3
• Glecaprevir/pibrentasvir for 8 weeks (no cirrhosis) or 12 weeks (cirrhosis) 3, 7

Prior NS5A inhibitor failure (without prior protease inhibitor):

• Glecaprevir/pibrentasvir for 16 weeks OR sofosbuvir/velpatasvir/voxilaprevir for 8 weeks 8, 7

Prior NS3/4A protease inhibitor failure (without prior NS5A inhibitor):

• Elbasvir/grazoprevir for 12 weeks OR glecaprevir/pibrentasvir for 12 weeks 3, 5

Genotype 3 (Higher Complexity)

Treatment-naïve without cirrhosis:

• Glecaprevir/pibrentasvir for 8 weeks OR sofosbuvir/velpatasvir for 12 weeks 3

Treatment-naïve with compensated cirrhosis:

• Glecaprevir/pibrentasvir for 12 weeks OR sofosbuvir/velpatasvir + ribavirin for 12 weeks 3
• Alternative: Sofosbuvir/velpatasvir/voxilaprevir for 8 weeks (96% SVR in cirrhotic patients) 3, 8

Treatment-experienced without cirrhosis:

• Glecaprevir/pibrentasvir for 16 weeks OR daclatasvir + sofosbuvir + ribavirin for 12 weeks 3

Treatment-experienced with cirrhosis:

• Daclatasvir + sofosbuvir + ribavirin for 24 weeks (SVR 82-95%) OR elbasvir/grazoprevir + sofosbuvir for 12 weeks (SVR 94-100%) 3

Genotype 3 with cirrhosis represents the most challenging scenario, requiring longer treatment duration or ribavirin addition due to lower SVR rates with standard regimens. 3

Genotype 4

Treatment-naïve (with or without cirrhosis):

• Ledipasvir/sofosbuvir for 12 weeks 3
• Elbasvir/grazoprevir for 12 weeks 3
• Glecaprevir/pibrentasvir for 8 weeks (no cirrhosis) or 12 weeks (cirrhosis) 3
• Ombitasvir/paritaprevir/ritonavir + ribavirin for 12 weeks 3

Treatment-experienced:

• Same regimens as treatment-naïve, with glecaprevir/pibrentasvir maintaining 8-12 week duration based on cirrhosis status 3

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Treatment in Special Populations

Decompensated Cirrhosis (Child-Pugh B/C)

Critical: Avoid protease inhibitors (glecaprevir, paritaprevir, grazoprevir) in decompensated cirrhosis due to hepatic metabolism concerns. 2, 6

Recommended regimens:

• Sofosbuvir + ledipasvir + ribavirin for 12 weeks 2, 6
• Sofosbuvir + velpatasvir + ribavirin for 12 weeks 2, 6
• Sofosbuvir + daclatasvir + ribavirin for 12 weeks 2, 6

Start ribavirin at 600 mg daily and titrate based on tolerance, as decompensated patients have higher adverse event rates. 2

HIV/HCV Coinfection

Treat with identical HCV regimens as HCV mono-infected patients, with equivalent virological outcomes. 2

Critical drug-drug interactions to avoid:

• Sofosbuvir/ledipasvir with tenofovir/emtricitabine plus boosted protease inhibitors (atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir) or elvitegravir/cobicistat 2
• Paritaprevir/ombitasvir/dasabuvir with efavirenz, etravirine, nevirapine, or elvitegravir/cobicistat 2

Always screen for drug-drug interactions before initiating therapy, particularly with antiretrovirals, cardiac medications, and acid-suppressing agents. 1, 2

Liver Transplant Recipients

Sofosbuvir/velpatasvir + ribavirin for 12 weeks is recommended for both pre- and post-transplant settings. 2

Calcineurin inhibitors (tacrolimus, cyclosporine) and mTOR inhibitors (sirolimus, everolimus) may be safely co-administered with sofosbuvir/ledipasvir and glecaprevir/pibrentasvir, though dose adjustments may be required for paritaprevir/ritonavir-containing regimens. 6

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Retreatment After DAA Failure

Confirm virologic failure by repeating HCV RNA testing to exclude laboratory error, and test for resistance-associated substitutions (RAS) if available. 8

Retreatment Algorithm by Prior Regimen

Failed sofosbuvir alone or sofosbuvir + ribavirin:

• Sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, or sofosbuvir/daclatasvir + ribavirin for 12 weeks (F0-F2) or 24 weeks (F3-F4) 2

Failed NS5A inhibitor-containing regimen:

• Sofosbuvir + protease inhibitor (grazoprevir/elbasvir or simeprevir) + ribavirin for 12 weeks (genotype 1b or 4 without cirrhosis) or 24 weeks (genotype 1a or with cirrhosis) 2

Failed any DAA regimen with compensated cirrhosis:

• Genotype 3: Sofosbuvir/velpatasvir/voxilaprevir for 8 weeks (preferred, 96% SVR) OR sofosbuvir/velpatasvir + ribavirin for 12 weeks 8
• Other genotypes: Glecaprevir/pibrentasvir for 16 weeks OR sofosbuvir/velpatasvir/voxilaprevir for 8 weeks 8

Patients with platelet count <75,000/μL require the most potent regimen available (sofosbuvir/velpatasvir/voxilaprevir) due to negative prognostic implications. 8

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Pre-Treatment Assessment Requirements

Mandatory testing before initiating DAA therapy:

• Hepatitis B screening: HBsAg and anti-HBc (HBV reactivation has caused fulminant hepatitis and death in coinfected patients) 7, 5
• HCV RNA quantitative testing (baseline viral load) 1, 2
• HCV genotype and subtype determination (genotype 1a vs 1b affects treatment selection) 1, 2
• Fibrosis staging using noninvasive methods (FibroScan, FIB-4, APRI) or liver biopsy if uncertainty exists 1, 2
• Comprehensive drug-drug interaction screening (particularly antiretrovirals, cardiac medications, acid suppressants) 1, 2
• Baseline liver function tests and MELD score (in cirrhotic patients) 2
• Renal function assessment (GFR calculation to guide DAA selection) 3

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Monitoring Protocol

On-treatment monitoring:

• HCV RNA at weeks 4 and 12 during treatment 2
• Liver function tests and close monitoring for decompensation in cirrhotic patients 2

Post-treatment monitoring:

• HCV RNA at end of treatment and 12 weeks post-treatment 1, 2
• SVR12 (undetectable HCV RNA 12 weeks after treatment completion) defines cure and is achieved in >99% of patients who reach this endpoint 2

Long-term surveillance:

• Patients with cirrhosis require lifelong HCC surveillance with ultrasound every 6 months, even after achieving SVR, as residual HCC risk persists 8, 1, 2

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Treatment Prioritization

Immediate treatment priority for:

• Advanced fibrosis (≥F3) or any cirrhosis 1, 2
• Decompensated cirrhosis awaiting liver transplantation 2
• Pre- and post-liver transplant patients 2
• Severe extrahepatic manifestations (symptomatic cryoglobulinemia, HCV immune complex nephropathy) 2
• Hepatocellular carcinoma with or without transplant indication 2

Patients with minimal or no fibrosis (F0-F2) should still be scheduled for treatment rather than deferred, though timing may be more flexible. 2

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Critical Pitfalls to Avoid

• Never use protease inhibitors (glecaprevir, grazoprevir, paritaprevir) in decompensated cirrhosis due to hepatic metabolism requirements 2, 6
• Never use sofosbuvir-based regimens in GFR <30 mL/min/1.73 m² without FDA approval due to renal excretion 3
• Never defer treatment in advanced fibrosis (F3-F4), as these patients have the most urgent need and greatest short-term benefit from viral eradication 1
• Never use P-glycoprotein inducers or moderate-to-strong CYP inducers with DAAs, as they significantly decrease DAA concentrations and reduce efficacy 1, 2
• Always verify HBV status before treatment, as HBV reactivation can be fatal in coinfected patients 7, 5
• Always continue HCC surveillance indefinitely in cirrhotic patients, even after SVR, as residual HCC risk remains at approximately 25% of baseline risk 8

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Expected Outcomes

Achieving SVR provides:

• 70-90% reduction in liver-related mortality 2
• 70-90% reduction in overall mortality 2
• 75-90% reduction in HCC incidence 8, 2
• Prevention of hepatic decompensation 2
• Improvement in liver histology in non-cirrhotic patients 2
• Resolution of extrahepatic manifestations 2

Modern DAA regimens achieve SVR rates exceeding 95% in most patient populations, including historically difficult-to-treat categories such as genotype 3 with cirrhosis, decompensated cirrhosis, and severe renal impairment. 3, 9, 10