What are the current hepatitis C treatment options, including direct‑acting antiviral regimens for patients without cirrhosis, with compensated or decompensated cirrhosis, renal impairment, pregnancy, or prior treatment failure?

Treatment Options for Hepatitis C

All patients with chronic hepatitis C should receive interferon-free, direct-acting antiviral (DAA) regimens, with pangenotypic combinations like sofosbuvir/velpatasvir or glecaprevir/pibrentasvir being the preferred first-line options for most patients. 1

First-Line Pangenotypic Regimens (Preferred for Most Patients)

For patients without cirrhosis and those with compensated cirrhosis (Child-Pugh A), the following pangenotypic regimens are recommended:

• Sofosbuvir/velpatasvir for 12 weeks across all genotypes 1
• Glecaprevir/pibrentasvir for 8 weeks in patients without cirrhosis, or 12 weeks in patients with compensated cirrhosis 1
• Sofosbuvir/velpatasvir/voxilaprevir for 8-12 weeks (particularly useful in treatment-experienced patients) 1

These regimens achieve sustained virological response (SVR) rates of 95-100% across all genotypes and patient populations 1, 2.

Treatment by Patient Population

Patients Without Cirrhosis (Treatment-Naïve)

• Glecaprevir/pibrentasvir for 8 weeks is the shortest effective regimen 1
• Sofosbuvir/velpatasvir for 12 weeks is an alternative pangenotypic option 1
• Treatment-naïve patients with minimal fibrosis (F0-F1) can still receive treatment, though timing may be individualized based on transmission risk and patient preference 1, 2

Patients With Compensated Cirrhosis (Child-Pugh A)

• Glecaprevir/pibrentasvir for 12 weeks 1
• Sofosbuvir/velpatasvir for 12 weeks 1
• Ledipasvir/sofosbuvir for 12 weeks (genotypes 1,4,5,6) 1
• Patients with significant fibrosis (F3) or cirrhosis (F4) should be prioritized for immediate treatment due to higher risk of complications 1, 2, 3

Patients With Decompensated Cirrhosis (Child-Pugh B and C)

These patients require urgent treatment but must avoid protease inhibitors (NS3/4A inhibitors) due to safety concerns. 1, 2

• Sofosbuvir/velpatasvir for 12 weeks with ribavirin (starting at 600 mg daily) 1
• Daclatasvir plus sofosbuvir for 12 weeks with low-dose ribavirin (600 mg) achieved 83% SVR in decompensated patients 1
• Ledipasvir/sofosbuvir with ribavirin for 12-24 weeks 4
• Patients with MELD scores ≥18-20 who are liver transplant candidates should generally be transplanted first and treated post-transplant 2
• Close monitoring is essential as 5% of patients died from variceal bleeding during treatment in clinical trials 1

Post-Liver Transplant Recipients

• Ledipasvir/sofosbuvir plus ribavirin for 12 weeks achieved 95% SVR in post-transplant patients without cirrhosis and 98% in those with Child-Pugh A cirrhosis 4
• SVR rates were lower (57%) in post-transplant patients with Child-Pugh C cirrhosis 4
• All 7 patients with fibrosing cholestatic hepatitis achieved SVR with 12 weeks of treatment 4

Patients With Severe Renal Impairment (eGFR <30 mL/min) or End-Stage Renal Disease

Avoid sofosbuvir-containing regimens when possible due to renal safety concerns; use protease inhibitor-based regimens instead. 1

For genotype 1a:

• Grazoprevir/elbasvir for 12 weeks (with ribavirin 200 mg/day if hemoglobin >10 g/dL) 1
• Ritonavir-boosted paritaprevir/ombitasvir/dasabuvir for 12 weeks (with ribavirin 200 mg/day if hemoglobin >10 g/dL) 1

For genotype 1b:

• Grazoprevir/elbasvir for 12 weeks without ribavirin 1
• Ritonavir-boosted paritaprevir/ombitasvir/dasabuvir for 12 weeks without ribavirin 1

For genotype 4:

• Grazoprevir/elbasvir for 12 weeks without ribavirin 1
• Ritonavir-boosted paritaprevir/ombitasvir for 12 weeks (with ribavirin 200 mg/day if hemoglobin >10 g/dL) 1

If urgent treatment is needed for genotypes 2 or 3 in dialysis patients:

• Sofosbuvir/velpatasvir or sofosbuvir/daclatasvir may be used with careful renal monitoring, but treatment should be stopped immediately if renal function deteriorates 1
• In a trial of 63 dialysis patients, ledipasvir/sofosbuvir achieved 93-100% SVR across 8,12, and 24-week treatment durations 4

Treatment-Experienced Patients (Prior DAA Failure)

For patients who failed NS5A inhibitor-containing regimens (genotypes 1 or 4):

• Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks with ribavirin 1
• Sofosbuvir plus ritonavir-boosted paritaprevir/ombitasvir/dasabuvir (genotype 1) or sofosbuvir plus ritonavir-boosted paritaprevir/ombitasvir (genotype 4) for 12-24 weeks with ribavirin 1
• Treatment duration should be 24 weeks for genotype 1a and for patients with F3 fibrosis or compensated cirrhosis 1

For patients who failed sofosbuvir-based regimens without NS5A inhibitors:

• Sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, or sofosbuvir/daclatasvir can be used for retreatment 1

For genotypes 2,3,5, or 6 with prior NS5A inhibitor failure:

• Sofosbuvir/velpatasvir for 24 weeks with ribavirin 1

Special Populations Requiring Priority Treatment

The following groups should receive immediate treatment regardless of fibrosis stage: 1, 2

• HIV or HBV coinfected patients 1, 2
• Pre- or post-liver transplant patients 1, 2
• Patients with clinically significant extrahepatic manifestations (symptomatic vasculitis, cryoglobulinemia, HCV-related nephropathy, non-Hodgkin B-cell lymphoma) 1, 2
• Active injection drug users 1, 2
• Men who have sex with men with high-risk sexual practices 1, 2
• Women of childbearing age who wish to become pregnant 1, 2
• Hemodialysis patients 1, 2
• Incarcerated individuals 1, 2

Pregnancy

No DAA regimens are currently approved for use during pregnancy. Treatment should be deferred until after delivery, as the evidence base for safety and efficacy in pregnancy is insufficient.

Genotype-Specific Considerations

While pangenotypic regimens are preferred, genotype-specific options remain available:

Genotype 1b (without cirrhosis, F0-F2 fibrosis):

• Grazoprevir/elbasvir for 8 weeks achieved 88-97% SVR in treatment-naïve patients 1

Genotypes 5 and 6:

• Ledipasvir/sofosbuvir for 12 weeks 1
• Daclatasvir plus sofosbuvir for 12 weeks 1
• Glecaprevir/pibrentasvir (8 weeks without cirrhosis, 12 weeks with cirrhosis) 1
• Sofosbuvir/velpatasvir for 12 weeks 1

Monitoring and Follow-Up

• SVR is defined as undetectable HCV RNA at 12 weeks post-treatment and represents cure in the vast majority of cases 2
• Patients with cirrhosis require lifelong HCC surveillance every 6 months even after achieving SVR, as the risk is reduced but not eliminated 2, 3
• Non-invasive fibrosis assessment should be performed before treatment to guide regimen selection 2, 3

Common Pitfalls to Avoid

• Never use protease inhibitors (grazoprevir, paritaprevir, simeprevir) in decompensated cirrhosis due to risk of hepatic decompensation 2
• Avoid sofosbuvir in severe renal impairment (eGFR <30) unless no alternatives exist, and monitor renal function closely if used 1
• When using ribavirin in renal impairment, start at 200 mg/day and monitor hemoglobin frequently; discontinue if hemoglobin drops below 8.5 g/dL 1
• Check for drug-drug interactions before starting treatment, particularly with CYP/P-gp inducers which can reduce DAA efficacy 2
• Do not defer treatment in patients with active substance use; these individuals should be prioritized to prevent transmission 1, 2

Alternative Options When Preferred Regimens Are Unavailable

In resource-limited settings where pangenotypic DAAs are unavailable or unaffordable:

• Generic sofosbuvir plus daclatasvir provides high SVR rates at low cost and should be used according to genotype-specific guidelines 1
• Peginterferon alfa plus weight-based ribavirin for 24 weeks remains acceptable for genotypes 5 and 6 if DAAs are completely unavailable, with SVR rates of 70-86% 1