Achieving Sustained Virologic Response (SVR) in Hepatitis C
Primary Treatment Recommendation
All patients with 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 SVR rates of 98%. 1, 2
Pre-Treatment Assessment Requirements
Before initiating any DAA therapy, the following tests are mandatory:
- HCV RNA quantitative testing to confirm active viremia 1, 3, 2
- HCV genotype and subtype determination to guide regimen selection 1, 3, 2
- Fibrosis staging using non-invasive methods (FibroScan, FIB-4, APRI) or liver biopsy if uncertainty exists 1, 2
- Comprehensive drug-drug interaction screening with all concurrent medications 1, 2
- Baseline liver function tests and MELD score calculation in cirrhotic patients 1
First-Line Treatment Regimens by Clinical Scenario
Treatment-Naïve Patients Without Cirrhosis (All Genotypes)
Preferred regimen: Sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks 1, 2, 4
Alternative regimen: Glecaprevir/pibrentasvir 300mg/120mg once daily with food for 8 weeks 1, 2, 5
Both regimens achieve SVR rates exceeding 95% across all genotypes. 1
Compensated Cirrhosis (Child-Pugh A)
For genotypes 1,2,4,5,6:
- Sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks 1, 4
- OR Glecaprevir/pibrentasvir 300mg/120mg once daily for 12 weeks (extended from 8 weeks) 1, 5
For genotype 3 with compensated cirrhosis (more challenging):
- Glecaprevir/pibrentasvir for 12 weeks 1
- OR Sofosbuvir/velpatasvir + weight-based ribavirin (1,000 mg if <75 kg, 1,200 mg if ≥75 kg) for 12 weeks 1
- OR Sofosbuvir/velpatasvir/voxilaprevir for 8 weeks (SVR 96%) 1
Genotype 3 with cirrhosis historically has lower SVR rates, making ribavirin addition or triple therapy preferable. 6, 1
Genotype-Specific Considerations
Genotype 1
Treatment-naïve without cirrhosis:
- Ledipasvir/sofosbuvir 90mg/400mg once daily for 12 weeks 1, 2
- OR Elbasvir/grazoprevir for 12 weeks 1, 2
- OR Glecaprevir/pibrentasvir for 8 weeks 1, 2
Treatment-naïve with compensated cirrhosis:
Genotype 1a with Q80K polymorphism: Avoid simeprevir-based regimens due to lower SVR rates 2
Genotype 2
Treatment-naïve without cirrhosis:
Treatment-experienced with cirrhosis:
- Sofosbuvir + weight-based ribavirin for 16-24 weeks 6
Genotype 3 (Requires Special Attention)
Treatment-naïve without cirrhosis:
Treatment-naïve with compensated cirrhosis:
- Sofosbuvir + weight-based ribavirin for 24 weeks 6
- OR Daclatasvir + sofosbuvir for 24 weeks ± ribavirin 6
Treatment-experienced with compensated cirrhosis:
- Daclatasvir + sofosbuvir + ribavirin for 24 weeks (SVR 82-95%) 1
- OR Elbasvir/grazoprevir + sofosbuvir for 12 weeks (SVR 94-100%) 1
Important caveat: Genotype 3b has lower SVR rates (70%) compared to genotype 3a, with higher virologic failure rates. 5
Genotype 4
Treatment-naïve or treatment-experienced:
- Ledipasvir/sofosbuvir for 12 weeks 6
- OR Elbasvir/grazoprevir for 12 weeks 6
- OR Ombitasvir/paritaprevir/ritonavir + weight-based ribavirin for 12 weeks 6
- OR Glecaprevir/pibrentasvir for 8 weeks (no cirrhosis) or 12 weeks (cirrhosis) 6
Genotypes 5 and 6
Treatment-naïve or treatment-experienced:
- Ledipasvir/sofosbuvir for 12 weeks (SVR 95-96%) 6
- OR Glecaprevir/pibrentasvir for 8-12 weeks depending on cirrhosis 6
Treatment Modifications for Special Populations
Decompensated Cirrhosis (Child-Pugh B or C)
Avoid protease inhibitors (glecaprevir/pibrentasvir, paritaprevir) in decompensated cirrhosis. 1
Recommended regimens:
- Sofosbuvir + ledipasvir + ribavirin for 12 weeks 1
- OR Sofosbuvir + velpatasvir + ribavirin for 12 weeks 1, 4
- OR Sofosbuvir + daclatasvir + ribavirin for 12 weeks 1
Start ribavirin at 600 mg daily and adjust based on tolerance. 1 In the ASTRAL-4 trial, sofosbuvir/velpatasvir with ribavirin for 12 weeks achieved 94% SVR in Child-Pugh B cirrhosis. 4
Severe Renal Impairment (eGFR <30 mL/min/1.73 m² or Dialysis)
Preferred regimen: Glecaprevir/pibrentasvir (97-98% SVR in EXPEDITION-4 trial) 1, 5
Alternative: Elbasvir/grazoprevir (94-98% SVR in C-SURFER trial) 1
Avoid all sofosbuvir-based regimens when eGFR <30 mL/min/1.73 m² due to renal excretion concerns and lack of FDA approval. 1
For eGFR ≥30 mL/min/1.73 m² (CKD stages G1-G3b), any FDA-approved DAA regimen may be used. 1
HIV/HCV Coinfection
Treat identically to HCV monoinfection with the same regimens and identical virological outcomes. 6, 1, 2
Critical drug-drug interactions to avoid:
- Sofosbuvir/ledipasvir with tenofovir/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, or elvitegravir/cobicistat 1
- Paritaprevir/ombitasvir/dasabuvir with efavirenz, etravirine, nevirapine, or elvitegravir/cobicistat 1
Verify antiretroviral drug interactions before prescribing and consult an HIV treatment expert if antiretroviral modification is needed. 6, 2
In the ASTRAL-5 trial, sofosbuvir/velpatasvir for 12 weeks achieved 95% SVR in HIV/HCV coinfected patients. 4
Liver or Kidney Transplant Recipients
Recommended regimen: Sofosbuvir/velpatasvir ± ribavirin for 12 weeks 1
In the MAGELLAN-2 trial, glecaprevir/pibrentasvir for 12 weeks achieved 98% SVR in post-transplant patients without cirrhosis. 5
Allowed immunosuppressants: Cyclosporine ≤100 mg, tacrolimus, sirolimus, everolimus, azathioprine, mycophenolic acid, prednisone, prednisolone. 5
Pregnancy
No DAA regimen is currently FDA-approved for use during pregnancy. Treatment should be deferred until after delivery unless severe extrahepatic manifestations mandate immediate therapy. 6
Retreatment After DAA Failure
Failed Sofosbuvir Alone or Sofosbuvir + Ribavirin (No NS5A Inhibitor)
- Sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, OR sofosbuvir/daclatasvir + ribavirin for 12 weeks (F0-F2) or 24 weeks (F3-F4) 1, 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) 1
Failed NS3/4A Protease Inhibitor Only (NS5A-Naïve)
Genotype 1:
Failed NS5A Inhibitor Only (Protease Inhibitor-Naïve)
Genotype 1:
- Glecaprevir/pibrentasvir for 16 weeks (94% SVR) 5
Important caveat: Data do not support treatment of genotype 1 patients who are both NS3/4A protease inhibitor and NS5A inhibitor-experienced due to high virologic failure rates and treatment-emergent resistance. 5
Treatment Prioritization (Immediate Treatment Required)
The following patients should receive immediate treatment without delay:
- Advanced fibrosis (≥F3) or any cirrhosis 1, 3, 2
- Pre- and post-liver transplant patients 1, 2
- Severe extrahepatic manifestations (symptomatic cryoglobulinemia, HCV immune complex nephropathy) 1, 3, 2
- Hepatocellular carcinoma (HCC) with or without transplant indication 1
- Decompensated cirrhosis awaiting liver transplantation 1
- Individuals at high risk of HCV transmission 1
Patients with minimal or no fibrosis (F0-F2) should still be scheduled for treatment rather than deferred, though timing may be more flexible. 3
Monitoring Protocol
During treatment:
- HCV RNA at baseline, weeks 4 and 12, and end of treatment 1, 2
- Liver function tests 1, 2
- Close monitoring for side effects and decompensation in cirrhotic patients 1, 3, 2
Post-treatment:
- SVR12: HCV RNA or HCV core antigen at 12 weeks post-treatment (primary measure of cure) 1, 3, 2
- SVR12 is achieved in >99% of patients who reach this endpoint and represents viral eradication 6, 1, 3, 2
- Fewer than 1% of patients relapse after achieving SVR12 3
SVR4 (4 weeks post-treatment) has >99% positive predictive value for SVR12 across all treatment durations with glecaprevir/pibrentasvir, suggesting long-term follow-up to confirm SVR may not be necessary for certain populations. 7, 8
Expected Clinical Benefits of Achieving SVR
Successful HCV eradication provides:
- 70-90% reduction in liver-related mortality 1
- 70-90% reduction in overall mortality 1
- 75-90% reduction in HCC incidence 1
- Prevention of hepatic decompensation 1
- Improvement in liver histology and regression of fibrosis 6, 1
- Resolution of extrahepatic manifestations 1, 2
- Reversal of cerebral MRI abnormalities in neurocognitive impairment 6
Important caveat: Patients with advanced cirrhosis retain residual HCC risk despite SVR (0.3-2.4% annually), requiring lifelong HCC surveillance with ultrasound every 6 months indefinitely for patients with cirrhosis (F4) or advanced fibrosis (F3). 1, 3, 2
Patients with cirrhosis who achieve SVR have significantly reduced risk of HCC compared to untreated patients, but interferon treatment without achieving SVR does not protect against HCC. 9
Common Pitfalls and Caveats
Drug-drug interactions: Absolute contraindications include P-glycoprotein (P-gp) inducers and moderate-to-strong CYP inducers, which significantly decrease DAA concentrations and reduce efficacy. 1
Hospitalization during treatment: Patients hospitalized during DAA treatment have reduced SVR rates (87.2% vs 95.2%), potentially driven by inpatient mortality and severity of liver disease. Educate patients to bring home supply of medication for use during admission. 10
Genotype 3b: Has numerically lower SVR rates (70%) compared to genotype 3a, with higher virologic failure rates. 5
Compensated cirrhosis monitoring: Patients with compensated cirrhosis should be monitored closely for side effects, as they are increased compared to non-cirrhotic patients. Treatment should be performed with special care when albumin <3.5 g/dL or platelets <100,000. 3
Ribavirin dosing in decompensated cirrhosis: Start at 600 mg daily and adjust based on tolerance rather than weight-based dosing. 1
Avoid protease inhibitors in decompensated cirrhosis: Glecaprevir/pibrentasvir and paritaprevir-containing regimens are contraindicated. 1