What is the recommended treatment approach for a patient diagnosed with Hepatitis C (HCV), considering factors such as liver function, presence of cirrhosis, and potential co-infections like HIV and Hepatitis B?

Treatment of Hepatitis C

Recommended First-Line Treatment

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 being the preferred first-line option across all genotypes, achieving cure rates exceeding 95-97%. 1

Pre-Treatment Assessment Requirements

Before initiating therapy, the following assessments are mandatory:

• Confirm active infection with quantitative HCV RNA testing to establish baseline viremia 1, 2
• Assess liver disease severity using noninvasive markers (FIB-4, APRI, or transient elastography) to determine presence or absence of cirrhosis, as this influences treatment duration 3, 1, 4
• Screen for coinfections: Test for HIV (antigen/antibody), HBsAg, anti-HBc, and anti-HBs antibodies, as these conditions accelerate liver fibrosis and require modified management 3, 1
• Test for hepatitis B surface antigen (HBsAg) in all patients, as HBV reactivation can occur during DAA therapy and may result in hepatic decompensation or death 3, 5, 6

Treatment Regimens by Clinical Scenario

Treatment-Naïve or Treatment-Experienced Patients Without Cirrhosis

• Sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks for all genotypes (1-6) 3, 1
• Alternative: Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients without cirrhosis 1, 4, 7

Patients With Compensated Cirrhosis (Child-Pugh A)

• Sofosbuvir/velpatasvir for 12 weeks for all genotypes 3, 1
• Glecaprevir/pibrentasvir for 8 weeks is also effective in treatment-naïve patients with compensated cirrhosis (except genotype 3 with cirrhosis in Europe) 7

Genotype-Specific Considerations

Genotype 3 with cirrhosis requires special attention:

• Sofosbuvir/velpatasvir for 12 weeks remains first-line 3
• Avoid sofosbuvir/ledipasvir for genotype 3 as ledipasvir has considerably less potency against this genotype 3
• Consider extended duration or addition of ribavirin for treatment-experienced patients with cirrhosis 3, 1

Genotype 1a treatment-experienced patients with NS5A resistance-associated substitutions (RASs):

• Add weight-based ribavirin (1000mg if <75kg, 1200mg if ≥75kg) to sofosbuvir/daclatasvir for 12 weeks 3

Decompensated Cirrhosis (Child-Pugh B or C)

• IFN-free regimens are the only options in patients with decompensated cirrhosis 3
• These patients require urgent treatment and should be managed by hepatology specialists 3

Management of Coinfections

HCV/HIV Coinfection

• Use the same DAA regimens as in HCV monoinfected patients 3, 1
• Adjust daclatasvir dosing based on antiretroviral therapy: 30mg with atazanavir or cobicistat-boosted elvitegravir; 90mg with efavirenz 3
• Review all antiretroviral medications for drug-drug interactions 3

HCV/HBV Coinfection

Critical warning: HBV reactivation can occur during or after DAA therapy and has resulted in deaths and liver transplantation. 3, 5, 6

• If HBsAg-positive or HBV DNA detectable, start concurrent HBV nucleoside/nucleotide analogue therapy (entecavir or tenofovir) before initiating DAA treatment 3
• Monitor HBV DNA and ALT levels during and after DAA therapy in all patients with any evidence of HBV exposure (HBsAg-positive or anti-HBc-positive) 3
• If using ledipasvir with tenofovir, monitor renal function closely as ledipasvir can increase tenofovir renal toxicity 3

HCV/HDV Coinfection

• Treat HCV with standard DAA regimens 3
• If meeting criteria for HBV treatment or if cirrhosis is present, initiate nucleoside analogues to prevent liver disease progression 3

Treatment Prioritization

Immediate treatment is indicated for:

• Advanced fibrosis (≥F3) or any degree of cirrhosis 1
• Pre- and post-liver transplant recipients 1
• Patients with decompensated cirrhosis (with or without transplant indication) 3

Drug Interactions and Contraindications

Absolute contraindications:

• Carbamazepine, efavirenz-containing regimens, or St. John's Wort with glecaprevir/pibrentasvir, as these reduce therapeutic effect 5

Important drug interactions:

• DAAs are metabolized via CYP3A4 and transported by P-glycoprotein 1
• Avoid hepatotoxic drugs (acetaminophen >2g/day, certain herbal supplements) in patients with cirrhosis 3, 1
• Avoid nephrotoxic drugs (NSAIDs) in patients with cirrhosis 3

Monitoring During and After Treatment

During Treatment

• Monitor HCV RNA at baseline, during treatment if clinically indicated, at end of treatment, and 12 weeks post-treatment 1
• Monitor for adverse events: headache (12%), fatigue (12%), anemia, dyspepsia, and insomnia 8, 7
• In HBV-coinfected patients, monitor HBV DNA and ALT levels regularly 3

Definition of Cure

Sustained virologic response (SVR12) is defined as undetectable HCV RNA 12 weeks after treatment completion, representing permanent viral eradication in >99% of cases 1

Post-SVR Follow-Up

Lifelong hepatocellular carcinoma (HCC) surveillance is mandatory for patients with established cirrhosis (F4) or advanced fibrosis (F3):

• Ultrasound every 6 months indefinitely 3, 1
• This applies even after achieving SVR, as HCC risk persists 3

Essential Patient Counseling

• Complete alcohol abstinence is mandatory, as there is no known safe level of alcohol use with chronic hepatitis C 3, 1, 9
• Prevent HCV transmission: Avoid sharing personal hygiene items (razors, nail clippers, toothbrushes), needles, or drug paraphernalia 1, 9
• Exposure to infected blood is the primary transmission mode 3, 1

Vaccination Recommendations

All HCV patients should receive:

• Hepatitis A vaccine (HAV superinfection can cause fulminant hepatitis) 9
• Hepatitis B vaccine (use double-dose 40µg regimen in cirrhotic patients; standard 20µg achieves only 57-74% seroconversion vs >90% in healthy individuals) 9
• Pneumococcal vaccination (PCV13 followed by PPSV23 at least 8 weeks later) in cirrhotic patients 9
• Annual influenza vaccine 9
• COVID-19 vaccination without discontinuing HCV therapy 9

Common Pitfalls to Avoid

• Never miss HBV screening before DAA initiation—HBV reactivation has caused deaths 3, 5, 6
• Do not use sofosbuvir/ledipasvir for genotype 3 due to inadequate potency 3
• Do not assume negative HCV antibody excludes infection in immunocompromised patients—order HCV RNA directly 2
• Do not discontinue HCC surveillance after achieving SVR in patients with cirrhosis or advanced fibrosis 3, 1
• Ongoing alcohol use is not a contraindication to antiviral therapy, though abstinence should be strongly encouraged 3