Hepatitis C

• HCV genotype
• Prior HCV treatment history
• Compensated versus decompensated liver disease
• Drug–drug interactions
• Chronic kidney disease
• Solid organ transplant recipients

• Previous treatment with DAAs
• Liver cirrhosis (Child–Pugh B and C)
• Poor treatment adherence

• Taking a detailed history and physical examination is essential, including the patient’s history of any other liver diseases and medical conditions that can adversely affect liver status, such as hepatitis B infection, alcoholism, autoimmunity, metabolic liver diseases, or hepatotoxic drugs. These should be inquired into and appropriate measures should be taken to reduce the risks.
• Other evaluations should be considered (cardiopulmonary and psychiatric evaluation) and the risk of nonadherence should be assessed. Appropriate measures should be taken to reduce these risks.
• Assessment for current/prior medications and adherence to previous treatments. Significant potential drug–drug interactions should also be assessed.
• The extent of hepatic fibrosis should be checked using noninvasive measures:
  — Studies have demonstrated that FibroScan is a sensitive alternative to liver biopsy. The amount of fibrosis can be quantified very easily and reliably in more than 95% of the patients [45]. A correct interpretation of transient elastography must have an interquartile range/median values of < 30% and serum ALT < 5 × upper limit of normal. There should be no ongoing excessive alcohol intake, and the patient’s BMI should be taken into account. If the BMI is over 30 kg/m2, using extralarge (XL) probes may be considered.
  — In resource-limited regions and in places where FibroScan is not readily available, scores such as the fibrosis 4 index (FIB4), AST to platelet ratio index (APRI), and acoustic radiation force impulse (ARFI) can be used. An APRI score ≥ 2 can be used to predict the presence of cirrhosis. At its cut-off point, the ARFI score has a sensitivity of 48% but a specificity of 94% for predicting cirrhosis. It can also be used to predict the presence of significant fibrosis (stages 2–4). Using a cut-off value of 1.5, the sensitivity is 37% and the specificity is 95% for significant fibrosis [46,47].
  — Liver biopsy can only be considered when there is possibility of additional etiology.
• Serum quantitation of HCV-RNA using a sensitive real-time PCR-based assay with a lower limit of detection of ≤ 15 IU/mL.
• HCV genotyping.
• In patients with suspected or known cirrhosis, the Child–Turcotte–Pugh score and Model for End-Stage Liver Disease (MELD) score should be calculated.

1. A complete blood count(CBC), liver function tests (LFTs), serum albumin, INR, glomerular filtration rate (GFR), and a thyroid-stimulating hormone (TSH) test (if an IFN regimen is planned) should be performed within 12 weeks of the start of therapy.
2. Quantitative PCR and genotyping anytime should be done before the start of therapy.
3. Women of childbearing age must undergo urinary pregnancy testing before the start of therapy. Currently, all new oral therapy regimens, with or without ribavirin, are contraindicated for use during pregnancy or during breastfeeding due to a lack of sufficient safety information in humans, and adequate measures of contraception are still routinely recommended for female patients of childbearing age [48].
4. With ribavirin-containing regimens, the patient’s age and cardiovascular comorbidity due to secondary anemia should be taken into account.

1. Compliance should be encouraged either at clinical visits or by phone. Any adverse events should be inquired about, and advice regarding drug–drug interactions should be given. The University of Liverpool provides a “HEP Drug Interaction Checker” (http://www.hep-druginteractions.org) [49].
2. CBC, serum creatinine, GFR, and LFT assessments should be performed after 4 weeks of treatment. CBCs can be done more often in patients receiving ribavirin, if clinically indicated.
3. TSH tests should be done at 12 weeks for those patients receiving interferon.
4. Quantitative PCR assessment should be performed at the end of treatment and then 12 weeks afterward.

When to stop the treatment because of side effects

• If there is a 10-fold or greater increase in ALT after 4 weeks of therapy.
• If there is a less than 10-fold increase in ALT with one of the following:
  — Symptoms developing (nausea, vomiting, weakness)
  — Jaundice
  —Increases in bilirubin, alkaline phosphatase (ALP), or INR
• If there is a less than 10-fold increase in ALT and the patient is asymptomatic, ALT assessment should be repeated at 6 weeks; if it is persistently high, one can consider stopping therapy.

1. LFTs, CBC, INR every 6–12 months to assess disease progression (F4 patients).
2. HCC surveillance for patients with advanced fibrosis (metavir F3/F4) using ultrasonography every 6 months.
3. Endoscopic surveillance for varices in cirrhotic patients.
4. Re-treatment evaluation once an effective alternative treatment is available. Pretreatment mutation testing is needed to select the best regimen at present. Currently, the guidelines recommend NS5A resistance evaluation in patients in whom DAAs fail, especially before considering elbasvir/grazoprevir for genotype 1a patients.

1. For patients with F0–F2 fibrosis, the same recommendations apply as if they were never infected with HCV.
2. For patients with F3–F4 fibrosis, twice-yearly ultrasound monitoring is recommended for HCC surveillance.
3. Baseline endoscopic surveillance for cirrhotic patients, and if varices are found they should be treated and followed up in the standard way.
4. If LFTs are persistently abnormal despite an SVR, other causes of liver disease should be assessed.

• In December 2013 and January 2014, second-generation DAAs were approved by the FDA for treatment of chronic hepatitis genotype 1, which is the most prevalent genotype and one that is considered to be difficult to treat. The first of these was sofosbuvir (SOF), which is an NS5B polymerase inhibitor. The first trial using SOF/RBV was the ELECTRON study. This reported SVRs in 84% of 25 treatment-naïve patients after 24 weeks of therapy (SVR 24). In a subsequent study of a regimen consisting of sofosbuvir and RBV for 24 weeks in 60 treatment-naïve patients with genotype 1 with poor prognostic factors such as African-American ethnicity, ccIL28B, and viral load more than 800,000 IU/mL, the SVR 24 rates were 68%.
• In the ELECTRON study, SOF/RBV was administered in genotype 2 and 3 patients without cirrhosis, and 100% achieved SVR 24. In the FISSION trial, with SOF/RBV administered for 12 weeks in 499 treatment-naïve patients, the SVR 12 rates were 97% for patients with HCV genotype 2. In genotype 3 patients, the SVR 12 rates were only 56%. Similarly, in the POSITRON trial the SVR 24 rates after 24 weeks of treatment were 61% for genotype 3 and 93% for genotype 2. Similar results were achieved in the FUSSION trial, with poor SVR rates of 62% for patients infected with genotype 3.
• Since then, a number of drugs in separate or fixed-dose combinations have been approved by the FDA, including daclatasvir, 3D Regimen, paritaprevir + dasabuvir/ombitasvir + ritonavir (Viekira pak).
• One of the most recent FDA-approved pan-genotype combinations, available under the trade name Epclusa, contains sofosbuvir + velpatasvir. In a phase 3 trial, Feld et al. administered this combination for 12 weeks and reported an SVR 12 of 99% in patients with genotypes 1, 2, 4, 5, and 6. The ASTRAL-3 trial reported an SVR 12 of 95% in genotype 3 patients treated with sofosbuvir + velpatasvir for 12 weeks. In another trial, Curry et al. used this combination in decompensated patients, with SVRs of 83% in patients who used the combination for 12 weeks, 86% in those who used it for 24 weeks, and 94% in patients who used the combination along with ribavirin for 12 weeks.
• Zepatier is another pan-genotypic DAA-based combination approved in 2016. The combination contains 100 mg of grazoprevir and 50 mg of elbasvir. A combination of Zepatier with sofosbuvir was investigated in the C-SWIFT study, with an efficacy of more than 90% when given for 8 weeks in patients with genotype 1 and 12 weeks in those with genotype 3.

• Regular laboratory monitoring with HCV RNA is recommended at least for 6 months in order to assess spontaneous clearance.
• Counseling is required for patients with acute HCV infection to ensure avoidance hepatotoxic drugs (e.g., acetaminophen) and alcohol. The patients should also take precautionary measures to reduce the risk of transmitting the disease to others.
• Early treatment can only be considered in special circumstances—e.g., in individuals who are at risk of transmitting the disease to others (such as intravenous drug abusers, or surgeons), patients who are already suffering from advanced liver disease for some other reason, and those in whom the chances of being lost to follow-up are greater. Even in these patients, one should at least wait for 12–16 weeks before starting therapy.
• If indicated, treatment for acute HCV infection can be administered using DAAs with the same regimens as for chronic disease.
• Prophylactic therapy is not recommended in needlestick injuries, as the infectivity rate is very low.