for Health Care Providers
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The 2009 American Association for the Study of Liver Diseases Practice Guidelines for the Diagnosis, Management, and Treatment of Hepatitis C describe that HCV antiviral therapy is indicated for patients with chronic HCV who are at greatest risk for progression to cirrhosis. These are patients with detectable serum HCV RNA and liver histology showing significant hepatic fibrosis (more than portal fibrosis, greater than stage 1) (18) . Additional patient risk factors for increased fibrosis progression include male gender, obesity, steatosis, heavy alcohol use, age, elevated serum alanine transaminase, and greater hepatic inflammation (21, 22, 23) . Pretreatment assessments are summarized in Table 2.
HCV antiviral therapy generally should be used only in patients with preserved liver function (serum bilirubin <1.5 mg/dl; International Normalized Ratio <1.5; albumin >3.0 g/dl; and no evidence of hepatic encephalopathy or ascites), along with adequate hematological and biochemical parameters to tolerate therapy (hemoglobin >12 g/ dl; neutrophil count >1.5 k/ mm 3; platelet count >75 k/mm 3; serum creatinine <1.5 mg/dl). HCV genotype should be determined, as it influences the selection of therapy and treatment duration. Baseline viral load should be measured using a quantitative HCV RNA assay, so that treatment response can be assessed later (see the section "Monitoring therapy").
Table 2. Pretreatment assessments in patients with chronic HCV infectiona
- Medical history, including complications of liver disease, presence of significant extrahepatic disease, and symptoms of chronic HCV that may diminish quality of life
- Psychiatric history, including past or ongoing psychiatric, and substance use disorders
- Screening for depression and alcohol use
- Biochemical markers of liver injury and assessment of hepatic function, including serum ALT, serum albumin, serum bilirubin (including direct bilirubin), and prothrombin time
- Hemoglobin, hematocrit, WBC with differential, and platelet count
- Serum creatinine
- Serum glucose
- Uric acid (while receiving TVR)
- Serum ferritin, iron saturation, and serum ANA
- Pregnancy test (in women of childbearing age)
- HIV serology
- Serum HBsAg, antiHBc, antiHBs, antiHAV (total)
- Quantitative HCV RNA measurement
- HCV genotype
- Previous antiviral therapies and response
- ECG in patients with preexisting cardiac disease
- Liver biopsy (if results will influence management)
- IL28B genotype (if results will influence management)
- Eye exam for retinopathy in patients with diabetes or hypertension
- Urine toxicology screen for opiates, cocaine, and amphetamines
Liver disease staging
Liver biopsy is the best method for staging the degree of fibrosis (typically staged from 0 to 4 with the METAVIR, and 0 to 6 with the Ishak scoring system) and grading inflammation (typically graded from 0 to 4) (22, 24) . In most cases, patients who initiate antiviral treatment for HCV should have more than portal fibrosis (greater than stage 1). Although liver biopsy is the preferred approach, it is invasive, is subject to sampling error, and carries a risk for severe complications (24) . As such, it is not required before reaching a treatment decision, and may be less useful among patients in whom the results are unlikely to alter management (18) . Alternative approaches, such as liver imaging and serum fibrosis markers, can be performed instead of a liver biopsy, although with careful recognition of their limitations (25, 26, 27, 28) .
All patients should be evaluated for psychiatric disorders, particularly depression and suicide risk. Uncontrolled depression or active suicidal ideation is an absolute contraindication to IFN-based therapies. Patients with psychiatric disorders that are stable or in remission may receive antiviral therapy. Standardized depression scales (e.g., Beck Depression Inventory or Patient Health Questionnaire) serve as useful tools for baseline and on-treatment psychiatric assessment. Patients may require referral to a psychiatrist or mental health professional for evaluation and therapy before initiation of antiviral treatment (29) .
Assessments for substance use disorders
All patients should be evaluated for current alcohol and other substance use, with validated screening instruments such as AUDIT C or CAGE (30) . The presence of current heavy alcohol use (>14 drinks per week for men or >7 drinks per week for women), binge alcohol use (>4 drinks per occasion at least once a month), or active injection drug use warrants referral to an addiction specialist before treatment initiation. Urine toxicology screens for opiates, cocaine, or amphetamines may be used to supplement patient self-report.
Alcohol and illicit drug use may affect HCV treatment adherence and response to therapy; however, on a case-by-case basis, individuals with active alcohol or substance use have been treated successfully (20) . Integrated care models have demonstrated that patients who have recently become abstinent can also be treated successfully (31) . Patients with past or recent substance abuse disorders often require close monitoring, and care should be coordinated with addiction specialists.
Adherence to a treatment plan is imperative to achieve SVR and to reduce the potential for HCV resistance associated with DAA agents. Although improved SVR is achieved with the addition of BOC or TVR to PegIFN injections and oral RBV in genotype 1-infected patients, these regimens are complex, involve response-guided therapy (RGT), have a high pill burden (12-18 pills per day), confer a potential for viral resistance, and require frequent follow-up. Treatment adherence should be discussed with patients considering antiviral therapy, and the likelihood of adherence should be assessed. Evidence of prior non-adherence to medical, psychiatric, or other therapies may predict non-adherence to HCV therapy. In patients who do not comply with pretreatment evaluations, treatment initiation should be deferred and attempts to improve adherence should be made.
Evaluation for HIV co-infection
There is significant overlap in the epidemiology of and risk factors for HIV and HCV infections. Patients with a new diagnosis of HIV infection may benefit from HIV antiretroviral therapy.
HIV/HCV co-infection increases the risk of HCV-related liver damage, may influence the duration of HCV therapy and lowers the likelihood of SVR. Because of the potential clinical and public health benefits of HIV detection, all patients with HCV infection considering antiviral therapy should be offered a voluntary HIV test if the HIV status has not been established previously.
RBV is potentially teratogenic (Pregnancy Category X). A pregnancy test should be obtained from women of childbearing potential before the initiation of HCV treatment, and women who are pregnant or attempting to conceive should not be treated. Pregnancy also must be avoided in the partner of an HCV-infected male patient receiving treatment. Contraception for both partners is required and should include at least one barrier method of contraception (condoms or diaphragm plus spermicide) throughout the course of HCV treatment and for 6 months after treatment cessation (32, 33) . Routine monthly pregnancy tests should be performed during this time, and if a patient or their partner becomes pregnant, RBV should be discontinued immediately and the pregnancy should be reported to the Ribavirin Pregnancy Registry at 1-800-593-2214 or www.ribavirinpregnancyregistry.com.
Although BOC and TVR are Pregnancy Category B agents, they must be used in combination with RBV. Due to drug-drug interactions (DDIs), oral contraceptives may be ineffective because of a decrease in their plasma levels when they are co-administered with either BOC or TVR. Thus, two alternative effective methods of contraception, such as intrauterine devices and barrier methods, should be used in at-risk patients and partners. After TVR has been discontinued for 2 weeks, oral contraceptives may be used as one of two forms of birth control (34, 35) .
Testing for IL28B genotype
Single-nucleotide polymorphisms in chromosome 19, in the region of the IL28B gene (which encodes IFN-λ3), are strongly associated with the probability of achieving SVR with PegIFN and RBV treatment in genotype 1-infected patients (36, 37, 38) . In particular, genotype 1-infected subjects carrying the favorable CC genotype at rs12979860 have an approximately two-fold increase in SVR to PegIFN and RBV, compared with those with the less favorable CT or TT genotypes. African Americans and Hispanics have a lower frequency of the CC genotype at rs12979860, which partially explains the lower SVR in these groups (36, 37, 38) . In genotype-2- or 3-infected patients, IL28B genotype does not appear to be strongly associated with SVR to PegIFN/RBV (39, 40, 41) .
Retrospective analyses suggest that treatment-naive, genotype 1-infected patients with IL28B genotype CT or TT have a higher SVR when treated with DAA-PegIFN and RBV as compared with PegIFN and RBV treatment alone. Among treatment-naive subjects with IL28B CC genotype, the addition of BOC to PegIFN and RBV did not appear to improve SVR rates compared with PegIFN and RBV alone (80-82 and 78%, respectively), whereas the addition of TVR to PegIFN and RBV resulted in higher SVR rates compared with PegIFN and RBV alone (90 and 64%, respectively). Among genotype 1-infected patients who failed PegIFN and RBV treatment, SVR rate was 60-80% with retreatment involving a HCV PI-containing regimen regardless of IL28B genotype. However, the results of these retrospective subgroup analyses should be viewed cautiously because of the small sample size and potential differences in demographic or clinical characteristics. Prospective studies evaluating IL28B genotype and SVR with DAA-containing regimens are needed (11, 12) .
Testing for IL28B genotype before starting treatment with PegIFN/RBV ± DAA agent is recommended if results might alter treatment decisions. For example, patients who are reluctant to receive treatment may be better informed of their chance of achieving an SVR if they know their IL28B genotype. After beginning treatment with PegIFN and RBV (± DAA agent), the decline in HCV RNA level during treatment (e.g., at weeks 4, 8, and 12) is more strongly associated with SVR than is IL28B genotype (11, 12, 13, 14, 42) .
Recommendation for IL28 genotype testing:
- IL28B genotype testing can be performed before PegIFN-RBV therapy, with or without a PI, if the information on the probability of treatment response or duration would alter treatment decisions (Class IIa, Level B).
Concomitant medical conditions
Treatment with IFN-based therapy may exacerbate the underlying autoimmune disorders. Patients with stable autoimmune thyroid disease or diabetes mellitus can generally be treated safely, but psoriasis, Crohn's disease or rheumatoid arthritis may be worsened by therapy, and should be co-managed with a specialist. HCV treatment should be administered with caution if liver histology reveals features suggestive of autoimmune hepatitis. Among patients with risk factors for retinal disease (e.g., hypertension or diabetes) or baseline visual abnormalities, a detailed eye exam should be performed before and during treatment as indicated, to identify any worsening of disease while receiving IFN (Table 2).
Recommendations in patients being considered for HCV therapy:
- Patients should receive pretreatment assessments as summarized in Table 2 (Class I, Level B).
- Patients with more than portal fibrosis, including those with compensated cirrhosis, who lack contraindications, should be considered for treatment (Class I, Level B).
- Patients should be counseled on their likelihood of achieving SVR, based upon individual factors such as body mass index, genotype, race, stage of fibrosis, and viral load before initiating therapy (Class I, Level B).