Monitoring Patients Who Are Starting HCV Treatment, Are On Treatment, Or Have Completed Therapy WV ECHO August 10, 2017
Selection of patients for HCV treatment Despite current guidance to treat everyone, patient selection should still be individualized after appropriate patient centered evaluation: Example of issues that might impact patient selection: Patient capacity to comply with treatment Risk of re-infection Medication interactions Access to medication (insurance) Pregnancy and/or willingness to avoid getting pregnant while on treatment (esp. if ribavirin used) Safety to patient (concern if decompensated cirrhotic)
Prior to treatment Recommended Assessments Prior to Starting Antiviral Therapy Staging of hepatic fibrosis Assessment of potential drug-drug interactions Education on dose/frequency, adverse effects, the crucial importance of adherence, and the necessity for close supervision and Since the safety of DAA regimens has not been established during pregnancy, counseling and serum pregnancy testing should be offered to women of childbearing age before beginning HCV treatment Ribavirin clearly contraindicated Laboratory tests are recommended within 12 weeks prior to starting antiviral therapy CBC INR Hepatic function panel albumin, total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels GFR HCV viral load
Prior to treatment All patients initiating HCV DAA therapy should be assessed for HBV coinfection with HBsAg, anti-hbs, and anti-hbc Recall "clinically silent Hep B" -- isolated core positive patients Boxed Warning Oct 2016 to all HCV DAAs: Risk of hepatitis B virus (HBV) becoming an active infection again in any patient who has a current or previous infection with HBV and is treated with direct-acting antiviral (DAA) medicines for hepatitis C monitoring of HBV DNA levels during and immediately after DAA therapy for HCV
Selection of HCV treatment regimen Factors that may impact particular DAA treatment selection & prescribing recommendations: No cirrhosis vs. cirrhosis present Hepatitis C viral load Prior interferon/ribavirin and/or PI exposure or DAA treatment Specifics lab tests may indicate decreased efficacy of certain medications Risk of drug interactions Available guidance of dosing with renal dysfunction Predicted issues with adherence Specific insurance/payer preferences HCV Genotype (and subtype 1a vs 1b) Predicated medication side effects (esp. if a regimen needs ribavirin) Potential for childbearing
New DAAs Vosevi (sofosbuvir, velpatasvir, voxilaprevir) by Gilead One tablet once daily for 12 weeks Genotypes 1-6 without cirrhosis or with compensated cirrhosis First treatment approved for patients who have been previously treated with sofosbuvir or NS5A inhibitors Use is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C) Sofosbuvir NS5B RNA-dependent RNA polymerase Velpatasvir NS5A inhibitor Voxilaprevir NS3/4A protease inhibitor
New DAAs Mavyret (glecaprevir and pibrentasvir) by AbbVie 3 tablets once daily for 8-16 weeks Genotypes 1-6 without cirrhosis or with compensated cirrhosis Use is not recommended in patients with severe hepatic impairment (Child- Pugh C) Glecaprevir NS3/4A protease inhibitor Pibrentasvir NS5A inhibitor
Selection of HCV treatment regimen FDA approved Hepatitis C direct acting antivirals (DAAs) Sovaldi (sofosbuvir) by Gilead Olysio (simeprevir) by Janssen Harvoni (sofosbuvir and ledipasvir) by Gilead Viekira Pak and Viekira XR (ombitasvir, paritaprevir, ritonavir and dasabuvir) by AbbVie Daklinza (daclatasvir) by Bristol-Myers Squibb Zepatier (elbasvir and grazoprevir) by Merck Epclusa (sofosbuvir and velpatasvir) by Gilead Vosevi (sofosbuvir, velpatasvir, and voxilaprevir) by Gilead Mavyret (glecaprevir and pibrentasvir) by AbbVie
Hepatitis C virus genome and proteins Grazoprevir Paritaprevir Simeprevir Voxilaprevir Glecaprevir Vincent Soriano et al. Clin Infect Dis. 2009;48:313-320 2009 by the Infectious Diseases Society of America Ledipasvir Elbasivir Daclatasivr Ombitasvir Velpatasvir Pibrentasvir Sofosbuvir(Nucleoside) Dasabuvir (Non-Nucleoside)
Protease inhibitors In October 2015, the FDA released a warning regarding the use of ombitasvir, paritaprevir, ritonavir and dasabuvir in patients with cirrhosis reported rapid onset of liver injury and in some cases hepatic decompensation in patients with cirrhosis including Child Turcotte Pugh (CTP) class A compensated cirrhosis contraindicated in patients with CTP class B or C hepatic impairment (decompensated liver disease) Patients scheduled to receive an HCV NS3 protease inhibitor should be assessed for a history of decompensated liver disease and for severity of liver disease using CTP score Patients with current or prior history of decompensated liver disease or with a current CTP score of 7 or greater should NOT receive treatment with regimens that contain NS3 protease inhibitors Patients with a CTP score of 5 or 6, who cannot be closely monitored for laboratory or clinical symptoms during treatment, should not receive treatment with a regimen that contains paritaprevir/ritonavir
NS5A Baseline RASs Testing NS5A Resistance-Associated Substitutions (RASs) have impact on treatment response with regimens that include an NS5A inhibitor magnitude of the impact on treatment response varies with the specific DAAs primarily with genotype 1a and genotype 3 testing prior to starting treatment should be performed as recommended for particular regimens / situations example: Genotype 1a w/ Zepatier example: Genotype 3 w/ Epclusa or daclatasvir for treatment-naive patients with cirrhosis or treatment-experienced patients without cirrhosis Recommendations on the need for NS5A testing, particularly at baseline is a rapidly evolving HCV guidlines.org "will be updated regularly to reflect new and emerging data"
Recommended Monitoring During Antiviral Therapy Clinic visits or telephone contact are recommended as clinically indicated during treatment to ensure medication adherence and to monitor for adverse events and potential drug-drug interactions with newly prescribed medications CBC, creatinine/gfr, and hepatic function panel are recommended after 4 weeks of treatment and as clinically indicated Patients receiving elbasvir/grazoprevir should be monitored with hepatic function panel at 8 weeks (and again at 12 weeks if receiving 16 weeks of treatment)
Recommended Monitoring During Antiviral Therapy A 10-fold increase in alanine aminotransferase (ALT) activity at week 4 should prompt discontinuation of therapy Increase in ALT of less than 10-fold at week 4 and accompanied by any weakness, nausea, vomiting, jaundice, or significantly increased bilirubin, alkaline phosphatase, or INR, should also prompt discontinuation of therapy Asymptomatic increases in ALT of less than 10-fold elevated at week 4 should be closely monitored and repeated at week 6 and week 8. If levels remain persistently elevated, consideration should be given to discontinuation of therapy Patients with compensated cirrhosis who are receiving protease inhibitor based regimens should be assessed for clinical signs of decompensated liver disease (eg, ascites, encephalopathy) and for biochemical evidence of liver injury with a hepatic function panel at week 2 and week 4 of treatment, and as needed during the remainder of treatment regimens should be discontinued if patients develop ascites or encephalopathy or a significant increase in direct bilirubin or ALT or AST
HCV Viral Load Monitoring Quantitative HCV viral load testing is recommended after 4 weeks of therapy and at 12 weeks following completion of therapy HCV viral load testing can be considered at the end of treatment HCV viral load testing can be considered 24 weeks or longer following the completion of therapy
HCV Viral Load Monitoring The assessment of HCV viral load at week 4 of therapy is useful to determine initial response to therapy and adherence Minimal data on how to use HCV RNA level during treatment to determine when to stop treatment for futility If HCV RNA is detectable at week 4 of treatment, repeat viral load testing is recommended after 2 additional weeks of treatment (treatment week 6) -- if quantitative HCV viral load has increased by greater than 10-fold (>1 log10 IU/mL) on repeat testing at week 6 (or thereafter), then discontinuation of HCV treatment is recommended The significance of a positive HCV RNA test result at week 4 that remains positive, but lower, at week 6 or week 8 is unknown No recommendation to stop therapy or extend therapy can be provided at this time Antiviral drug therapy should NOT be interrupted or discontinued if HCV RNA levels are not performed or available during treatment
Treatment Terminology: Defining Treatment Success The goal of antiviral therapy in patients with chronic HCV is to eradicate HCV RNA, which is predicted by attaining a sustained virologic response (SVR) SVR is defined as the absence of HCV RNA by polymerase chain reaction after stopping treatment for some defined time period Traditionally this has been an assessment of viral load at 6 months, but w/ DAAs 12 weeks (SVR12) is being used as a clinical endpoint. An SVR is associated with a 97 to 100 percent chance of being HCV RNA negative during long-term follow-up
Treatment Terminology: Defining Treatment Success Monitoring Patients Who Have Completed Treatment Patients who achieve a sustained virologicresponse (SVR) If do not have advanced fibrosis (Metavir stage F0-F2), follow-up as if they were never infected with HCV If advanced fibrosis (Metavir stage F3 or F4), surveillance for hepatocellular carcinoma with twice-yearly liver ultrasound testing. If cirrhosis is present, referral for endoscopy to screen for varices as well. Assessment for HCV recurrence or reinfection only if the patient has ongoing risk or otherwise unexplained hepatic dysfunction develops PCR testing, not serology Assessment of other causes of liver disease is recommended for patients who develop persistently abnormal liver tests after achieving an SVR Prospective monitoring for HCV recurrence among patients who achieved a sustained virologic response and who are receiving immunosuppressive treatment (eg, systemic corticosteroids, antimetabolites, chemotherapy, etc) is NOT recommended
Treatment failures Monitoring for Patients in Whom Treatment Failed to Achieve SVR Disease progression assessment every 6 months to 12 months with a hepatic function panel, CBC, and INR Screening for hepatocellular carcinoma with ultrasound examination every 6 months is recommended for patients with advanced fibrosis (F3 or F4) Endoscopic screening for esophageal varices is recommended if cirrhosis is present Evaluation for retreatment as effective alternative treatments become available