The New World of HCV Therapy

Transcription

1 HCV: Assessing the Patient Prior to Treatment: Diagnostic Testing and Strategy JORGE L. HERRERA M.D., MACG UNIVERSITY OF SOUTH ALABAMA COLLEGE OF MEDICINE, MOBILE, AL The New World of HCV Therapy Interferon-free therapy is here Cure is an almost certain outcome Hand-holding is no longer needed Patient assessment prior to therapy continues to be of paramount importance Page 1 of 17

2 Predictors of Response WHAT S OUT Race BMI IL28b HIV co-infection Type of prior non-response WHAT S IN Fibrosis Genotype RAV s Advanced fibrosis has remained as an important significant negative predictor of response Importance of Assessing Fibrosis Determines urgency of therapy Selects patients in need of additional screening Varices Hepatocellular carcinoma Allows for selection of proper treatment plan and duration of therapy Used by many payors as a way to restrict access to therapy Page 2 of 17

3 Assessing Fibrosis Liver biopsy Widely available In real life, it is not as good as advertised Vibration-controlled transient elastography VCTE (Fibroscan) FDA approved, not yet widely available in in the US MRI elastography Expensive, not readily available Serum tests and formulas: Fibrosure, APRI, AST/ALT ratio, Forns index, FIB-4, etc. Work well in cases of no fibrosis or established cirrhosis No single test is accurate enough! How Good is Liver Biopsy? Widely regarded as the Gold Standard Compared to what? Published data may not represent real-life results What is an optimal liver biopsy? Page 3 of 17

4 Liver Biopsy in HCV Specimen size matters >11 portal tracts should be represented Colloredo G, et al. J Hepatol 2003;39: How Can You Get an Accurate Liver Biopsy Interpretation? Size matters! Ideal specimen: >2 cm, 16 or 14 gauge needle (1.4 mm width) 93.7% of biopsies 2 cm long had >11 portal tracts Pathologist matters! 391 HCV patients underwent liver biopsies 2 hepatopathologists read the biopsies, reading compared to community pathologist Agreement among readings: 50% Community pathologists under-staged fibrosis in 73% of cases Colloredo G, et al. J Hepatol 2003;39: Robert M, et al. Clin Gastroenterol Hepatol 2009;7: Page 4 of 17

5 Interobserver Agreement Between Hepatopathologists and Community Pathologists Kappa values: >0.75 = excellent; 0.4 to 0.74 = good; <0.4 = poor Robert M, et al. Clin Gastroenterol Hepatol 2009;7: Liver Biopsy May Not be As Good As Advertised How many of your biopsies: Are >2 cm in length and a single intact specimen? Obtained with a 14 or 16 gauge needle? Pathology report states the number of portal tract present? Read by a hepatopathologist? Liver biopsy is one of several components of fibrosis assessment Page 5 of 17

6 Vibration-Controlled Transient Elastography (VCTE) (Fibroscan) Non-invasive method to assess fibrosis Tapper EB, et al. Clin Gastroenterol Hepatol 2015;13:27-36 VCTE Analyzes a Larger Volume of Liver Tissue VCTE LIVER BIOPSY ~ 1 cm x 4 cm ~ 0.14 cm x 2-3 cm Page 6 of 17

7 VCTE vs. Liver Biopsy ADVANTAGES DISADVANTAGES Non-invasive Safer, less expensive Can be used for serial assessment of fibrosis Test failure or unreliable results BMI >30 kg/m 2 Inexperienced operator (<100 exams; best: >500) Best to differentiate F0/F1 from F4 Gives no information on inflammation Cutoffs to diagnose cirrhosis vary according to the etiology HCV: >7.3 kpa suggests significant fibrosis; >12.5 kpa suggests cirrhosis Tapper EB, et al. Clin Gastroenterol Hepatol 2015;13:27-36 Take Home Message: Use All Your Tools! Serum fibrosis tests AST/ALT ratio >0.8 suggests advanced fibrosis if no alcohol APRI AST/ULN divided by platelet count x 100; >2 suggests cirrhosis Platelet count <150,000 suggests portal hypertension Ultrasound Splenomegaly or PV diameter >13 mm suggests portal hypertension VTCE >7.3 kpa suggests advanced fibrosis Page 7 of 17

8 Non-Invasive Assessment of Fibrosis VCTE + serum markers fibrosis Discordant results Concordant results Recheck Cirrhosis No Cirrhosis Still discordant Liver Biopsy Cancer and Varices Screen Diseasespecific follow-up Tapper EB, et al. Clin Gastroenterol Hepatol 2015;13:27-36 Cumulative Mortality (%) Be Careful Using Fibrosis as the Only Indication for Therapy Anti-HCV+, HCV RNA detectable Anti-HCV ( ) All Causes (n=2394) %* % 12.4% Follow-Up (Years) Liver Cancer (n=115) 10.4%* 2 1.6% 0 0.3% Follow-Up (Years) ,800 adults, 16.2 y f/u Extrahepatic Diseases (n=2199) 19.8%* 12.2% 11.0% Follow-Up (Years) Lee M-H, et al. J Infect Dis. 2012;206: Page 8 of 17

9 Most Patients with HCV Viremia Should be Considered Treatment Candidates AASLD-IDSA Treatment Guidelines: Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy (accessed March 20, 2016) Co-morbidities WHAT S OUT WHAT S IN Careful psychiatric evaluation Need for family/friend support system Avoidance of therapy in patients with psychiatric illness Assessing patient s commitment to therapy Willingness to comply with medical plan Understands the implications of HCV infection? Understands the importance of a cure? Starting therapy on the initial visit is usually not a good idea, even in 2016 Page 9 of 17

10 Co-morbidities WHAT S OUT Exclusions due to Thrombocytopenia Neutropenia Autoimmune disease Organ transplant WHAT S IN Assessing renal function for some regimens GFR >50 for ribavirin GFR >30 for sofosbuvir Assessing hemoglobin levels for ribavirin-containing regimens Recognizing decompensated liver disease Need to understand the pharmacology of new agents to select the best treatment DAA s that can be used in CKD without dose adjustment Sofosbuvir Only if GFR >30 ml/min Ledipasvir Any GFR, but ledipasvir is not available without sofosbuvir Daclatasvir Any GFR Paritaprevir/ritonavir-dasabuvir-ombitasvir combination therapy GFR >15 ml/min, limited experience in dialysis Elbasvir-grazoprevir combination therapy Any GFR Ample safety and efficacy data in CKD 4 & 5 including dialysis patients Page 10 of 17

11 Drug-Drug Interactions (DDI s) Very important element in pre-therapy assessment List of prohibited drugs is relatively short Varies depending on regimen chosen List of potential interaction drugs is longer Be alert for interactions with common drugs Statins, proton pump inhibitors, birth control preparations No herbs! In particular, no St. John s Wort Use online tools to help assess DDI s Remember: Patients rarely tell you all the pills they are taking! Pre-therapy Assessment New for 2016 Baseline resistance testing Testing for resistance associated variants (RAV s) or polymorphisms Many treatment naïve patients harbor RAV s ~15% have NS5a RAV s In most cases, it does not affect SVR rates as multiple drugs are used in combination RAV s do not affect SVR in G1b, but may reduce SVR in G1a Baseline RAV testing recommended when using elbasvir/grazoprevir combination therapy to treat GENOTYPE 1A infection Page 11 of 17

12 Impact of RAV s on SVR Elbasvir/grazoprevir therapy for G1a SVR 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 98% No RAV s 12 weeks Genotype 1a 70% RAV s 12 weeks 100% 441/450 39/56 6/6 RAV s 16 weeks + ribavirin Pre-treatment RAV Testing When Using Daclatasvir Consider screening for the presence of NS5A polymorphisms in patients with cirrhosis who are infected with genotype 1a prior to the initiation of treatment with Daclatasvir and sofosbuvir with or without ribavirin. But. No guidance is provided as to what to do if polymorphism is present. Page 12 of 17

13 Jorge L. Herrera, MD, MACG Impact of RAV s in G1a Cirrhosis Daclatasvir + Sofosbuvir (Ally 1 & 2 studies) Data on file DACL 041 nad 042; Bristol-Myers Squibb, 2016 NS5a RAV s of Importance Order a genotype 1 NS5a resistance panel Genotype testing will be repeated Look for one of the following mutations: M28 Q30 L31 Y93 Page 13 of 17

14 Pre-Therapy RAV Testing Take Home Points NS5a Resistance testing: Recommended for G1a patients treated with elbasvir + grazoprevir Consider for G1a cirrhosis patients treated with Daclatasvir + sofosbuvir Mandatory for patients who previously failed a regimen containing NS5a DAA NS3/4 Resistance testing: No role for testing in treatment-naïve patients, unless using simeprevir Important role in patients who previously failed a regimen containing NS5a with or without a protease inhibitor. Pregnancy Issues Ribavirin containing regimens are teratogenic Two contraceptive methods NO OCP containing ethinyl estradiol if using paritaprevir/ritonavirdasabuvir-ombitasvir combination therapy. Continue contraception for up to 6 months after completion of therapy Ribavirin free regimens Pregnancy Category B Avoid therapy during pregnancy or lactation Recommend contraception during therapy Page 14 of 17

15 Pre-treatment Laboratory Assessment Basic labs should include Genotype assessment at least once in the past Viral load relatively recent Some insurances require within 3 months Resistance testing if using certain DAA combination therapies Exclusion of HBV and HIV infection Assessment of liver function Assessment of renal function (creatinine, GFR) CBC for patients who will be on ribavirin Assessment of liver fibrosis Drug/alcohol screening if required by payors Choosing a Regimen In many cases, the choice will be made for you by the payors Deciding factors SVR rates similar among existing regimens Ribavirin free regimens tend to be better tolerated Duration of therapy 24 vs 12 wk; 12 vs 8 wk Impaired renal function will favor regimens not renally excreted Genotype will determine choice of regimens Page 15 of 17

16 Is There a Need for a Teaching Visit? YES! (we now call it a pre-treatment visit) Many issues should be addressed: Importance of adherence Review of concurrent medications Pregnancy issues Proper storage of medications Instructions on how to manage missed doses Arranging follow-up lab tests and visits This is very expensive therapy Do it right the first time! Dealing With Payors Many have developed their own approval criteria Denying therapy to patients with fibrosis stage <2-3 is common Resist the temptation not to try to get approval Liability issues Fibrosis assessment may have underestimated true fibrosis stage Patient may develop extra-hepatic complications of HCV Approval rules change frequently you will be the last one to know Appealing a denial may get your patient approved Having a denial letter in the medical record will help you when your patient develops unexpected complications of untreated HCV! Page 16 of 17

17 Getting Medications Approved Use a specialty pharmacy Not all are the same Appeal the first denial Some will get automatically approved Your letter should state the specific reasons you want to treat your patient Therapy is FDA-approved Recommended by the AASLD/ISDA guidelines Increased risk of non-hepatic complications Recently published data Provide a copy of the letter to the patient Take Home Message Get it right the first time! There may not be a second chance Page 17 of 17