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HCV Tx Update 2012 Townshend

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  • Unlike most other viruses, we can get rid of hepatitis C through treatment. Not only that, a whole cascade of good things can happen from treatment.Liver is a very forgiving organ if not pushed too far. You get regeneration of healthy liver cells following HCV tx. This in turn reduces the risk of HCC.First and foremost, if patient achieves a sustained…. It is a virologic cure.<1% have HCV RNA in serum, PBMC or liver tissue on long-term f/u
  • Prioritize: Those with bridging fib/cirrhosis, don’t have time on their side to wait for better, easier drugs to come along.HIV – More likely to die from liver disease. There is a 2-fold increase in risk of cirrhosis in HIV coinfection. However, you’d like to have the CD4 count up to at least 350, so you want to start HIV therapy first.Mild disease – easiest to treat.
  • This is a blood test that looks for a change/polymorphism on chromosome 19 and can tell whether a patient is likely to respond to interferon-based therapy.Associated with 2 fold difference in response to Peg IFN/RBV treatment – with CC genotype responding the best, TT the worst and CT a little better than TT.In Alaska, I’ve tested 63 patients for IL-28b. So far,…
  • 1137 patients studied. This shows IL28b and treatment response in different ethnic groups. TT responds the worst among all ethnic groups.
  • This study looked at vitamin D levels in hepatitis C patients on treatmentFindings were that lower Vit D levels were associated with…
  • Of the 223 AN/AI patients tested, 73% had sub-optimal levels of vitamin D.
  • So, if no other health contraindications, drink coffee.Add reference
  • Starting in 1992, there was plain Interferon alfa, and response rates were 9% for genotype 1 and 30% for genotypes 2/3.Then ribavirin came along in 1998 and response rate increasedto 29% G1, 62% G2/3In 2002 came the start of pegylated interferon tx along with ribavirin…
  • When I think of these early years of treatment, I can relate to this cartoon which says…
  • Here are genotype 1 treatment response rates for peg/rib by ethnicity. This data was pulled from a number of peer-reviewed journal articles.
  • Data since 2002. SVR – intent-to-treat response rates not very good, completed tx response much better. Since I started looking into this when I began tx’g patients at ANTHC in 2007, I have worked on preventing discontinuation of tx through increased teaching, increased follow up especially in the 1st month, weekly phone call follow up, and using a side effects inventory to hone in on what’s bothering them.
  • This is a VA study, that showed that 77.5% of their patients quit treatment.
  • With the current medications which I am going to discuss in more detail, you cannot treat someone with significant heart disease, uncontrolled thyroid disease, rheumatoid arthritis, significant depression, unresolved addiction issues and those who are pregnant/contemplating pregnancy.Add reference
  • Genotype 1 tx with protease inhibitor and peg/rib requires more frequent monitoring for anemias.ANC = Absolute neutrophil count or estimate: WBCs x PMNs (aka PMLs or granulocytes) x .01
  • Be alert to these red flags before treating a patient with any of these issues
  • I put this cartoon here because I get patients who look up tx on the internet and assume that everyone gets the new protease inhibitors: telaprevir or boceprevir and I have to tell the genotype 2 or 3 patient, you don’t need telap or boceprevir and that’s good news – but they don’t want to take just ribavirin.
  • A little lower starting counts acceptable for coinfection treatment
  • This is what a protease inhibtor does…next slide
  • Significant anemia seen. Check CBC every 1-2 weeks while on telaprevir.
  • The side effects of current genotype 1 treatment are no joke.
  • Alfuzosin – for BPH. Midazolam (versed), Triazolam – halcion, pimozide (Tourette’s)Atorvastatin, lovastatin and simvastatin were only statins studied in clinical trials but recommendations are to avoid all statins.
  • Not all inclusive. Major ones noted here. Check drug interactions prior to starting patient on tx.Combination with drugs that are highly dependent on CYP50 (CYP3A4/5) pathway. Salmeterol (Advair, Serevent). Fluticasone (Flovent). Budesonide (Pulmicort). Buprenorphine/naloxone (Suboxone).
  • Progression of liver disease is more rapid in HIV/HCV coinfection with a 2-fold increased risk of cirrhosis.If you are going to treat HCV, start anti-retroviral therapy first. Give enough time to work out the side effects from that, before starting HCV tx.Provisional guidance means not FDA approved.
  • Now if you are going to put someone on any of these drugs, you need to know whether they have had previous treatment and how they responded.These terms are used in next several slides. 2 log – taking two 0s off count. So if they started out at 1 million, it went down to 10,000 or below
  • Add in the cost of erythropoeitin if needed: $400 to 2000/weekly injection. Telaprevir will assist pts making < $100k/ and Boceprevir for $89,400/family of 4. Most major insurances will cover the drugs but you need to check first if you’re not sure. Get pre-approval.
  • A special requirement withtelaprevir – it needs to be taken with 20g of fat 3x/day. You may want to talk to your nutritionist for sample traditional Native American foods containing 20g of fat.
  • Telaprevir now recommends this algorithm for ribavirin dose reduction when anemia occurs. When Hgb gets below 10,…There currently aren’t any recommendations for growth factors but if Hgb continues to drop despite ribavirin dose reduction, you need to consider adding erythropoeitin
  • You want to know that your lab uses a sensitive real-time PCR assay with Limit of Detection of 10-15 IU/ml must be used for monitoring HCV RNA during telaprevir/boceprevirtx. Roche COBAS TaqMan HCV Test v2.0, Abbott Real Time HCV Test are approved.
  • Cirrhosis:
  • This is an old slide that showed in 2008, bocep and telap were in clinical trials, they’ve now made it to market. Several of the phase 2 drugs have moved on to phase 3, although some of these went to the research drug graveyard because of side effects
  • The Holy Grail of hepatitis C treatment is all oral medications and once daily treatment. We’re not there yet. May get there in the next 5 years.

Transcript

  • 1. Hepatitis C TREATMENT 2012 Lisa Townshend-Bulson, MSN, FNP-C Alaska Native Tribal Health Consortium
  • 2. Objectives Define Sustained Virologic Response (SVR) Identify candidates for hepatitis C treatment Differentiate appropriate treatment by genotype Identify factors associated with treatment response Recognize common side effects of treatment Recognize key drug interactions with telaprevir and boceprevir Discuss future treatment of hepatitis C
  • 3. Why Treat HCV? Sustained Virologic Response (SVR) = Undetectable HCV RNA 6 months after completing treatment SVR is considered a cure (Swain, Gastroenterology Nov 2010; 139(5):1593-601.) Risk of developing decompensated cirrhosis is greatly reduced and Regression of cirrhosis can occur (Mallet Ann Int Med 2008;149:399-403) Risk of hepatocellular carcinoma (HCC) in those with cirrhosis reduced
  • 4. Consider Treatment Now Patients with bridging fibrosis or cirrhosis on liver biopsy Patients with HCV and HIV coinfection (early and mild disease) Patients with acute hepatitis C who do not clear virus spontaneously Patients with mild disease  Not urgent  If circumstances are right and no contraindications
  • 5. Candidates for HCV Treatment Persons who are motivated to get better  Genotype 1 after biopsy (recommended, not req’d)  Genotype 2 & 3 without biopsy Persons not interested in getting pregnant/fathering a child in next 12-24 months Rehabilitated alcoholics/drug abusers: 6-month abstinence from alcohol & drugs before treatment  AUDIT-C Alcohol Screening Tool  Random drug screening Persons not depressed or depression well-controlled  PHQ-9/Prime-MD Depression Screening Tool
  • 6. Do Not Treat Clinically decompensated cirrhosis ascites variceal bleeding coagulopathy encephalopathy Kidney,liver, heart or other solid-organ transplant When contraindications to peginterferon, ribavirin and protease inhibitors exist (see later slides)
  • 7. Factors Affecting TreatmentResponse Genotype Viral load Age Fibrosis stage Insulin resistance Steatosis IL28B genotype Vitamin D level Coffee Consumption
  • 8. IL28B and Hepatitis C  CC= Good response  TT = Poor response  CT = Intermediate response (heterozygous) IL-28b in AN/AIs in Alaska 8% CC 40% CT 52% TT
  • 9. Percentage of treatment induced SVR by genotypes of rs12979860DL Ge et al. Nature, 461, 399-401, 2009.
  • 10. Vitamin D Levels and HCV 197 HCV genotype 1 patients receiving IFN-RBV therapy; 49 healthy controls matched by age and sex 25 (OH) D levels significantly lower in HCV persons (25) vs. controls (43); p<0.001) Low levels significantly associated with: Female sex, increased liver inflammation, increased liver fibrosis and decreased SVRHepatology 2010;51:1158-67
  • 11. Vitamin D Levels inAN/AIs with Hepatitis C in Alaska 27% <30 >30 223 tested 73%
  • 12. Coffee Consumption and HCV  HALT-C trial serial liver biopsies q2 years  Coffee consumption > 3 cups/day associated with:  Significantly reduced fibrosis (Hepatology 2009;50:1360-9)  Significantly better response to Peg IFN+RBV (Freedman et al, Gastroenterology 2011; 140(7): 1961-1969)  Quantity of coffee consumption associated with decreased risk of HCC (Hepatology 2008; 48:129-36)
  • 13. History of Hepatitis CTreatment SVR100 90 80 75 75 70 62 60 G1 SVR % 50 44 G 2/3 SVR % 40 30 29 30 20 9 10 0 Interferon α 1992-1998 Inf α/Rib 1998-2002 PegInf/Rib 2002-2011 PegInf/Rib/PI 2011…
  • 14. Genotype 1 Peginterferon/RibavirinTreatment Response Rates by Ethnicity  Asian: ~60%+  Caucasian: ~50%  Hispanic: ~30%  African American: ~10%-20%  Alaska Native/American Indian Persons (AI/AN): 32- 46%
  • 15. AN/AI Treatment OutcomesPeg-IFN/RBV through 2011 SVR in those whoGenotype Treated Discontinued Failed Relapsed SVR* completed tx 1 43 20 (47%) 10 3 10 (23%) 10/23 (43%) 2 37 7 (19%) 3 3 26 *(70%) 24/30 (80%) 3 20 7 (35%) 1 2 10 (50%) 10/13 (77%) Total 100 34 (34%) 14 8 46 (46%) 46/66 (70)% *Includes pts who discontinued tx and still achieved SVRS Livingston et al, ANTHC, Circumpolar Health Conference Abstract 2012
  • 16. How Often Do PersonsComplete Treatment Peginterferon/ribavirin clinical trials: Dropout rates 10-15% VA study: Dropout rate 77.5%  134,934 patients with HCV, 16,043 treated (12%)  10,641 with 1 year data: 2,394 completed treatment (22.5%)  Only 1 in 56 patients with known HCV finish treatment (AA Butt et al. Liver Int. 2010 Aug;30(7):1082)
  • 17. Difficulties in Treating HCV Many patients have medical or psychiatric contraindications  Prospective study done at ANMC  40% of patients are treatment candidates  60% are not treatment candidates (S Livingston et al. Int J Circumpolar Health 2012, 71:18445) As long as treatment includes interferon, HCV infection will be difficult to treat
  • 18. Hepatitis C Treatment 2012Genotype 1  Peginterferon, ribavirin AND a protease inhibitor (telaprevir or boceprevir)  24-48 weeks – depends on response, stage of liver disease, history of treatment response  SVR (Details in later slide) – Boceprevir and Telaprevir - Not apples to apples comparisonGenotypes 2 & 3  Peginterferon and ribavirin only  24weeks  68%-79% SVROther Genotypes (4,5,6)  Peginterferon and ribavirin for 48 weeks  Underrepresented in U.S.
  • 19. Pre-treatment Screening Medical/psychiatric history for contraindications  Review ALL medications EKG (men over 40 & women over 50) Stress test (all patients with hx of cardiac disease) Dilated retinal exam recommended Pre-treatment labs, including HCV RNA, genotype, CBC, PT, CMP, AFP, TSH, uric acid, and pregnancy testing for females of childbearing age. Consider biopsy - Genotype 1
  • 20. Follow Up During Treatment Monitor closely for side effects & tolerability Genotypes 2 & 3, labs at weeks 0 (Start), 1, 2 and 4, then monthly after that unless:  Significant anemia  Thrombocytopenia  Neutropenia Adjust medication doses (refer to prescribing information)  Hgb < 10 (Ribavirin)  Platelets < 50 (Peginterferon)  ANC < 0.5 (Peginterferon)
  • 21. HCV Treatment Medications:Peginterferon (PegInf) Pegylated interferon  Polyethylene glycol added to interferon  Extends half-life of interferon  Provides a more constant level in the blood  Given weekly, subcutaneously Pharmacodynamics:  Immunomodulation  Increases T cell activity  Stimulates B cells for increased antibody response
  • 22. Contraindications to Peginterferon Known hypersensitivity reactions to alpha interferons Autoimmune hepatitis Hepatic decompensation (Child-Pugh > 6 mono- infection, ≥ 6 for HIV coinfection) Women who are pregnant and men whose female partners are pregnant Cardiac disease Severe pulmonary disease Bone marrow suppression Autoimmune disorders incl. RA, thyroid disease, uncontrolled DM, ulcerative colitis
  • 23. Use Extreme Caution Severe depression & serious psychiatric conditions  Bipolar depression/Mania  Psychosis/Hallucinations  Suicidal ideation and past attempts  Homicidal ideation or history Active substance or alcohol abuse Patients who can’t practice birth control
  • 24. HCV Treatment Medications:Ribavirin (RBV) Oral antiviral agent Does not cause a reduction in serum HCV RNA when used alone Enhances the virologic response to interferon Prevents breakthrough and reduces relapse rates Important not to miss doses Reduce dose in adverse event rather than stop dose, if possible
  • 25. Contraindications to Ribavirin Anemia (Hgb <11, Hct <33%) Renal disease (CrCl < 50) Unstable coronary artery or cerebrovascular disease Pregnancy, those contemplating pregnancy (men & women), breastfeeding Inability to practice birth control (men & women) Didanosine use (lactic acidosis, hepatic failure)
  • 26. Peginterferon & RibavirinSide Effects ≥ 20% ≥ 10% ≥ 5% Depression Anxiety Thyroid problems Fatigue Pain Abdominal pain Nausea/Vomiting Diarrhea Dry mouth Fever Lymphopenia Dyspepsia Insomnia Anemia Thrombocytopenia Dizziness Weakness Dyspnea on exertion Headache Weight Loss Memory impairment Neutropenia Inability to concentrate Mood alteration Anorexia Dyspnea Back pain Myalgia Cough Rash Arthralgia Pruritis Increase in sweating Alopecia Dermatitis Eczema Rigors Dry skin Blurred vision Injection site reaction
  • 27. Baseline Lab Parameters Before TreatmentMono-infection HIV Coinfection Plt ≥ 90,000 cells/mm3  Plt ≥ 70,000 cells/mm3 or 75,000 cirrhosis  ANC ≥ 1500 cells/mm3 ANC ≥ 1500 cells/mm3  CD4 count ≥ 200 Cr ≤ 1.5 ULN cells/mm3 TSH and T4 WNL  Cr ≤ 1.5 ULN Hgb ≥ 12g/dL  TSH and T4 WNL women, 13g/dL men  Hgb ≥ 11g/dL women, 12g/dL men
  • 28. 1st Generation Protease Inhibitorsfor Genotype 1-New Std of Care 1st two drugs, telaprevir and boceprevir approved 2011 Telaprevir – Incivek® Boceprevir – Victrelis® Must be used with peginterferon and ribavirin  Cannot be used alone May shorten treatment to 24-28 weeks
  • 29. Protease Inhibitors (PI)Mechanism of Action NS3/4A protease is necessary for cleavage of the HCV encoded polyprotein into mature proteins Inhibits HCV NS3/4A protease  This inhibits viral replication in HCV- infected host cells
  • 30. The Down Side Increased side effects  Telepavir: Rash (moderate/severe in 56%) , anemia (36%), GI Side Effects (29%)  Boceprevir: Severe anemia requiring drug modification in 39% (EPO) Many drug interactions including non- prescription meds Can develop resistance. Must follow futility (stopping) rules
  • 31. Drug Contraindications withTelaprevir or Boceprevir  Atorvastatin, lovastatin, simvastatin  Alfuzosin  Rifampin  Cisapride  Ergot derivatives  Midazolam (oral), triazolam  PDE5 Inhibitors (PAH doses)  Pimozide  St. John’s wort
  • 32. Potential Significant Drug InteractionsTelaprevir, Boceprevir * Antiarrhythmics ↑ Tenofovir ↑ Antifungals ↑ Cyclosporine ↑ Anticonvulsants ↑ or ↓ Sirolimus ↑ -Mycin antibiotics ↑ Tacrolimus ↑ Colchicine ↓ Salmeterol ↑ Alprazolam ↑ Fluticasone ↑ Zolpidem ↓ Budesonide ↑ Ca++ channel blockers ↑ Methadone ↓ Corticosteroids ↑ PDE5 Inhibitors for ED ↑ Bosentan ↑ Rifabutin ↑ Escitalopram ↓ Warfarin ↑ or ↓ Buprenorphine/naloxone ↑* Not all inclusive. Check individual drug interactions before starting treatment.
  • 33. Hepatitis C and HIV CoinfectionTreatment  Treatment unchanged genotypes 2 through 6  Provisional guidance for genotype 1 and PIs: boceprevir and telaprevir*  No shortened treatment with PIs  More drug interactions  Consult specialist*Thomas, D. et al. CID 2012(54): 979-983.
  • 34. TermsRelapser – HCV RNA undetectable at end of treatment (EOT) with PegInf/RBV but detectable 24 weeks after treatmentPartial Responder – Greater than 2 log drop at week 12 but not achieving undetectable RNA by week 24 of a prior course of therapy with PegInf/RBVNull Responder – Less than 2 log reduction in HCV RNA at week 12 of prior course of therapy with PegInf/RBV
  • 35. Comparison Boceprevir Telaprevir PegInf/Rib# of pills 17-18/day 11-12/day 5-6 Rib/day (4 Bocep TID) (2 Telap TID w/fat)How to take? With food q8h With 20g fat q8h BID with foodNew Side Effects Anemia requiring Rash, GI SEs, N/A EPO, Dysgeusia AnemiaHow long on this 24-44 weeks 12 weeks 48 weeksmed?Tx Length incl. 28, 36 or 48 24 or 48 weeks 48 weeksPegInf/Rib weeksSVR in Tx Naive 63-66% 79% 38%SVR in Relapsers 70-75% 86% 22%SVR in Partial 40-52% 59% 7%RespondersSVR in Null Not studied 32% 5%RespondersSVR in Advanced 41-52% 62% 10-38%FibrosisTotal Cost 31,680-$58,080 $59,080 $20,000-40,000
  • 36. Fatty Foods for Absorptionof Telaprevir ½ cup trail mix  15 dark chocolate 2 ounces of cheese covered almonds ¾ cup regular ice  2 T peanut butter cream  35 almonds/peanuts 1 container Total  ½ cup Agutuk Classic Fage (berries, seal Fruit yogurt and 1 oz oil, shortening, sugar) coconut  5 ½ oz cooked king 2 oz potato chips salmon ½ c or 4oz avocado  1 ½ Tablespoon seal oil  3 oz smoked hooligan
  • 37. Ribavirin Dose Modification Algorithm for Telaprevir ≥10 g/dl Continue at current dose Test Hgb <10 g/dl Reduce dose to 600mg/d Weeks <8.5 g/dl Discontinue RBV 0-2-4-8-12* Hgb < 12 Reduce Test Hgb >2g/dL drop in g/dL after 4 D/C RBV to Hgb during wks at RBV 600mg/d any 4 wk tx pd reduced dose *More frequent monitoring may be clinically appropriateSource: Vertex Incivek® Treatment Management Guide
  • 38. Financial Resources for HCVTreatment  Boceprevir (and Pegintron®)  www.Merck-CARES.com  1-866-939-4372  Telaprevir  www.VertexGPS.com  1-855-837-8394  Peginterferon alfa 2a (Pegasys®)  www.genentechaccesssolutions.com  1-800-530-3083
  • 39. Response Guided Therapy(RGT) The opportunity to shorten treatment duration based on HCV RNA decline at specific timepoints during treatment Key RGT HCV RNA Timepoints: Telaprevir - Weeks 4, 12, 24 Boceprevir – Weeks 8, 12, 24
  • 40. Interpreting HCV RNA Results  Virus must be “not detected” or “undetectable” to be considered negative for genotype 1 RGT  <43 or <25 IU/ml – Unclear  Result should specify:  Detected/Below Level of Quantification (Still detected – Not negative)  Not Detected/Below Level of Detection (Negative result – Proceed with RGT)Harrington, P., Wen Zeng, L. Naeger. Hepatology, 2012 (online 10/1011)
  • 41. Boceprevir Treatment Algorithm Boceprevir Treatment Duration Lead-in: Wk 8 Wk 24 Triple therapy: Peg/RBV Total Peg/RBV RNA RNA Peg/RBV/BOC DurationTreatment- 4 wks Neg Neg 24 wks - 28 wksnaïve 4 wks Pos Neg 32 wks 12 wks 48 wksPrior Relapser 4 wks Neg Neg 32 wks - 36 wksor 4 wks Pos Neg 32 wks 12 wks 48 wksPartialResponderCirrhotics 4 wks Neg 44 wks 48 wksNull responder No dataPeg = Peginterferon RBV = Ribavirin BOC = Boceprevir STOPPING RULES/TREATMENT FUTILITY: If HCV RNA ≥100 IU/mL at wk 12, or detectable at any level at wk 24, discontinue all treatment. It isn’t working.
  • 42. Telaprevir Treatment Algorithm Telaprevir Treatment Duration Wk 4 Wk 12 Wk 24 Triple therapy: Peg/Rib Total RNA RNA RNA Peg/Rib/TPR DurationTreatment- Neg Neg Neg 12 wks 12 wks 24 wksnaïve or Prior Pos Pos 12 wks 36 wks 48 wksRelapserPrior Partial Neg/Pos Neg/Pos Neg 12 wks 36 wks 48 wksResponder orNull ResponderCirrhosis Neg/Pos Neg/Pos Neg 12 wks 36 wks 48 wksPeg = Peginterferon RBV = Ribavirin TPR = Telaprevir STOPPING RULES/TREATMENT FUTILITY: If >1000 IU/mL at wks 4 or 12, or detectable at any level at wk 24, discontinue all treatment. It isn’t working.
  • 43. PI Treatment Caution HCV/HIV - provisional guidance HCV/HBV Coinfection – not studied Children – not studied Patients over 65 - not studied sufficiently (35 subjects in telaprevir study >65 yrs) Cirrhotics – limited study ESRD or patients on hemodialysis – not studied Solid Organ Transplantation – not studied
  • 44. “Now this is not the end. It isnot even the beginning of theend. But it is, perhaps, the endof the beginning” -Winston Churchill
  • 45. New Drugs for HCVClass Drug Potency Resistance Active Active Examples Barrier Genotype 1 Genotype 2 &31st Gen PI Telaprevir Mod. Lowest Yes No(NS3/4A) Boceprevir high2nd Gen PI Simeprevir High Low Yes Low/moderate Asunaprevir GS 9256 MK 5172 ACH 2684Nucleotide GS 7977 High High Yes YesInhibitorsPolymerase Tegobuvir High Low Yes YesInh/NS5B ABT-072NS5A Daclatasvir High Intermediate Yes ?ProteaseInhibitorsCyclophilin Alisporivir YesInhibitors
  • 46. Future Treatment withDirect Acting Antivirals (DAAs)  Interferon-free  Fewer side effects  More drug options  Tailored treatment  Less frequent administration (QD or BID)  Fewer pills (Combining drugs)
  • 47. Thank You! My contact info:  ltownshend@anthc.org  907-729-1573 ANTHC Hepatitis Website  http://www.anthctoday.org/community/hep /providerinformation.html