* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download What is HCV?
Survey
Document related concepts
Oesophagostomum wikipedia , lookup
Microbicides for sexually transmitted diseases wikipedia , lookup
Neonatal infection wikipedia , lookup
Ebola virus disease wikipedia , lookup
Diagnosis of HIV/AIDS wikipedia , lookup
Sexually transmitted infection wikipedia , lookup
Influenza A virus wikipedia , lookup
Middle East respiratory syndrome wikipedia , lookup
Orthohantavirus wikipedia , lookup
West Nile fever wikipedia , lookup
Human cytomegalovirus wikipedia , lookup
Marburg virus disease wikipedia , lookup
Herpes simplex virus wikipedia , lookup
Henipavirus wikipedia , lookup
Antiviral drug wikipedia , lookup
Transcript
Hepatitis C Update Primary Care Guidance Michael J. Tan, MD, FACP, FIDSA Associate Professor of Internal Medicine Northeast Ohio Medical University Summa Health System Akron, OH Objectives Review basic epidemiology of HCV Understand testing and interpretation of HCV labs Review new therapeutics Primary source for recommendations is IDSA-AASLD, accessible from www.hcvguidelines.org 2 What is HCV? Non-A, Non-B small, single stranded, enveloped RNA virus Family: Flaviviridae • Genera: Hepacivirus, HCV • Genera: Flavivirus: Dengue, Yellow Fever, WNV Targets hepatocytes Blood-borne 2-3% of world’s population (130-170mil) US <2%, Egypt > 10% 3 A and B, Electron microscopic images of hepatitis C virus (HCV) virions concentrated from human plasma by high-speed centrifugation. The virions are identified by staining with gold-labeled antibodies to the HCV envelope proteins. (From Kaito M, Watanabe S, Tsukiyama-Koham K, et al. Hepatitis C virus particle detected by immunoelectron microscopic study. J Gen Virol . 1994;75:1755-1760.) (From Kaito M, Watanabe S, Tsukiyama-Koham K, et al. Hepatitis C virus particle detected by immunoelectron microscopic study. J Gen Virol . 1994;75:17551760.) Hepatitis C RAY, STUART C., Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 154, 2157-2185 Copyright © 2010 Copyright © 2010, 2005, 2000, 1995, 1990, 1985, 1979 Elsevier Inc. Hepatitis C Virus • Primary target hepatocytes • Genome encodes a polyprotein consists of 3011 amino acids – Structural (core, E1, E2)and Non-structural (regulatory NS2, NS3, NS4A/B, NS5A/B) proteins – Robust viral replication ~10 trillion particles/day – RNA-dependent RNA polymerase-lacks proofreading and no DNA intermediates – Does not integrate into host genomes (vs. HIV) HIV vs. HCV • RNA virus-Retrovirus • CD4, macrophages, dendritic cells • mutation rate • Blood-borne, moderate sexual transmission • Fatal if untreated • Treatable not curable • Many drugs • Life-long therapy • • • • • • • • RNA virus-Flavivirus Hepatocytes mutation rate Blood-borne, low sexual transmission Might be fatal (cirrhosis, HCC) Both treatable AND potentially curable Few drugs (more to come) Finite duration Hepatitis C Virus • Genotypes 1 to 6, multiple subtypes • Geographical distribution differences around the world • Genotypes important to stratify duration and dosing – Genotype 1 harder and longer therapy – Genotype 2,3 “easier” and shorter duration – Less important with new and more potent agents Geographic distribution of hepatitis C virus genotype. (Adapted from Fang JW, Chow V, Lau JY: Virology of hepatitis C virus. Clin Liver Dis 1997;1:493 - 514.) (Adapted from Fang JW, Chow V, Lau JY: Virology of hepatitis C virus. Clin Liver Dis 1997;1:493 - 514.) Viral Hepatitis Cleveland Clinic,, Current Clinical Medicine, ${parentCitation.chapternum}, 539-551 Copyright © 2010 Copyright © 2009, 2010 by The Cleveland Clinic Foundation. Published by Saunders, a imprint of Elsevier Inc. HCV Genotype (used to) matter • Genotype 1 historically the most difficult type to treat – Unfavorable characteristics • Advanced fibrosis, especially cirrhosis • African-American • IL-28B CT or TT genotype – Polymorphism encodes gene products for IFN-III – Favorable response to CC genotype • Baseline high viral load • Prior non-responders • New agents might relegate above characteristics, except for cirrhosis The Prevalence of Hepatitis C Virus Infection in the United States, 1999 through 2002 • • • • • • • NHANES data->15,000 Prevalence ~1.6% ~4.1 million + HCV Ab ~3.2 million with chronic HCV Peak age 40-49 (4.3%) Between age 20-59 (48.4%) Risk factors: IVDU, >20 life-time sex partners, blood transfusions >1992 Ann Intern Med. 2006;144(10):705-714. doi:10.7326/0003-4819-144-10-200605160-00004 From: The Prevalence of Hepatitis C Virus Infection in the United States, 1999 through 2002 Ann Intern Med. 2006;144(10):705-714. doi:10.7326/0003-4819-144-10-200605160-00004 Figure Legend: Prevalence of antibodies to hepatitis C virus (HCV) by age group (A) and year of birth (B) in the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) and the current NHANES (1999–2002).The vertical bars represent 95% CIs. Date of download: 4/2/2014 Copyright © American College of Physicians. All rights reserved. From: The Increasing Burden of Mortality From Viral Hepatitis in the United States Between 1999 and 2007 Ann Intern Med. 2012;156(4):271-278. doi:10.7326/0003-4819-156-4-201202210-00004 Figure Legend: Annual age-adjusted mortality rates from hepatitis B and hepatitis C virus and HIV infections listed as causes of death in the United States between 1999 and 2007. Because a decedent can have multiple causes of death, a record listing more than 1 type of infection was counted for each type of infection. Date of download: 4/7/2014 Copyright © American College of Physicians. All rights reserved. • Traditional risk factors Illegal drug injection (once or a few times many years ago) Clotting factors before 1987 Hemodialysis Abnormal ALT Prior transfusions or organ transplantations before July 1992 HCW after needle sticks or mucosal exposures with HCV + blood Children born to HCV + women • Traditional risk factors Illegal drug injection (once or a few times many years ago) Clotting factors before 1987 Hemodialysis Abnormal ALT Prior transfusions or organ transplantations before July 1992 HCW after needle sticks or mucosal exposures with HCV + blood Children born to HCV + women “Adults born during 1945-1965 should received onetime testing for HCV without prior ascertainment of HCV risk” Brief alcohol screening and intervention, if indicated HIV-infected patients Hepatitis C-not just an urban problem Notes from the Field: Hepatitis C Virus Infections Among Young Adults-Rural Wisconsin 2010 • Increased HCV infections among persons <30 age in 6 contiguous rural counties 2004-2008 ~8 cases/year 2009-2010 ~24 cases/year Investigated all 25 patients-all HCV Ab positive 17 patients-sharing hypodermic needles, drug preparation equipment or drug snorting equipment 16 patients-injected/snorted/both 6 specimens with similar NS5B regions Subanalysis of quasispecies not related Staging Histologic Stages of HCV Infection. Lauer GM, Walker BD. N Engl J Med 2001;345:41-52. Liver staging Important to identify cirrhotic patients Higher incidence of HCC • Initiate surveillance, risk still present even patient is cured Decreased response rate Risk of liver decompensation (while on therapy) Candidacy for response-guided therapy (1st generation protease inhibitors: boceprevir and telaprevir) Distribution of hepatic fibrosis in patients with chronic hepatitis C virus infection and normal or persistently elevated serum alanine aminotransferase (ALT) levels. Shiftman M L et al. J Infect Dis. 2000;182:1595-1601 © 2000 by the Infectious Diseases Society of America Distribution of hepatic fibrosis in patients with chronic hepatitis C virus infection and normal or persistently elevated serum alanine aminotransferase (ALT) levels. Shiftman M L et al. J Infect Dis. 2000;182:1595-1601 © 2000 by the Infectious Diseases Society of America ALT not reliable to predict severity of liver disease Liver Biopsy Still considers as gold standard Might be replaced by serum markers Values: Best way to assess fibrosis Assess other liver disease(s) Definitive staging Liver Biopsy Cons: Invasive Relative more expensive than serum markers Expertise in acquiring specimen and interpreting histopathology • Adequacy of specimen • Which classification is used (Metavir, Ishak, etc.) Bleeding risk Fig. 5 Source: Journal of Hepatology 2007; 47:598-607 (DOI:10.1016/j.jhep.2007.07.006 ) Copyright © 2007 Terms and Conditions Liver Biopsy-size matters!! >3 cm 1.5 cm 1 cm 22.4±4.9 10.3±2.2 6.4±1.2 Mild (≤6) 80 (49.7%) 97 (60.2%) 133 (86.6%) Moderate (7-12) 62 (38.5%) 63 (39.1%) 28 (17.4%) Severe (≥13) 19 (11.8%) 1 (0.6%) 0 Mild (1-2) 95 (59%) 110 (68.3%) 120 (80.1%) Moderate (3-4) 48 (29.8%) 39 (24.2%) 24 (14.9%) Severe (5-6) 18 (11.2%) 12 (7.4%) 8 (4.9%) No. of portal tracts Complete Grading Staging Colloredo et al. Journal of Hepatology 39 (2004):239-244 FibroSure • Serum biomarkers as surrogate to test for fibrosis • Non-invasive • Biochemical markers: α2 macroglobulin, haptoglobin, bilirubin, GGT, apolipoprotein A1 and ALT • Coupled with patient’s age and gender and using a proprietary artificial intelligence algorithm to generate a score FibroSure Provides a numerical quantitative estimate of liver fibrosis ranging 0.00 to 1.00-corresponds to Metavir scroing F0-F4 F0=no fibrosis, F1= portal fibrosis, F2= bridging fibrosis with septa, F3= bridging fibrosis with many septa, F4= cirrhosis Provides a numerical quantitative estimate of necroinflammatory activity from 0.00 to 1.00 corresponds to A0 to A3 A0= no activity, A1= minimal activity, A2= moderate activity, A3= severe activity FibroSure Correlates fairly well with liver biopsy Multiple studies indicated AUROC predictive value between 0.70 to 0.80 Should not be used: Hemolysis, acute hepatitis, autoimmune hepatitis, low haptoglobin, genetic liver disease Discordant liver biopsy vs. FibroSure Biopsy size (<15 mm) Hepatitis C More Background Risks About 10% spontaneous clearance Non-cleared—risk of cirrhosis, liver failure, HCC Previous treatments: Peg-Interferon + Ribavirin Treatment up to 12mos Sustained virologic response: • Genotype 1: 70% (less with HIV) • Genotype 2-3: 80-90% (less with HIV) Anemia Influenza-like illness Depression 33 Treatment Ghany et al. Hepatology, Vol. 49, April 2009 Therapy For decades only two major classes of medications: interferon and ribavirin Standard IFN-1991; Pegylated IFN-early 2000’s Response rate poor to fair at best (genotype 1 especially) Moderately significant side-effects Direct Acting Anti-virals (DAAs)-2011 revolutionized treatment paradigm Ribavirin • Nucleoside purine analogs • 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide • Broad spectrum of DNA and RNA viruses – Exact mechanism on HCV not clear • Major metabolite ribavirin-5’-triphosphate – Erythrocytes lack necessary enzymes to degrade metabolite-leads to accumulation of metabolites – Exerts oxidative damage to cell membrane and increased extravascular hemolysis by RE system Gilbert et al. AAC, Aug 1986, p.201-205 Evolution of HCV Therapy McHutchison NEJM 1998; 339:1485-1492 Fried NEJM 2002; 347:975-982 Manns Lancet 2001; 358:958-965 Boceprevir Telaprevir Simeprevir Asunaprevir Sofosbuvir Ledipasvir Daclastavir Organization of the hepatitis C virus (HCV) genome and polyprotein. ( A ) Organization of the HCV genome with nontranslated RNA segments shown as lines and the open reading frame as a box; the region encoding the nonstructural proteins required for replication is shaded. ( B ) Functional organization and processing of the viral polyprotein, showing approximate membrane topologies of the mature HCV proteins. Sites of cleavage by host cell and viral proteases are indicated by triangles. (Redrawn from Lemon SM, Walker C, Alter MJ, et al. Hepatitis C virus. In: Knipe DM, Howley PM, eds. Fields’ Virology, 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:1253.) (Redrawn from Lemon SM, Walker C, Alter MJ, et al. Hepatitis C virus. In: Knipe DM, Howley PM, eds. Fields’ Virology, 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:1253.) Viral Hepatitis C Alter, Miriam J., Tropical Infectious Diseases: Principles, Pathogens and Practice, CHAPTER 65, 427-432 Anti-Hep C 4/2011, Recommended for approval 5/2011, Telaprevir, boceprevir-APPROVED! Approval for recurrence/treatment New Agents for HCV Combination with PEG-IFN, RBV Anemia biggest AE Apparently better SVR than standard of care Cost? Role? Efficacy in HIV? Anti-Hep C-Boceprevir N Eng J Med 2011;364:1195-206. Boceprevir for untreated HCV Genotype 1 • Gp 1: pegIFN-RBV + Placebo 44wks • Gp 2: peg IFN-RBV + boceprevir 24 wks • Gp 3: peg IFN-RBV + boceprevir 44wks SVR non-black: Gp 1 40% vs Gp 2 67% vs Gp 3 68% SVR black: 23% vs 42% vs 53% Anemia 13% controls vs 21% boceprevir SVR rates improve with new DAAs Adapted from: Poordad et al. NEJM 2011;364:1195; Jacobson et al. NEJM 20111:364:2405; Bacon et al. NEMJ 2011;364:1207; Zeuzem et al. NEJM 2011;364:2417 Side-effects Boceprevir Fatigue Anemia Nausea Dysgeusia Telaprevir Anemia Rash Fatigue Pruritis Nausea Diarrhea Vomiting Hemorrhoids Anorectal discomfort Sofosbuvir (SOF, GS-7977) HCV-specific uridine nucleotide NS5B polymerase inhibitor (chain terminator) Potent antiviral activity against HCV genotypes 1–6 High barrier to resistance Once-daily, oral, 400-mg tablet Favorable clinical pharmacology profile No food effect Renally cleared - limited potential for drug interactions No CYP3A/4 metabolism limited potential for drug interactions Generally safe and well tolerated in clinical studies to date (>3000 patients) Gilead Anti-HCV Simeprevir (Janssen) Oral 150mg q24 x12wk + Peg/Rib x24wk. SVR 79-80% Approval for naïve and treatment experienced Genotype 1 Once daily pill option APPROVED Sofosbuvir (Gilead) Once daily nucleotide analogue Approval in chronic HCV in adults with GT2, 3 • PEGIFN + Riba + sofosbuvir, Chronic HCV 1 and 4 treatment Naïve • Riba + sofosbuvir, Chronic HCV 2, 3 (24wk) • SVR in as little as 12 weeks Sup or non-inf to current treatments. Sofosbuvir Indications Genotype 1 and 4: P/R/SOF x 12 weeks • If INF ineligible: SOF + RBV x 24 weeks Genotype 2: RBV + SOF x 12 weeks Genotype 3: RBV + SOF x 24 weeks Hepatocellular carcinoma awaiting transplant: RBV + SOF up to 48 weeks HIV/HCV co-infection Simeprevir (Olysio) NS3/4A protease inhibitor Combination therapy with PEG-IFN/RBV for genotype 1 only Treatment naïve/prior relapses: 12 weeks then 12 more weeks with P/R Partial/null responders and cirrhotics: 12 weeks then 36 more weeks with P/R Simeprevir Off label use-combination of sofosbuvir + simeprevir (sim-sof combo) As recommended by recent AASLD/IDSA joint guidelines for IFN intolerant GT-1 patient Significant: interferon free! Data derived from ongoing study COSMOS ledipasvir/sofosbovir (Harvoni) Approved for genotype 1 in adults (too early to be added to guidelines) One tablet (90/400) PO q24h Naïve with or without cirrhosis 12 wk Experiencec without cirrhosis 12 wk Experienced with cirrhosis 12 wk Interferon sparing AE: Fatigue, Headache, nausea, diarrhea, insomnia GT-1 96-99% SVR with minimal relapse 49 DAA daclatasvir (Daklinza,) paritaprevir/ritonovir/ombitasvir (daily) + dasabuvir (twice/day) (Viekira Pak) sofosbuvir (Sovaldi) ledipasvir + sofosbuvir (Harvoni) Simeprevir (Olysio) When and in Whom to Initiate Therapy? All patients with chronic HCV except those with short life expectancies that cannot be remediated by treating HCV, by transplatation, or by other directed therapy. Prioritization tables have been removed Earlier treatment leads to augmented benefit of SVR Treatment in setting of fibrosis or cirrhosis and reduce decompensation Recommendations-Treatment Naive Genotype 1 daclatasvir + sofosbuvir x12 weeks (no cirrhosis) (1a, 1b) daclatasvir + sofosbuvir x24 weeks +/- ribavrin (cirrhosis) (1a, 1b) ledipasvir + sofosbuvir x12 weeks (1a, 1b) paritaprevir/ritonovir/ombitasvir (daily) + dasabuvir (twice/day) x12 weeks (no cirrhosis) or 24 weeks (cirrhosis) (1a) paritaprevir/ritonovir/ombitasvir (daily) + dasabuvir (twice/day) x12 weeks (1b) simeprevir + sofosbuvir x12 weeks (no cirrhosis) or +/- ribavirin (cirrhosis) x 24 weeks (1b) Not recommended: • sofosbuvir + RBV x24wks • PEG-IFN + RBV +/- Sofosbuvir, simeprevir, telaprevir, or boceprevir for 1248 weeks. • Monotherapy with PEG-IFN, RBV, or DAA 52 www.hcvguidelines.com Recommendations-Treatment Naive Genotype 2 daclatasvir + sofosbuvir x12 weeks (2) *Intolerant of ribavirin sofosbuvir + RBV x12 wks Extend treatment to 16 weeks with cirrhosis Not recommended: • PEG-IFN + RBV x24wks • Monotherapy with PEG-IFN, RBV, or DAA • Telaprevir, boceprevir, or ledipasvir containing regimens Genotype 3 daclatasvir + sofosbuvir x12 weeks (no cirrhosis) or 24 weeks +/- RBV x24 weeks (cirrhosis) sofosbuvir + RBV + PEG-IFN x12wks (24 wks if no PEG-IFN) Not recommended: • PEG-IFN + RBV x24-48wks • Monotherapy with PEG-IFN, RBV, or DAA • Telaprevir, boceprevir, or ledipasvir containing regimens Recommendations-Treatment Naive Genotype 4 ledipasvir/sofosbuvir x12 weeks paritaprevir/ritonovir/ombitasvir + RBV x12 weeks sofosbuvir + RBV x24 weeks Alternative: sofosbuvir + RBV + PEG/IFN x12 weeks. Not recommended: • PEG-IFN + RBV +/- simeprevir x24-48wks • Monotherapy with PEG-IFN, RBV, or DAA • Telaprevir, boceprevir, containing regimens Genotype 5/6 ledipasvir/sofosbuvir x12 weeks Alternative: sofosbuvir + RBV + PEG-IFN x12wks Not recommended: • PEG-IFN + RBV +/- simeprevir x24-48wks • Monotherapy with PEG-IFN, RBV, or DAA • Telaprevir, boceprevir, or containing regimens Recommendations-Retreatment Genotype 1a, 1b, no cirrhosis, failed PEG-IFN-RBV daclatasvir + sofosbuvir x12 weeks ledipasvir + sofosbuvir x12 weeks paritaprevir/ritonovir/ombitasvir (daily) + dasabuvir (twice/day) x12 weeks simeprevir + sofosbuvir x12 weeks 1a, 1b, compensated cirrhosis, failed PEG-IFN-RBV daclatasvir + sofosbuvir x24 weeks ledipasvir + sofosbuvir x24 weeks (or with RBV for 12 weeks) paritaprevir/ritonovir/ombitasvir (daily) + dasabuvir (twice/day) x12 weeks 1b, 24wks + RBV for 1a simeprevir + sofosbuvir x24 weeks (1a Q80k (-)), 1b 55 www.hcvguidelines.com Recommendations-Retreatment Failed Sofosbuvir/RBV +/- PEG-IFN ledipasvir/sofosbuvir + RBV x12 weeks (no cirrhosis) ledipasvir/sofosbuvir + RBV x24 weeks (cirrhosis) Failed tela/bocep/simep + PEG-IFN/RBV or sim/sof (NoNS5A), geno 1 daclatasvir + sofos x12 weeks Ledipasvir/sofos x12 weeks Other combinations exist Avoid in GT 1 for any protease failure: Simepmrevir, sofosbuvir, telaprevir, or boceprevir with PEG-IFN/RBV or PEG-IFN RBV alone DAA or PEG-IFN, RBV monotherpay PEG-IFN/RBV alone. Any IFN-Free regimen containing Simeprevir or Paritaprevir Recommendations-Retreatment Genotype 2 Failed PEG-IFN, RBV: Sofosbuvir + RBV x16-24 wks • Add RBV and PEG-IFN for 12 weeks if eligible to receive PEG-IFN Failed sofosbuvir and RBV: • daclatasvir + sofosbuvir x24 wk +/- RBV • Sofosbuvir + RBV + PEG-IFN x12 weeks. Not recommended: • PEG-IFN + RBV with or without telap or bocep • Monotherapy with PEG-IFN, RBV, or DAA • Ledipasvir/sofosbuvir Genotype 3 daclatasvir + sofosbuvir x12 weeks (no cirrhosis) or + RBV x24 weeks (cirrhosis) sofosbuvir + RBV + PEG-IFN x12 weeks Prior sofos/RBV: daclatasvir + sofosbuvir + RBV x24 wks or sofos + RBV + PEG-IFN x12 weeks. Not recommended: • PEG-IFN + RBV x24-48wks • Monotherapy with PEG-IFN, RBV, or DAA • Telaprevir, boceprevir, or ledipasvir containing regimens Recommendations-Retreatment Genotype 4 ledipasvir/sofosbuvir x12 weeks paritaprevir/ritonovir/ombitasvir + RBV x12 weeks Sofosbuvir x12 wks + RBV + PEG/IFN x12 weeks sofosbuvir + RBV x24 weeks. Not recommended: • PEG-IFN + RBV +/- telaprevir or boceprevir • Monotherapy with PEG-IFN, RBV, or DAA Genotype 5/6 ledipasvir/sofosbuvir x12 weeks Alternative: sofosbuvir + RBV + PEG-IFN x12wks Not recommended: • Monotherapy with PEG-IFN, RBV, or DAA • Telaprevir, boceprevir, or containing regimens Monitoring Drug-Drug interactions HCV Geno/Subtype, Qunatitative HCV Within 12 weeks prior to start CBC, INR, LFT, Calculated GFR TSH (if IFN) During therapy CBC, Creat, GFR, LFT after4 weeks TSH q12k weeks if IFN Discontinue Tx for 10 fold rise in ALT at week 4. • If less than 10 fold rise, check LFT wk 6 and 8 Quantitative @ 4 weeks, and 12 weeks after completion, +/- 24 weeks after completion. HCV and HIV Still want to treat HIV fully Follow guidelines for HCV Watch for drug interactions with HAART HCV Decompensated disease has recommendations but should be done with consultation with liver specialist Post-liver transplant has recommendations Specific recommendations for patients with impaired crt cl <30 Acute infection? HCV Ab and HCV RNA (viral load) Pre-exposure prophy and post-exp prophy not recommended F/U VL for clearance, no treatment for spontaneous clearance. (min 6 mos) Monitoring If HCV detectable @ wk 4, repeat at wk 6 If HCV increases 10 fold at week 6, stop therapy If comes down at week 6 and 8, no recommendation Check serum HCG RBV not recommended in pregnancy No SVR: LFT, CBC, INR for disease progression Surveillance for HCC q6mos Endoscopic surveillance for varices if cirrhosis Evaluate for retreatment as new alternatives become available. SVR Achieved No fibrosis (f/u as if no HCV) Check Quant if ongoing risk of HCV or if unexplained hepatic dysfunction If F3 or F4, ultrasound 2x/year surveillance for HCC Baseline endoscopy for varices if cirrhosis Assess for other causes of liver disease in those who develop persistently abnormal LFT after SVR Not recommended to prospectively monitor for HCV recurrence in those receiving immunosuppressive therapy. Conclusions HCV is a huge problem Cases on increase, especially with screening Therapy is easier than it used to be Cure is possible Cost is an issue