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Chronic Hepatitis C Among Special Patient Populations: Impact of Triple Therapy.

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Presentation on theme: "Chronic Hepatitis C Among Special Patient Populations: Impact of Triple Therapy."— Presentation transcript:

1 Chronic Hepatitis C Among Special Patient Populations: Impact of Triple Therapy

2 Faculty Disclosure It is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a faculty member with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation has identified and resolved any and all faculty conflicts of interest prior to the release of this activity. Sponsored by The France Foundation Supported by an educational grant from Vertex Pharmaceuticals

3 Educational Learning Objectives Recognize the prevalence and incidence of HCV within your patient population and implement a management strategy that is appropriate to your clinical setting Integrate new information regarding the current landscape of HCV appropriate for your patient population and formulate specific strategies for optimal management

4 HCV and Special Populations at Risk “Special populations” in this context refer to individuals with: Increased prevalence of HCV Challenges related to access to care Therapeutic difficulties –Eligibility for therapy, suboptimal response to therapy, etc These individuals include: Racial and ethnic minority groups Military veterans Socioeconomically disadvantaged Homeless/unstable housing Prior or active substance use History of incarceration HIV-infected Renal insufficiency Solid organ transplant recipients

5 Prevalence of Chronic Hepatitis C Infection Centers for Disease Control and Prevention. Hepatitis C FAQs for Health Professionals. Available at: Accessed January 6, Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C; In the US, 2.7–3.9 million people are living with chronic HCV infection; 75% are unaware they are infected In the US, 2.7–3.9 million people are living with chronic HCV infection; 75% are unaware they are infected

6 Hepatitis C Disease Burden in the US Wise M, et al. Hepatology. 2008;47: Infectivity –Most common blood-borne viral infection –Approximately 1.3% (~4 million) of the general population is chronically infected Liver cirrhosis: within 20–30 years –10-20% of chronically infected individuals will develop cirrhosis –1–5% may develop hepatocellular carcinoma Leading indication for liver transplant Growing cause of death in patients with HIV

7 Aging of HCV-Infected Persons in the US: Disease Progression Davis G, et al. Gastroenterology. 2010;138:

8 Projected Cases of Hepatocellular Carcinoma and Decompensated Cirrhosis Due to HCV Davis GL, et al. Gastroenterology. 2010;138(2): Year Number of cases 160, , , ,000 80,000 60,000 40,000 20,000 Decompensated cirrhosis Hepatocellular cancer

9 Adapted from: 1. CDC. MMWR. 2003;52(RR-1):1-33; 2. Edlin B. Hepatol. 2002;36(5 suppl 1):S210-S219; 3. NHSDA Report 2003; 4. Poles M, et al. Clin Infect Dis. 2000;31: ; 5. LaBrecque D, et al. Hepatitis C Choices. 2002:7-15; 6. Alter M, et al. N Engl J Med. 1999;341: ; 7. Nyamathi A, et al. J Gen Intern Med. 2002;17: ; 8. Dominitz J, et al. Hepatology. 2005;41:88-96; 9. Jonas M. Hepatol. 2002;36(5 suppl 1):S173-S178. Incarcerated ~ 330,000 to 860,000 (16–41%) 1 Homeless ~ 175,000 (22%) 7 Children (6–18 years old) ~ 100,000 (0.1%) 9 Living below poverty level ~ 940,000 (3.2%) 6 Injection drug users ~ 300,000 (80–90%) 2,3 Alcoholics ~ 240,000 (11–36%) 5 Veterans ~ 280,000 (4%) 8 HIV-infected ~ 300,000 (30%) 4 Male 63% 37% Female Prevalence of HCV in Select Populations

10 Colvin HM, Mitchell AE, Editors. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Institute of Medicine HepatitisAndLiverCancerReport.pdf. Accessed June Number of Persons Infected (in millions) 1,100,000 2,700,000–3,900,000 3X-4X Hepatitis C is 3-4 Times More Prevalent Than HIV

11 Estimated Prevalence of HCV by Subgroup Armstrong G, et al. Ann Intern Med. 2006;144; Prevalence of HCV Antibodies (%)

12 Relative Risk of Being HCV Positive by Race Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease. New York, NY: Milliman, Inc; 2009.

13 Two-Thirds of Those With Chronic HCV in the US Were Born Between 1946 and 1964 Individuals (n) Birth Year Group 0 1,600,000 1,400,000 1,200,000 1,000, , , , , <1920 Estimated Prevalence by Age Group Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease. New York, NY: Milliman, Inc; 2009.

14 HCV Genotypes in US Germer JJ, et al. J Clin Microbiol May 25. [Epub ahead of print]

15 HCV Genotypes and Race Nainan OV, et al. Gastroenterology. 2006;131:

16 Natural History of HCV Infection in Blacks/African Americans Negative prognostic considerations –High prevalence of genotype 1 –Appear to be unable to clear HCV as efficiently compared with Whites –Impaired CD4 cell cytokine response Positive prognostic considerations –More likely to have lower ALT levels than other populations –Lower piecemeal necrosis scores –May have less fibrosis than Whites –Fewer cases of cirrhosis Hepatocellular carcinoma –Incidence (histologically documented): 6.1 and 2.8 per 100,000 persons in Blacks/African Americans and Whites, respectively –HCC-associated mortality rate is twice that of Whites Jeffers LJ. Liver Int. 2007;27:

17 Ethnicity and Cirrhosis on Liver Biopsy Kallwitz ER, et al. Clin Gastro Hepatol. 2010; 8: P < FactorOR95% CIP-value Hispanic* Non-Hispanic White* BMI Duration of infection Diabetes mellitus Past alcohol Clinical Factors Associated with Cirrhosis– Multivariate Analysis *Compared with African Americans as the reference group

18 Annual Hepatitis C Mortality Rates: Race/Ethnicity Wise M, et al. Hepatology. 2008;47:1128−1135.

19 Prevalence of HCV in Users of US Veterans Medical Centers –Demographics Vietnam-era service –Lifestyle Factors Injected illicit drugs; snorted drugs Test for HIV In jail > 48 hrs Unprotected sex with injection drug user Tattoo; body piercing –Clinical Diagnoses Prior diagnosis of HCV Hepatitis B Drug use disorders Alcohol abuse Cirrhosis Mental illness Liver transplantation Hemodialysis Dominitiz J, et al. Hepatology. 2005;41: Among those testing positive, 78% either had a transfusion or used injection drugs Unadjusted prevalence: 4% HCV seropositivity higher with:

20 Veterans with Chronic HCV in VHA Care US Dept of Veterans Affairs. Accessed June Number of Veterans Year , ,000 80,000 40,000 0 Among the 20,477 veterans who initiated their 1 st course of PegIFN + ribavirin between 2002 and 2006, SVR was: 26% for genotype 1 62% for genotype 2 52% for genotype 3

21 Veterans with Chronic HCV in VHA Care: 2008 Comorbid Conditions US Dept of Veterans Affairs. Accessed June 2011.

22 HCV and Incarcerated Individuals 16–41% of prison inmates have serological evidence of HCV infection 12–35% chronically infected Primarily associated with injection drug use Only 7–27% of inmates identified through screening begin treatment –Large numbers excluded from therapy  Clinical contraindications  Short prison stay  Drug/alcohol use Release planning –Counseling –Referral to substance use treatment –Medical referrals to specialists for future treatment CDC. Morb Mortal Wkly Rep Recomm Rep. 2003;52(RR1):1-36.

23 HCV and Incarcerated Individuals (cont) Rhode Island Department of Corrections Study –71 male patients with chronic HCV –Treated with weight-based Pegylated interferon-α2b + ribavirin –SVR– overall: 28%; genotype1: 18%; genotype 2: 60%; genotype 3: 50% Chew K, et al. J Clin Gastroenterol. 2009;43:

24 The Majority of Patients are Asymptomatic Symptoms of HCV may include: Fatigue Nausea Poor appetite/weight loss Muscle and joint pains/weakness Jaundice Abdominal pain or swelling Dark urine Itching Fluid retention Some patients may not have any symptoms for up to 20 years, and yet have liver disease progression CDC. Accessed June 2011.

25 Risk Factors and Modes of Transmission for Hepatitis C Ghany MG, et al. Hepatology. 2009;49:1335–1374. MSM = men who have sex with men; STD = sexually transmitted disease The CDC and AASLD recommend screening for all patients with 1 or more risk factors for HCV Illicit injection or intranasal drug use Infection with HIV or HBV Recipients of blood products – Transfusion or organ transplant before 1992 – Any blood products before 1987 Hemodialysis Infected mother at birth Unexplained ALT/AST elevations Multiple sex partners, MSM or history of STD Tattoos and body piercings Exposure to HCV-contaminated blood

26 ~75% of Patients with HCV Have Not Been Diagnosed Increase screening efforts –Identify risk factors –AND consider birth cohort ( ) Many individuals with HCV (symptomatic and asymptomatic) do not seek treatment Engage patients in treatment –Identify and address barriers Assist patients in successful completion of treatment CDC. Accessed May IOM. Hepatitis and Liver Cancer A National Strategy for Prevention and Control of Hepatitis B and C Southern WN, et al. J Viral Hepatitis May 20. [Epub ahead of print]

27 HCV Antibody Test Recommended use: screening for HCV Tests for antibodies against infection Specificity for HCV antibodies is greater than 99% Quantitative HCV RNA Recommended use – Obtain viral load and confirm HCV diagnosis – Determine viral load during treatment (weeks 4, 8,12, 24 and 48) and follow-up (week 48 or 72) Currently available assays have 98%–99% specificity Genotype Used to determine HCV genotype after confirmation of diagnosis Screening and Diagnosing HCV Adapted from Ghany MG, et al. Hepatology. 2009;49:1335–1374. There is no longer need for qualitative assays due to the increased sensitivity of quantitative assays

28 Treatment Considerations

29 2009 AASLD Treatment Guidelines Criteria for Treatment Age ≥ 18 years HCV RNA positive in serum and Liver biopsy showing chronic hepatitis with significant fibrosis (bridging fibrosis or higher) Compensated liver disease Acceptable hematological and biochemical indices Willing to be treated and adhere to treatment requirements No contraindications Contraindications Major uncontrolled depressive illness Solid organ transplant (renal, heart, lung) Autoimmune hepatitis Untreated thyroid disease Pregnant or unwilling to comply with appropriate contraception Severe concurrent medical disease Age less than 2 years Known hypersensitivity to drugs used to treat HCV Patients for Whom Therapy Should be Individualized Failed prior treatment Current users of illicit drugs or alcohol, but willing to participate in a substance abuse program Liver biopsy evidence of either no or mild fibrosis Acute hepatitis C Coinfection with HIV Under 18 years of age Chronic renal disease Decompensated cirrhosis Liver transplant recipients Ghany M, et al. Hepatology. 2009;49(4):

30 Factors Associated with Fibrosis in HCV Age at infection Duration of infection Metabolic factors (steatosis, obesity, diabetes) Compromised immune system Genetic factors HIV co-infection HBV co-infection Heavy alcohol use Poynard T, et al. Lancet.1997;349: Monto A, et al. Hepatology. 2002;36: Marcolongo M, et al. Hepatology. 2009;50: Cecil Medicine 23 rd edition. Saunders Elsevier, Philadelphia, PA Normal liver Cirrhosis

31 Metavir Staging of Fibrosis Stage F3Stage F4 Stage F1Stage F2 Faria SC, et al. RadioGraphics. 2009;29:1615−1635. Many bridges of fibrosis that link up portal and central areas of the liver Enlargement of the portal areas by fibrosis Fibrosis extending out from the portal areas with rare bridges between portal areas Cirrhosis

32 Utility of Liver Biopsy Brunt E. Hepatology. 2000;31:241−246. Dienstag JL. Hepatology. 2002;36:S152−S160. Herrine SK, Friedman LS. J Hepatol. 2005;43:374−376. Carey E, Carey WD. Clev Clin J Med. 2010;77: Assess severity of necroinflammation Assess fibrosis Evaluate possible concomitant disease processes Noninvasive Approaches Transient Elastography (FibroScan) Indirect serological markers –APRI (AST: platelet ratio index) –FIB-4 Index –Fibrotest, Fibrosure –ActiTest –Sequential Algorithm for Fibrosis Evaluation (SAFE)

33 HCV Treatment Completion Rates in Routine Clinical Care: Veterans-in-Care Butt A, et al. Liver Int. 2010;30: % Factors associated with failure to complete treatment: –Pretreatment anemia –Preexisting depression –Low-volume treatment sites

34 Conditions That May Require Treatment Before Starting Antiviral Therapy Diabetes with poor glycemic control Metabolic syndrome –Obesity –Glucose intolerance –Hypertension –Hyper- and dyslipidemia Depression and other mental illnesses Drug or alcohol dependence HIV disease

35 Screening for Mental Health Problems Depression and alcohol dependence –Require immediate attention; extended treatment Basic screening tools available For patients with a positive screen –Treatment or referral to a trained health care provider or treatment facility Life-threatening or fatal neuropsychiatric reactions may manifest in patients receiving therapy for HCV –Suicide/suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose Use clinical judgment when assessing patients for appropriate treatment SAMSHA. Accessed June Kroenke K, et al. Medical Care. 2003;41(11):1284–1292.

36 Alcohol Use The NIH consensus states that past alcohol use/abuse is not a contraindication to therapy However, continued alcohol use during therapy may adversely affect outcomes and, therefore, abstinence from alcohol during therapy is highly recommended Practitioners should administer a ‘brief intervention’ to encourage patients to cut down or quit alcohol use Patients should be –Encouraged to attend weekly Alcoholics Anonymous (AA) or Narcotics Anonymous (NA) meetings, if there is current alcohol/substance abuse –Educated on the possible impact of alcohol on HCV treatment –Discouraged from drinking alcohol during treatment NIH consensus statement on management of hepatitis C. Gastroenterology. 2002;123: Dieperink E, et al. Psychosomatics. 2010;51:

37 Treatment decisions need to be individualized –Current users or those on methadone maintenance programs HCV treatment should be coordinated with substance abuse specialists Factors to consider –Adherence to treatment –Preexisting psychiatric disorders –Side effects of treatment –Consult package inserts regarding drug interactions between protease inhibitors and methadone Ghany M, et al. Hepatology. 2009;49(4): Edlin BR, et al. N Engl J Med. 2001;345:211−214. Davis G, et al. N Engl J Med. 2001;345:215−217. Treatment of Injection Drug Users

38 Impact of Injection Drug Use on HCV Therapy: Swiss Hepatitis C Cohort Study Bruggmann P, et al. J Viral Hepatol. 2008;15: SVR (%) SVR (80:80:80) SVR (Overall) Controls IDUs 500 patients treated, most with PegIFN and RBV –199 active injection drug users (30% GT1, 62% GT3) –301 controls (47% GT1, 29% GT3)  IDUs equally adherent vs controls –66% vs 60% received ≥ 80% cumulative drug dose –87% vs 86% received ≥ 80% treatment duration  Overall SVR: 63%

39 PegIFN + RBV Response Rates in Treatment Naïve Populations All Genotypes 1 Genotype 1 US Patients 2 HIV/HCV Genotype –41 17–35 SVR (%) 1.Hadziyannis S, et al. Ann Intern Med. 2004;140: McHutchison J, et al. N Engl J Med. 2009;361: Conjeevaram H, et al. Gastroenterol. 2006;131: Jeffers LJ, et al. Hepatology. 2004;39: African American Genotype – Muir AJ, et al. N Engl J Med. 2004;350: Torriani FJ, et al. N Engl J Med. 2004;351: Carrat F, et al. JAMA. 2004;292: Nunez M, et al. AIDS Res Human Retroviruses. 2007;23:

40 HCV Genotype: Major Predictor of Treatment Response to Pegylated Interferon + Ribavirin Hadziyannis SJ, et al. Ann Intern Med. 2004;140: SVR at End of Follow-up 24 wks of RBV 800 mg/day + PegIFN alfa-2a 24 wks of RBV mg/day + PegIFN alfa-2a 48 wks of RBV 800 mg/day + PegIFN alfa-2a 48 wks of RBV mg/day + PegIFN alfa-2a Patients (%) Advanced FibrosisMinimal Fibrosis Genotype 1Genotype 2/3Genotype 1Genotype 2/3

41 Peginterferon Alfa-2b + Ribavirin: Treatment of HCV in Blacks/African Americans and Non-Hispanic Whites Muir A, et al. N Engl J Med. 2004;350: Early virological response: reduction in HCV RNA level by at least 2 log IU/mL at 12 weeks of treatment 98% of patients in both groups were genotype 1 *P < 0.001

42 Peginterferon Alfa-2a + Ribavirin: HCV Treatment by Race/Ethnicity Early Virologic Response End-of-Treatment Response Sustained Virologic Response Black/AA (n = 196) White (n = 205) Patients (%) 61% 78%* 40% 70% † 28% Conjeevaram HS, et al. Gastroenterology. 2006;131: % † *P = and † P < versus Blacks/African Americans. All patients were treatment naïve with genotype 1 HCV

43 PegIFN + Ribavirin in Latino and Non-Latino Whites with HCV Rodriguez-Torres M, et al. N Engl J Med. 2009;360: Treatment naïve, genotype 1 Virologic Response (Undetectable HCV RNA) Patients (%) Virologic Outcome LatinoNon-Latino White No responseRelapse SVR Week Latino Non-Latino White (N = 269) (N = 300)

44 IL28B Genetic Variation and SVR Treatment with Pegylated Interferon + Ribavirin A polymorphism on chromosome 19, rs (T/T, C/T, or C/C), was strongly associated with SVR in all patient groups Ge D, et al. Nature. 2009;461:

45 Predictors of Virologic Response Pegylated interferon + Ribavirin Host IL28B genotype (rs ) T/TC/TC/C Other important pretreatment factors Genotype 1Viral GenotypeGenotypes 2 and 3 > 600,000Viral Load (IU/mL)< 600,000 African American (AA)RaceNon-AA F3 and F4 Fibrosis (METAVIR grade) F0 and F1 MaleGenderFemale > 40Age (years)< 40 LowLDLHigh ObeseWeightSlender Less likely to respondMore likely to respond Clark, PJ et al. Am J Gastroenterol. 2011;106:38-45.

46 The Importance of Sustained Virological Response Tantamount to cure Associated with improvement in liver histology (inflammation, fibrosis) Less frequent liver-related complications Reduced risk of decompensation Reduced risk of hepatocellular carcinoma Reduced liver-related mortality Pearlman B, Traub N. Clin Infect Dis. 2011;52:

47 SVR and Reduced Risk of All-Cause Mortality US VA Study: Treatment with Pegylated Interferon/Ribavirin Backus L, et al. Clin Gastroenterol Hepatol. 2011;9: Cumulative Mortality P (log-rank) < No SVR SVR HCV Genotype 1 Years GenotypeNSVRHazard Ratio for Death with SVRP-value 112,16635%0.70< % %

48 Viral Monitoring on Treatment: Terms TermsDefinition Rapid virological response (RVR) HCV RNA undetectable after 4 weeks of treatment Extended rapid virological response (eRVR) HCV RNA undetectable at treatment week 4 and extending to week 12 Early virological response (EVR) ≥ 2 log reduction in HCV RNA at 12 weeks compared to baseline (partial EVR) or HCV negative RNA at treatment week 12 (complete EVR) End of treatment response (ETR) HCV RNA negative by a sensitive test at the end of 24 or 48 weeks of treatment Sustained virological response (SVR) HCV RNA negative 24 weeks after cessation of treatment Response-guided therapy (RGT) Using assessments of viral kinetics during treatment to make individualized therapeutic adjustments and optimize outcomes Ghany M, et al. Hepatology. 2009;49(4):

49 Viral Monitoring on Treatment: Terms TermsDefinition Breakthrough Reappearance of previously undetectable HCV RNA in plasma while still on therapy Relapse Reappearance of HCV RNA in plasma after therapy is discontinued Nonresponder Failure to clear HCV RNA after 24 weeks of therapy Null response Failure to reduce HCV RNA by ≥ 2 log after 12 weeks of treatment Early null response Failure to reduce HCV RNA by ≥ 1 log after 4 weeks of treatment Partial response ≥ 2 log reduction in HCV RNA, but still HCV RNA positive at week 24 Ghany M, et al. Hepatology. 2009;49(4): Reau N, et al. Am J Gatroenterol. 2010;106(3):

50 Treatment Outcomes: Virological Response Adapted from Ghany M, et al. Hepatology. 2009;49(4): HCV RNA Log 10 IU/mL Undetectable RVR EVR ETR SVR Null Response Relapse Partial Response Treatment Period RVR: rapid virological response eRVR: extended rapid virological response EVR: early virological response ETR: end of treatment response SVR: sustained virological response eRVR

51 HCV Genome and Gene Products Potential Targets for Direct Acting Antiviral Agents TenCate V, et al. Hepat Med. 2010;2: Protease Inhibitors: boceprevir; telaprevir

52 Triple Combination Therapy for Hepatitis C: Phase 3 Studies with Protease Inhibitors

53 Triple Therapy for Treatment Naïve Patients

54 Phase 3 Boceprevir SPRINT-2: Genotype1 Treatment Naïve Patients PR Placebo + PR FW 24TW 48 Follow-up TW 28TW 4 Boceprevir +PR PR BOC: boceprevir 800 mg q8h; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day † HCV RNA TW 8-24 undetectable *HCV RNA TW 8 detectable; TW 24 undetectable Early Responder † PegIFN  -2b/Ribavirin 48 Weeks (PR 48) N = 363 PR TW 0 Placebo +PR Late Responder* Boceprevir Response-Guided Therapy (RGT) N = 368 Boceprevir/PR 48 Weeks (BOC/PR48) N = 366 Follow-up Futility Rule TW 24 FDA. Committee/ucm htm. Accessed June 2011.

55 Boceprevir: Treatment Naïve Patients SVR and Relapse FDA. Accessed June BOC: boceprevir 800 mg q8h; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day; RGT: boceprevir response-guided therapy

56 Boceprevir: SVR in Early and Late Responders 155/162155/16145/6855/73 Early Responder: HCV RNA TW 8-24 undetectable Late Responder: HCV RNA TW 8 detectable; TW 24 undetectable FDA. Committee/ucm htm. Accessed June BOC: boceprevir 800 mg q8h; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day RGT: boceprevir response-guided therapy

57 Boceprevir: Treatment Naïve Patients SVR and Race n = 311n = 316n = 311 Non-Black/African-AmericanBlack/African American n = 52 n = 55 P < P < P < FDA. Accessed June BOC: boceprevir 800 mg q8h; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day RGT: boceprevir response-guided therapy

58 Boceprevir: SVR by Race and METAVIR Fibrosis Score Non-Black/African-AmericanBlack/African-American FDA. Committee/ucm htm. Accessed June BOC: boceprevir 800 mg q8h; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day RGT: boceprevir response-guided therapy

59 Boceprevir: Treatment Naïve Patients IL28B Genotype and SVR FDA. Accessed June PR48: PegIFN α-2b + ribavirin 48 weeks RGT: boceprevir/response-guided therapy BOC-PR48: boceprevir/PR48 weeks BOC: boceprevir 800 mg q8h; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day

60 Phase 3 Telaprevir ADVANCE: Genotype1 Treatment Naïve Patients Placebo/PR PR Wk 72Wk 48 Follow-up Wk 4 PegIFN  -2a /Ribavirin 48 Weeks (Pbo/PR) N = 361 TVR 8/PR Wk 0 PR to Wk 48 Telaprevir + PR 8 Weeks; Response Guided Therapy (TVR8/PR) N = 364 N = 363 Follow-up Wk 12Wk 8 Pbo/ PR Wk 24 PR eRVR + eRVR - TVR 12/PR PR to Wk 48 PR eRVR + eRVR - Telaprevir + PR 12 Weeks; Response Guided Therapy (TVR12/PR) N = 363 TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk; weight-based RBV mg/day eRVR: extended rapid virological response; undetectable HCV RNA at weeks 4 and 12 SVR Follow-up FDA Antiviral Drugs Advisory Committee. Committee/ucm htm. Accessed June 2011.

61 Telaprevir: Treatment Naïve Patients SVR and eRVR P < TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day; Pbo: placebo FDA. Accessed June eRVR: extended rapid virological response; undetectable HCV RNA at weeks 4 and 12

62 Telaprevir: Treatment Naïve Patients SVR Rates by eRVR Status 24-Week Regimen48-Week Regimen eRVR: extended rapid virological response; undetectable HCV RNA at weeks 4 and 12 Pbo/PR eRVR+ eRVR /212179/20790/15182/157 27/29139/332 TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day; Pbo: placebo FDA. Accessed June 2011.

63 Telaprevir: Treatment Naïve Patients SVR Rates by Fibrosis Stage 237/290216/ /288 48/73 45/85 26/73 TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day; Pbo: placebo FDA Antiviral Drugs Advisory Committee. ucm htm. Accessed June 2011.

64 Telaprevir: Treatment Naïve Patients SVR Rates by Race or Ethnicity 258/325229/315153/31816/2624/408/2827/3530/4415/38 TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day; Pbo: placebo FDA Antiviral Drugs Advisory Committee. m htm. Accessed June 2011.

65 Telaprevir: Treatment Naïve Patients IL28B Genotype and SVR TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day FDA Antiviral Drugs Advisory Committee. m htm. Accessed June 2011.

66 Telaprevir ILLUMINATE: Response-Guided Therapy for Genotype1Treatment Naïve Patients Open-label, randomized trial Wk 72 Wk 48 Wk 0 Wk 12 Wk 24 TVR/PR PR to Wk 48 PR eRVR N = 540 Follow-up for SVR No eRVR D/C Before Wk 20 Wk 24 Wk 20 Follow-up for SVR PR to Wk 48Follow-up for SVR TVR: Telaprevir 750 mg q8h; PR: Peg IFN  -2a 180 µg/wk + weight-based RBV mg/day eRVR: extended rapid virological response; undetectable HCV RNA at weeks 4 and 12 FDA Antiviral Drugs Advisory Committee. m htm. Accessed June 2011.

67 ILLUMINATE Treatment Naïve Patients SVR Rates 149/162144/160 eRVR Positive Non-inferiority of TVR12/PR24 vs TVR12/PR48 65% of Subjects Achieved an eRVR eRVR: extended rapid virological response; undetectable HCV RNA at weeks 4 and 12 TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day; Pbo: placebo FDA. Accessed June 2011.

68 Triple Therapy for Treatment Experienced Patients

69 Phase 3 Boceprevir RESPOND-2: Genotype1 Treatment Experienced ‡ Patients PR Placebo + PR FW 24TW 48 Follow-up TW 36TW 4 Boceprevir +PR PR ‡ Treatment experienced: partial responders and relapsers; null responders were excluded RGT: boceprevir /response-guided therapy 800 mg q8h; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day † HCV RNA TW 8-12 undetectable *HCV RNA TW 8 detectable; TW 12 undetectable Early Responder † PegIFN  -2b/Ribavirin 48 Weeks (PR 48) N = 80 PR TW 0 Placebo +PR Late Responder* Boceprevir Response-Guided Therapy (RGT) N = 162 Boceprevir/PR 48 Weeks (BOC/PR48) N = 161 Follow-up Futility Rule TW 12 FDA.http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommitt ee/ucm htm. Accessed June 2011.

70 Boceprevir: Treatment Experienced Patients SVR and Relapse P < FDA. Accessed June BOC: boceprevir 800 mg q8h; RGT: boceprevir response-guided therapy; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day

71 Boceprevir: SVR by Response to Previous PegIFN/Ribavirin Therapy 16/5173/10577/103 2/29 23/5730/58 FDA. Accessed June BOC: boceprevir 800 mg q8h; RGT: boceprevir response-guided therapy; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day

72 Boceprevir: Treatment Experienced Patients SVR in Early and Late Responders Early Responder: HCV RNA TW 8-12 undetectable; Late Responder: HCV RNA TW 8 detectable; TW 12 undetectable FDA Antiviral Drugs Advisory Committee. m htm. Accessed June BOC: boceprevir 800 mg q8h; RGT: boceprevir response-guided therapy; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day

73 Boceprevir: Treatment Experienced Patients SVR by Cirrhosis (METAVIR Fibrosis Score) 85/12885/13216/6617/226/170/10 FDA Antiviral Drugs Advisory Committee. m htm. Accessed June BOC: boceprevir 800 mg q8h; RGT: boceprevir response-guided therapy; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day

74 Boceprevir: SVR for Treatment Experienced Patients by Race Bacon B, et al. N Engl J Med. 2011;364: % of the RESPOND-2 study population was Black/African American BOC: boceprevir 800 mg q8h; RGT: boceprevir/response-guided therapy; PR: PegIFN  -2b 1.5 µg/kg/wk + weight-based RBV mg/day Percent of patients

75 Boceprevir: Treatment Experienced Patients IL28B Genotype and SVR PR48: PegIFN α-2b + ribavirin 48 weeks RGT: boceprevir/response-guided therapy BOC-PR48: boceprevir/PR48 weeks FDA. Accessed June 2011.

76 Phase 3 REALIZE: Telaprevir Treatment Experienced * Patients Placebo/PR PR Follow-up PegIFN  -2a /Ribavirin 48 Weeks (Pbo/PR) N = 132 Wk 0 Wk 72Wk 48Wk 4Wk 12 Wk 16 * Treatment experienced: partial responders, relapsers, and null responders Pbo/ PR TVR 12/PRPR Telaprevir + PR 12 Weeks; PR Through Wk 48 (TVR12/PR) N = 266 Pbo/ PR TVR 12/PRPR Placebo/PR 4 Week Lead-in; 12 weeks Telaprevir + PR; PR Through Wk 48 (PR LI/TVR12) N = 264 Follow-up TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day; Pbo: placebo FDA Antiviral Drugs Advisory Committee. Accessed June 2011.

77 Telaprevir: SVR by Response to Previous PegIFN/Ribavirin Therapy TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day; Pbo: placebo Lead-in and immediate start TVR12/PR groups were pooled FDA. Accessed June 2011.

78 Telaprevir: Relapse Rates by Response to Previous PegIFN/Ribavirin Therapy TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day; Pbo: placebo Lead-in and immediate start TVR12/PR groups were pooled FDA. Accessed June 2011.

79 Telaprevir: SVR for Treatment Experienced Patients with Cirrhosis TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day; Pbo: placebo FDA Antiviral Drugs Advisory Committee. m htm. Accessed June 2011.

80 Telaprevir: SVR for Treatment Experienced Patients by Race 4% of treatment experienced patients in REALIZE were Black/African American Treatment: TVR12/PR48 TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day FDA. Accessed June 2011.

81 Telaprevir: Treatment Experienced Patients IL28B Genotype and SVR TVR: Telaprevir 750 mg q8h; PR: PegIFN  -2a 180 µg/wk + weight-based RBV mg/day Lead-in and immediate start TVR12/PR groups were pooled FDA. Accessed June 2011.

82 Protease Inhibitors: Safety

83 Boceprevir Safety Most Common Treatment-Related Adverse Events Adverse Event PR (N = 547 patients) BOC/PR (N = 1548 patients) Fatigue57% Anemia29%49% Nausea40%45% Headache43%44% Dysgeusia15%37% Chills29%33% Insomnia31%32% Pyrexia31% Alopecia25%26% Decreased appetite23%25% Myalgia24%23% Diarrhea18%23% Neutropenia18%23% Influenza-like illness25%22% PR: PegIFN  -2b + ribavirin; BOC: boceprevir FDA Antiviral Drugs Advisory Committee. m htm. Accessed June 2011.

84 Anemia in Phase 3 Boceprevir Trials BOC/PR (N = 1057)PR (N = 443) Anemia (Clinical Adverse Event)52%30% Anemia (Laboratory Event) Hgb ≤ 10 g/dL Hgb ≤ 8.5 g/dL 52% 9% 32% 4% Serious Anemia Adverse Event1%<1% Anemia resulting in: Drug discontinuation (any drug) Dose Reduction (any drug) Dose interruption (any drug) 2% 25% 3% 1% 13% 2% FDA Antiviral Drugs Advisory Committee. m htm. Accessed June 2011.

85 Telaprevir Safety Adverse Events ≥ 5% Higher Frequency in Telaprevir Subjects Adverse Event Pbo/PR (N = 493) TVR/PR (N = 1797) Rash*34%56% Fatigue50%56% Pruritus28%47% Nausea28%39% Anemia*17%36% Diarrhea17%26% Vomiting8%13% Hemorrhoids3%12% Anorectal discomfort3%11% Dysgeusia3%10% Anal pruritis1%6% *Rash and anemia based on special search category (SSC) grouped terms FDA. Accessed June 2011.

86 Rash in Patients from Phase 3 Studies Treated with Telaprevir + PegIFN/RBV Mild (localized)Moderate (< 50% BSA)Severe (> 50% BSA) BSA: body surface area 93% of all rash events were mild -to-moderate severity Less than 1% of subjects experienced suspected serious cutaneous adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms-DRESS) Rash events resulted in discontinuation of telaprevir alone in 6% of patients and discontinuation of telaprevir and Peginterferon alfa + ribavirin combination in 1% of patients Rash may take weeks to resolve FDA Antiviral Drugs Advisory Committee. m htm. Accessed June 2011.

87 Protease Inhibitors and Resistance Replication of HCV is dependent on an error-prone RNA- dependent RNA polymerase –Gives rise to resistant variants that pre-exist before therapy and can be selected by antiviral agents Pre-existing resistance associated variants present at baseline are not predictive of outcome (SVR) While SVR was achieved in many patients treated with triple therapy, resistant variants were detected in 15% of patients treated with boceprevir and 12-22% of patients treated with telaprevir Resistant variants decline over time Patients who fail 1 protease inhibitor should not be treated with another FDA. m htm. Accessed June 2011.

88 Practical Considerations Associated with the Use of Triple Therapy for Patients with HCV

89 Treatment Naïve Genotype1 Patients: Boceprevir Assessment (HCV RNA) Recommendation Treatment Week 8 Treatment Week 24 *Boceprevir + PegIFN alfa/ ribavirin Undetectable Complete 3-medicine regimen at TW28 DetectableUndetectable 1.Continue all three medicines and finish through TW36; and then 2.Administer PegIFN/ribavirin and finish through TW48 Futility rules: If HCV-RNA ≥ 100 IU/mL at TW12, discontinue three-medicine regimen. If the patient has confirmed, detectable HCV-RNA at TW24, discontinue three-medicine regimen. Patients with cirrhosis: *Boceprevir + PegIFN alfa/ribavirin for 44 weeks *Following 4 wk lead in with PegIFN/ribavirin FDA. Accessed June 2011.

90 Treatment Naïve and Prior Relapse Genotype1 Patients: Telaprevir FDA. Accessed June HCV-RNA Triple Therapy Telaprevir, Peginterferon alfa/ ribavirin Dual Therapy Peginterferon alfa/ ribavirin Total Treatment Duration Undetectable at Weeks 4 and 12 First 12 weeksAdditional 12 weeks24 weeks Detectable (1000 IU/mL or less) at Weeks 4 and 12 First 12 weeksAdditional 36 weeks48 weeks Futility Rules HCV RNA Week 4 or 12 > 1000 IU/mL: Discontinue telaprevir + Peginterferon alfa/ribavirin HCV RNA Week 24 detectable: Discontinue Peginterferon alfa/ribavirin Treatment naïve patients with cirrhosis with undetectable HCV-RNA at weeks 4 and 12 of triple therapy may benefit from an additional 36 weeks of Peginterferon alfa/ribavirin (48 weeks total)

91 Previous Partial Responders or Relapsers Boceprevir Assessment (HCV RNA) Recommendation Treatment Week 8 Treatment Week 24 *Boceprevir + PegIFN/ ribavirin Undetectable Complete 3-medicine regimen at TW36 DetectableUndetectable 1.Continue all three medicines and finish through TW36; and then 2.Administer PegIFN/ribavirin and finish through TW48 Stopping rules: If HCV-RNA ≥ 100 IU/mL at TW12, discontinue three-medicine regimen. If the patient has confirmed, detectable HCV-RNA at TW24, discontinue three-medicine regimen. Patients with cirrhosis: *Boceprevir + PegIFN + ribavirin for 44 weeks *Following 4 wk lead in with PegIFN + ribavirin FDA. Accessed June 2011.

92 Prior Partial and Null Responder Patients Telaprevir FDA. Accessed June Triple Therapy Telaprevir, Peginterferon alfa/ ribavirin Dual Therapy Peginterferon alfa/ ribavirin Total Treatment Duration All patientsFirst 12 weeksAdditional 36 weeks48 weeks Futility Rules HCV RNA Week 4 or 12 > 1000 IU/mL: Discontinue telaprevir and Peginterferon alfa/ribavirin HCV RNA Week 24 detectable: Discontinue Peginterferon alfa/ribavirin

93 Monitoring During Treatment Monthly visit with HCV provider to assess adherence and side effects; frequency can be adjusted as clinically needed Assess response to treatment: HCV RNA – Response guided therapy milestones – Boceprevir: wk 4 (lead-in), wk 8 and 24 – Telaprevir: wk 4 and 12 – EOT/ SVR – Assay with LLQ of < 25 IU/ml and LLD <10 IU/ml Laboratory monitoring LLQ: lower limit of quantitation; LLD: lower limit of detectability

94 Treatment Monitoring Guidelines WeeksFrequency thereafter Labs Every 4 wks PRN Week 24 End of Tx 6 mo Post-tx CBC LFTs Psychiatric analysis Renal/Uric acid Glucose TSH Pregnancy HCV RNA

95 Pretreatment Counseling and Patient Education Dosing schedules Importance of medication adherence Protease inhibitors should not be used as monotherapy Protease inhibitors are not to be dose-reduced or interrupted Managing missed doses Contraception/Pregnancy –Important for both partners –Requires 2 forms of contraception during and extending ≥ 6 months after treatment Signs and symptoms of possible side effects –Such as rash, anemia, neutropenia, dysgeusia –Supportive care for side effects

96 Boceprevir and Telaprevir Contraindications Drug ClassContraindicated DrugsBoceprevirTelaprevir Alpha 1- Adrenoreceptor antagonist Alfuzosin Anticonvulsants Carbamazepine, phenobarbital, phenytoin AntimycobacterialRifampin Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI Motility AgentCisapride Herbal Products St. John’s Wort (hypericum perforatum) FDA. Accessed June FDA. Accessed June 2011.

97 Boceprevir and Telaprevir Contraindications (cont) Drug Class Contraindicated Drugs BoceprevirTelaprevir HMG CoA Reductase Inhibitors Lovastatin, simvastatin (also atorvastatin) Oral Contraceptives Drosperinone PDE5 Enzyme Inhibitor Sildenafil or tadalafil when used for the treatment of pulmonary arterial hypertension NeurolepticPimozide Sedative/Hypnotics Triazolam; orally administered midazolam FDA. Accessed June FDA. Accessed June 2011.

98 Drug-Drug Interactions Both boceprevir and telaprevir are inhibitors of CYP3A Many common medications are metabolized by this enzyme, and boceprevir and telaprevir may affect their plasma concentrations Consult the package inserts for all drugs used for triple therapy for specific drug interactions FDA. Accessed June FDA. Accessed June 2011.

99 Approach to Managing Psychiatric Issues During HCV Treatment Education, monitoring, and support –Information, psychoeducation and monitoring before and during treatment –Assessment of current or previous substance abuse –Supportive psychotherapy and counseling –Management of sleep disturbances Pharmaceutical strategies: –Antidepressant treatment Some antidepressants have drug interactions with protease inhibitors; consult package inserts –Antiviral therapy dose reduction, discontinuation if needed Schaefer M, et al. Curr Drug Abuse Rev. 2008;1:

100 Adherence to PegIFN/RBV: Essential but Challenging Only ~ 60% of US patients adhere to HCV therapy [2] Drug exposure correlates with SVR; ≥ 80% adherence correlates with SVR [1,3] Patient self-report overestimates adherence [4] Adherence wanes over time [4] 1. McHutchison JG, et al. Gastroenterology. 2002;123: Mitra D, et al. Value Health. 2010;13: Raptopoulou M, et al. J Viral Hepat. 2005;12: Smith SR, et al. Ann Pharmacother. 2007;41: Retrospective analysis of PegIFN alfa-2b/RBV trials (N = 511) [1] Adherence Rate (%) n = SVR (%)

101 The Importance of Treatment Adherence Poor medication adherence may increase the risk for treatment failure and development of resistance to protease inhibitors STRATEGIES Collaborative approach to care Emphasize the importance and value of treatment adherence to desired outcome Identify barriers to medication adherence, and work with patients to address barriers Simple, clear instructions Encourage the use of a medication-taking system Obtain help from the patient’s support system (family, friends) and community services Claxton AJ, et al. Clin Ther. 2001;23: Osterberg L, Blaschke T. N Engl J Med. 2005;353: Mitra D, et al. Value Health. 2010;13:

102 Models of Care for Underserved Populations Co-management and co-located services Primary care-based networks Linkages to community-based organizations Linkages to post-release community care by correctional facilities Substance use treatment program-based care Remote networking/telehealth technology

103 Community Health Centers (CHCs) Are Medical Home to ~ 20 million Americans Adashi E, et al. N Engl J Med. 2010;362(22): Dedicated to delivery of primary medical, dental, behavioral and social services to medically underserved populations Large numbers of young women and children ~40% of patients are uninsured Patients served include those geographically isolated, migrant, and living in urban settings (including homeless) Linguistic and cultural barriers 7 of 10 patients live in poverty Over half are members of minority groups

104 Underserved Communities Often Have Decreased Access to Specialty Care Cook NL, et al. Health Affairs. 2007;26: Sequist T. N Engl J Med. 2011; 364: Financial and health insurance barriers Disparities in rates of referral for specialty services Lack of availability of specialists CHC Patients with Difficult Access (%) Private Insurance Medicaid Uninsured Diagnostic Tests Medical Specialists Specialized Services Hospital Admissions High-tech Services

105 The Extension for Community Healthcare Outcomes (ECHO) Model Objectives of ECHO Improve access of minorities and other underserved populations to best-practice care for HCV Determine the safety and efficacy of treatment for HCV based on the ECHO model in rural communities Compare the effectiveness of the ECHO model with university-based clinic treatment Arora S, et al. N Engl J Med. 2011;364: Project ECHO at The University of New Mexico:

106 How the ECHO Model is Structured Each ECHO partner site Lead clinician (physician, NP or PA) Nurse or medical assistant Weekly HCV clinics (“knowledge networks”) Video conference or teleconference Providers present cases UNM Specialists (hepatology, infectious diseases, psychiatry, pharmacology) provide advice and clinical mentoring Community providers + specialists manage patient care according to evidence-based protocols Learning from other community-based providers Didactic presentations by interdisciplinary experts to improve content knowledge Arora S, et al. N Engl J Med. 2011;364:

107 The ECHO Model: Outcomes of Treatment for HCV by Primary Care Providers Arora S, et al. N Engl J Med. 2011;364: Sustained Virological Response (SVR) N = 407 patients with chronic HCV, treatment naïve Treatment with Pegylated interferon alfa + weight-based ribavirin ECHO sites included community- based health centers and prisons

108 Integrated Care Several systematic reviews have explored integrated care models for mental health and chronic illness with consistent findings of what improves outcomes: Formal integration of services Multidisciplinary teams Revision of professional roles (increased role of nurses) Bower P, et al. British J Psych. 2006;189, Gilbody S. et al. JAMA. 2003;289: Ouwens M, et al. Int J Qual Health Care. 2005;17: Soto TA, et al. AIDS Care. 2004;16:S43-S55. Butler M, et al. Agency for Healthcare Research and Quality, October 2008.

109 Characteristics of Integrated Models Systematic Screening Identify mental health problem Integrating Providers Co-location Systematic communication method Shared medical records Shared decision making Integrated care/proactive follow up New service offered Standardized follow up Formal adherence, clinical monitoring and feedback Education Primary Care/Mental Health Provider Teams Awareness of mental health problems Comfort treating patients with mental illness and/or coordinating services Adherence to evidence- based guidelines Patients Access to care Reduced stigma Engagement in care Adherence Process of Care Butler M, et al. Agency for Healthcare Research and Quality October 2008.

110 Improving Clinical Quality and Efficiency for the Management of Patients with HCV Pocha C. Curr Clin Pract. 2008;2:1-6. A dedicated HCV clinical care team –Clinical care coordinator, mid-level practitioner, physician, clinical pharmacist Optimized scheduling process Streamlined visit process Preset order menus for blood work and medications HCV group education class

111 Integrated Care Models for Optimizing the Management of HCV Ho S, et al. Am J Gastroenterol. 2008;103: Knott A, et al. Am J Gastroenterol. 2006;101(10): Screen for psychiatric/substance use disorders Integrate psychiatric and substance use disorder management into the HCV clinic –Provide brief interventions for active substance use –Implement depression treatment –Use case managers/mid-level providers for psychiatric and substance use treatment in HCV clinic –Identify collaborators in psychiatry, psychology, and SUDs Integrate patient education and lifestyle management

112 Summary Most patients with HCV are asymptomatic and ~75% have not been diagnosed Expand risk factor-based screening to include birth cohort ( ) Engage and retain patients in treatment Improved outcomes associated with triple therapy with new protease inhibitors (telaprevir and boceprevir) –Significant improvement in SVR over PegIFN/ribavirin for treatment naïve and treatment experienced genotype1 patients –Response-guided therapy with triple therapy may allow shortened duration of therapy compared with PegIFN/ribavirin

113 Summary (cont) Risks associated with triple therapy –Adverse events such as rash, anemia, fatigue, nausea, dysgeusia, etc –Emergence of resistance –Drug-drug interactions Importance of a strong therapeutic alliance and patient education about new treatment options Integrated models of care to optimize management of HCV

114 Thank you for participating in this live educational activity. For additional HCV educational opportunities HCV, please visit


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