Meet the Professor: HIV/HCV Coinfection

Transcription

1

2 Meet the Professor: HIV/HCV Coinfection Vincent Lo Re, MD, MSCE Assistant Professor of Medicine and Epidemiology Division of Infectious Diseases Center for Clinical Epidemiology and Biostatistics University of Pennsylvania

3 Learning Objectives Upon completion of this presentation, learners should be better able to: Discuss necessary evaluations with HIV/HCV Appreciate impact of HIV suppression on liver outcomes Identify risk factors for HCV liver disease progression Consider antiretroviral-hcv drug-drug interactions Review HCV treatment options in 2016

4 Faculty and Planning Committee Disclosures Please consult your program book. Off-Label Disclosure There will be no off-label/investigational uses discussed in this presentation.

5 Case: 43 yo Caucasian Man with HIV and HCV Infection HIV (11/2004): Atazanavir/ritonavir, tenofovir/emtricitabine 2/2014: CD4+ 641/mm 3 (26%); HIV 0 copies/ml HCV antibody-positive (12/2004): HCV genotype 1a; HCV RNA 7.1 log IU/mL Liver biopsy (2005): stage 1 fibrosis, steatosis Never received treatment for chronic HCV

6 Case: 43 yo Caucasian Man with HIV and HCV Infection Past History: hyperlipidemia, depression Medications: Atazanavir/ritonavir, tenofovir/emtricitabine Simvastatin, sertraline Social History: Past IV heroin use ( ) Drinks beer ( oz cans of beer weekend)

7 Case: 43 yo Caucasian Man with HIV and HCV Infection Physical exam: Ht 5 9 ; Wt 87 kg; BMI 28.4 kg/m 2 No hepatomegaly, stigmata of liver disease Laboratory data: TB 0.8; Alb 3.8; INR 1.1; ALT 57; AST 61 WBC 6.3; Hgb 13.9; platelets 98 HAV IgG (+) HBV sag ( ); anti-hbc (+); anti-hbs (+)

8 Question: What Would You Do Next? A. Monitor him, he had stage 1 fibrosis B. Initiate sofosbuvir + simeprevir C. Stage his liver fibrosis D. Initiate sofosbuvir-ledipasvir

9 View results in your browser: p-9rw7fa

10 Natural History of HCV Infection Acute HCV 14-45% Spontaneous Clearance 55-86% Chronic HCV 20% in 20 yrs Hepatic Inflammation Hepatic Fibrosis Extrahepatic Complications Cirrhosis 2-4% per yr 2-5% per yr Hepatocellular Carcinoma Hepatic Decompensation Seeff LB. Hepatology 2002;36 (Suppl 1):S35-46.

11 Complications of Cirrhosis Ascites/Peritonitis Variceal Hemorrhage Hepatic Encephalopathy Hepatocellular Carcinoma

12 HIV Adversely Affects Every Aspect of Natural History of HCV clearance of HCV HCV RNA vs. HCV only risk of end-stage liver disease (ESLD) vs. HCV only risk of hepatocellular carcinoma (HCC) vs. HIV only Spontaneous Clearance Acute HCV HIV + Chronic HCV Cirrhosis HCC ESLD Weber R. Arch Intern Med 2006;166;

13 Risk of ESLD by ART Status and Time Since Initiation 10,090 HIV/HCV patients Veterans Aging Cohort Study (VACS), ART initiation, ESLD events ascertained ART risk of ESLD ART Status No ART Adjusted HR of ESLD (95% CI) Ref. Initiated ART 0.72 ( ) Time Since ART Initiation No ART Adjusted HR of ESLD (95% CI) Ref. <2 years 0.75 ( ) 2-4 years 0.69 ( ) >4 years 0.53 ( ) Anderson JP. Clin Infect Dis 2014;58:

14 Liver Decompensation Rates are Higher in HIV/HCV vs. HCV Only Patients 4,280 ART-Treated HIV/HCV-Coinfected 6,079 HCV-Monoinfected Veterans Aging Cohort Study ( ) Lo Re V. Ann Intern Med 2014;160;

15 Decompensation Rates are Reduced with HIV Suppression HCV-Monoinfected Veterans Aging Cohort Study ( ) Lo Re V. Ann Intern Med 2014;160;

16 Risk Factors for Decompensation in HIV/HCV Patients on ART Risk Factor Adjusted HR * (95% CI) Diabetes mellitus 1.85 ( ) BMI 30 kg/m ( ) Hepatitis B surface Ag ( ) Non-black race 2.12 ( ) Pre-ART CD4 <200 cells/mm ( ) Hemoglobin <10 g/dl 3.34 ( ) Lo Re V. Ann Intern Med 2014;160;

17 Risk Factors for Decompensation in HIV/HCV Patients on ART Risk Factor HCV RNA (IU/mL) <400, ,000 HCV RNA (IU/mL) <800, ,000 Hazard Ratio (95% CI) Ref 0.78 ( ) Ref 0.73 ( ) Lo Re V. Ann Intern Med 2014;160;

18 What Data are Needed for Decision to Treat Chronic HCV in HIV in 2016? HCV RNA, genotype (GT) Previous treatment, outcome Medications (drug-drug interactions) Alcohol use Hepatitis B status Stage of liver fibrosis (cirrhosis?)

19 What Data are Needed for Decision to Treat Chronic HCV in HIV in 2016? HCV RNA, genotype (GT) Previous treatment, outcome Medications (drug-drug interactions) Alcohol use Hepatitis B status Stage of liver fibrosis (cirrhosis?)

20 Case: 43 yo Caucasian Man with HIV and HCV Infection Past History: hyperlipidemia, depression Medications: Atazanavir, ritonavir, tenofovir/emtricitabine Simvastatin, sertraline Social History: Past IV heroin use ( ) Drinks beer ( oz cans of beer weekend)

21

22 Advanced Liver Fibrosis (FIB-4>3.25), By Level of Alcohol Use and HIV/HCV Prevalence of Advanced Fibrosis Odds Ratio of Advanced Fibrosis Lim JK. Clin Infect Dis 2014;58:

23 What Data are Needed for Decision to Treat Chronic HCV in HIV in 2016? HCV RNA, genotype (GT) Previous treatment, outcome Medications (drug-drug interactions) Alcohol use Hepatitis B status Stage of liver fibrosis (cirrhosis?)

24 Anti-HBV Therapy Reduces Risk of Decompensation in HIV/HBV/HCV Incidence Rate (events/1,000 person-years) HIV/HBV/HCV (n=149) 24.1 HIV/HCV (n=4,902) 10.8 Group Risk (95% CI) of Decompensation HIV/HBV/HCV with no anti-hbv therapy 2.48 ( ) HIV/HBV/HCV on anti-hbv therapy 1.09 ( ) Lo Re V. Clin Infect Dis 2014;59:1-16.

25 What Data are Needed for Decision to Treat Chronic HCV in HIV in 2016? HCV RNA, genotype (GT) Previous treatment, outcome Medications (drug-drug interactions) Alcohol use Hepatitis B status Stage of liver fibrosis (cirrhosis?)

26 Staging HCV Liver Fibrosis Important part of chronic HCV work-up Identify cirrhosis: Strongly consider antiviral therapy Influences treatment duration hepatocellular ca risk: need to screen Monitor for varices (endoscopy), decompensation Determine cirrhosis: biopsy, non-invasive

27 Gold standard for fibrosis assessment Fibrosis stage Liver Biopsy Other diagnoses (steatosis) Limitations Invasive Sampling error Small portion of liver, sample Liver Biopsy: Cirrhosis Inter-observer variability Bravo AA. N Engl J Med 2001;344:

28 Validity of Non-Invasive Methods to Detect Significant* Fibrosis in HIV/HCV Test (n) Prev % Sens % Spec ROC FibroSure (130) 45% FIB-4 (830) 21% APRI (263) 58% Forns (263) 58% * METAVIR 2-4 or MHAI 3-6 (FIB-4, METAVIR 3-4) Area under Receiver Operating Characteristic Curve Myers RP et al. AIDS 2003;17: Kelleher TB et al. J Hepatol 2005;43: Sterling RK et al Hepatology 2006;43:

29 Risk of ESLD in HIV/HCV Patients on ART, By Race FIB-4 Score Risk of ESLD Over Time 1 Yr 3 Yrs 5 Yrs 7 Yrs < % 1% 3% 5% % 3% 8% 13% >3.25 8% 18% 26% 37% FIB-4 Score Risk of ESLD Over Time 1 Yr 3 Yrs 5 Yrs 7 Yrs < % 0.5% 2% 4% % 2% 5% 7% >3.25 2% 9% 14% 20% Lo Re V. Open Forum Infect Dis 2015;2:ofv109.

30 Transient Elastography Uses ultrasound to measure velocity of elastic shear wave Liver stiffness (kpa) fibrosis Good correlation with liver biopsy in HIV/HCV * *Kirk GD et al. Clin Infect Dis 2009;48:

31 Question: What Would You Do Next? A. Monitor him, he had stage 1 fibrosis B. Initiate sofosbuvir + simeprevir C. Stage his liver fibrosis D. Initiate sofosbuvir-ledipasvir

32 Case: 43 yo Caucasian Man with HIV and HCV Infection Liver fibrosis transient elastography: Liver stiffness measure = 14.2 kpa cirrhosis FIB-4 = 3.55 (26% risk of ESLD in 5 years) Made decision to abstain from alcohol Abdominal ultrasound: no masses, ascites Endoscopy: varices nadolol

33 Question: What Would You Do Next? A. Initiate sofosbuvir-ledipasvir B. Modify ART in advance of HCV treatment C. Initiate Peg-IFN + ribavirin + sofosbuvir D. Initiate sofosbuvir + simeprevir

34 View results in your browser: poxzwgn

35 Who Should be Considered for HCV Treatment? Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, transplantation, or other directed therapy.

36 Goals of Antiviral Therapy Target Virus Viral Cure (SVR) * Target Disease Prevent Complications Delay Cirrhosis Prevent Hepatocellular Carcinoma SVR = Sustained virologic response (no HCV RNA 12 wks after end of therapy)

37 Direct-Acting Antivirals (DAAs) Target Specific HCV Proteins Structural Non-Structural Core E1 E2 P7 NS2 NS3 NS4A NS4B NS5A NS5B

38 Direct-Acting Antivirals (DAAs) Target Specific HCV Proteins Structural Non-Structural Core E1 E2 P7 NS2 NS3 NS4A NS4B NS5A NS5B NS3/4A Protease Inhibitors 1 st : Boceprevir, telaprevir 2 nd : Simeprevir, paritaprevir, grazoprevir Low-intermediate barrier to resistance Narrow genotypic coverage

39 Direct-Acting Antivirals (DAAs) Target Specific HCV Proteins Structural Non-Structural Core E1 E2 P7 NS2 NS3 NS4A NS4B NS5A NS5B NS5A Inhibitors 1 st : Ledipasvir, ombitasvir, elbasvir, daclatasvir Intermediate barrier to resistance Multi-genotypic coverage

40 Direct-Acting Antivirals (DAAs) Target Specific HCV Proteins Structural Non-Structural Core E1 E2 P7 NS2 NS3 NS4A NS4B NS5A NS5B NS5B Polymerase Inhibitors Nucleos(t)ide Analogues Sofosbuvir High barrier to resistance Pan-genotypic coverage Non-Nucleoside Analogues Dasabuvir Low barrier to resistance Limited genotypic coverage

41 HCV Genotype 1a Regimens (2016): HCV Treatment-Naïve + HIV Treatment Regimens for GT 1a Elbasvir-grazoprevir x 12 wks or x 16 wks + RBV (baseline high fold-change NS5A RAVs) Sofosbuvir-ledipasvir x 12 wks Paritaprevir/Ritonavir-Ombitasvir + Dasabuvir + RBV x 12 wks (no cirrhosis) or x 24 wks (cirrhosis) Sofosbuvir + Simeprevir x 12 wks (no cirrhosis) or x 24 wks RBV (cirrhosis) Daclatasvir + Sofosbuvir x 12 wks (no cirrhosis) or x 24 wks RBV (cirrhosis) RBV = ribavirin; RAV=resistance-associated variants

42 HCV Genotype 1b Regimens (2016): HCV Treatment-Naïve + HIV Treatment Regimens for GT 1b RBV = ribavirin Elbasvir-grazoprevir x 12 wks Sofosbuvir-ledipasvir x 12 wks Paritaprevir/Ritonavir-Ombitasvir + Dasabuvir x 12 wks Sofosbuvir + Simeprevir x 12 wks (no cirrhosis) or x 24 wks RBV (cirrhosis) Daclatasvir + Sofosbuvir x 12 wks (no cirrhosis) or x 24 wks RBV (cirrhosis)

43 HCV Genotype 2, 3 Regimens (2016): HCV Treatment-Naïve GT 2 3 Treatment Regimens Sofosbuvir + RBV x 12 wks (no cirrhosis) or x wks (cirrhosis) Daclatasvir + Sofosbuvir x 12 wks or x wks RBV (cirrhosis) Daclatasvir + Sofosbuvir x 12 wks (no cirrhosis) or x 24 wks RBV (cirrhosis) Sofosbuvir + PEG-IFN + RBV x 12 wks (cirrhosis) Sofosbuvir + RBV x 12 wks GT=genotype; PEG-IFN=pegylated interferon; RBV=ribavirin

44 Liver-related mortality or liver transplantation, % All-cause mortality, % Sustained Virologic Response (SVR) Reduces Mortality in HCV SVR=HCV RNA 24 weeks (now 12 weeks) after stopping therapy 530 patients followed median 8.4 years after interferon treatment 30 Liver-Related Mortality or Liver Transplantation 30 All-Cause Mortality P<0.001 P< Without SVR 10 Without SVR With SVR Time, y With SVR Time, y Van der Meer AJ. JAMA 2012:308:

45 Case: 43 yo Caucasian Man with HIV and HCV Infection Discussed care with care providers Changed ART: Dolutegravir + tenofovir/emtricitabine

46 Question: How Long to Wait Before Re-Checking HIV RNA? A. 1 week B. 2 weeks C. 4 weeks D. 12 weeks

47 View results in your browser: pc2wzhe

48 Case: 43 yo Caucasian Man with HIV and HCV Infection Discussed care with care providers Changed ART: Dolutegravir + tenofovir/emtricitabine 4 weeks later: No complaints on new regimen Tolerating without adverse effects HIV RNA = 0 copies/ml

49 Question: How Would You Treat This Patient? A. Initiate sofosbuvir + simeprevir x 12 weeks B. Initiate sofosbuvir-ledipasvir x 12 weeks C. Initiate elbasvir/grazoprevir x 12 weeks D. Initiate sofosbuvir + ribavirin x 24 weeks

50 View results in your browser: pn3jgvs

51 HCV Genotype 1a Regimens (2016): HCV Treatment-Naïve + Cirrhosis Treatment Regimens for GT 1a Elbasvir-grazoprevir x 12 wks (no NS5A RAVs) Sofosbuvir-ledipasvir x 12 wks Paritaprevir/Ritonavir-Ombitasvir + Dasabuvir + RBV x 24 wks Sofosbuvir + Simeprevir x 24 wks RBV (no Q80K RAV) Daclatasvir + Sofosbuvir x 24 wks RBV Elbasvir-grazoprevir x 16 wks + RBV (baseline high fold-change NS5A RAVs) RBV = ribavirin; RAV=resistance-associated variant Recommended Alternative

52 Case: 43 yo Caucasian Man with HIV and HCV Infection Initiated HCV therapy Sofosbuvir-ledipasvir once daily x 12 weeks Week 4 of HCV therapy: Missed 2-3 treatment doses HCV RNA <43 IU/mL (detectable); ALT 16 Week 8 of HCV therapy: HCV RNA 0 IU/mL

53 Case: 43 yo Caucasian Man with HIV and HCV Infection Week 12 of HCV therapy: HCV RNA 0 IU/mL CD4+ 662/mm 3 (26%); HIV 0 copies/ml 4 weeks after end of HCV treatment: HCV RNA 0 IU/mL 12 weeks after end of HCV treatment: HCV RNA 0 IU/mL (achieved SVR = viral cure)

54 Adherence to HCV Antivirals Can Change Over Time Mean PEG-Interferon Adherence (%, SD) Mean Ribavirin Adherence (%, SD) Adherence Interval (Weeks) N Adherence N Adherence P-Value , % (23%) 5,706 97% (38%) < ,542 95% (23%) 3,497 86% (38%) < ,501 94% (24%) 2,453 84% (38%) < % (30%) % (40%) <0.001 Mean : 3.4% / 12 wks p<0.001 Mean : 6.6% / 12 wks p<0.001 Lo Re V et al. Ann Intern Med 2011;155:

55 Reinfection After SVR in HIV/HCV True incidence unknown 191 HIV/HCV MSM with SVR 44 reinfected (median follow-up, 2.1 years) Need for: Surveillance for reinfection after SVR Ongoing education on potential for reinfection Preventive intervention studies

56 Take-Home Points Suppression of HIV with ART ESLD May be no safe level of alcohol in HIV/HCV DAAs efficacious, well tolerated in HIV/HCV Encourage DAA adherence SVR ESLD, mortality in HIV/HCV Important to educate regarding reinfection

57