Hepatitis C in HIV-infected Persons. Andrea Cox, MDPhD, Ashwin Balagopal, MD

Transcription

1 Hepatitis C in HIV-infected Persons Andrea Cox, MDPhD, Ashwin Balagopal, MD

2 Case 1 45 year old Caucasian man with HIV, CD4+ lymphocyte 756/mm 3 HIV RNA undetectable presents for routine follow up with no symptoms. On Atripla(TDF/FTC/EFV). Works in IT job; no IDU; moderate ETOH; acknowledges unprotected sex. PMH: anxiety; several STDs

3 Case 1 Baseline (4 years earlier) HIV RNA 27,348 c/ml; CD4+ lymphocyte 385/mm 3 HBsAg neg; anti-hbs neg; anti-hbc positive; anti- HCV neg HAV and HBV vaccine initiated Atriplastarted Routine lab work comes back as follows: ALT 785; AST 764; Total BR 1.8; INR 1.1; AlkPhos 232; HIV undetect; CD4+ lymphocyte 756/mm 3

4 Which test is most likely to be helpful? 1. IL28B test 2. HCV RNA 3. Total antibodies to HBV core (anti-hbc) 4. HAV RNA 5. HEV antibody

5 Differential diagnosis and testing Acute HAV Acute HBV Acute HCV Alcohol Medication Other

6 Differential diagnosis and testing Acute HAV Acute HBV Acute HCV Alcohol Medication Other IgM anti-hav HBsAg, IgM anti-core

7 What about isolated anti-hbc Witt CID 2013; French CID 2009

8 Differential diagnosis and testing Acute HAV Acute HBV Acute HCV Alcohol Medication Other IgM anti-hav HBsAg, IgM anti-core HCV RNA test and anti- HCV

9 Antibody and RNA testing to Diagnose Hepatitis C HCV RNA Anti-HCV Infection ALT Acute hepatitis HCV RNA Anti-HCV ALT Infection Acute hepatitis Chronic hepatitis

10 HCV RNA was 6.4 log IU/ml. Genotype 1a. What would you do next? 1. Liver biopsy 2. Peg interferon alfa and ribavirin for 24 weeks 3. #2 plus telaprevir for 12 weeks 4. Monitor

11 Case 2 50 year old man with HIV, CD4+ lymphocyte 756/mm 3 HIV RNA undetectable on AZT/3TC/DRV/r. When he learned that he could be reinfected, he decided not to undergo INF treatment 5 years have passed and he wants to know is my liver in trouble? ALT IU/ml, AST IU/ml, total bili0.6, creat0.9, INR 1.1, platelets 154,000.

12 Which test is most likely to be helpful? 1. Liver biopsy 2. FibroSure 3. Fibroscan 4. Liver ultrasound 5. APRI and FIB4

13 Stages of Fibrosis in Chronic Hepatitis Periportal Periportal Portal Portal Septal Septal Cirrhosis Cirrhosis

14 Significant Fibrosis F 1 Portal tract fibrosis F 3 Numerous septa F 2 Few septa F 4 Cirrhosis N Afdhal,

15 Liver Biopsy is an Imperfect Method to Stage Liver Fibrosis Pro-Biopsy Experience/tradition Other forms of liver disease (steatosis) Informs treatment and HCC screening Predicts ESLD (HIV neg) Anti-Biopsy 1/3000 risk of major complication $1500-2,000 USD Limited availability Limited repeatability Limited validity

16 Sampling error of liver biopsy Fibrosis area: 65% Courtesy Courtesy of of M. M. Pinzani, Pinzani, Florence Florence Fibrosis area: 15%

17 APRI is cheap Wai Hepatology 2003

18 Hepatic Elastography

19 Elastography performs well Kirk CID 2009

20 Validity of Fibroscan Versus Liver Biopsy

21 Chronic hepatitis con t His FibroSure is 0.32 and Fibroscan is 6 kpa, each consistent with < F3-4

22 Case 2, Question 2: Which is true? 1. He has a very low risk of disease and should definitely be monitored 2. He needs to be treated immediately with a PI, peginterferon and ribavirin 3. Change antiretroviral therapy then #2, knowing SVR is <50% 4. Change antiretroviral therapy and tell him his chance of SVR >50%

23 Higher percent HCV undetectable with telaprevir, peginterferon, and ribavirin compared to placebo Dieterich CROI 2012

24 Higher percent of SVR12 in HIV/HCV coinfected persons taking boceprevir, peginterferon, and ribavirin compared to Peg/RBV and placebo Sulkowski CROI 2012

25 Boceprevir interacts with antiretrovirals Antiretroviral Atazanavir/r Darunavir/r Lopinavir/r Not recommended Recommendation Efavirenz Etravirine Raltegravir (non CYP) Reduction in boceprevir levels; not recommended No dose adjustment required* No dose adjustment required** Tenofovir No change in TFV AUC but Cmax increased by 32%. No dose adjustment but clinical/laboratory monitoring warranted

26 Telaprevir interacts with antiretrovirals Antiretroviral Darunavir/r Fosamprenavir/r Lopinavir/r Not recommended Recommendation Efavirenz Atazanavir/r Etravirine Rilpivirine Raltegravir (non CYP) Tenofovir TVR dose increase necessary (1125 mg q8h) Clinical and laboratory monitoring for hyperbilirubinemia is recommended No dose adjustment required* No dose adjustment required* No dose adjustment required** Increase in TFV (30%). Clinical and laboratory monitoring is warranted

27 Which is true regarding his risk of liver cancer? 1. He is at high risk and needs regular testing 2. The risk is higher than if he were <40 yrs old 3. Alfa-feto protein testing is the best way to monitor 4. Liver ultrasound has sensitivity >90% for HCC 5. His risk is higher than if he had chronic hepatitis B

28 Screen for HCC in HCV-infected persons with F3-4 and most with chronic HBV HCC risk higher: Older age HIV Male HBV Cirrhosis Tobacco HCC screening reduces HCC mortality Incidence of HCC in 866 patient by FScan Zhang J Cancer Res Clin Oncol 2004; Masuzaki, Hepatol 2009

29 Case 3 A 55 year-old African American HIV/HCV coinfected man presents with fatigue. He has had each infection at least 10 years. HIV has been suppressed on Atripla (TDF/FTC/EFV), but he has never been treated for HCV. His HCV viral load is 7.6 log IU/ml, HCV genotype is 1a; IL28Bis CT; CD4 count nadir was 45 cells/µl and current is 495 cells/µl; platelet count 78,000. ALT is 45 IU/ml; AST 66 IU/ml. Total bilirubin is 1.6 mg/dl; creatinine 1.2 mg/dl; INR 1.4; and albumin 3.6 mg/dl. Liver biopsy shows cirrhosis. Ultrasound of right upper quadrant is read as normal.

30 Which of the following is most accurate about his liver disease? A. The risk of progression would be less if he had genotype 2 HCV B. Without HCV treatment, within 5 years the chance of decompensation to Child B cirrhosis is more than 15% C. The risk of liver disease progression would be higher if he were female D. The risk of liver disease progression would be lower if he were obese E. His increased risk of hepatocellular carcinoma would be eliminated by successful HCV treatment

31 Case 4 A 50 year old HIV infected man is 5 years out from sustained virologic response to peginterferon and ribavirin for genotype 3 HCV infection. He has had yearly HCV RNA testing that is undetectable. ALT and AST have been <20 IU/ml.

32 Which of the following is true? A. HCV infection can be reconstituted from HCV proviral DNA integrated in hepatocyte nuclei B. He should take peginterferon alfa if he needs immunosuppression for cancer C. He could be reinfected if he were exposed again D. Serotonin uptake inhibitors are indicated due to depressive effects of low level CNS reservoirs E. HCV antibodies should be retested yearly

33 Case 5 A 56 year old African American HIV/HCV coinfected patient presents for consideration of HCV treatment. HIV is suppressed on raltegravir and truvada. CD4+ lymphocyte is 454/mm 3. A liver biopsy was done 5 years ago and had minimal fibrosis, metavir 1. HCV RNA is 6.1 log IU/ml and genotype 1a. platelet count is 152,000; ALT 55 IU/ml; AST 48 IU/ml; total bilirubin is 0.8; serum creatinine 0.9 mg/dl; albumin 4.2 mg/dl.

34 Which of the following is true regarding treatment for HCV? A. His chance of SVR is similar to an HIV negative person with otherwise similar data B. Drug interactions would prevent HCV treatment without changing antiretroviral therapy C. Antiretroviral therapy alone should be sufficient to prevent liver fibrosis progression D. Peginterferon alfa would increase his CD4+ lymphocyte count by about 50 cells E. There is no indication for treatment

35 AB9 Drugs nearing approval (US) Sofosbuvir (NS5B inhibitor) 2013 approval (US FDA) Daclatasvir (NS5A inhibitor) Dustin LB and Rice CM, Ann Rev Immunol, Simeprevir Asunaprevir Danoprevir (Protease Inhibitor)

36 Slide 35 AB9 polyprotein Ashwin Balagopal; 15/04/2013

37 Anti-HCV Drugs in Development Others Cyclophilin. I EK2 ACH-2928 (Achillion) DAA combinations NS5A inhibitors Vitamine D Nitazoxamide (Romark) Celgosivir Bavituximab Silibinine SCY-835 PPI-461 MSD Idenix719 AZD-7295 (AZN) Vertex BMS PPI-1301 (BMS) GSK EDP-239 (Enanta) Debio 025/ IFN λ NIM811 (Novartis) BMS (BMS) ABT267 (ABT) Abbott Vertex GS-5885 Preclinical Boceprevir (MSD) Phase I Phase II Phase III Filed Telaprevir (Vertex/JJ) BI TMC-435 (BI) (Tibotec/JJ) ITMN191/R7227 MK7009 (Roche/Intermune) (MSD) ABT450 (ABT) IDX 077 (Idenix) IDX 079 (Idenix) Gilead BMS EK3 BI ROCHE VBY-376 VX-985 (Vertex) VX-813 (Vertex) MK5172 (MSD) AVL-181 (Avila) GS9256 (Gilead) IDX 184 (Idenix) R7128 (Roche) JS1 BMS (BMS) GS9451 (Gilead) AVL-192 (Avila) (Inhibitrex) GS Gilead) BMS Filibuvir (BMS) (PFE) GS9190 (Gilead) ACH2684 (Achillion) BI ANA598 BI (Anadys) (BI) Japan Tobacco INX 189 Vx222 (Vertex) ABT333 ABT072 (ABT) VX-759 Nucleotide NS5B Polymerase Inhibitors R0622 (Roche) Medivir (Tibotec) EK1 GLS9393 (GSK) Biocryst IDX 375 (Idenix) RG7348 (Roche) TMC (Tibotec) A (Abbott) VX-916 Nucleoside NS5B Polymerase Inhibitors Non Nuc NS5B Polymerase inhibitors NS3/4A Protease inhibitors Adapted from Bourliere M, et al. Clin Res Hepatol Gastroenterol. 2011;35(suppl 2):S84-S95.

38 Slide 36 EK1 Change to BMS? Edward King; 29/05/2012 EK2 delete ". I"? Edward King; 29/05/2012 EK3 JS1 Change to daclatasvir? Edward King; 29/05/2012 Is this asunaprevir? jschulz; 29/05/2012

39 Sofosbuvir Treatment-naïve (GT 2/3) SVR 24 = 100% SVR 24 = 100% SVR 24 = 100% SVR 24 = 100% SVR 24 = 60% SVR 24 = 100% Treatment-naive(GT 1) 12 wk sofosbuvir-ribavirin SVR 24 = 84% Treatment-experienced (GT 1) 12 wk sofosbuvir-ribavirin SVR 24 = 10% Gane EJ et al., NEJM 2013.

40 Daclatasvir + Asunaprevir Lok AS et al., NEJM 2012.

41 Case 6 A 29 year old HIV infected man comes to you after a night of partying in which he admits he shared needles with a HCV infected person to inject crystal methamphetamine. He has no medical conditions besides anxiety and HIV. You draw blood from the patient and it is pending, but he is anti-hbs positive because you vaccinated him last year.

42 Which of the following should you do? A. test him for IL28B if not already done B. start peginterferon, telaprevir, and ribavirin within 2 hours C. Give pooled immune globulin intramuscularly D. follow up with HCV RNA testing in several weeks E. Give HCV enriched immune globulin and HCV vaccine as soon as possible

43 Case 7 A 32 year-old woman with newly diagnosed HIV and HCV was started on HAART with tenofovir, emtricitabine, and ritonavirboosted darunavir two weeks ago. Her liver enzymes were normal, and show total bilirubin 2.3 mg/dl, AST 125 U/L, ALT 161 U/L, Alkaline phosphatase 89 U/L. His HCV RNA is 6.5 log10 IU/mL and she is genotype 1 with minimal liver disease.

44 Which of the following is indicated? 1. High-dose corticosteroids to treat IRIS 2. Discontinue HAART 3. Monitor LFT trend 4. Obtain liver biopsy 5. Start pegylated-interferon, ribavirin, and a protease inhibitor within the next week

45 Thank you