Hepatitis and HIV Co-Infection

1. Hepatitis and HIV Co-Infection Sandra G. Gompf, MD, FACP, FIDSA Associate Professor, Infectious Diseases and International Medicine University of South Florida College of Medicine

2. Mortality trends in HIV: HIV Outpatient Study (HOPS) The HIV Outpatient Study (HOPS) included 5561 participants treated at 2 public, 4 university, and 2 private clinics from 1996 to 2002.1 Rates of death due to nonopportunistic causes and nonopportunistic illnesses contributing to death (as a percentage of all deaths) were calculated. Nonopportunistic illnesses were categorized based on disease, including pulmonary, hepatic, renal, and cardiovascular. Patients were followed for a median of 35.3 months. Overall death and opportunistic infection rates remained low through the seventh year of highly prevalent HAART usage in the HOPS; the proportion of deaths attributable to nonopportunistic illness increased and was positively associated with the number of years having received antiretroviral therapy (ART). Of 473 deaths included in this analysis, the proportion of all primary and secondary causes of deaths that were nonopportunistic illnesses increased over time from 45.7% in 1996 to 71.7% in 2002 (P <.0001 for trend). For the calendar years 2000, 2001, and 2002, the most frequent nonopportunistic illnesses cited as contributing to death, as a percentage of all deaths in this 3-year period were: hepatic (35.6%), pulmonary (22.7%), cardiovascular (17.2%), and renal (9.8%). Reference 1. Palella FJ, Baker R, Moorman AC, Chmiel J, Wood K, Holmberg SD, and the HOPS Investigators. Mortality and morbidity in the HAART era: changing causes of death and disease in the HIV Outpatient Study. Presented at: 11th Conference on Retroviruses and Opportunistic Infections, 2004; February 8-11, 2004; San Francisco, Calif. Abstract 872. The HIV Outpatient Study (HOPS) included 5561 participants treated at 2 public, 4 university, and 2 private clinics from 1996 to 2002.1 Rates of death due to nonopportunistic causes and nonopportunistic illnesses contributing to death (as a percentage of all deaths) were calculated. Nonopportunistic illnesses were categorized based on disease, including pulmonary, hepatic, renal, and cardiovascular. Patients were followed for a median of 35.3 months. Overall death and opportunistic infection rates remained low through the seventh year of highly prevalent HAART usage in the HOPS; the proportion of deaths attributable to nonopportunistic illness increased and was positively associated with the number of years having received antiretroviral therapy (ART). Of 473 deaths included in this analysis, the proportion of all primary and secondary causes of deaths that were nonopportunistic illnesses increased over time from 45.7% in 1996 to 71.7% in 2002 (P <.0001 for trend). For the calendar years 2000, 2001, and 2002, the most frequent nonopportunistic illnesses cited as contributing to death, as a percentage of all deaths in this 3-year period were: hepatic (35.6%), pulmonary (22.7%), cardiovascular (17.2%), and renal (9.8%). Reference 1. Palella FJ, Baker R, Moorman AC, Chmiel J, Wood K, Holmberg SD, and the HOPS Investigators. Mortality and morbidity in the HAART era: changing causes of death and disease in the HIV Outpatient Study. Presented at: 11th Conference on Retroviruses and Opportunistic Infections, 2004; February 8-11, 2004; San Francisco, Calif. Abstract 872.

3. The big picture of hepatitis Damage to liver cells caused by inflammation or cell death Can be caused by infections, drug toxicity, poisoning, biliary tract obstruction If persists, can lead to progressive scarring of the liver (cirrhosis) and end-stage liver dysfunction

4. Causes of hepatitis in the HIV + patient Drugs HAART Metabolic complications Treatment of opportunistic infection Viral pathogens Hepatitis A, B, C CMV Overlap is common HAART-older PIs Metabolic complications-mitochondrial dysfunction Treatment of opportunistic infection-azole antifungalsHAART-older PIs Metabolic complications-mitochondrial dysfunction Treatment of opportunistic infection-azole antifungals

5. Drug-induced hepatotoxicity, besides HAART trimethoprim-sulfamethoxazole, antituberculars, azole antifungals anabolic steroids acetaminophen statins & fibrates

6. HAART-induced hepatotoxicity Elevated transaminases mostly with PIs, but also w/ NNRTIs May be related to “hyperimmunity” or “immune restoration syndrome” Often subsides over several months HIV/HCV+ are 3-5-fold more likely to develop severe transaminitis

7. Viral Hepatitis in HIV + patients Acute viral hepatitis be severe or fatal Acute viral hepatitis can add to liver damage already present from other causes E.g. Acute hepatitis A on chronic hepatitis C may be deadly

8. Viral Hepatitis Overview

9. GBV-C infection: the role ofHepatitis G may reduce mortality in late HIV may reduce HIV viral loads

10. Hepatitis A & HIV, in brief role seems significant 35 HIV+ with acute HAV 80% treatment interrupted X ~ 2 months 25% lost efficacy on resuming HAART safe, effective VACCINE available

11. Hepatitis C Transmitted via IVDU/blood, less often sex (more likely for MSM) In U.S., 4 million HCV+ ? 85% chronic If chronic ? 20% cirrhotic @ 20 years Once cirrhotic ? 25% hepatocellular CA (0.5% of total HCV+) Alcohol & HIV worsen prognosis Usually no symptoms sometimes fatigue, RUQ ache, difficulty concentrating

12. Hepatitis C 6 Genotypes 1, 2, & 3 are commonest in US/W Europe ~75% Genotype 1 ~25% “Non-1” Most are 2 & 3 4 occurs less often African Americans less likely to have sustained response to treatment SVR 28% AA vs. 52% Cauc

13. Hepatitis C Like HIV, antigenic variation occurs ? Hepatitis C antibody is not protective ? no vaccine Unlike HIV & HBV, does not integrate into the host genome ? eradication is possible / more likely with treatment

14. Sources of Infection for Persons with Hepatitis C 30-50% HIV+ have chronic HCV HIV/HCV: IVDU 90% hemophilia 8% MSM 4-8% Sexual/household exposure to HCV+ contact Sexual transmission in monogamous couples ~ 1-5% razors Multiple sex partners Sexual practices that may damage mucosa Birth to HCV-infected mother Acute maternal infection during pregnancy Vietnam-era veterans (~7% vs. 2% general US pop.)Sexual/household exposure to HCV+ contact Sexual transmission in monogamous couples ~ 1-5% razors Multiple sex partners Sexual practices that may damage mucosa Birth to HCV-infected mother Acute maternal infection during pregnancy Vietnam-era veterans (~7% vs. 2% general US pop.)

15. Sources of Infection for Persons with Hepatitis C Sexual/household exposure to HCV+ contact Sexual transmission in monogamous couples ~ 1-5% Razors Multiple sex partners Sexual practices that may damage mucosa Birth to HCV-infected mother Acute maternal infection during pregnancy Vietnam-era veterans (~7% vs. 2% general US pop.) Sexual/household exposure to HCV+ contact Sexual transmission in monogamous couples ~ 1-5% razors Multiple sex partners Sexual practices that may damage mucosa Birth to HCV-infected mother Acute maternal infection during pregnancy Vietnam-era veterans (~7% vs. 2% general US pop.)Sexual/household exposure to HCV+ contact Sexual transmission in monogamous couples ~ 1-5% razors Multiple sex partners Sexual practices that may damage mucosa Birth to HCV-infected mother Acute maternal infection during pregnancy Vietnam-era veterans (~7% vs. 2% general US pop.)

16. HIV/HCV Co-infection is associated with Rapid Progression to Cirrhosis Soto, et al. J Hepat 1997 compared 547 HIV- with 116 HIV+ all with chronic hepatitis C Incidence of cirrhosis HIV- 2.6% (mean HCV duration 23.2 years) HIV+ 14.9% (mean HCV duration 6.9 years)

17. Other interactions between Hepatitis C & HIV chronic HCV is more likely in advanced HIV (low CD4 & high HIV viral load) high HCV viral load predicts progression to AIDS regardless of HIV viral load chronic HCV blunts CD4 response to HAART cirrhosis suppresses immunity May affect total CD4

18. Diagnosing HCV in HIV Do not rely on transaminases! There is no correlation between transaminase levels and disease severity. HCV ELISA antibody screening +Antibody means “infected at some point”, need to determine if active or chronic infection in advanced HIV, may be falsely negative HCV RNA PCR confirms or excludes active disease +Viral load means “active hepatitis”

19. Diagnosing HCV in HIV HCV ELISA antibody (low-threshold, sensitive) If + (or advanced HIV)? HCV RNA quantitative PCR. If HCV ELISA or RNA PCR -, no further intervention. If HCV RNA PCR + ? active hepatitis is present…

20. Doc, I have chronic hepatitis, now what? STOP ALL ETHANOL Genotyping is helpful in predicting response to therapy 1 is more refractory to treatment Non-1 are very responsive Rule out other causes of liver disease if liver enzymes are abnormal Autoimmune hepatitis, biliary disease, hemochromatosis

21. Look for complications of chronic hepatitis Liver biopsy? Gold standard in evaluating hepatitis and cirrhosis—how “close” to cirrhosis is your patient? 1% serious bleed Fibrosure™(blood) & Fibroscan ™ (liver stiffness) not validated in HIV yet, but non-invasive measures of fibrosis Sonogram – screen for other liver disease, CA Alpha-fetoprotein alone is not enough to screen out CA FIBROSURE™ uses a combination of six serum biochemical markers plus age and gender in a patented algorithm to determine the degree of liver fibrosis and the level of ongoing necroinflammatory activity. BioPredictive is currently researching clinical use of this test for other disease populations, including hepatitis B, HIV-HCV, and alcoholic and non-alcoholic steato hepatitis (NASH). FIBROSCAN ™ (transient elastography) measures liver stiffness & correlates w/ fibrosis.FIBROSURE™ uses a combination of six serum biochemical markers plus age and gender in a patented algorithm to determine the degree of liver fibrosis and the level of ongoing necroinflammatory activity. BioPredictive is currently researching clinical use of this test for other disease populations, including hepatitis B, HIV-HCV, and alcoholic and non-alcoholic steato hepatitis (NASH). FIBROSCAN ™ (transient elastography) measures liver stiffness & correlates w/ fibrosis.

22. Look for complications of chronic hepatitis Extra-hepatic manifestations of Hepatitis C Mixed cryoglobulinemia (rash, joint pain) Membranous glomerulonephritis (proteinuria) These may be reasons to treat BUT: extrahepatic manifestations may differ in HIV-HCV may or may not improve

23. Talking to your patient: Benefits & goals of treating chronic hepatitis C in HIV Viral eradication (“sustained viral remission”, SVR) Delay progression of fibrosis Prevent/delay bad clinical outcomes of cirrhosis Liver decompensation Hepatocellular carcinoma Death Improve tolerance and effectiveness of HAART Allows aggressive antiretroviral drug therapy Enhance immune reconstitution?

24. Note bene:Which hepatitis drugs are which?? PEG aINF 2b Schering-Plough PEG-Intron A ™ ribavirin (Rebetol™) PEG aINF 2a Roche Pegasys™ ribavirin (Copegus™) lamivudine Epivir-HBV™, 50mg Epivir™, 150mg (HIV) adefovir, Hepsera™ entecavir, Baraclude™ telbivudine, Tyzeka™ Schering’s interferon, entecavir, adefovir, & telbivudine not indicated in HIV Those highlighted in red are rx that are FDA approved for use in HIV Schering’s interferon, entecavir, adefovir, & telbivudine not indicated in HIV Those highlighted in red are rx that are FDA approved for use in HIV

25. Talking to your patient: Benefits & goals of treating chronic hepatitis C in HIV In studies, sustained viral remission w/ newer treatments: PEG ?IFN + ribavirin Genotype 1 & 4 (~ 30 - 70 % SVR) Genotype 2 & 3 (>80% SVR) HIV disease is not worsened by ?IFN or ribavirin

26. Talking to your patient: Risks, problems, & adverse effects of treating chronic hepatitis C in HIV There’s still more to talk about…..

27. Hepatitis C Treatment Toxicities Pegylated aINF 2a or 2b flu-like symptoms depression/suicidal fatigue, dizziness anorexia, nausea/diarrhea bone marrow suppression immune suppression, infection autoimmune disease thyroid, diabetes hair loss, oral ulcers pulmonary fibrosis Ribavirin anemia/hemolysis dose dependent 2.5-3g ? within 4 weeks erythopoietin bone marrow depression embryocidal / Category X teratogenic for up to 6 months after treatment FDA Ribavirin Pregnancy Registry

28. Talking to your patient: Whom NOT to treat Major contraindications: pregnant or planning to be untreated/severe depression or psych disease significant ischemic cardiovascular disease decompensated cirrhosis before/during treatment hemoglobinopathies (thalassemia/sickle cell) significant asthma, lung disease malignancy end-stage renal disease

29. Talking to your patient: Whom to delay or re-consider treating Relative contraindications: untreated depression or psych disease “street” drug or ethanol abuse uncontrolled diabetes or thyroid disease seizure disorders infections poor ADHERENCE (predicts poor adherence to treatment, BIRTH CONTROL, follow-up visits)

30. Talking to your patient: Best odds and best reasons to treat Stable HIV disease with intact immune function (to eradicate virus, delay cirrhosis/CA) Advanced hepatic fibrosis (to delay cirrhosis/CA) Starting HAART (to limit HAART interruptions & improve response )

31. Talking with your patient: Which to treat first? HIV or HCV? CD4 < 350 ? treat HIV Higher risk of HIV morbidity/mortality Lower HCV response to tx CD4 > 350 ? treat HCV HCV response is better @ higher CD4s lower pressure to start HAART possibly avoid HAART interruptions due to hepatotoxicity

32. Talking to your patient: Other Issues ex-IVDU & needle aversions… “Needle fixation” Ritual of injecting Injection = euphoric experience Risk of recidivism

33. Ribavirin interacts with HAART

34. Other HAART considerations with Hepatitis C

35. Treatment of HCV in HIV+ PEG aINF 2a (fixed 180 mcg) or 2b (wgt-based) subcutaneously every week X 48 weeks + Ribavirin 800mg PO daily (up to 1200mg for genotype 1 or 4) X 48 weeks If HCV undetectable @ 12 weeks ? continue if not, D/C If HCV undetectable @ 48 weeks ? repeat @ 72 weeks if still undetectable ? SVR!!

36. Prescreening and Monitoring during Treatment Prescreening tests: serum or urine ß HCG serum TSH serum ANA iron, ferritin HAV & HBV serology CBC & differential PT, PTT fasting blood glucose, lytes, creatinine, liver enzymes Monitoring: Monthly CBC & diff (& @ 2 weeks of start) lytes, FBS, creatinine, liver enzymes serum or urine ß HCG @ 12, 48, & 72 weeks HCV RNA PCR Every 12 weeks serum TSH

37. Managing adverse effects Avoid dose reductions where possible Moderate depression – MH care, reduce PEG; D/C if severe or suicidal Neutropenia & thrombocytopenia G-CSF 300 mcg SC TIW to keep ANC > 750 ANC < 750: reduce PEG ANC > 750: hold PEG, resume at lower dose once over 750 PLT < 50K: reduce PEG; at < 25K, D/C PEG Anemia Erythropoietin alfa 40K IU SC weekly if Hgb <12 mg/dL Reduce RBV if Hgb <10 mg/dL, D/C if < 8 mg/dL

38. The future of HIV/HCV? Longer courses of pegylated INF + ribavirin 72 weeks maximum ribavirin dose Improved SVR, reduced relapse AST-to-platelet ratio index (APRI) may prove useful as a non-invasive marker for fibrosis

39. Key points about HCV/HIV

40. Hepatitis B Hepatitis B sex, perinatal, IVDU, blood >300,000/year in U.S. Only 25% symptomatic: acute jaundice, elevated liver enzymes, fatigue, NVD Lifetime risk up to 100% if risks (avg U.S. 5%) 10% become chronic ? cirrhosis/CA in 20-30 yrs Ethanol, HIV, other hepatitis viruses Over 1 million have chronic HBV in US Relative risk of HBV from needle stick in HCW is 30%, vs. HIV 3% Over 1 million have chronic HBV in US Relative risk of HBV from needle stick in HCW is 30%, vs. HIV 3%

41. Hepatitis B & HIV acute HBV may be more severe ~10% of HIV+ 5-6x > chronicity than HBV+ impaired cell-mediated immunity can cause chronicity HIV/HBV 19x > liver deaths than HBV+ 8x > liver deaths than HIV+

42. Hepatitis B & HIV 7 genotypes (data evolving) A commonest in HIV/HBV/U.S.– 75% may respond best G least common – 25% marker of rapid fibrosis efavirenz exposure duration of HIV Chronic hepatitis B does not change mortality Chronic hepatitis B does not change mortality

43. Serology & Mutations in Chronic HBV HBsAg HBsAb HBeAg HBV DNA + - +* + *Pre-core protein/core promoter mutation don’t express HBeAg, DNA ?? severe inflammation ?cirrhosis longer duration of disease?older more resistant to therapy non-A genotypes, Asia/Europe Mutations prevents expression of eAg, poorer immune control/greater inflammatory responseMutations prevents expression of eAg, poorer immune control/greater inflammatory response

44. Serology & Mutations in Chronic HBV YMDD mutation = lamivudine resistance 1000x rise in resistance Up to 90% resistance @ 4 years lamivudine Mutations in RT region of HBV DNA pol YMDD motif = tyrosine, methionine, aspartic acid, aspartic acid 2 forms: M ? valine or M ? isoleucine

45. Hepatitis B & HIV: “Occult” HBV Isolated HBcAb + and DNA low level +: HBsAg HBsAb HBV DNA - - + commoner in HIV+ Chronic hepatitis B does not change mortality Chronic hepatitis B does not change mortality

46. Hepatitis B & HIV: “Occult” HBV may account for acute flare in: HAART initiation/immune reconstitution With immune suppression (CD4? or chemo-therapy) Should get HBV vaccine Poor anamnestic response Chronic hepatitis B does not change mortality Chronic hepatitis B does not change mortality

47. Therapies for Chronic HBV in HIV+ First line: lamivudine (Epivir™)—NOT Epivir-HBV™ emtricitabine (Emtriva™, off-label for HBV) inhibit HBV DNA pol YMDD resistance with lamivudine 15% @ 1 yr 30-40% @ 2 yr 70-90% @ 4 yrs emtricitabine is equivalent, delayed resistance/may overcome YMDD

48. Therapies for Chronic HBV in HIV+ Unlike HAART, combination therapy is no better than sequential monotherapy in HBV lamivudine = tenofovir/lamivudine sequencing or combo depends on HIV & HAART

49. Therapies for Chronic HBV in HIV+ Second line: interferon PEG aINF 2a x 48 wk ~30% SVR Roche, 1st PEG FDA approved for HIV/HBV, 2005 Schering PEG aINF 2b used off-label?, more data for HIV/HCV but not HIV/HBV

50. Therapies for Chronic HBV in HIV:Other agents? adefovir (Hepsera™) –NO dosing for HBV is too low to suppress HIV promotes tenofovir resistance entecavir (Baraclude™)–CAUTION may be associated with M184V (FDA MedWatch 2/2007) Famciclovir -modest to good HBV DNA suppression -improvement in ALT/histology is more significant -may achieve HBeAg - in 40% -better in combo w/ lamivudine -possible consideration in future Famciclovir -modest to good HBV DNA suppression -improvement in ALT/histology is more significant -may achieve HBeAg - in 40% -better in combo w/ lamivudine -possible consideration in future

51. Therapies for Chronic HBV in HIV:Other agents? telbivudine (Tyzeka™)—maybe?? nucleoside analog alternative to lamivudine, tenofovir pre-HAART? may have additive benefit with other agents—combination therapy? no HIV-1 activity, no apparent NRTI antagonism in vitro but no data in HIV+ Famciclovir -modest to good HBV DNA suppression -improvement in ALT/histology is more significant -may achieve HBeAg - in 40% -better in combo w/ lamivudine -possible consideration in future Famciclovir -modest to good HBV DNA suppression -improvement in ALT/histology is more significant -may achieve HBeAg - in 40% -better in combo w/ lamivudine -possible consideration in future

52. When to treat & with what Ready for HAART? lamivudine & emtricitabine/tenofovir backbones indefinite tx FLARES with stopping meds or onset of YMDD resistance — USE CAUTION Not ready for HAART? Consider PEG aINF 2a + ribavirin x 48 weeks advanced fibrosis HIV/HBV/HCV improves fibrosis may clear virus Consider earlier HAART w/ HBV-active agents… Famciclovir -modest to good HBV DNA suppression -improvement in ALT/histology is more significant -may achieve HBeAg - in 40% -better in combo w/ lamivudine -possible consideration in future Famciclovir -modest to good HBV DNA suppression -improvement in ALT/histology is more significant -may achieve HBeAg - in 40% -better in combo w/ lamivudine -possible consideration in future

53. Earlier HAART…? 79 HBsAg+ (39 also HBeAg+) 37% lamivudine experienced 58% lamivudine & tenofovir experienced Followed on HAART that included HBV agents @ 52 wks, undetectable HBV PCR was most likely in those with greater CD4 increases & undetectable HIV ? will starting HAART earlier be beneficial? Famciclovir -modest to good HBV DNA suppression -improvement in ALT/histology is more significant -may achieve HBeAg - in 40% -better in combo w/ lamivudine -possible consideration in future Famciclovir -modest to good HBV DNA suppression -improvement in ALT/histology is more significant -may achieve HBeAg - in 40% -better in combo w/ lamivudine -possible consideration in future

54. Treatment options for lamivudine-resistant HBV (YMDD mutants) emtricitabine may still work in YMDD+ tenofovir (off-label for HBV) entecavir with caution? telbivudine?? consider PEG aINF 2a + ribavirin expectant management

55. What about the patient with end-stage liver disease? Liver transplantation may be a viable option in selected HIV+ individuals Experimental, outcomes ~ non-HIV+ good HIV control good adherence/compliance HCV recurrence is common in new liver Re-treatment may need to be longer In recent years, several research teams have found that outcomes of liver transplantation in HIV positive patients are nearly as good as those in HIV negative people. However, in HIV positive and negative individuals alike, HCV infection typically recurs in the new liver following the procedure. In recent years, several research teams have found that outcomes of liver transplantation in HIV positive patients are nearly as good as those in HIV negative people. However, in HIV positive and negative individuals alike, HCV infection typically recurs in the new liver following the procedure.

56. Hepatitis A, B, C & HIV Prevention is KEY Screen & vaccinate early Lower CD4s will lower antibody response CD4 < 200 ~15-40% antibody CD4 >500 ~ 90% antibody Counsel about risk factors

58. Disclosure of Financial Relationships This speaker has no significant financial relationships with commercial entities to disclose. Use this slide if you have no significant financial relationships with any commercial entities. If you use this slide, please delete slide 3.Use this slide if you have no significant financial relationships with any commercial entities. If you use this slide, please delete slide 3.