Hepatitis and HIV Co-Infection

1. Hepatitis and HIV Co-Infection Jeffrey A. Beal, M.D., AAHIVs Clinical Director, Florida/Caribbean AETC Medical Director, Ryan White Part C Program Hendry County Health Department AETCBeal@embarqmail.com

2. Disclosure of Financial Relationships This speaker has no significant financial relationships with commercial entities to disclose.

4. Viral Hepatitis in HIV+ Patients Acute viral hepatitis may be severe or fatal Acute viral hepatitis may add to liver damage already present from other causes e.g. Acute hepatitis A on other chronic viral hepatitides may be deadly

5. 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 for Hepatitis A and B – vaccinate!

6. Hepatitis C Transmitted via IVDU/contaminated blood/perinatal > sex (receptive AS & STD) In U.S., 4 million HCV+ ? 85% chronic If chronic ? 20% cirrhotic @ 20 - 40 years Once cirrhotic ? 25% hepatocellular CA (0.5% of total HCV+) Alcohol & HIV worsen prognosis Usually no symptoms but sometimes fatigue, RUQ ache, difficulty concentrating or isolated ? ALT/AST Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Exposed and HIV-Infected Children – June 20, 2008 HCV is 10 times more likely to be transmitted by percutaneous blood exposure than is HIV. Less than 20% of patients have symptoms which Acute Hep C infection. HCV is 10 times more likely to be transmitted by percutaneous blood exposure than is HIV. Less than 20% of patients have symptoms which Acute Hep C infection.

7. Hepatitis C 6 Genotypes Genotypes 1-3 are most common in US, W. Europe: 75% are 1 (accounts for 90% of cases in AA) 25% are “Non-1” Most are 2 & 3 4-6 Middle East/Africa/Spain African Americans less likely to achieve sustained virologic response (SVR) to treatment 28% AA versus 52% Caucasians In us, 90% of african american cases are Genotype 1.In us, 90% of african american cases are Genotype 1.

8. 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

9. Sources of Infection forPersons with Hepatitis C 30-50% HIV+ have chronic HCV HIV/HCV: IDU 90% Hemophilia 80% MSM 4-8% Delete 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.)Delete 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.)

10. HIV/HCV Co-Infection is Clearly Associated with More 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) DeleteDelete

11. Compared to HCV mono-infection, co-infected patients have: More rapid progression to cirrhosis decompensated liver disease HCC death

12. Liver Disease: A Major Cause of Death ART has slowed the progression of HIV disease and decreased the rate of HIV-associated mortality. With increased longevity, other comorbidities, such as chronic liver disease, have assumed greater importance. HCV and HIV share routes of transmission, so coinfection with is common, especially in injection drug users and hemophiliacs [2–6]. HCV-infected patients have a 20% risk of developing cirrhosis within 20 years; it leads to chronic hepatitis in 85% of patient]. HIV disease may modify chronic HCV infection’s natural history, accelerating progression from chronic active hepatitis to cirrhosis, end-stage liver disease, and death. Enhanced risk of liver toxicity using antiretroviral agents in the presence of underlying chronic hepatitis C is a serious consideration. In injection drug users, rates of coinfection with HIV and HCV range from 52% to 93%. Strategies to prevent infection by hepatitis viruses (hepatitis B vaccine) and specific treatment (interferon plus ribavirin for hepatitis C virus) should be encouraged among HIV-infected persons. ART has slowed the progression of HIV disease and decreased the rate of HIV-associated mortality. With increased longevity, other comorbidities, such as chronic liver disease, have assumed greater importance. HCV and HIV share routes of transmission, so coinfection with is common, especially in injection drug users and hemophiliacs [2–6]. HCV-infected patients have a 20% risk of developing cirrhosis within 20 years; it leads to chronic hepatitis in 85% of patient]. HIV disease may modify chronic HCV infection’s natural history, accelerating progression from chronic active hepatitis to cirrhosis, end-stage liver disease, and death. Enhanced risk of liver toxicity using antiretroviral agents in the presence of underlying chronic hepatitis C is a serious consideration. In injection drug users, rates of coinfection with HIV and HCV range from 52% to 93%. Strategies to prevent infection by hepatitis viruses (hepatitis B vaccine) and specific treatment (interferon plus ribavirin for hepatitis C virus) should be encouraged among HIV-infected persons.

13. Other Hep C & HIV Interactions HCV does not appear to consistently affect progression of HIV disease Chronic HCV does not appear to consistently affect CD4 response to HAART Cirrhosis suppresses immunity—may affect CD4 May be associated with changes in psychiatric fxn., ? QOL, ? prevalence DM

14. 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” Quantitative HCV VL does not correlate with degree of liver damage and is not a surrogate marker for disease progression

15. Chronic Hepatitis C STOP ALL ETHANOL Consider opioid substitution therapy if active drug abuse Assure immunity to Hepatitis A & B; in not immune, offer vaccines Obtain Genotype Counsel on condoms and safer sex Introduce risks vs. benefits of treatment Assess if benefit of treatment outweighs risk

16. Treatment of Disease – Benefit > Risk If no contraindication to Peg-IFN/RBV HCV genotype 2 or 3 HCV genotype 1 with HCV RNA < 800,000 IU/ml Sig. hepatic fibrosis (bridging or cirrhosis) Stable HIV not requiring ART Acute HCV (< 6 mo. duration) Cryoglobulinemic vasculitis or cryoglobulinemic membranoproliferative glomerulonephritis Patient motivated for treatment Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Exposed and HIV-Infected Children June 20, 2008

17. Treatment of Disease –Risk > Benefit Pregnancy or unwilling to use birth control Advanced HIV uncontrolled on ART Hepatic decompensation Cancer or cardiopulmonary disease Active depression, suicidal ideation Hgb < 10.5 g/dL, ANC < 1000/µL, Platelet Count < 50,000/µL Creatinine > 1.5 or Cr.Cl. < 50cc/min Liver decompensation = coagulopathy, hyperbilirubinemia, encephalopathy, ascites – refer to transplant center Active depression, suicidal ideation – can treat with successful psychiatric care. Elevated Cr – consider PegIFN alone as treatment Liver decompensation = coagulopathy, hyperbilirubinemia, encephalopathy, ascites – refer to transplant center Active depression, suicidal ideation – can treat with successful psychiatric care. Elevated Cr – consider PegIFN alone as treatment

18. Treatment of Disease –Risk > Benefit Sarcoidosis Active, uncontrolled autoimmune conditions systemic lupus erythematosus rheumatoid arthritis Sarcoidosis due to increased risk of disease exacerbation with IFN therapy Lupus or RheumatoidSarcoidosis due to increased risk of disease exacerbation with IFN therapy Lupus or Rheumatoid

19. Hepatitis C Screening Genotyping & Hep C VL are helpful in predicting response to therapy 1 ( & 4) is more refractory to treatment If VL < 800,000 IU/mL, Geno 1 easier to treat 2 & 3 are very responsive Attempt to get CD4>200 with ART Pts with CD4% > 25% are more likely to have SVR Preg. test unless hysterectomy or tubal ligation CBC, Platelet, CMP/Lipid, PT with INR, PTT TSH (autoimmune thyroiditis potential complication of therapy)

20. Hepatitis C Screening Rule out other causes of liver disease if liver enzymes are abnormal Auto-immune hepatitis (ANA, AMA, ASMA) Biliary disease (ultrasound of liver) Hemochromatosis (Ferritin, Iron, TIBC, %Sat) Insulin level1(EACS Guidelines) HOMA IR score at http://www.dtu.ox.ac.uk/homa Insulin resistance reported as neg. predictor to achieve SVR Baseline ECG if hx. pre-existing cardiac ds. or = 50 y/o If significant risk of CV disease stress testing recommended If significant risk of CV disease stress testing recommended

21. Look for Complicationsof Chronic Hepatitis Alpha-fetoprotein alone not enough to screen for HCC Abd. US to r/o mass lesion, ascites, organomegaly Liver biopsy? Gold standard in evaluating hepatitis and cirrhosis—how “close” to cirrhosis is your patient? Fibrosure™ & Fibroscan™ not validated in HIV yet, but non-invasive measures of fibrosis Cannot rule our concurrent diseases Over-diagnoses fibrosis Fibrosure™ may be affected by elevated bilirubin due to atazanavir or indinavir Surveillance for HCC from American Association for the Study of liver Diseases (AASLD) guidelines= For HCV infected patients with cirrhosis, Ultrasound liver every 6-12 months. If US not available, AFP testing is suggested. NOTE: only HCV-infected patients with cirrhosis or advanced fibrosis have an indication for screening because the risk of HCC is very low in patients without cirrhosis. (Current Hepatitis Report; Special Populations; Hepatitis C and Hepatocellular Carcinoma; Leach, et.al. ;page 88; Low grade liver fibrosis – option to observe and not treat (F0-F1) Non-invasive tests (transient elastography (TE, Fibroscan), the SHASTA score, or combination of both) can be used initially, and IF NEGATIVE for fibrosis, observation may be reasonable. Tx warranted if METAVIR fibrosis stage is greater than F2, reserving liver biopsy for indeterminate results. (Current Hepatitis Report; Special Populations; Viral Hepatitis in Patients with HIV Infection; Dieterich, et.al. ;page 108. Surveillance for HCC from American Association for the Study of liver Diseases (AASLD) guidelines= For HCV infected patients with cirrhosis, Ultrasound liver every 6-12 months. If US not available, AFP testing is suggested. NOTE: only HCV-infected patients with cirrhosis or advanced fibrosis have an indication for screening because the risk of HCC is very low in patients without cirrhosis. (Current Hepatitis Report; Special Populations; Hepatitis C and Hepatocellular Carcinoma; Leach, et.al. ;page 88; Low grade liver fibrosis – option to observe and not treat (F0-F1) Non-invasive tests (transient elastography (TE, Fibroscan), the SHASTA score, or combination of both) can be used initially, and IF NEGATIVE for fibrosis, observation may be reasonable. Tx warranted if METAVIR fibrosis stage is greater than F2, reserving liver biopsy for indeterminate results. (Current Hepatitis Report; Special Populations; Viral Hepatitis in Patients with HIV Infection; Dieterich, et.al. ;page 108.

22. 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 Look for Complicationsof Chronic Hepatitis CHC is associated with risk of developing chronic kidney diseases such as cryoglobulinemia, membranoproliferative glomerulonephritis and membranous glomerulonephritis which can increase the risk of developing ESRD. (Current Hepatitis Report; Special Populations; Hepatitis C in Patients with Chronic Kidney Disease: Course and Management; Hu, et.al. ;page 96) Cryoglobulinemia: Vasculitis, kidney disease (hematuria & proteinuria due to deposition of proteins in the kidney), arthralgia, arthritis, itching, fatigue, pain, lymph node enlargement, peripheral neuropathy, stomach pain, bleeding disorders. Total Qualitative Urine Protein, 24 hourCHC is associated with risk of developing chronic kidney diseases such as cryoglobulinemia, membranoproliferative glomerulonephritis and membranous glomerulonephritis which can increase the risk of developing ESRD. (Current Hepatitis Report; Special Populations; Hepatitis C in Patients with Chronic Kidney Disease: Course and Management; Hu, et.al. ;page 96) Cryoglobulinemia: Vasculitis, kidney disease (hematuria & proteinuria due to deposition of proteins in the kidney), arthralgia, arthritis, itching, fatigue, pain, lymph node enlargement, peripheral neuropathy, stomach pain, bleeding disorders. Total Qualitative Urine Protein, 24 hour

23. Talking to Your Patient: Benefits & Goals of Treating Chronic Hepatitis C 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 Enhanced immune reconstitution? Increases survival

24. Hepatitis C Drugs IFN a-2b, PEG IFN a-2b Schering-Plough Intron A™, PEGIntron A™ ribavirin (Rebetol™) INF a-2a, PEG INF a-2a Roche Roferon-A™, PEGASYS® ribavirin (Copegus™) 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 PEG-Intron/Rebetol was approved by the EU in 2007 for use in co-infected patients based on RIBAVIC study confirming its efficacy vs. Intron A/Rebetol. 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 PEG-Intron/Rebetol was approved by the EU in 2007 for use in co-infected patients based on RIBAVIC study confirming its efficacy vs. Intron A/Rebetol.

25. In studies, sustained viral remission w/ newer treatments: PEG ?IFN + ribavirin Genotype 1 & 4 (~ 30 -70% SVR) Genotype 2 & 3 (>80% SVR) SVR with PEG ?IFN + ribavirin reduces cirrhosis, HCC, transplant, death by 9-fold HIV disease is not affected by ?IFN or ribavirin Talking to Your Patient: Benefits & Goals of Treating Chronic Hepatitis C

26. Talking to Your Patient: Risks, Problems, & AdverseEffects of Treating ChronicHepatitis 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 serious infections autoimmune disease thyroid, diabetes hair loss, oral ulcers pulmonary fibrosis Stevens-Johnson, hypersensitivity

28. Hepatitis C Treatment Toxicities 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

29. Talking to Your Patient: Major contraindications: pregnant or planning Suicidal ideation untreated/severe depression or psych disease significant ischemic cardiovascular disease decompensated cirrhosis before/during treatment Hemoglobinopathy (thalassemia/sickle cell) significant asthma, lung disease malignancy end-stage renal disease

30. Talking to Your Patient: 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) Delay or reconsider treatmentDelay or reconsider treatment

31. Talking to Your Patient: Best Odds and Best Reasons to Treat Stable HIV disease with intact immune function (to eradicate virus, delay cirrhosis/HCC) Advanced hepatic fibrosis (to delay cirrhosis/HCC) Starting HAART (to limit HAART interruptions by hepatotoxicity )

32. Which to Treat First? HIV or HCV? CD4 < 350 ? treat HIV Higher risk of HIV morbidity/mortality Lower chance of SVR with lower CD4 counts CD4 > 350 ? treat HCV HCV response is better @ higher CD4s lower pressure to start HAART possibly avoid HAART interruptions due to hepatotoxicity

33. Talking to Your Patient: Other Issues ex-IDU & needle-aversions, needle-fixations… in-office treatment is reasonable for weekly injections

34. Ribavirin Interacts with HAART

35. Other HAART Considerations with Hepatitis C

36. Treatment of HCV co-infection PEG IFN a-2a [PEGASYS ®] (fixed 180 mcg) or a-2b [PegIntron™] (wt-based 1.5 µg/kg)* subcutaneously every week + Ribavirin 1000 mg (wt. <75 kg) -1200mg mg (wt. >75 kg) all genotypes1. Duration all genotypes is 48 weeks.2

37. Defining Success RVR = Rapid viral response (undetectable VL) at week 4 predicts SVR EVR = Early viral response, 12 week viral load is undetectable or decreased by 2 log10 ETR = End of treatment response, undetectable viral load at end of treatment SVR = Sustained viral response, undetectable 6 or more months after therapy

38. Defining Response in HIV/HCV Lack of Early Virologic Response (<2 log10 IU/mL ? HCV VL from baseline or undetectable) at wk 12 predictive of virologic failure. (<3% chance SVR) Current guideline: discontinue treatment if EVR not seen If HCV undetectable @ 12 weeks (EVR) ? continue If HCV undetectable @ end of tx (ETR) ? repeat @ 72 weeks if still undetectable ? SVR!! Monitor q 6-12 mo X 1-5 years

39. HCV Treatment Genotype 1 or 4 who achieve EVR, but not RVR might benefit from extended (60-72 weeks) of therapy1 Genotype 2 or 3 with HCV VL <400,000 & mild fibrosis who achieve 4 week RVR may only need 24 wk treatment2 1www.hivandhepatitis.com/hiv_co_inf/2007/060107_a.html 2EACS guidelines; Rockstroh, et.al.; HIV Medicine (2008), 9, 82-88.

40. Prescreening Prescreening tests: HCV VL & genotype serum or urine ß HCG serum TSH serum ANA, AMA, ASMA iron, ferritin, TIBC, %Sat HAV & HBV serology CBC & differential, platelets PT, PTT fasting CMP/ lipid/ insulin Alpha-feto-protein Ophthalmology ECG &/or exercise tolerance test Liver US & biopsy (latter not requirement of treatment) Depression screen Prophylactic antidepressant therapy

41. Monitoring During Treatment Monitoring: Monthly CBC & diff (& @ 2 weeks of start) Comprehensive metabolic profile serum or urine ß HCG HCV RNA PCR @ 4, 12, 24, 48, & 72 weeks Every 12 weeks serum TSH Ophthalmology exam @ 2 , 6, 12, 24, and 48 weeks Routine HIV monitoring lab as indicated Depression screenings regularly

42. Managing Adverse Effects Avoid dose reductions where feasible Moderate depression ?PEG IFN a-2a [PEGASYS®] to 135 mcg and further ? to 90 mcg may be needed ? PEG IFN a-2b [PegIntron™] by 50% Severe depression or suicidal – D/C Treatment! HIV and Hepatitis Coinfections, Management & Treatment Guidelines; Raymond Johnson, M.D., Ph.D; www.hcvadvocate.org

43. Managing Adverse Effects

47. Managing Adverse Effects ?ALT above baseline (progressive or with ? bili) Dose reduce IFN as in Depression dose adjustment. If progressive ?, stop tx. Premedicate midday of PEG IFN injection Ibuprofen 600 mg or Acetaminophen 500 - 650 mg, then one with dinner and hs. Thereafter one tid prn. No more than 2000 mg of acetaminophen in 24 hours though. Diphenhydramine (Benadryl®) 25 mg tablet, one or two at bedtime day of injection prn Transient elevations in ALT (2-fold to 5-fold above baseline) were observed in some patients receiving PEGASYS, including patients with virologic response. Transient elevations were not associated with deterioration of other liver function tests. However, when the increase in ALT levels is progressive despite dose reduction or is accompanied by increased bilirubin, therapy should be discontinued Transient elevations in ALT (2-fold to 5-fold above baseline) were observed in some patients receiving PEGASYS, including patients with virologic response. Transient elevations were not associated with deterioration of other liver function tests. However, when the increase in ALT levels is progressive despite dose reduction or is accompanied by increased bilirubin, therapy should be discontinued

48. Managing Adverse Effects Insomnia Doxepin (Sinequan) 10 mg tablets1-2 po hs prn sleep; may increase by one tab daily up to 5/day prn sleep Note: if insomnia persists taper up in 25 mg increments to 150 mg q hs.

49. Managing Adverse Effects Considerations for treating depression: Citalopram (Celexa) 20-40 mg po daily Escitalopram (Lexapro) 10-20 mg po daily Fluoxetine (Prozac) 20-40 mg po daily Sertraline (Zoloft) 50-200 mg po daily Paroxetine (Paxil) 10-50 mg po daily

50. Managing Adverse Effects Nausea: Dronabinol (Marinol) 2.5-10 mg po bid for RBV induced nausea Or Premedicate with 12.5-25 mg promethazine (Phenergan) or 5-10 mg prochlorperazine (Compazine)

51. What if ESLD develops? Liver transplantation may be a viable option in selected HIV+ individuals Experimental, outcomes similar to HIV-/HCV+ need good HIV control, adherence HCV recurrence is common in new liver re-treatment x 3 months after transplant 5-year survival is 51% (vs.81% in HIV-/HCV+) 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.

52. Key Points about HCV/HIV

53. The Future of HIV/HCV? Longer courses of pegylated INF + ribavirin 72 weeks (indefinite maintenance found of ? benefit in HIV/HCV who relapse) maximize ribavirin dose Non-invasive fibrosis markers? eltrombopag for thrombocytopenia? HCV protease & polymerase inhibitors? Liver transplantation?...

55. CHRONIC ACTIVE HEPATITIS B

56. Hepatitis B Hepatitis B sex, perinatal, IDU, 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%

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

58. Hepatitis B & HIV 7 genotypes [A?G] (data evolving) Genotype A Most common in HIV/HBV in U.S.– 75% may respond best Genotype G least common – 25% marker of rapid fibrosis Chronic hepatitis B does not change mortality Additional data on relationship between genotype and treatment outcome needed before routine genotyping of Hep B is indicated. Chronic hepatitis B does not change mortality Additional data on relationship between genotype and treatment outcome needed before routine genotyping of Hep B is indicated.

59. Serology of 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

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

61. Hepatitis B & HIV: “Occult” HBV may account for acute hepatitis in: HAART initiation/immune reconstitution Immune suppression (CD4? or chemo-tx) probably need HBV vaccine Poor amnestic response, ~ HBcAb – most common in HIV/HCV/HBV Chronic hepatitis B does not change mortality Chronic hepatitis B does not change mortality

62. Who to treat? Patient needs ART – treat the Hepatitis B regardless of Hep B VL level. If ART not required, then treatment is same as for HBV monoinfected patients. Chronic Hep B defined if HBV VL present greater than or equal to 6 months.Chronic Hep B defined if HBV VL present greater than or equal to 6 months.

63. When to treat? HBV VL + = 6 months Anti-HBV treatment indicated if ? ALT and HBV DNA level > 20,000 IU/mL if HBeAg-positive 2,000 IU/mL if HBeAg-negative Some experts treat any level of HBV DNA especially if ALT is ? or if significant inflammation &/or fibrosis on biopsy

64. Screening Evaluations CBC with platelet LFTs, PT/INR Hepatitis Delta Antibody AFP Liver Ultrasound Pregnancy test ECG and TSH if considering IFN What about Delta HepatitisWhat about Delta Hepatitis

65. Treatment Options

67. Entecavir (Baraclude®) caused M184V mutation in patient when used as monotherapy. Can cause hepatomegaly and lactic acidosis Adefovir (Hepsera®) has not caused HIV mutatation (similar structure to TDF) 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 telbivudine (Tyzeka®) nucleoside analog more effective than lamivudine, adefovir may consider for combination therapy? Not active if lamivudine-resistant HBV; monotherapy not recommended no HIV-1 activity, no apparent NRTI antagonism in vitro, but no data in HIV+ Canadian gov’t warning: peripheral neuropathy with INFsEntecavir (Baraclude®) caused M184V mutation in patient when used as monotherapy. Can cause hepatomegaly and lactic acidosis Adefovir (Hepsera®) has not caused HIV mutatation (similar structure to TDF) 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 telbivudine (Tyzeka®) nucleoside analog more effective than lamivudine, adefovir may consider for combination therapy? Not active if lamivudine-resistant HBV; monotherapy not recommended no HIV-1 activity, no apparent NRTI antagonism in vitro, but no data in HIV+ Canadian gov’t warning: peripheral neuropathy with INFs

68. When to Treat & with What Ready for HAART? lamivudine or emtricitabine/tenofovir backbone indefinite tx FLARES with stopping meds or onset of YMDD resistance — USE CAUTION Not ready for HAART? Consider PEG aINF 2a x 48 weeks advanced fibrosis HIV/HBV/HCV improves fibrosis may clear virus Adefovir X 48 weeks Consider earlier HAART w/ HBV-active agent (telbivudine?) 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

69. Pairs to Avoid emtricitabine + lamivudine adefovir + tenofovir (closely related with similar resistance profiles) emtricitabine or lamivudine + telbivudine (shared resistance profiles) Adefovir and tenofovir are closely related drugs with similar resistance profiles. emtricitabine or lamivudine + telbivudine have shared resistance profile mutations. Adefovir and tenofovir are closely related drugs with similar resistance profiles. emtricitabine or lamivudine + telbivudine have shared resistance profile mutations.

71. Serology in Chronic HBV, cont. YMDD mutation (M204V/I) = lamivudine resistance 1000x rise in resistance Up to 90% resistance @ 4 years lamivudine Increased risk for entecavir resistance in presence of these mutations (monitor closely) Treatment option: Replace 3TC/FTC with TDF or ADF or pegIFN

72. Treatment Duration Treated when not on ART/HBeAg+/and become HBeAg – and eAB +, treat 6-12 mos beyond eAg seroconversion. Some would continue treatment indefinitely All pts on ART when HBV treated need to continue on HBV treatment even if seroconverted to anti-HBe

73. Last words aboutHepatitis B, C & HIV Liver transplantation may be a viable option in selected HIV+ individuals Experimental, outcomes similar to HIV-/HCV+ need good HIV control, adherence HCV recurrence is common in new liver re-treatment x 3 months after transplant 5-year survival is 51% (vs.81% in HIV-/HCV+) 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.

74. Last words: Hepatitis A, B, C & HIV Prevention is KEY Screen & vaccinate early Lower CD4s ? lower antibody response CD4 < 200 ~15-40% antibody CD4 >500 ~ 90% antibody ?Re-vaccinate w/ double-dose (50.7% response in previous non-responders in Dutch prospective open-label study) Counsel about risk factors

75. Last words: Hepatitis A, B, C & HIV Remember to monitor if chronic ongoing infection is the outcome of treatment or if patient not candidate for treatment Yearly ultrasound of liver AFP yearly Liver biopsy q 2-3 years Hepatitis B patients need ongoing coverage lifelong in setting of CAH B