1. HIV and Hepatitis Co-infection Lucille Sanzero Eller, PhD, RN Associate Professor Rutgers, The State University of New Jersey College of Nursing A Local Performance Site of the NY/NJ AETC September 2009

2. Objectives (1) 1. Describe transmission, signs and symptoms of Hepatitis A. 2. Describe transmission, signs and symptoms, testing, and treatment of Hepatitis B.

3. Objectives (2) 3. Describe transmission, signs and symptoms, testing, and treatment of Hepatitis C. 4. Discuss education of HCV infected patient.

4. Viral Hepatitis Viruses that cause hepatitis include hepatitis A, B, C, D, E, F and G. Over 90% of hepatitis is caused by viruses A, B or C.

5. Hepatitis A Virus (HAV) Transmitted through contact with fecal matter containing the virus Causes acute hepatitis; symptoms include – fever – malaise – anorexia – nausea – abdominal pain – dark urine – jaundice

6. Hepatitis A Virus (HAV) Signs and symptoms usually last <2 months 10% to 15% of those infected have prolonged or relapsing disease (lasts 6-9 months) Once recovered, those who have had HAV are immune to the disease

7. Hepatitis B Virus (HBV) (1) Most common hepatitis virus A DNA virus from the Hepadnaviridae family Transmitted through exposure to infected blood and body fluids – perinatal – percutaneous – sexual

8. Hepatitis B Virus (HBV) (2) Replication begins with attachment to hepatocytes Covalently closed circular DNA (CCCDNA), the template for the eventual production of new virus particles, is synthesized HBV can evade the innate immune response; HBV specific T-cells and trace amounts of HBV DNA in hepatocytes persist many years after recovery from acute HBV

9. Hepatitis B Virus (HBV) (3) Symptoms occur in about 70% of patients within 9-21 weeks after exposure to HBV, and include – fever – malaise – anorexia – nausea – abdominal pain – dark urine – jaundice

10. Hepatitis B Virus (HBV) (4) Chronic HBV infection (5-10% of those infected) can cause cirrhosis, hepatocellular carcinoma (HCC), and liver failure The CDC estimates that 1.25 million people in the United States are infected with HBV HBV vaccine, available since 1982, is recommended for all age groups to prevent HBV

11. HIV/HBV Co-infection Those co-infected 3 to 6 X more likely to develop chronic HBV than if monoinfected with HBV. Since HBV genetic material remains in human cells, the virus may be reactivated as immune function deteriorates. About 25% of people with chronic HBV develop liver damage including cirrhosis or HCC; rate of liver damage is higher and hepatitis B disease progression is more rapid in those with HIV/HBV.

12. Hepatitis C Virus (HCV) (1) A single-stranded ribonucleic (RNA) virus Flaviviridae family 6 major subtypes; with genotype 1 responsible for more than 70% of infections in U. S. Most common bloodborne infection in the U.S. There is no vaccine for HCV

13. Hepatitis C Virus (HCV) (2) 1.8% of Americans (3.9 million) infected with HCV; most (2.7 million) are chronically infected (50-80% of those infected) (CDC, 2006) Prevalence estimated from the third National Health and Nutrition Examination Survey – civilian, non-institutionalized U.S. population NHANES III survey did not include incarcerated, homeless – these groups have high prevalence of HCV, so estimate is conservative

14. Hepatitis C Virus (HCV) (3) 80% of those infected are asymptomatic 50-80% of immunocompetent people who become infected become chronically infected

15. Hepatitis C Virus (HCV) (4)  Among the chronically infected – 60% to 70% develop chronic hepatitis – 10% to 20% develop cirrhosis over a period of 20-30 years – 1% to 5% develop HCC – End-stage liver disease (ESLD) and HCC cause between 10,000 and 12,000 deaths per year in the U.S.

16. Sources of Infection with HCV (1) (CDC, 2006)

17. Sources of Infection with HCV (2)  60% of cases due to past or current IDU  60% to 80% of IDUs injecting drugs for at least 5 years are HCV infected vs. 30% of them HIV infected  Risk of HCV transmission through sexual exposure is low  However, general population’s frequency of sexual behaviors, plus prevalence of HCV, explains the high proportion (15%) of HCV transmitted through sexual exposure

18. Sources of Infection with HCV (3)  10% due to transfusion (prior to screening)  Viral inactivation techniques for clotting factors introduced in 1985 (Factor VIII); 1987 (Factor IX)  By 2001, risk of infection from a unit of transfused blood less than one per million transfused units  Currently, all immune globulin products undergo a virus inactivation procedure or test negative for HCV prior to release

19. Sources of Infection with HCV (4)  5% of cases due to  exposures from hemodialysis  employment in the health care field  birth to an HCV-infected mother 10% of cases have no recognized source of infection

20. HIV/HCV Co-infection (1)  HIV increases the levels of HCV viremia and progression to cirrhosis, liver failure and death  Risk of liver-related mortality in the co- infected is related to HIV viral load and CD4 count

21. HIV/HCV Co-infection (2)  Study compared 265 with HCV/HIV, 251 with HCV alone, 227 with HIV alone  Mortality over a 3-year period was:  17% in those HIV/HCV co-infected  9% in those with HIV alone  6% in those with HCV alone  In co-infected, mortality varied by race  Whites 31%  Blacks 15% (Merriman et al., 2006)

22. HIV/HCV Co-infection (3)  Effects of HCV co-infection on HIV progression unknown  accelerated clinical progression of HIV-1 (Mathurin et al., 1998; Tong, El-Farra, Reikes & Co, 1995)  impaired CD4-cell recovery and faster HIV disease progression in HCV co-infected patients despite their receiving ART (Grueb, 2000)  no impact on CD4 count, viral load, HIV progression or survival (Hayashi et al, 1991; Thomas et al., 1996; Mayor, 2006; Merriman et al., 2006)

23. HIV/HBV Co-infection  Mortality Rates:  14.2/1000 in HIV/HBV co-infected  1.7/1000 in HIV monoinfected  0.8/1000 in HBV monoinfected

24. HBV Testing  Recommended for specific at-risk groups  men who have sex with men  injection drug users  patients on dialysis  people with HIV  pregnant women  families, household members and sexual contacts of HBV-infected persons

25. HBV Testing- Serologic Markers (1)  Evaluation includes serologic testing for viral markers  HBsAg: hepatitis B surface antigen; indicates acute or chronic HBV infection  HBsAb: antibody to HBV surface antigen, a marker of HBV immunity  HBeAg: usually positive when HBV is present; a marker of high infectivity

26. HBV Testing- Serologic Markers (2)  Evaluation includes serologic testing for viral markers  Anti-HBc: antibody to the hepatitis B core antigen; indicates past infection, either acute or chronic  Anti-HBe: antibody to the hepatitis B e antigen. In those recovered from acute or chronic HBV infection, anti-HBe, anti-HBc and anti-HBs will be present

27. HBV Testing  HBV DNA Tests  Used in conjunction with serologic testing for patients being considered for treatment and to evaluate response to treatment  An unamplified HBV DNA assay with detection limits of 10 5 to 10 6 copies/mL is the diagnostic criterion for chronic HBV  Liver biopsy or alanine aminotransferase (ALT) are recommended to assess the degree of necroinflammation

28. HBV Treatment (1)  Goals of treatment  viral suppression  remission of liver disease

29. HBV Treatment (2)  First line treatment options  interferons  IFN-  -2a and 2b  Pegylated IFN-  -2a and 2b  nucleoside/nucleotide analogs  lamivudine  adefovir dipivoxil  entecavir  telbivudine  tenofovir

30. HBV Treatment (3)  Emtricitabine is effective against both HBV and HIV but not yet FDA approved for HBV infection  Recent data indicate that entecavir has HIV activity and should not be used as monotherapy for HBV in HIV-infected patients who are not taking other ARVs

31. HBV Treatment (4)  Indicators of adequate response to treatment  undetectable serum HBV DNA  HBeAg loss or seroconversion  improved liver histology on biopsy

32. HIV/HBV Co-infection Treatment (1)  If need to treat HIV in an HIV/HBV co- infected patient: NRTI backbone of an antiretroviral regimen could be  tenofovir + emtricitabine  tenofovir + lamivudine  Monotherapy of HBV with lamivudine, emtricitabine, or tenofovir should be avoided if possible because of risk of resistance

33. HIV/HBV Co-infection Treatment (2)  If need to treat HIV and HBV  combination of tenofovir + lamivudine or tenofovir + emtricitabine should be considered as first-choice NRTI backbones  additional options include entecavir only in combination with one of the three nucleosides with activity against both viruses  use of lamivudine, emtricitabine, or tenofovir as the only active anti-HBV agent should be avoided because of risk of HIV resistance

34. HIV/HBV Co-infection Treatment (3)  Treatment of HBV and not HIV  Pegylated interferon-alpha, one option, does not lead to development of drug-resistant HIV or HBV mutations  Adefovir dipivoxil is active against HBV but not against HIV at the 10 mg dose; however, a theoretical risk for development of HIV mutants exists, because it is related to tenofovir.  use of emtricitabine, lamivudine, or tenofovir without a full HAART regimen should be avoided because of the rapid development of drug-resistant HIV mutations

35. HIV/HBV Co-infection Treatment (4)  If there is a need to discontinue lamivudine, tenofovir, or emtricitabine  Monitor clinical course with frequent liver function tests, and consider the use of adefovir dipivoxil or entecavir to prevent flares, especially in patients with marginal hepatic reserve

36. HCV Testing  Routinely test all HIV-infected patients  First use the enzyme immunoassay (EIA) test for anti-HCV antibodies  if EIA is positive, use an HCV RNA assay to document viremia Note: Patients co-infected with HCV/HIV may have negative HCV antibody tests because of immunosuppression

37. HCV RNA Assays (1)  Used to confirm results of less sensitive HCV antibody assay  qualitative and quantitative assays to detect HCV RNA use target amplification (PCR, TMA) or signal amplification (branched DNA) techniques  HCV RNA can be used to predict and monitor response to treatment  results of different assays are not easily compared, so use same assay to monitor response to treatment

38. HCV RNA Assays (2)  HCV RNA assays can be used in those with HIV to establish HCV infection within 2 weeks of infection  HCV RNA assays can detect HCV RNA in most patients with chronic HCV

39. Liver biopsy  Recommended by most experts to stage degree of hepatic necrosis, inflammation and fibrosis  Used to determine need for HCV treatment  False negatives can occur in 10%-30% of cases (due to small size of biopsy specimens and heterogeneous distribution of liver fibrosis)

40. HCV RNA Genotyping  6 known genotypes of HCV  Genotype 1 most common in the U.S.  Use of genotyping  to determine the type and duration of treatment  to assess likelihood of response to therapy  Patients with genotype 1 have much lower rates of response to treatment than those with genotype 2 or 3

41. ALT and AST  ALT- alanine aminotransferase  AST- aspartate aminotransferase  Markers of hepatic cell damage  Not sensitive or specific markers of disease progression  Can be useful in monitoring treatment effects

42. HCV Treatment Goals  Goals of treatment for chronic HCV  Viral eradication (undetectable viral load)  Prevent progression of liver disease  Best indicator of treatment is sustained virologic response (SVR)

43. Sustained Virologic Response  Serum HCV RNA is undetectable based on a qualitative HCV RNA assay with lower limit of detection of 50 IU/mL or less at 24 weeks after treatment ends

44. HCV Treatment (1)  Combination therapy with pegylated interferon (PEG-IFN) alfa plus ribavirin is most effective treatment for HCV in patients with or without HIV; with this treatment:  50% of HCV genotype 1 monoinfected patients achieve HCV viral clearance  HCV/HIV-coinfected genotype 1 patients have a 22%-29% SVR rate if treated for 48 weeks  with other genotypes, there is a 55% SVR rate

45. HCV Treatment (2)  Ribavirin is teratogenic  Both men and women must use contraception during and for 6 months after treatment with ribavirin

46. HCV Treatment (3)  Those who are not candidates for treatment for HCV include:  those actively using alcohol  those with untreated depression  those with renal disease  those with advanced cirrhosis  pregnant women (NIH, 2002)

47. HCV Treatment (4)  Although pregnant women and persons with active alcohol use should not receive HCV treatment, certain individuals with renal disease, depression, injection drug use, and lower degrees of hepatic fibrosis can be considered for HCV treatment

48. Considerations in HCV Treatment (1)  Ribavirin should not be given with didanosine; drug-drug interactions can cause pancreatitis and lactic acidosis  Some NRTIs and all NNRTIs and PIs can be hepatotoxic, so transaminase levels should be monitored (Panel on Clinical Practices for Treatment of HIV Infection, 2008)

49. Considerations in HCV Treatment (2)  Higher rates of anemia are associated with zidovudine combined with ribavirin  Growth factors may be needed manage IFN- associated neutropenia and ribavirin- associated anemia (Panel on Clinical Practices for Treatment of HIV Infection, 2008)

50. Considerations in HCV Treatment (3)  In HIV/HCV co-infected  Decision when to initiate HCV treatment is case by case  Initiating HIV treatment first can increase CD4 counts, may improve response to HCV therapy  Initiating HCV treatment first (in those with high CD4 counts and low viral load) can simplify treatment and improve ART tolerability

51. HCV Patient Education (1)  To avoid infecting others avoid sharing:  toothbrushes  dental appliances  razors  sex toys  tattoo equipment  injection equipment  personal care items that may have blood on them  Educate and encourage use of safer sex practices

52. HCV Patient Education (2)  Recommend alcohol abstinence before and during antiviral therapy  Alcohol is a cofactor in progression of liver disease to cirrhosis and HCC  Alcohol use during therapy adversely affects response to treatment  Assess readiness and refer to alcohol treatment if appropriate

53. HCV Patient Education (3)  Assess readiness and counsel regarding drug treatment programs if using injection drugs  If drug treatment is not an option, provide risk reduction education  cleansing of injection equipment  provide patient with a source of clean, single- use needles if possible

54. HCV Patient Education (4)  Instruct to avoid exposure to hepatotoxins, including hepatotoxic medications (eg, acetaminophen in large doses, fluconazole, and isoniazid)  Instruct to consult a health care professional before taking any new medicines, including over-the-counter, alternative or herbal products

55. HCV Patient Education (5)  Instruct to avoid exposure to environmental toxins  solvents  paint thinners  pesticides  If using toxic chemicals  work in a well-ventilated area  wear gloves  wear a protective face mask

56. HCV Patient Education (6) If patient is pregnant or considering pregnancy, discuss ways to decrease the infection risk for the baby

57. HCV Patient Education (7) Recommended Vaccinations:  Anyone with HCV should be tested for immunity to HAV and HBV; those not immune should receive the vaccines  All persons with chronic liver disease should be vaccinated annually against influenza and should receive pneumoccocal vaccine

58. HCV Patient Education (8)  Side effects of interferon (fatigue, depression, confusion) can interfere with appointment and medication adherence  Provide support to maximize adherence  Conduct ongoing assessments and treat and refer as needed for depression

59. HCV Patient Education (9)  To reduce adverse effects instruct patients to:  increase fluid intake  eat small, frequent, well-balanced meals  exercise as tolerated  get adequate sleep and rest  avoid crowds to prevent infection  take interferon injections before going to bed so will sleep through some of the adverse effects

60. Key Points (1) 1. Hepatitis A is transmitted through contact with infected fecal matter. 2. Hepatitis B and C are transmitted through exposure to infected blood and body fluids. 3. Chronic HBV (5-10% of those infected) and chronic HCV infection (50-80% of those infected) can cause cirrhosis, HCC and liver failure.

61. Key Points (2) 4. HBV Testing i. serologic testing for viral markers recommended for  men who have sex with men  injection drug users  patients on dialysis  people with HIV  pregnant women  families, household members and sexual contacts of HBV-infected persons

62. Key Points (3) 4. HBV Testing (cont.) ii. HBV DNA tests used for patients being considered for treatment and to evaluate response to treatment iii. Liver biopsy and ALT to assess degree of necroinflammation

63. Key Points (4) 5. HBV Treatment A. First line treatment options 1) Interferons 2) Nucleoside/nucleotide analogs B. Indicators of adequate response 1) undetectable serum HBV DNA 2) HBeAg loss or seroconversion 3) improved liver histology on biopsy

64. Key Points (5) 6. HCV Testing i. Test all HIV+ patients ii. Use EIA for anti-HCV antibodies iii. If EIA positive, confirm with HCV RNA assay to document viremia iv. HCV genotying to determine type/duration of treatment v. Liver biopsy to determine need for treatment

65. Key Points (6) 7. HCV Treatment i. PEG-IFN alfa plus ribavirin ii. Educate patients and assess readiness for treatment i.avoid infecting others ii.avoid alcohol and drugs iii.avoid hepatotoxins iv.receive HAV and HBV vaccines