HBV/HCV COINFECTIONS IN PATIENTS WITH HIV. Dr Reena Harania MBBS, MRCP, MSc Infectious Disease

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1 HBV/HCV COINFECTIONS IN PATIENTS WITH HIV Dr Reena Harania MBBS, MRCP, MSc Infectious Disease

2 Adults and children estimated to be living with HIV as of end 2005 North America 1.2 million [ million] Caribbean [ ] Latin America 1.8 million [ million] Western & Central Europe [ ] North Africa & Middle East [ million] Sub-Saharan Africa 25.8 million [ million] Eastern Europe & Central Asia 1.6 million [ million] East Asia [ million] South & South-East Asia 7.4 million [ million] Oceania [ ] Total: 40.3 million 25.8 million in Sub-Saharan Africa Kenya Prevalence 6.7%

3 Geographic Distribution of Chronic HBV Infection HBsAg Prevalence 8% - High 2-7% - Intermediate <2% - Low CDC

4 Hepatitis C: A Global Health Problem Million (M) Carriers Worldwide United States 3-4 M Americas M Western Europe 5 M Africa M Eastern Europe 10 M Far East Asia 60 M Southeast Asia M Australia 0.2 M World Health Organization. Weekly epidemiological record. 1999;74:

5 HIV/HBV/HCV TRANSMISSION Virus Means of transmission HIV Hepatitis B Hepatitis C Sexual, Vertical, Blood transfusion, IDU, traditional procedures Sexual, mother-to-child, blood exposure (transfusion, IDU, tattoo) Blood exposure (transfusion, IDU, tattoo); sexual, mother-to-child less common

6 VCT clients Karuru, Lule et al SUB GROUP HCV HIV HIV-HCV coinfection Blood donors 0.79% 1.07% 0.02% Clinical Hosp Staff 5.2% - - Non-clinical Hosp Staff 2.5% - - HIV/AIDS patients 3.7% 3.7% HIV-ve patients 4.4% - -

7 HCV Lule et al in 1995 found the prevalence rate of HCV to be 2.8% among patients with chronic liver disease in Kenyatta National Hospital. Mwangi (1998), found a prevalence rate of 1.8% in blood donors.

8 Pregnant women in Kenya HBV 2241 pregnant women enrolled 9.3% HepBsAg +ve (205) 8.8% HepBeAg +ve Okoth FA, Mbuthia J et al EAMJ, 2006

9 HBV Ogotu et al, in 1990, found that 12.2% of 40 consecutive patients with AIDS were HBsAg positive, 24.4% were HBsAb positive and 75.6% were HBcAb positive This is in comparison with 6-10% HBsAg positivity in the general population.

10 A OTEDO Screened patients with jaundice-519 Excluded 185 other causes Recruited % HBV +ve HIV-ve 53% HBV +ve HIV+ve

11 HBV infection is much more common than HCV in Kenya and globally

12 OBJECTIVES To determine the prevalence of HCV and HBV infection among HIV/AIDS patients presenting to AKUH, Nairobi To identify possible risk factors To assess response of Co-infections to HAART

13 WHY? Share transmission routes Interactions of viruses Treatment decisions Drug interactions

14 Hepatitis C HIV/ HCV COINFECTION 10%-30% w HIV also have HCV (Western data) Rate of HCV depends on risk factor Hemophiliacs >90% IDUs 70%-90% MSM 5%-10%

15 HCV/HIV Coinfection HIV accelerates Hep C liver disease (may cut time to cirrhosis in half!) Hep C may impair immune reconstitution after HAART HCC may occur at an earlier age with coinfection

16 Hepatitis C HIV/ HCV COINFECTION HCV liver disease is more severe in HIV+ HCV liver disease is now more important HIV deaths are decreasing Deaths related to liver disease are increasing Effect of HCV infection on HIV/AIDS progression is not known

17 Drug interactions in Coinfection ddi and d4t plus interferon/ribavirin appear to cause mitochondrial toxicity result: lactic acidosis, peripheral neuropathy Avoid starting these drugs if plan to treat HCV later

18 10-20 years Natural History of Hepatitis C Most patients with chronic HCV infection are asymptomatic Acute Hepatitis C Chronic Hepatitis 75%-85 % Cirrhosis 20 % Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S Di Bisceglie, Hepatology, 2000

19 Hepatitis B CDC Acute and chronic forms 2-10% develop chronic disease over 5 years of age Asymptomatic or symptomatic Clinical illness <5 yrs of age: <10% (jaundice) >5 yrs of age: 30%-50% Incubation: days Average days Most common cause of cirrhosis and hepatocellular carcinoma worldwide

20 Risk of Chronic Disease if Untreated/Unvaccinated Neonates % HBsAg + Children 20-40% HBsAg + Adults <5% HBsAg + Nearly 40% of children with chronic hepatitis B will develop end-stage liver disease in years Peters M 9 th CROI Seattle, 2002

21 Hepatitis B Serologies HBsAg acute disease or chronic carrier HBsAb: past infection or vaccinated Hbcore Ab (HBcAb) IgM: acute infection HBcore Ab total: past infection Combined IgM & IgG serology

22 Hepatitis B(e) Serologies HBe Ag: more infectious HBe Ab: less infectious Marker of treatment response Determines treatment duration

23 Acute Hepatitis B Virus Infection: RECOVERY Symptoms HBeAg HBe Ab Titer Core Total Ab HBs Ag Core IgM HBs Ab Weeks after Exposure CDC

24 Chronic Hepatitis B Virus Infection Acute (6 months) HBeAg Chronic (Years) anti-hbe HBsAg Titer Core Total Ab IgM anti-hbc Years Weeks after Exposure CDC

25 HIV Co-infection Increases the Risk of ESLD due to HBV MACS, 4,967 men HIV, 47% HBV, 6% (n=326) HIV/HBV, 4.3% (n=213) 15 Liver Mortaility by HIV and HBV Status 14.1 HIV/HBV: 17-fold higher risk of liver death compared to HBV alone Alcohol Low CD4 Increased risk after No HIV or HBV 0.8 HBV only 1.7 HIV only HIV and HBV Thio C et al. Lancet 2002;360:9349.

26 Hepatitis B and HIV Co-infection Higher HBV DNA viral loads than with HBV alone Higher mortality with HIV co-infection Hepatic damage with uncontrolled HIV Immune reconstitution increases hepatic injury due to inflammatory response Peters M 9 th CROI Seattle, 2002

27 Chronic Hepatitis B Treatment: FDA-approved Alfa interferon; pegylated interferon Lamivudine (Epivir HB) HBV rebound possible if lamivudine stopped Adefovir (Hepsera) - active against lamivudineresistant HBV; pilot study N = 35; 5.15 log 10 decrease in viral load Mean CD cells/cmm Benhamou Lancet 2001:358 Entecavir (Baraclude) Active against lamivudine-resistant HBV

28 Dual Hepatitis B/HIV Co-infection Therapies Lamivudine (Epivir) Off-label uses Emtricitabine (Emtriva) Tenofovir DF (Viread) active against lamivudine-resistant HBV Truvada (emtricitabine/tenofovir)

29 METHODOLOGY HIV POSITIVE CONSECUTIVE PATIENTS CONSENT OBTAINED QUESTIONNAIRE FILLED RE-RISKS BLOOD OBTAINED FOR FBC LFTs CD4 VL HepBsAG HCVab

30 METHODOLOGY 2 HepBsAg +ve : HBV VL, HepBeAg HCV Viral load Started on ARVs if required

31 TOTAL RECRUITED 378 HIV ONLY % HIV/HBV 23 6% HIV/HCV 4 1%

32 Demographics: ALL PATIENTS

33 Patients with HIV/HBV Co infection

34 HIV/HBV males being co-infected is 3 times that of females, which is statistically significant 95% range of the odds ratio ranges from 1.1 to 8.3.

35 HIV/HCV

36 ETHNIC GROUPS

37 HBV/HIV CO INFECTION BY ETHNICITY

38 Distribution of the HCV patients by ethnic group. Kikuyu Luo Kamba Ugandan

39 Summary HIV positive and co-infection (HIV and HBsAg positive) HIV+ve, HBsAg-ve HIV+ve, HBsAg+ve Total P-value No. of patients <.0001 Age (yrs) Mean (±SD) 39.2(±8.15) 42.7(±9.13) 39.5(±8.30) 0.05

40 HIV/HBV BY GENDER MALE FEMALE HIV ONLY HIV/HBV P=0.024

41 HIV ONLY VERSUS HIV/HBV NO DIFFERENCE IN THE 2 GROUPS IN TERMS OF VIRAL LOAD P=0.25 CD4 COUNTS P=0.405 LFTS P=212

42 HIV ONLY VERSUS HIV/HVC ONLY 4 PTS HAD HIV/HCV COINFECTION M:F 1:3 Deranged LFTs 3 Patients with HIV/HCV infections were fewer, more females (75%), were more likely to have abnormal LFTs although none of these were statistically significant.

43 Only 1 patient admitted homosexual No intravenous drug users

44 only HIV HBV co-infection HCV co-infection P-value No. of patients 351 (93%) 23 (6%) 4 (1%) <.0001 Age (yrs) Mean (±SD) 39.2(±8.15) 42.7(±9.13) 42.5(±14.01) Logarithm of HIV Viral Load 9.3(±3.47) 9.6(±2.71) 11.0(±2.03) CD (±237) 180.6(±174.9) 292.0(±125) Gender Female 161 ( 45.87%) 5 ( 21.74%) 3( 75.00%) ( 54.13%) 18 ( 78.26%) 1( 25.00%) Male Liver Function Normal 137 ( 39.03%) 12 ( 52.17%) 1( 25.00%) ( 60.97%) 11 ( 47.83%) 3( 75.00%) Abnormal

45 CD4 counts by HBV- versus HBV+ status

46 HIV Viral Load by HIV only and HIV/HBV infections

47 Comparing only HIV infection and HBV co-infection by the risk factors only HIV HBV co-infection P-value Circumcision No 215( 61.43%) 13( 56.52%) yes 135( 38.57%) 10( 43.48%) Education primary 31( 9.54%) 0( 0.00%) secondary 105( 32.31%) 6( 31.58%) tertiary 189( 58.15%) 13( 68.42%) HepB_vaccination no 286( 81.71%) 23(100.00%) yes 64( 18.29%) 0( 0.00%) Transfusion No 293( 83.95%) 20( 86.96%) Yes 56( 16.05%) 3( 13.04%)

48 Comparing only HIV infection and HCV co-infection by the risk factors only HIV HCV co-infection P-value Circumcision No 215 ( 61.43%) 3( 75.00%) yes 135 ( 38.57%) 1( 25.00%) Education primary 31 ( 9.54%) 0( 0.00%) secondary 105 ( 32.31%) 3( 75.00%) tertiary 189 ( 58.15%) 1( 25.00%) HepB_vaccination no 286 ( 81.71%) 4(100.00%) yes 64 ( 18.29%) 0( 0.00%) Transfusion No 293 ( 83.95%) 2( 50.00%) Yes 56 ( 16.05%) 2( 50.00%)

49 HEPBsAG+ve 23 HEPBeAG+ve 17% (4) HEPBeAG-ve 83% (19) (p = ). 70 % of HEPBsAG (HBV+) patients used ARVs: 16

50 ARVs USED BY PATIENTS HIV/HBV CO INFECTION 4% 30% 40% CBV/NVP CBV/STO TRU/STO Other 26%

51 HBV viral load before and after treatment p = Before After Frequency < ,000 >10,000 Total < , >10, Total

52 TRU/STO had marked improvement in HBV viral load (p = ). Before After Frequency < ,000 >10,000 Total < , >10, Total

53 Use of TRU/STO combination against any other treatment for the HBV co-infected (p= )

54 DISCUSSION HIV/HBV COMMON 6% HIV/HBV MORE COMMON IN MALES AND GREATER THAN 35 YEARS (MAYBE MISSED PTS WITH HEP B CORE IGM +VE) HIV/HBV RESPONSE TO TREATMENT HIV/HCV LESS COMMON 1%

55 TDF/3TC more effective than 3TC alone in drug-naïve HIV/HBV co-infected Week 1 Week 2 Week 3 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 0 Change in log 10 HBVDNA from baseline Lam for 24 wks then ADD TDF TDF 245 mgod Lam and TDF 245 mgod P= Error bars are 95% CI of the slope Using DAVG analysis Nelson M, et al. 13th CROI, Denver, CO, February 5-8, Abst. 831

56 Similar Anti-HBV Activity of Tenofovir and Adefovir in Coinfected Patients Interim data from ACTG A5127: HBV/HIV-1 coinfected pts HBV DNA 100,000 Stable antiretroviral therapy; HIV-1 RNA 10,000 Reduction in HBV DNA with tenofovir noninferior to adefovir HBV DNA (log 10 ) Adefovir Tenofovir DF Peters M, et al. Abstract 124. Weeks

57 Recommendations TEST ALL HIV PAITENTS FOR HBV Coinfection VACCINATE?HCV TESTING IN OUR SET UP (COST)?TREAT WITH TNF/FTC RATHER THAN LAMIVUDINE ALONE.

58 THANK YOU

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60 Only Hbcore Ab Positive (Total IgG + IgM) HBs antigen and HBs antibody negative Common with HIV co-infection IgM component negative with chronic disease May be carrier (chronically infected), despite negative HBsAg Can distinguish by hepatitis B DNA PCR

61 Where are we now in Hepatitis B No requirement for HAART-Pegylated Interferon - Adefovir - Entecavir Requirement for HAART

62 Where are we now in Hepatitis B No requirement for HAART-Pegylated Interferon - Adefovir - Entecavir Requirement for HAART Lamivudine Failures

63 Current HBV status of HIV/HBV coinfected patients TDF+3TC TDF /21 33/42 proportion of patients (%) HBV-DNA<1000 copies/ml 12/21 24/41 6/19 12/38 4/28 1/11 ALT<45 U/L loss Hbe-antigen loss HBs-antigen

64 Criteria for Treatment American Association for the Study of Liver Diseases AST/ALT > 2 times ULN HBV DNA PCR > 100,000 c/ml Liver histology showing moderate or severe hepatitis Lok A et al. Hepatology 2004;39,(3).

65 Rebound Hepatitis Associated with removal of hepatitis B therapy Could occur inadvertently with change in HIV therapy for virologic failure Consider maintaining HIV therapy with activity against HBV when changing ART

66 Incidence of LAM Resistance in HBV and HBV/HIV Patients 100% HIV negative HIV positive 90% 80% 67% 60% 40% 20% 20% 38% 47% 49% 0% Benhamou et al., Hepatology, 1999)

67 Hepatitis C HIV/ HCV COINFECTION HIV treatments can cause liver problems/liver enzyme elevations In some studies these liver problems are increased in those w/hcv Some report worsening of HCV liver disease after HIV treatment is started

68 Chronic Hepatitis B 10-20% will develop cirrhosis 25% of these will develop decompensated liver disease 6-15% of those with chronic disease will develop hepatocellular carcinoma HBV not directly cytopathic to hepatocytes The host immune response causes much of the damage Peters M 9 th CROI Seattle, 2002

69 Risk factors for Hepatitis C infection 10% 10% 20% 5% 55% IVDU Cocaine Exposure to infected sex partner or multiple partners Occupational, hemodialysis, household, perinatal No recognized source modes; 2000