HIV/HBV co-infection Les Liasions Dangereuses Sanjay Bhagani Infectious Diseases/HIV Medicine Royal Free Hospital Sanjay Bhagani, Royal Free Hospital, London Reena Shah, AKUH, Nairobi
Liver Related Mortality in HIV Infected Patients in HAART Era Liver Related Mortality (%) 60 50 40 30 20 10 0 (16/46) 35% (35/305) (3/26) 50% 13% 14% 11.5% 1 (11/22) (15/312) 4.8% 45% Pre-HAART Post-HAART (21/1426) 1.5% (38/265) Brescia, Italy Boston, USA Madrid, Spain Germivic, France (9/20) 2 3 4 1 Puoti, et al. J AIDS. 2000;24: 211-217. 2 Bica I, et al. Clin Infect Dis. 2001;32:492-497. 3 Soriano V, et al. Eur J Epidemiol. 1999;15:1-4. 4 Rosenthal E, et al. AIDS. 2003;17:1803-1809.
Prevalence of HBV: Global Estimates HBsAg Prevalence High ( 8%) Intermediate (2% to 8%) Low (<2%) Taiwan Vietnam China Africa Philippines Thailand Japan Indonesia South Korea India Russia US HBsAG +ve, % 10.0 13.8 5.7 10.0 5.3 12.0 5.0 19.0 5.0 16.0 4.6 8.0 4.4 13.0 4.0 2.6 5.1 2.4 4.7 1.4 8.0 0.2 0.5 Mast EE, et al. MMWR Recomm Rep. 2006;55:1 33 Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):s158-s168
HBV/HIV co-infection Prevalence 40% 35% 30% 25% 20% 15% 10% 5% 0% EUROSIDA (HBsAg) Australia Australia (anti-hbc) MACS (HBsAg) RFH (HBsAg) N.Europe C.Europe S.Europe E.Europe
Global HIV/HBV Thio, C. Hepatology 2009; 49(5): s138
AKUH HIV and viral hep co-infection study Reena Shah et al, AIDS 2008 HIV POSITIVE CONSECUTIVE PATIENTS CONSENT OBTAINED QUESTIONNAIRE FILLED RE-RISKS BLOOD OBTAINED FOR FBC LFTs CD4 VL HBsAg HCV-ab HBsAg +ve : HBV VL, HBeAg HCV Viral load Started on ARVs if required
Total Recruited 378 HIV ONLY 351 93% HIV/HBV 23 6% HIV/HCV 4 1%
HIV and hep B/C coinfection Local scenario: 378 HIV-infected in- and outpatients 6% 1% 378 HIV infected in- and out patients 93% hep B hep C no coinfection Harania RS AIDS 2008 Harania RS AIDS 2008
Patients with HIV/HBV Co infection
HIV ONLY VERSUS HIV/HBV NO DIFFERENCE IN THE 2 GROUPS IN TERMS OF VIRAL LOAD CD4 COUNTS LFTS P=0.25 P=0.405 P=0.212
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%) 0.640 yes 135( 38.57%) 10( 43.48%) Education primary 31( 9.54%) 0( 0.00%) 0.343 secondary 105( 32.31%) 6( 31.58%) tertiary 189( 58.15%) 13( 68.42%) HepB_vaccination no 286( 81.71%) 23(100.00%) 0.024 yes 64( 18.29%) 0( 0.00%) Transfusion No 293( 83.95%) 20( 86.96%) 0.703 Yes 56( 16.05%) 3( 13.04%)
HBsAg+ve 23 HBeAg +ve 17% (4) HBeAg-ve 83% (19) (p = 0.0018) 70% of HBsAg patients used ARVs: 16
ARVs USED BY PATIENTS HIV/HBV CO INFECTION 4% 30% 40% CBV/NVP CBV/STO TRU/STO Other 26%
Clinical disease and HBV/HIV co-infection
HIV/HBV Co-infection: Increased risk of ESLD due to HBV 16 P<0.0001 Liver-related Mortality Rate (per 1000 person-years) 14 12 10 8 6 4 2 P<0.001 P=0.04 0 HIV+ HBV+ HIV/HBV HIV-/HBsAg- HIV+ HBsAg+ HIV+/HBsAg+ Thio CL, et al. Lancet. 2002:360:1921-26.
HBV Replication Adapted from: Diestag, N Engl J Med, 2008
Geographical distribution of HBV genotypes A to H North Europe & USA - A Mediterranean basin - D Africa E & D E & D India A Rare types: F Latin America Far East B & C G France, USA H Mexico, Latin America
Natural history of HBV infection where does co-infection fit in? Early Childhood > 95% Immune Tolerance Adulthood < 5% HIV/HBV Increased likelihood HIV/HBV Higher Viral loads HBeAg- Chronic Hepatitis B HCC HBeAg+ Chronic Hepatitis B HIV/HBV: Increased VL Lower ALT Increased Fibrosis Inactive Carrier HIV/HBV Reduced seroconversion Chen DS, et al. J Gastroenterol Hep. 1993;8:470 475; Seeff L, et al. N Engl J Med. 1987;316:965 970
Phases of chronic HBV Marker Patient Populations in Chronic Hepatitis B Immune Tolerant (Type 1) Immune Active (Type 2) Inactive HBsAg Carrier (Type 3) HBeAg neg. CHB (Precore/Core Promoter Mutant) (Type 4) HBsAg + + + + HBeAg + + Anti-HBe + + ALT Normal Normal HBV DNA (IU/mL) Inflammation on Histology > 2x10 4 > 2x10 4 < 2x10 2 > 2x10 3 Normal/Mild Active Normal Active
African Patients RFH HIV/HBV cohort (n=79) 35% female Median age 42yrs More likely eag ve disease (OR 2.7 p=0.048) More likely advanced liver disease (F3/4) (OR 7.3 p=0.002) Similar HBV DNA levels (median = 5.74 x 10 6 c/ml) Similar response to TDF+FTC (85% < 200 IU/l at max F/U) Armenis et al, 5 th International HIV/Hepatitis Workshop 2009
When do we need to Rx HBV? Everybody with detectable HBV DNA? Based on HBV DNA levels? Those with evidence of significant liver disease? Based on abnormal ALTs? Histological activity on a liver biopsy? Other tests?
Level of HBV DNA (PCR-assays) at entry & progression to cirrhosis in a population-based cohort study 3582 HBsAg untreated asian carriers mean follow-up 11 yrs 365 patients newly diagnosed with cirrhosis 14 All Participants (n = 3582) 14 HBeAg(-), Normal ALT (n = 2923) 12 10 RR * (95% CI) 8 6 *P <.001 * 5.6 * 6.5 12 10 8 6 *P <.001 * 5.6 * 6.6 4 2 1.4 * 2.5 4 2 1.4 * 2.5 0 300 - < 10 4 10 4-10 5 10 5-10 6 HBV DNA copies/ml > 10 6 * Adjusted for age, sex, cigarette smoking, and alcohol consumption. Iloeje UH, Gastroenterology 2006; 130: 678-686 0 300 - < 10 4 10 4-10 5 10 5-10 6 > 10 6 HBV DNA copies/ml HBV-DNA viral load (> 10 4 cp/ml) strongest predictor of progression to cirrhosis independent of ALT and HBeAg status
How do we stage liver disease in HIV/HBV co-infected patients? Liver enzyme testing (ALT/AST) unreliable Liver biopsies prohibitively expensive and need access to an experienced histopathologist Non-invasive tests Serum markers combined to work out a probability index Elastometry
Why not liver enzyme testing? Lower ALT/AST in HIV/HBV coinfected patients BUT more advanced hepatic fibrosis Possible explanations Direct fibrogentic effect of HBV HIV directly stimulates stallete cells Systemic immune activation as a result of HIV hepatic fibrosis
HIV infection increases stellate cell activation 2.5 Fold change qrt-pcr 2 1.5 1 0.5 0 mock HIV IIIB gp120 mock HIV IIIB Collagen I a-sma (smooth muscle actin) Tuyama et al CROI Boston 2008
Immune activation and liver disease Cirrhosis HCV Alcohol Hepatic fibrosis HSC activation Altered portal vein circulation HIV -> GIT CD4+ T-cell depletion IL-1 TNF-a IFN-a IL-12 macrophage Microbial translocation LPS Immune activation DCs Mathurin et al., Hepatology 2000; 32:1008-1017; Paik et al., Hepatology 2003; 37:1043-1055; Balagopal et al., Gastroenterology 2008; 135:226-233..
Practical non-invasive tests Biochemical markers APRI = (AST(/ULN)/PLATELET(109/l) 100) FIB-4 = (age (yrs)) x AST(IU/)/Platelets (109/l) x ALT (IU/l) 1/2
Elastography
Elastography in HIV/HCV co-infected patients JAIDS 2006; 41: 175-9
Treatment of HBV AIMS Halt/slow progression to cirrhosis Prevent HCC END POINTS: Normalization of serum ALT Negative or low HBV DNA level Loss of HBeAg + - appearance of anti-hbe Improvement in liver histology Loss of HBsAg +/- appearance of HBsAb
What does Rx aim to achieve? Immune Tolerance HBeAg- Chronic Hepatitis B Inactive Carrier eab+, sag+ HBV DNA undetectable HBeAg+ Chronic Hepatitis B Viral Clearance e-ab seroconversion S-Ab seronversion
Anti-HBV Therapies Immune modulators Polymerase Inhibitors IFN-alpha Pegylated-Interferonalpha Lamivudine Adefovir Entacavir Telbivudine Tenofovir Emtricitabine
Treatment of HBV/HIV: key issues TDF/FTC works What choices if HAART is not indicated What is the impact of lamivudine monotherapy
Similar (more potent) anti-hbv Activity of Tenofovir compared to Adefovir in Co-infected Patients ACTG A5127: HBV/HIV-1 co-infected pts HBV DNA 100,000 Stable antiretroviral therapy; HIV-1 RNA 10,000 Reduction in HBV DNA with tenofovir non-inferior to adefovir HBV DNA (log 10 ) 10 8 6 4 2 Adefovir Tenofovir DF 0 0 20 40 48 60 80 90 Peters M, et al. Abstract 124. Weeks
TDF+FTC RFH experience over 4years Characteristic Baseline (n=59) 4-8 months (n=55) Maximal follow up (n=68) Median HBV DNA 4.6 x 10 6 215 25 (copies/ml) 25-6.4 x 10 6 25-1.12 x 10 7 25-8.9 x IQR 10 5 HBV DNA <10 2 6 (10%) 25 (45%) 53 (78%) 10 2-10 3 10 (17%) 14 (25%) 7 (10%) 10 3-10 4 7 (12%) 6 (11%) 2 (3%) 10 4-10 5 0 (0%) 4 (7%) 0 (0%) 10 5-10 6 2 (3%) 3 (5%) 4 (6%) > 10 7 34 (58%) 3 (5%) 2 (3%) Rodger et al. AP&T 2009 (in press)
Treatment Algorithm: Patients with Compensated Liver Disease and No indication for HIV therapy (CD4 count > 350/µl) HIV/HBV* HBV DNA <2,000 IU/mL** HBV DNA ³2,000 IU/mL ALT Normal ALT Elevated No treatment Monitor every 6 12 months Monitor ALT every 3-12 months Consider biopsy and treat if disease present*** PEG IFN**** (favorable response factors are: HBeAg+ - HBV Genotype A elevated ALT and low HBV-DNA) Telbivudine (if HBV-DNA ist still detectable at week 24 add adefovir to minimize resistance development risk) Adefovor and telbivudine de novo therapy Early HAART initiation including Tenofovir+3TC/FTC Soriano V, et al. 4 th IAS, Sydney 2007, #MoBS104; Benhamou Y, 3rd International Workshop on HIV and hepatitis coinfection, Paris 2007
Can immune control really be restored and maintained in HIV+ patients? Wursthorn K et al. Antiviral Therapy 2006;11:647 52.
Telbuvidine?anti-HIV activity Viral load copies/ml 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 HIV viral load over time 26/2/8 LdT & ADV started 23/10/07 23/11/07 23/12/07 23/01/08 23/02/08 23/03/08 23/04/08 23/05/08 23/06/08 11/11/8 LdT re-started VL 1074 25/11/8 29/7/8 LdT stopped VL 127 6/5/8 VL <50 23/07/08 23/08/08 LdT 2 wks VL 127 23/09/08 23/10/08 23/11/08 75 50 25 0 Inhibition (%) 100 75 50 25 0 Inhibition (%) 100 HIV isolate ID 71 subtype C Patient Ref Entecavir 0.01 0.10 1 10 100 Drug concentration (µ M) Patient Ref Telbivudine 0.1 1 10 100 HIV isolate ID 75 subtype C Patient Ref Entecavir 0.01 0.10 1 10 100 Patient Ref Telbivudine 0.1 1 10 100 Drug concentration (µ M) No in vitro activity against 8 wild-type HIV-1, 2 drug resistant HIV-1 isolates E Low, et al. CROI 2009;P813a C Avila, et al. CROI 2009;P813b
HIV/HBV Co-infection CD4 >500 or No indication of HAART CD4 < 500 or Symptomatic HIV or Cirrhosis a HBV Rx Indicated b No HBV Rx indicated b Lamivudine experienced Lamivudine Naive a) PegIFN if Genotype A, high ALT, low HBV DNA Monitor Closely Add or substitute one NRTI with TDF d HAART Including TDF+3TC or FTC c b) Early HAART including TDF + FTC/3TC e
Incidence of HBV Resistance in Patients Treated with LAM in HBV infection vs HIV/HBV coinfection Incidence of Resistance 100% 80% 60% 40% 20% 24% 42% 47% LAM 1 (YMDD ) Triple HBV mutation twice as common in HIV/HBV 3 53% LAM 2 (YMDD in HIV/HBV) 70% 90% 0% year 1 year 2 year 3 year 4 1. Lai C.L., et al., Clinical Infectious Diseases (2003) 36:687 2. Benhamou Y et al. Hepatology 1999; 30:1302-6 3. Matthews GV, et al. AIDS 2006;20(6):863-70. * Year 4 resistance rate for ADV not yet available
Impact of lamivudine resistance on progression of liver disease Patients with severe fibrosis or cirrhosis Disease Progression, % 25 20 15 10 5 Placebo (n = 215) YMDDm (n = 209) (49%) Wild-Type (n = 221) Placebo YMDDm WT 21% 13% 5% 0 0 6 12 18 24 30 36 Time after Randomization (months) Liaw, N Engl J Med. 2004
Envelope/Polymerase Mutations and Antigen/Antibody Binding Capacity in HBV/HIV Co-infected Subjects with LAM Resistance TWO Important consequences a) Vaccine escape HBV b) Detection escape HBV Envelope changes Polymerase changes Ag Ab binding [IC 50 (µ g/ml)] Wild type Wild type 1.09 HBIG escape sg145r Anti-viral drug resistant se164d sw196s si195m sm198i se164d/i195m Cooley L et al. AIDS 2003;17:1649 57. rtw153g rtv173l rtm204i rtm204v rtv207i rtv173/rtl180/rtm204v >55.0 14.86 8.29 5.26 12.5 54.53
Case Study Patient MN 40 years, nurse, HIV positive ARVs (CBV/stocrin) since 2002, adherent HIV VL<50 since 2003 Admitted with hepatic failure to ICU Died within 24 hours despite supportive measures
Results: CD4 550, VL<50 Hep A negative HBsAg +ve, HBV DNA >1 000,000 c/ml eag negative Liver enzymes greater that 4 times normal INR 3 Albumin 22
ARV Rollout AZT/d4T+LAM+NNRTI?Global Impact
Unequal Burden?
Even the best are only human