HIV and viral hepatitis co-infection . Wirach Maek-a-nantawat, MD. 11 July 2011. Contents. Epidemiology Natural history Lab for diagnosis and treatment Prevention and vaccination Postexposure prophylaxis for HCP. Epidemiology. High prevalence of HBV infection in Thailand .
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HIV and viral hepatitis co-infection Wirach Maek-a-nantawat, MD. 11 July 2011
Contents • Epidemiology • Natural history • Lab for diagnosis and treatment • Prevention and vaccination • Postexposure prophylaxis for HCP
Epidemiology • High prevalence of HBV infection in Thailand • Prevalence(HBV) 4.6-8% • Prevalence (HIV-HBV)= 8 – 10% • Genotype C (58-87%) predominating genotypes B (11-24%) and A (1-5%) • 2 Subtypes: adr (80%) and adw (20%) • Genotype C significantly more common in HCC patients <40 years old • Routes of transmission of HBV • coinfection • IDU, MSM (highprevalence) • Perinatal esp. youngage Zone of High HBV prevelence (>8%) Duanthanorm T, J Sci Soc Thailand 2004 Suwqnnqkarn K, et al. 2005 Tangkijvanich P, et al. World J Gastroenterol 2005
Europe 34%* 75%† Asia 26% USA 16%* 89%† Spain 69%* 88%† Australia 13%* Prevalence of HCV/HIV co-infectionin Thailand • HIV/HCV infection = 7-9% • Risk factor: IDU, MSM • Among IDUs, HCV 49.5% in HIV • contrast with 2.2% in non-HIV • Among Pregnant women, HCV • 3.8% in HIV VS 0.3% in non-HIV • Among military conscripts, HCV • 8.4% in HIV VS 2.2% in non-HIV • Genotype 3 most prevalent (70%) • - Genotype 6 30% * General HIV-infected population † IVDU population Chanbancherd P, et al SEA J Trop Med Public Health 2003 Beyrer C, et al. AIDS 2005 Jamieson DJ, et al. Infec Dis Obstet Gynecol 2008 Jatapai A, et al. Am J Trop Med Hyg 2010
Natural History of Chronic HBV Reactivation Hepatic Flare Non-replicative
Natural Progression of CHB 15%–40% of CHB patients may experience disease progression Liver Cancer (HCC) 5%–10% 10%–15% in 5 yr Liver Transplantation Cirrhosis Death Chronic Infection 30% 23% in 5 yr Acute flare Liver Failure Adapted from: Fattovich, et al. Gastroenterology. 2004;127:S35-S50. Torresi, et al. Gastroenterology. 2000;118:S83-S103. Fattovich, et al. Hepatology. 1995;21:77-82. Perrillo, et al. Hepatology. 2001;33:424-432.
Factors Influencing Natural History of HBV Host immune status Age at infection HBV viral load Gender Liver cirrhosis Hepatocarcinoma Liver failure Death • HBV infection • Perinatal • IDU, MSM • Heterosexual Disease progression HBeAgstatus Alcoholuse Co-infection withHCV or HIV Viral mutations Fattovich. Semin Liver Dis. 2003;23:47-58. Chen, et al. JAMA. 2006;295:65-73.
Influence of HIV on HBV • Longer period of acute infection with lower rates of clearance of HBeAg • Increased serum HBV DNA viral load • Less hepatic necroinflammation in immunocompromised • Reactivation of hepatitis in asymptomatic carriers • Increased liver injury associated CD4 cell counts • Faster fibrosis cirrhosis and HCC • Higher mortality and morbidity Gilson RJ, et al. AIDS 1997 Manegold C, et al. CID 2001 Thio C, et al. Lancet 2002 Di Martino V, Gastroenterology 2002
Hepatitis B Virus – Replication Viral accessory proteins: HBeAg and HBX Export Viral entry ER Uncoating Assembly & budding Positive strand synthesis HBsAg Nuclear import Removal of pregenome cccDNA Repair Transcription Negative strand synthesis 5’ 3’ 2.4/2.1 kb RNA 5’ 3’ Translation 3.5 kb RNA Encapsidation CL Thio, Clinical Update, August 2006.
HBV Treatment Landscape in 2010 Peginterferon alfa-2a Entecavir Tenofovir Lamivudine 1990 1998 2002 2005 2006 2008 Interferon alfa-2b Telbivudine Adefovir
Undetectable* HBV DNA After 1 Yr of Treatment Not head-to-head trials; different patient populations and trial designs HBeAg Positive HBeAg Negative 100 100 90 93 88 76 80 80 60-73 67 63 51-63 60 60 60 Undetectable* HBV DNA (%) 40-44 40 40 25 13-21 20 20 0 0 Peg-IFN Peg-IFN LAM ADV LdT ETV TDF LAM ADV LdT ETV TDF *By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies. Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2009;50:661-662.
Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients Not head-to-head trials; different patient populations and trial designs Yr 6 Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Drug Generation 1st LAM 24% 49% 67% 38% 70% ADV 29% 0% 3% 11% 18% 2nd LdT 4% 17% ETV 0.2% 0.5% 1.2% 1.2% 1.2% 1.2% 3rd TDF 0% 0% 0% EASL. J Hepatol. 2009;50:227-242. Tenny DJ, et al. EASL 2009. Abstract 20. Marcellin P, et al. AASLD 2009. Abstract 481. Heathcote E, et al. AASLD 2009. Abstract 483.
Why treat HBV in HIV-infected persons • Co-infection is common-10% of HIV-infected • More rapid progression of liver disease • Increased risk of liver-related mortality • Increased risk of HAART-related hepatotoxicity • ?Immune reconstitution syndrome
Strategies to treat HBV and HIV • All of the following should be used with HAART • LMV naive • First line: TDF plus LMV/FTC (emtricitabine) • Other considerations • Entecavir +/- TDF • PEG-IFN • LMV experienced • First line: Add TDF to LMV • Other considerations • Entecavir 1.0 mg- resistance with LMV-R HBV • Add ADV
Natural history of HCV infection HCV infection 4% Hepatoma 20 yr Chronic infection 17% 70-85% 3.6% Death 15-25 yr 15-25% Cirrhosis Resolved 13% • Extrahepaticmanifectations • Arthritis • Glomerulonephritis • Mixed cryoglobulinemia Complications and Liver failure
Risk Factors Associated with Transmission of HCV • Transfusion or transplant from infected donor • Injecting drug use • Hemodialysis (yrs on treatment) • Accidental injuries with needles/sharps • Sexual/household exposure to anti-HCV-positive contact • Multiple sex partners • Birth to HCV-infected mother
Impact of HIV on HCV • HIV infection worsens HCV-related liver disease (in pre-HAART era) • ALT levels higher • Fibrosis more severe • Cirrhosis, liver failure, and HCC more common • Death rates higher • Vertical HCV transmission enhanced
Predictors of liver death in 812 HIV+ :age adjusted HR for liver death of risk factors for liver injury according to Cox’s proportional hazards modelInfectious Diseases Dept. – Brescia, Italy *LTH life threatening hepatotoxicity; time dependent covariate °Daily alcohol consumption > 80 g (men) or 60 g (women) for > 5 years
Impact of HCV on HIV • Impaired Th1 function in HIV infection affects appropriate immune response to HCV • Conflicting clinical results • More rapid progression to AIDS or death for HCV genotype 1 • Increasing HIV RNA and decreasing CD4 more likely in co-infected pts
HCV Treatment Rationale • HCV is curable disease. • Treatment can improve HCV outcomes • Decrease fibrosis • Increase T-cell responsiveness to HCV antigens • Decrease rate of fatal hepatocellular carcinomas • Treatment may improve HIV outcomes • Reduce hepatic toxicity of ARVs
HCV Treatment Options • Pegylated Interferon-ribavirin combination therapy • Trials ongoing • Preliminary findings encouraging • Short duration for genotype 2/3 • New protease inhibitors: Boceprevir, Telaprevir (combined with pegIFN+RBV for genotype 1) • No data
Host IL28B genotype and other importantcharacteristics to help predict response to therapy
Reginal distribution of IL-28B polymorphism Thomas DL, et al. Nature 2009
Access to Therapy Only a minority of HCV-HIV and HBV-HIV coinfected are treated for their hepatitis. To increase the applicability and availability of treatment especially invulnerable groups such as in immigrants, IDUs, prisoners, people with psychiatric illnesses and people with excessive use of alcohol
Lower rate of screening for hepatitis virus infection • 58% were screened for HBV and 43% screened for HCV infection in tertiary care institutes • 9.7% had HBV infection and 8.8% had HCV infection • LEE prior to the initiation of ART and undetectable HIV RNA at screening significantly associated with the finding of HBV co-infection. • The limited resources for HIV, HBV and HCV treatment & care in a resource-limited setting and unawareness of long term complications may affect rate of screening for HBV and HCV infections. Sungkanuparph S, et al. Southeast Asian J Trop Med Public Health 2008 Chotiprasitsakul D, et al. J Infect Dis Antimicrob Agents 2010
HBV Virological Assessment A. Immunological Assays 1. HBsAg/Anti-HBs 2. HBeAg/Anti-HBe 3. Anti-HBc and Anti-HBcIgM B. Molecular or nucleic acid assays 1. Quantitative HBV-DNA 2. HBV Genotyping 3. HBV Resistance evaluation (sequencing Pol)
Diagnosis • HBsAg- Used as a general marker of infection. • HBsAb- Used to document recovery and/or immunity to HBV infection. • anti-HBcIgM - Marker of acute infection. • anti-HBcIgG- Past or chronic infection. • HBeAg - Active replication of virus and therefore infectiveness. • Anti-HBe- No longer viral replication. However, the patient can still be positive for HBsAg which is made by integrated HBV. • HBV-DNA - Indicating active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.
Incubation 4-12 weeks Acute infection (2-12 weeks) Early recovery (12-24 weeks) Recovery (24-48 weeks) Symptoms HBeAg anti-HBe HBV-DNA Total anti-HBc anti-HBs IgM anti-HBc HBsAg 0 4 8 12 16 24 28 32 52 100 20 36 Weeks after Exposure Acute Hepatitis B with Recovery Titer
Incubation 4-12 weeks Typical Serologic Course in Chronic HBV Infection Acute (6 months) Chronic (Years) HBeAg anti-HBe HBV-DNA HBsAg Total anti-HBc Titer IgManti-HBc Years 0 4 8 16 20 24 28 36 12 32 52 Weeks after Exposure
Isolated antibody to HB core antigen • Frequently detected in HIV/HBV co-infection (20%-30%) • IVDU (OR 30.8, p < 0.001) and anti-HCV seropositive (OR 6.7, p = 0.002) were independent risk factors • Low anamnestic response to hepatitis B vaccination (7%) Jongjirawisan Y, et al. J Med Assoc Thai 2006
Challenges in HBsAg Serological Diagnosis • Analytic sensitivity: WHO standard 0.028–0.156IU/ml • Abbott ad standard 0.18–0.73 ng/ml • Abbot ay standard 0.13–0.26 ng/ml • Clinical sensitivity: 89.3–99.8% • Specificity: 97.6–100% • Surface mutants • Detection of HBV serotypes
HBV history and markers in Thailand • Significant higher ALT in genotype C than B • HBeAg significantly more frequent in genotype C than B patients (50.8 VS 30.8%,p=0.03) • Levels of HBV DNA were comparable in both genotypes • Genotype C showed higher ALT levels and more necroinflammation activity and fibrosis of liver • Progression to cirrhosis and HCC trended to be younger in genotype C • Lower response rate to IFNα therapy in genotype C • The risk of development of HCC may not be different between genotypes B and C-related chronic liver disease. Tangkijvanich P, 2004 Tangkijvanich P, 2005
1 10 102 103 104 105 106 107 108 109 1010 HBV DNA IU/mL Available HBV DNA Assays Real Art HBV LC PCR Artus Biotech Digene Corp. HBV DigeneHybrid-Capture I HBV DigeneHybrid-Capture II Ultra-Sensitive DigeneHybrid-Capture II Amplicor HBV Monitor Roche MolecularSystems CobasAmplicor HBV Monitor CobasTaqman 48 HBV Bayer Corp. Versant HBV DNA 1.0 NA Versant HBV DNA 3.0 Other HBV DNA Assays not CE marked are NAXCOR and TMA-HPA Locarnini et al., Antiv.Therapy 2004
HBV DNA levels in HBV chronic carriers 10 9 Chronic Hepatitis B HBeAg+ 8 Chronic Hepatitis B HBeAg- 7 Liquid Hybridization 6 bDNA - Hybrid Capture 1 HBV DNA Log copies/mL 5 Inactive carriers 4 Hybrid Capture 2 3 Amplicor PCR 2 COBAS PCR Villeneuve JP et al. Gastroenterology 1994; Martinot –Peignoux M et al. J.Hepatol 2002; Hsu et al Hepatology 2002; Mommeja-Marin H et al. Hepatology 2003; Manno, Gastroenterology 2004
1010 109 108 107 106 105 104 103 102 HBV mono-infection: HBV DNA and CHB In HIV co-infected ? CHB HBeAg + CHB HBeAg – Serum HBV DNA (copies/ml) ~30% Virological objective Inactive Patients Villeneuve JP et al. Gastroenterology 1994. Martinot –Peignoux M et al. J.Hepatol 2002. Hsu YS et al. Hepatology 2002. Mommeja-Marin H et al. Hepatology 2003
Antiviral Treatment Effect Antiviral treatment effect is defined as a sustained ≥1 log10 IU/ml reduction of HBV DNA from baseline levels during therapy and within 3 months of starting therapy. A decrease of ≥1 log10 IU/ml can be used to assess the early virological response. Development of resistance while on treatment is characterized by a rise of ≥1 log10 IU/ml.
Secondary Antiviral Treatment Failure Log HBV DNA Log HBV DNA Antiviral Drug Antiviral Drug +1.0 +1.0 0.0 0.0 1 log 1 log 1 log -1.0 -1.0 -2.0 -2.0 -3.0 -3.0 1 log -4.0 -4.0 Primary Antiviral Treatment Failure
Demonstration of HBV Resistance in Clinical Practice with Approved Anti-HBV Drugs • Diagnose primary or secondarytreatmentfailure- HBV DNA assay • Eliminate non-HBV-related causes of failure- drug dosage • Demonstrateemergence of HBV mutant duringtherapy- direct sequencing Two options: • The selected mutant isknown to beassociatedwith viral resistance to the drug: HBV resistanceisdiagnosed • The selected mutant is not known to beassociatedwithviral resistance: furthercharacterizationisneeded
Antiviral Resistance Testing • Genotypic Assays • Phenotypic Assays • Virtual Phenotyping
Genotypic Assays Genotyping • Analysis of the nucleicacidsequence of the region of the HBV genomethatistargeted by the antiviral of interest • Identify signature sequences and/or aminoacid substitutions atspecific positions Assays • Direct sequencing of PCR products (population) • Full sequence of the analysed fragment • Detect any mutation • Line Probe Assay (LiPA) • Detectselectedknown mutations associatedwithdrugresistance • Sequencing molecular clones (quasispecies)
Genotypic AssaysTRUGENE HBV 1.0 Sequences a region of 507 nucleotides • RT codons 110 – 278 • S protein codons 100 – 227 Generates a genotype report (genotypes A–H) • Based on closest match to a panel of consensus reference sequences (% homology) Generates a mutation report • A list of observed changes when compared against the closest match reference sequence, sorted by published, unpublished and silent changes
INNO-LiPA HBV DR v2 • Can detect: • Wild-type • Mutant motifs for LAM resistance and compensatory mutations: • M204V/I/S, L80V/I, V/G173L, L180M • ADV resistance mutations: • A181T/V and N236T INNO-LiPA HBV DR v2 prototype strip Doutreloigne J et al., AASLD 2004
Lamivudine 100mg/day 600 - - 8 500 - - 7 - 6 200 - HBV DNA log copies:mLU/ml ALT (U/L) - 5 150 - - 4 100 - - 3 50 - 0 - Days 1 148 325 407 450 519 542 L L/M M M M L M Codon 180 M/V M M M M Codon 204 M V V V V V V Codon 207 V V Example of a patient treated with LAM YMDD (V204) mutation isdetected on day 450 INNO-LiPAassay: Results
INNO-LiPA HBV Genotyping Identification of HBV genotypes A to G Halfon et al., EASL 2003.
Antiviral Resistance TestingPhenotypic Assays Phenotyping • Measure the ability of viruses to grow in various concentrations of antiviral drugs • Could predict the clinical response to these drugs Assays • Cell-culture-based • Enzymatic • Animal models • Patient-derived clones
100 75 % viral replication 50 25 0 0.001 0.01 0.1 1 10 IC50 Drug Concentration Antiviral Resistance TestingPhenotypic Assays IC50 • Concentration of drugthatinhibits 50% of viral replication Foldincrease in IC50 or foldresistance • Ratio of the IC50s of the tested virus and the reference virus (wt)