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 (high prevalence) Perinatal esp. young age 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

Prevalence of HCV/HIV co-infection in Thailand PEGASYS® HCV Global Slide Kit Prevalence of HCV/HIV co-infection in Thailand Asia 26% Europe 34%* 75%† Spain 69%* 88%† USA 16%* 89%† Australia 13%* 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 Cirrhosis Liver Transplantation 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 HBeAg status Alcohol use Co-infection with HCV 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 Export Viral entry Uncoating ER Assembly & budding Positive strand synthesis Nuclear import HBsAg cccDNA Removal of pregenome Repair Transcription Viral accessory proteins: HBeAg and HBX 5’ 3’ Negative strand synthesis 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 Schering-Plough PPT Template 4/21/2017 1:45 AM HBV Treatment Landscape in 2010 Peginterferon alfa-2a Entecavir Lamivudine Tenofovir 1990 1998 2002 2005 2006 2008 Interferon alfa-2b Adefovir Telbivudine HBV, hepatitis B virus.   The hepatitis B treatment landscape is changing. In the early 1990s, the only treatment available for HBV was interferon alfa-2b. This agent was given for a short period, and only a few patients responded to treatment. In 1998, the first oral nucleoside analogue, lamivudine, was introduced, followed fairly rapidly by the nucleotide analogue adefovir. Standard interferon alfa-2b was then replaced by peginterferon alfa-2a, which was administered via once-weekly injections as opposed to daily treatment. Other nucleoside and nucleotide analogues, that is, entecavir, telbivudine, and tenofovir, soon followed. 11

Undetectable* HBV DNA After 1 Yr of Treatment Schering-Plough PPT Template 4/21/2017 1:45 AM 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 51-63 63 60 60 60 Undetectable* HBV DNA (%) 40-44 40 40 ADV, adefovir; ETV, entecavir; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; LAM, lamivudine; LdT, telbivudine; LLD, lower limit of detection; PCR, polymerase chain reaction; PegIFN, peginterferon; TDF, tenofovir.   This slide illustrates reported rates of undetectable HBV DNA after 1 year of treatment across the different anti-HBV therapies. It is important to note that these data were not derived from head-to-head comparative trials but instead reflect a number of studies conducted in different patient populations, with varying trial designs and endpoints. Treatment response rates vary in both HBeAg-positive and HBeAg-negative patients. Among HBeAg-positive patients, HBV DNA suppression rates ranged from 13% to 21% for adefovir to 76% for tenofovir at 1 year of treatment. For HBeAg-negative patients, response rates are somewhat better because HBeAg-negative patients often have significantly lower levels of HBV DNA at baseline and therefore are more likely to achieve undetectable HBV DNA on therapy. In this patient group, the range of reported response rates varied from 51% to 63% for adefovir to 93% for tenofovir. More recent studies have used polymerase chain reaction (PCR)–based assays for measuring HBV DNA, which have lower limits of detection of approximately 50 IU/mL. This is an accepted definition of HBV DNA negativity in routine clinical practice. 13-21 25 20 20 LAM ADV LdT ETV TDF Peg-IFN LAM ADV LdT ETV TDF Peg-IFN *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. 12

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 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Drug Generation 1st LAM 24% 38% 49% 67% 70% ADV, adefovir; ETV, entecavir; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir.   Exposure to oral anti-HBV agents presents a risk of evolving drug resistance. Cumulative rates of resistance differ between agents, with higher rates reported with the use of older agents. In nucleos(t)ide-naive patients, treatment with lamivudine was associated with relatively high rates of resistance: 24% at Year 1, rising to 70% by Year 5. Reported rates of resistance were lower with use of the second-generation drugs adefovir and telbivudine. Data on telbivudine are limited to 2 years of follow-up, at which point resistance was reported in 17% of patients on first-line therapy. The cumulative rate for adefovir was 29% at Year 5. The resistance profile of the third-generation agents entecavir and tenofovir is different. For tenofovir, 3-year follow-up of naive patients found no evidence of emergent resistance. For entecavir, the rate of resistance in comparable populations remained low: 1.2% at Year 6 of therapy. For more information, go online to http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Copenhagen%202009/Tracks/HBV%20Treatment/Capsules/20.aspx ADV 0% 3% 11% 18% 29% 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 Entecavir 1.0 mg- resistance with LMV-R HBV Add ADV

Natural history of HCV infection 4% Hepatoma 20 yr Chronic infection 17% 70-85% 3.6% Death 15-25 yr 15-25% Cirrhosis Resolved 13% Extrahepatic manifectations 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 11 11 11

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

Variable HR 95% CI p HCVRNA+ 10.35 2.46- 43.57 0.0014 Alcohol abuse° 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 model Infectious Diseases Dept. – Brescia, Italy Variable HR 95% CI p HCVRNA+ 10.35 2.46- 43.57 0.0014 Alcohol abuse° 2.71 1.47- 4.99 HBsAg 2.91 1.42-5.98 0.0036 LTH* 2.25 1.02-4.98 0.0453 *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 important characteristics 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 in vulnerable 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-HBc IgM 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-HBc IgM - Marker of acute infection. anti-HBc IgG - 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.

Acute Hepatitis B with Recovery Weeks after Exposure Symptoms anti-HBe Total anti-HBc IgM anti-HBc anti-HBs HBsAg 4 8 12 16 20 24 28 32 36 52 100 Incubation 4-12 weeks Early recovery (12-24 weeks) HBeAg HBV-DNA Acute infection (2-12 weeks) Recovery (24-48 weeks) Titer

Typical Serologic Course in Chronic HBV Infection Incubation 4-12 weeks Acute (6 months) Chronic (Years) HBeAg anti-HBe HBV-DNA HBsAg Total anti-HBc Titer IgM anti-HBc 4 8 12 16 20 24 28 32 36 52 Years 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

Initial serologic assessment in HBV/HIV

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

Available HBV DNA Assays Real Art HBV LC PCR Artus Biotech HBV Digene Hybrid-Capture I HBV Digene Hybrid-Capture II Digene Corp. Ultra-Sensitive Digene Hybrid-Capture II Roche Molecular Systems Amplicor HBV Monitor Cobas Amplicor HBV Monitor Cobas Taqman 48 HBV Bayer Corp. Versant HBV DNA 1.0 NA Versant HBV DNA 3.0 102 104 103 105 106 107 108 1010 109 10 1 HBV DNA IU/mL 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

HBV mono-infection: HBV DNA and CHB 102 103 106 107 108 109 1010 104 105 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

Management plan

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.

Primary Antiviral Treatment Failure Antiviral Drug Log HBV DNA 1 log 0.0 -1.0 -2.0 -3.0 -4.0 +1.0 Secondary Antiviral Treatment Failure Antiviral Drug Log HBV DNA 1 log 0.0 -1.0 -2.0 -3.0 -4.0 +1.0

Diagnose primary or secondary treatment failure - HBV DNA assay Demonstration of HBV Resistance in Clinical Practice with Approved Anti-HBV Drugs Diagnose primary or secondary treatment failure - HBV DNA assay Eliminate non-HBV-related causes of failure - drug dosage Demonstrate emergence of HBV mutant during therapy - direct sequencing Two options: The selected mutant is known to be associated with viral resistance to the drug: HBV resistance is diagnosed The selected mutant is not known to be associated with viral resistance: further characterization is needed

Antiviral Resistance Testing Genotypic Assays Phenotypic Assays Virtual Phenotyping Other study data obtained show that there is a clear correlation between clinical resistance and the results of genotypic and phenotypic assays. Antiviral resistance testing should be used in future to monitor therapy and adapt treatment protocols. Genotypic assays, some of which will be available in the clinic will show the polymerase mutants associated with viral resistance. Phenotypic assays are important to confirm that the mutation confers resistance. Several have been developed.

Genotypic Assays Genotyping Assays Analysis of the nucleic acid sequence of the region of the HBV genome that is targeted by the antiviral of interest Identify signature sequences and/or amino acid substitutions at specific positions Assays Direct sequencing of PCR products (population) Full sequence of the analysed fragment Detect any mutation Line Probe Assay (LiPA) Detect selected known mutations associated with drug resistance Sequencing molecular clones (quasispecies)

Genotypic Assays TRUGENE 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

Mutant motifs for LAM resistance and compensatory mutations: 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

 Example of a patient treated with LAM V M/V L L/M Codon 180 Codon 204 Codon 207 600 - 500 - 200 - 150 - 100 - 50 - 0 - - 8 - 7 - 6 - 5 - 4 - 3 1 148 325 407 450 519 542 ALT (U/L) HBV DNA log copies:mLU/ml Lamivudine 100mg/day  Days Example of a patient treated with LAM YMDD (V204) mutation is detected on day 450 INNO-LiPA assay: Results

INNO-LiPA HBV Genotyping Identification of HBV genotypes A to G Halfon et al., EASL 2003.

Antiviral Resistance Testing Phenotypic 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

Antiviral Resistance Testing Phenotypic Assays Concentration of drug that inhibits 50% of viral replication Fold increase in IC50 or fold resistance Ratio of the IC50s of the tested virus and the reference virus (wt) IC50 Drug Concentration 0.001 0.01 0.1 1 10 25 50 75 100 % viral replication

HBV Phenotyping Using Patient-Derived HBV Clones PCR Patient Serum Whole genome HBV clones Cloning Transient Transfection (Fitness assay) Lab Strain Clone 8 Clone 17 Clone 23 Clone 24 Clone 30 Southern analysis HepG2 Clones reliably obtained when viral load >105 On average, 70% of clones replicate in vitro Yang H et al., EASL 2003

Virtual Phenotyping Matching polymerase sequences from a HBV strain to (near) identical sequences with known antiviral drug phenotype held in a large database A “virtual” phenotype is assigned by extrapolation providing a mean IC50 of all matched sequences and a fold change to wild-type If insufficient matches are found in the database a “rules-based” interpretation is provided Virco, SeqHepB (VIDRL)

The complex natural history of HBV serological markers Acute hepatitis B Immunological tolerance Immune response Chronic hepatitis B Anti-HBe (+) HBeAg (+) Anti-HBe (+) Resolution HBV DNA (+) HBV DNA (+) HBV DNA (+) ALT normal/raised ALT raised ALT raised Hepatitis Immune response Spontaneous Viral mutations Antiviral therapy Cirrhosis Hepatic HBsAg + Anti-HBe (+) decompensation HCC HBV DNA (low) Immune response Transplant

Occult HBV Infection Chronic hepatitis 32.8% HCC 63.5% Persistence of HBV genomes in liver tissue (± serum) by PCR-based methods in the absence of HBsAg in serum Chronic hepatitis 32.8% HCC 63.5% Cacciola et al, NEJM 1999 Pollicino et al, Gastroenterology 2004 Minuk et al, Hepatology 2004 Besissik et al, J Hepatol 2003 Torbenson et al, Hepatology 2004 Toyoda et al, J Med Virol 2004 Haemodialysis pts 3.5 - 36 % IDU 45 % Haemophiliac pts 51.2 %

Chronic hepatitis B: Criteria for HCC Surveillance Evidence supports surveillance in: Cirrhosis Family history of HCC Asian men over 40 and women over 50 years age Africans over 20 years age >40 years age with high HBV DNA and high ALT Frequency: Every 6 months Method: Liver ultrasound +/- alpha-fetoprotein (Bruix & Sherman 2005)

Thai Guidelines for HIV/HBV co-infection All HIV/HBV infected individuals should be evaluated: - LFT, αFP, HBe Ag, (±HBV DNA) advised: - alcohol abstinence, safe sex practices, Hep A vaccination (if HAV Ab neg) If ART or HBV treatment (+hepatitis) is indicated, the prefered regimen should include TDF/3TC or FTC as a background regimen. If TDF, 3TC or FTC is discontinued, need close monitoring for hepatic flare or consider using adefovir dipivoxil or telbivudine for preventing hepatic flares National guidelines on HIV/AIDS diagnosis and treatment: Thailand 2010

Hepatitis B vaccination Thailand adopted the policy for HB immunization in 1988 Universal HB vaccination of newborns has been integrated into the national expanded programme on immunization (EPI) since 1992. Coverage of HBV immunization in group age<18 yr-old estimated 71.7%-91.3% Chongsrisawan V, et al. 2006

Hepatitis B vaccination in HIV on ART Serologic response 54.8-71.4% CD4 counts or NNRTI may associate with response of surface seroconversion Coverage of vaccine among HIV infection? - lower rates of antibody response in HIV - lower levels of antibody response in HIV Flare of HBV in cases of occult infection with isolated core antibody HIV-NAT unpublished data Paitoonpong L, et al. 2008

Hepatitis C Virus Infection Typical Serologic Course anti-HCV Symptoms Titre ALT Normal 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure 10 10 10

Hepatitis C Virus Infection: Diagnosis HCV antibody HCV viral load HCV genotype Liver function tests Liver biopsy is gold standard for assessing disease status ALT and AST do not predict liver histology HCV RNA does not predict liver histology or outcomes

Laboratory Diagnosis HCV antibody - generally used for diagnosis Not useful in the acute phase as it takes at least 4 weeks after infection before antibody appears. HCV-RNA - various techniques are available e.g. PCR and branched DNA. May be used to diagnose HCV infection in the acute phase. However, its main use is in monitoring the response to antiviral therapy. HCV-antigen - an EIA for HCV antigen is available. It is used in the same capacity as HCV-RNA tests but is much easier to carry out.

Diagnostic tests http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2011. Antibodies do not identify the presence of the virus or distinguish between acute, chronic or resolved infection

HCV Diagnosis Enzyme immunoassays ( 2nd or 3rd gen EIA) Initial screening test for patients with liver disease False positives in low risk patients Occasional false negatives, esp. With HIV+ Recombinant immunoblot assays (RIBA) Confirmatory test if EIA positive in low risk pt HCV RNA by PCR Confirmatory if RIBA is “indeterminant”

OraQuick HCV Rapid Test The first Rapid HCV Test Approved for Sale in the U.S. uses whole blood drawn from a vein, does not require laboratory processing, and returns results in about 20 minutes

Detection of antibodies to HCV (anti-HCV) in HIV/HCV co-infected individuals Anti-HCV screening with 3rd generation EIA 944 HIV-negative IDU 825 anti-HCV + 1 HCV-RNA + 118 HCV-RNA - 119 anti-HCV - 559 HIV-positive IDU 12 anti-HCV - 1 HCV-RNA + 11 HCV-RNA - 547 anti-HCV + * Both anti-HCV negative HCV-RNA positive individuals became anti-HCV positive on their next visit Thio et al, J Clin Microbiol 2000;38:575-7

Qualitative Detection of HCV-RNA HCV monoinfected vs. HIV/HCV coinfected HCV mono-infection HCV/HIV co-infection Anti-HCV positive Anti-HCV positive Confirm HCV replication if other causes of liver disease Confirm HCV clearance in acute hepatitis Confirm HCV clearance at the end of treatment and follow-up Anti-HCV negative Acute hepatitis (window phase) Liver test abnormalities Severe immunosuppressed patients

HCV RNA Quantification Assays 10 102 103 104 105 106 107 108 Cobas Amplicor HCV Monitor v2.0 (Roche) LCx HCV RNA Assay (Abbott) Versant HCV RNA 3.0 (Bayer) SuperQuant (NGI) Cobas Taqman 48 (Roche) HCV Quant ASR (Abbott) 95% of untreated hepatitis C

Tests for treatment monitoring

HCV-RNA concentration HCV-RNA concentration Quantitative HCV-RNA HCV mono-infection HCV/HIV co-infection HCV-RNA concentration HCV-RNA concentration Week 12 after treatment initiation Before therapy (predictor of response) Co-infected pregnant mother (risk of transmission)

Which role for HCV genotypes ? Independent predictors of response to therapy Some correlation with liver disease outcome in HIV-negative patients G3 steatosis G2 hepatitis flares Lonardo, Gastroenterology 2004; Rumi, Gut 2005

Predictors of Response Patients infected with genotype 2 and 3. low viral load (< 800,000 IU/ml). Absence of cirrhosis. Age <40 years. High ALT levels (>3x ULN). RVR at week 4 after RX

Thai Guidelines for HIV/HCV co-infection All HIV/HCV infected individuals should be encouraged to get early ART and HCV treatment If ART is indicated, should avoid using NVP, d4T, ddI (NRTIs). Avoid using AZT, d4T, ddI in a case treated with RBV Should monitor AST, ALT after ART at 1 mo and every 3 mo. Elevation of ALT ≥ 5 times ULN, investigate for HAV, HBV, alcohol, liver disease, and may discontinue ART if suspecting drug related causes. National guidelines on HIV/AIDS diagnosis and treatment: Thailand 2010

PEP for HCP

Concentration of Hepatitis B Virus in Various Body Fluids Low/Not High Moderate Detectable blood semen urine serum vaginal fluid feces wound exudates saliva sweat tears breastmilk 1 1 1

Occupational Blood-borne Exposures Relative Risk of Seroconversion with Percutanous Injury From: CDC. MMWR 2001;50 (RR11):1-42. . 1

Risk for HBV in HCP Needle injuries with blood containing HBs Ag+ and HBe Ag+ Developing clinical hepatitis 22-31% Seroconversion 37-62% Needle injuries with blood containing HBs Ag+ and HBe Ag - Developing clinical hepatitis 1-6% Seroconversion 23-37% Werner BG, Grady GF. Ann Intern Med 1982

Hepatitis B can be prevented! If you have never had hepatitis B, you can get 3 shots . . . 3 2 1 . . . and get long lasting protection.

How Is HCV Transmitted? Infected blood ?Infected body fluids Needlestick Needle sharing Transfusion ?Infected body fluids Amniotic fluid Breast milk semen

Risk for HCV in HCP Percutaneous exposure from an HCV person is 1.8% Limited data on survival of HCV in the environment Risk for transmission from exposure to fluids other than blood expected to be low MMWR 2001

Who Should Be Tested? Drug users Recipients of blood products or organ transplant before 1992 Long-term partners of infected individuals Persons with occupational exposures Children born to HCV-infected mothers HIV-infected individuals

Consider Testing For Persons with tattoos or body piercing Persons with multiple sexual partners Tissue transplant recipients

Take Home HBV/HCV + HIV is common Treat HCV where indicated/possible Screen For HBV in HIV infection HBV vaccination for all HIV+ patients who are HBsAg- Treat HBV where indicated and carefully select your nucleotides Screen for HCV in selected patients with risks Treat HCV where indicated/possible Beware of hepatotoxicity and dangerous combinations