1. HIV and viral hepatitis co-infection
Wirach Maek-a-nantawat, MD.
11 July 2011

2. Contents Epidemiology Natural history Lab for diagnosis and treatment
Prevention and vaccination
Postexposure prophylaxis for HCP

3. 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

4. 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

6. Natural History of Chronic HBV
Reactivation
Hepatic Flare
Non-replicative

7. 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: Perrillo, et al. Hepatology. 2001;33:

8. 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.

9. 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

10. 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.

11. 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

12. 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: Lok AS, et al. Hepatology. 2009;50: 12

13. 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
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: Tenny DJ, et al. EASL Abstract 20. Marcellin P, et al. AASLD Abstract 481. Heathcote E, et al. AASLD Abstract 483.

14. 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

15. 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

16. Natural history of HCV infection4%
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

17. 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

18. 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

19. 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
0.0014
Alcohol abuse°
2.71
HBsAg
2.91
0.0036
LTH*
2.25
0.0453
*LTH life threatening hepatotoxicity; time dependent covariate
°Daily alcohol consumption > 80 g (men) or 60 g (women) for > 5 years

20. 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

21. 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

22. 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

23. Host IL28B genotype and other important characteristics to help predict response to therapy

24. Reginal distribution of IL-28B polymorphism
Thomas DL, et al. Nature 2009

25. 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

26. 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

27. 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)

28. 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.

29. 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

30. 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

32. 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

33. 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: –100%
Surface mutants
Detection of HBV serotypes

34. Initial serologic assessment in HBV/HIV

35. 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

36. 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

37. HBV DNA levels in HBV chronic carriers10 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

38. 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 Martinot –Peignoux M et al. J.Hepatol Hsu YS et al. Hepatology Mommeja-Marin H et al. Hepatology 2003

39. Management plan

40. 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.

41. 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

42. 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

43. 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.

44. 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)

45. 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

46. 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

47.  Example of a patient treated with LAMV
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

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

49. 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

50. 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

51. 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

52. 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)

53. 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

54. 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 %
HCC %
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 %
IDU %
Haemophiliac pts %

55. 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)

56. 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

57. 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

58. Hepatitis B vaccination in HIV on ART
Serologic response %
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

60. 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

61. 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

62. 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.

63. Diagnostic tests
Accessed April 10, 2011.
Antibodies do not identify the presence of the virus or distinguish between acute, chronic or resolved infection

64. 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”

65. 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

66. Detection of antibodies to HCV (anti-HCV)
in HIV/HCV co-infected individuals
Anti-HCV screening with 3rd generation EIA
944 HIV-negative IDU
anti-HCV +
HCV-RNA +
HCV-RNA -
anti-HCV -
559 HIV-positive IDU
anti-HCV -
HCV-RNA +
HCV-RNA -
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

67. 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

68. HCV RNA Quantification Assays10
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

69. Tests for treatment monitoring

70. 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)

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

72. 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

73. 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

74. PEP for HCP

75. 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

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

77. 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

79. 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.

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

81. 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

82. 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

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

84. 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