Download Hepatitis C in Pregnancy

Hepatitis C
In Pregnancy
Craig V. Towers, M.D. F.A.C.O.G.
Professor Dept. Obstetrics & Gynecology
Division of Maternal-Fetal Medicine
University Tennessee Medical Center, Knoxville
Disclosures
I have no disclosures
or conflicts of interest
Viral Hepatitis
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Hepatitis viruses – A/B/C/D/E and G/TT ??
CMV - cytomegalovirus
EBV - Epstein-Barr virus
HSV I and II - herpes virus types I and II
Coxsackie virus and mumps virus
Hepatitis C
Areas to Cover
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History
Impact
Classification
Structure
Lab Work-up
General Transmission
Vertical Transmission
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Mode of Delivery
Fetal Scalp Electrode
Duration of ROM
Breastfeeding
Treatment
“Straws”
NON “A” NON “B”
(1950’s through 1980’s)
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viral type was unknown
at least 2 forms existed parenterally
transmission - percutaneous / permucosal
#1 cause of post-transfusion hepatitis
no marker existed so the true impact of the
disease was unknown
Perinatal transmission was thought to occur but
the exact risk was unknown
Hepatitis C Virus
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1989 - Choo and Kuo identified RNA virus
classified as a separate genus to flavivirus
RNA virus that is 9379 to 9481 nucleotides
long and is 30 to 38 nm in diameter
HCV Public Impact
HCV – Consensus Conf. 2010
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170 - 200 million carriers worldwide
4.1 million infected in the United States
3.2 to 3.5 million chronic carriers in the USA
80% asymptomatic – 20% symptomatic
10% - 30% chronic carriers progress to cirrhosis
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~ 2% - 5% risk of hepatocellular CA per year
Potential impact on healthcare is enormous
Hepatitis C Virus
Genetic Variants
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7 major genotypes exist (over 225 subtypes / species)
 1 – over 35 and counting
 2 – over 40 and counting
 3 – over 25 and counting
 4 – over 50 and counting
 5 – over 60 and counting
 6 – 8 and counting
 7 – only 1 (so far)
The most common geno/subtypes in Europe, USA, and
Japan are 1a, 1b, 2a, 2b, 3a, 4a, and 6a
Genotype 1 is the most resistant to treatment
Hepatitis C Virus
Cell Culture
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Cell culture-derived HCV became a reality in 2005
by 3 different groups (Lindenbach et al, Wakita et
al, and Zhong et al)
This has allowed every step of the viral life cycle
to be studied including viral entry – replication –
virion assembly – and release
Animal hosts are still limited (non-human
primates ?? / human liver transplanted mice, etc.)
Hepatitis C Virus
Structure
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Structural proteins (3)
 Core protein
 Envelope proteins E1 and E2
Nonstructural proteins (8)
 P7 ion channel protein / NS2 protease / NS3-4A
complex protease / NTPase-RNA helicase / NS4B
/ NS5A / NS5B RNA-dependent RNA polymerase
Orange is the assembly module & Green is the
replication module
Hepatitis C Virus
Hepatocyte Entry
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HCV enters the blood stream
HCV envelope glycoproteins E1 & E2 bind to
apolipoproteins (B, C1, and E) of circulating
VLDL and LDL lipoproteins
These (HCV) lipoviral particles then physically
circulate together and this union allows the viral
particle to gain access to the hepatocyte
It enters the cell through receptor-mediated
endocytosis
Hepatitis C Virus
MicroRNAs
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Cells contain microRNAs of ~ 22 nucleotides
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These inhibit and help degrade the translation (into
proteins) of messenger RNAs that contain only
partially complemented sequences of RNA
The most abundant microRNA in the liver is
microRNA-122
microRNA-122 binds to all types of HCV but
instead of destroying HCV it protects it
All genotypes require microRNA-122 to survive
Hepatitis C Virus
LABORATORY EVALUATION
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CDC-MMWR – May 2013
screening tests – are rapid HCV antibody tests
 Calculate signal-to-cut-off ratios
 Measure the optical density absorbance of
(HCV) antibody present compared to the
optical density cut off for that specific test
 high false positive rate in low risk population
Hepatitis C Virus
LABORATORY EVALUATION
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CDC-MMWR – May 2013
Positive screening tests would then be
confirmed with a RIBA
 RIBA is a series of antibodies to HCV from
more than one region of the virus
 No longer available as of mid-2012 ***
Confirmatory test is HCV-RNA by PCR
 5 Qualitative tests and 7 Quantitative tests
Hepatitis C Virus
LABORATORY EVALUATION
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Positive HCV antibody screen and a negative
HCV-RNA PCR
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??? Never infected (false positive screen)
??? Infected but is one of ~ 20% that develops immunity
Implications of this can affect insurability and the
??? of possible reactivation later in life ???
Hepatitis C Virus
General Transmission
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The main concern is transmission from
blood or blood products
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post-transfusion
IV drug abuse
organ transplantation
Others (tattoo ink or needles ?? / straws ??)
Perinatal – vertical transmission occurs
Sexual transmission – rare
Hepatitis C Virus
VERTICAL TRANSMISSION
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all infants are anti-HCV positive at birth
the antibody in most cases clears within 12
months, but can last up to 18 months
at this time, no proven treatment exists to
prevent vertical transmission
the anti-HCV antibody is not protective
Hepatitis C Virus
VERTICAL TRANSMISSION
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Over 450 studies have been published on this
topic – the data is still not clear
From studies analyzing anti-HCV positive
pregnant women – the average perinatal
transmission rate is about 5% (with a range of
0% to 14%)
The transmission rate in patients who are HCV
and HIV co-infected is 15% to 23%
Hepatitis C Virus Diagnosis of
VERTICAL TRANSMISSION
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Diagnosis is positive HCV-RNA on 2 occasions 3
to 4 months apart after the infant is at least 2
months of age and/or a positive HCV antibody
after 18 months of age
Recent data has shown that transmission
primarily only occurs in pregnant patients who
are HCV-RNA positive by PCR at the time of
delivery (with transmission rates of 3% to 8%)
Most vertical transmission occurs intrapartum
Hepatitis C Virus Timing of
VERTICAL TRANSMISSION
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No infant has ever been delivered
with active acute HCV infection
Sensitivity of PCR
For HCV – up to ~ 7 x 107 viral particles / cc
 Newborn has approx. 80cc blood / kg body
weight
Assume HCV-RNA + mom (with 106 viral load /
cc) delivers a 4000 gram baby
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If 1 tenth of 1cc of mother’s blood gets into the
baby ------ There would be 313 viral particles / cc
in the baby’s blood
Perinatal Transmission and
Mode of Delivery
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Cochrane Review 2010
Hepatitis C & Mode of Delivery
No randomized controlled trials have occurred
No overall benefit to cesarean section
Perinatal Transmission and
Mode of Delivery
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Cottrell et al – Annals of IM 2013 – US Task Force
4 studies on elective c-section prior to onset of labor
versus vaginal or cesarean section after labor onset
Study
EPHcN (good)
Year
2005
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1404
Mast et al (good)
McMenamin (fair)
2005
2008
181
441
Gibb et al (fair)
Total
2000
424
2450
Results
35/480 (7.3%) v 50/924 (5.4%)
p=.19
0/12 v 7/169 (4.1%) p=.61
1/33 (3%) v 17/408 (4.2%)
p=.60
0/31 v 29/393 (7.4%) p=.10
36/556 (6.5%) versus
103/1894 (5.4%) p=.80
Cesarean Section Neonate
Perinatal Transmission HCV
Fetal Scalp Electrode
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Cottrell et al – Annals of IM 2013 – US Task Force
2 studies (905 MC pairs) on FSE versus External
2 good quality studies
Mast et al 2005 (USA) – 3/16 (18.8%) with FSE versus
4/165 no FSE (2.4%) p=0.02
EPHcN 2001 – 11/93 with FSE (11.8%) versus 58/631
(9.2%) no FSE p=.54
Combined data 14/109 (12.8%) versus 62/796 (7.8%)
p=.10
Perinatal Transmission HCV
Duration of Membrane Rupture
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Cottrell et al – Annals of IM 2013 – US Task Force
2 studies (245 MC pairs)
1 good / 1 poor quality
Mast et al 2005 (USA) – 182 MC pairs
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0/53 (0%) < 1 hour
1/59 (1.7%) 1-5 hours
4/40 (10%) 6-12 hours
2/30 (6.7%) > 13 hours
Membrane rupture duration of > 6 hours p=0.02
Spencer et al 1997 (Australia) – 63 MC pairs
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HCV infected mean duration ROM 28 hours (+/- 10 hours)
HCV non-infected duration ROM 16 hours (+/- 4 Hours) p=0.03
Hepatitis C Virus and
Amniocentesis
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Delmare et al 1999 Hepatology
22 HCV antibody positive amniocentesis cases
(16 HCV-RNA positive)
21 fluids HCV-RNA negative – 1 was positive at
230 copies/mL (mom at 340,000 copies/mL) –
the procedure was transplacental
This child and 9 others tested at birth were
HCV-RNA negative – conclusion was maternal
contamination since transplacental
Hepatitis C Virus and
Viral Load / Genotype
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6 studies found a higher transmission rate with
higher viral loads – all small studies (1994,
1994,1995, 1995, 2000, 2001)
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Transmission was seen in cases that were HCV-RNA
negative ???
3 studies did not find viral load an issue –
(1998, 2000, 2005)
No critical titer has been found if it is a risk
No study has found any genotype a greater risk
Hepatitis C Virus and
Breast-Feeding
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Several studies have evaluated breast milk for
HCV-RNA and most samples are negative – a
few are positive (?? Maternal blood ??)
It is uncertain whether the virus can withstand
the intestinal tract
ACOG – Practice Bulletin #86 – October 2007
(reaffirmed 2012) states that breast-feeding is
not contraindicated (AAP-ACOG 2006 BreastFeeding Handbook)
Hepatitis C Virus Perinatal
Transmission Summary
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Timing of transmission is intrapartum in most cases
Mode of delivery – Cesarean section prior to labor ???
Co-infection with HIV increases the risk
Fetal scalp electrode +/– increases the risk
Membrane rupture duration may increase the risk
Amniocentesis risk is unknown
Higher viral load increases the risk but at what titer ??
Genotype does not appear to be an issue
Breast Feeding is considered acceptable
Hepatitis C Virus
Neonatal Infection
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Zuccotti et al 2006 – 17 HCV infected neonates
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All had elevated ALT’s
16 had positive HCV-RNA PCR at 3 months
Only one had positive HCV-RNA at 12 months
Several other small reports describe positive
HCV-RNA at delivery but negative later
Does the immune system of some neonates
fight off infection or is the newborn liver more
resistant ??? – does it take a certain level of
inoculum to cause infection ???
Hepatitis C Virus
Treatment
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Treatment recommendations still complex
With the addition of Ribavirin to pegylated
interferon alpha-2a
 80% long term response with genotypes 2-6
 40% long term response with genotype 1
 Relapses still occur, especially genotype 1
Cure is defined as HCV-RNA negative 24 weeks
after drug treatment completion
Hepatitis C Virus
Treatment Explosion
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Boceprevir and Telaprevir are NS3/4A protease
inhibitors for use with genotype 1 (approved 2011)
 Cure rates are up to 70% to 80%
 Issues, however, are side effects / DAA-resistance
/ complex dosing schedule
Sofosbuvir (nucleoside inhibitor of RNA-dependent
RNA polymerase) for use in all genotypes especially
for those that cannot take PEG-INF (approved 2013)
Hepatitis C Virus
New Treatments
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Over 35 more Anti-HCV DAA’s are in FDA Phase
I and II trials that are targeting:
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NS3-4A protease
Nucleoside inhibitors of HCV RNA-dependent RNA
polymerase
Non-nucleoside inhibitors of HCV RNA-dependent
RNA polymerase
NS5A inhibitors
Cyclophilin inhibitors
micro-RNA-122 antagonists (Miravirsen)
Hepatitis C Virus
Treatment in Pregnancy
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Pegylated-Interferon alpha-2a not
recommended for use during pregnancy
Ribavirin not recommended for use
during pregnancy
??? New DAA’s and others ???
HCV Vaccine
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Many hurdles exist in the development of
an effective HCV vaccine
1.
2.
3.
4.
5.
Only way to test infectivity is HCV-RNA PCR
Only species to be infected – humans
Many HCV viral proteins have high mutability
7 different genotypes (over 200 species)
No currently identified antibody kills the virus
HCV Epidemic
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Huge number of opiate abusers (60% +)
in Tennessee are also HCV infected
HCV testing is now a routine part of our
prenatal care laboratory assessment
Many patients strongly argued that they
did not use intravenous drugs nor had
they ever used IV drugs in the past
HCV Epidemic in
East Tennessee
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Could it be snorting utensils ? Straws ?
HCV Infection Risk Factor
Study Purpose
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Fernandez, Towers et al. Obstetrics &
Gynecology August 2016
To evaluate possible modes of HCV
transmission through common routes, as
well as, possible straw transmission in
HCV-infected pregnant women
Methods
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Prospective study of pregnant women
who were HCV-RNA positive
Anonymous survey with no patient
identification
March 2014 through June 2015
21 questions with 6 sub-questions on a
single page
Methods
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To test biological plausibility we
obtained snorting utensils (straws)
from local law enforcement agencies
that were confiscated from drug arrests
Tested these for the presence of
human blood
Results
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189 HCV-infected pregnant patients were
consented
Mean age 26.5 – 84% Caucasian
None were HIV positive
None had received a blood or clotting
transfusion or organ transplant prior to 1992
None were on hemodialysis
Results
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136 (72%) admitted to IV drug use
 89 (65%) admitted to sharing needles etc.
 This 89 represents 47% of the study group
178 (94%) admitted to sorting drugs
 164 (92%) admitted to sharing straws
 This 164 represents 87% of the study group
 This difference was highly significant p <.001
Results
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29 (15%) HCV-infected pregnant women
snorted drugs and shared straws but were
negative for all other potential risk factors
except sexual transmission
80 (42%) patients reported sharing snorting
utensils but denied sharing needles/syringes
Results
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133 (70%) did not know when they became
infected with HCV
127 (67%) found out they were infected with
HCV from the routine prenatal lab work drawn
at the start of prenatal care
Results
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54 straws were obtained from local law
enforcement agencies (a different
population of patients from the study
group)
13 (24%) tested positive for human
blood
A Future Concern
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95% of the drugs snorted were crushed
prescription opiates
If HIV gets into the blood pool of
Appalachia we will have even a greater
problem
Conclusions
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Sharing of snorting utensils (straws) in
the process of snorting opiates (or any
other drug) is probably an additional risk
factor becoming infected with HCV (or
any other blood-borne viral infection)
Questions