2/20/2018 Hepatitis C Virus Screening & Treatment: What does an - - PDF document

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Hepatitis C Virus Screening & Treatment: What does an Ob/Gyn need to know?

Ricardo A. Franco, MD Assistant Professor of Infectious Diseases University of Alabama at Birmingham

Disclosures

I disclosed that I have received funds for research support from Merck, Janssen and Gilead and consulting fees from Gilead

Outline

• Epidemiological trends concerning women’s health
• Hepatitis C and Perinatal Care
• Hepatitis C Care and Treatment in 2018

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Estimated prevalence of anti-HCV and HCV RNA in persons aged ≥6 y - NHANES

Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5):293-300.

Blood supply screening Disease incidence decreases Steady liver dz death rates Limited treatment options

Number of Individuals in the United States With Hepatitis C Antibody and Viremia

Edlin BR, Eckhardt BJ, Shu MA, et al. Toward a more accurate estimate of the prevalence of hepatitis C in the United States.

• Hepatology. 2015 Nov;62(5):1353-63

500 1,000 1,500 2,000 2,500 3,000 3,500 Number of cases Year

Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)

30 000 incident infections in 2014

Reported Number of Acute Hepatitis C Cases, United States, 2000-2014

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Emerging HCV Epidemic Among Young Nonurban Persons Who Inject Drugs in the US, 2006–2012

Clin Infect Dis. 2014;59:1411-9 Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)

Trends in acute HCV incidence among young persons by Urbanicity, 2006–2012

Clin Infect Dis. 2014;59:1411-9

Among young persons who inject drugs, about half are women in reproductive age

Vertical Transmission of Hepatitis C Virus: Systematic Review and Meta-analysis

Clinical Infectious Diseases, Volume 59, Issue 6, 15 September 2014, Pages 765 773

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HCV detection rate (females aged 15–44 years) and testing rate (children aged = 2 years) —US and KY 2011-14

MMWR Morb Mortal Wkly Rep 2016;65:705–710

22% 14% 213% 151% Source: Quest Diagnostics reporting to CDC

Proportion of infants born to hepatitis C virus (HCV)- infected women — US and KY, 2011–2014

MMWR Morb Mortal Wkly Rep 2016;65:705–710

68% 124% Source: Birth Certificate data

Prevalence of HCV Infection in Pregnancy

• This has been difficult to determine

– Estimated in 1-8% worldwide; 1-2.5% in the US (as high as 4% in high risk populations) – Routine screening is not performed in this population (but rather is risk based)

• Many HCV infections go undetected (under-recognition of risk behaviors)

– Concerns about stigmatization or legal consequences of risk behaviors – Even when HCV infection is detected, most at-risk children are not screened subsequently and do not receive appropriate medical care

MMWR Morb Mortal Wkly Rep. 2016 Jul 22;65(28):705-10 Clin Infect Dis. 2016; 62: 980-5

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CDC Analysis of the National Notifiable Diseases Surveillance System and the Quest Diagnostics Health Trends

Number of reported cases of HCV infection among women aged 15–44 years and 45–64 years in the United States, 2006–2014 Estimated Number of HCV-Infected Women Who Gave Birth and of HCV-Infected Infants – 2011 to 14

• 3.9 million live births occurred/year
• 0.73% of pregnant women tested for

HCV infection were found to have the infection

• 29 000 women (0.73%) with HCV

infection gave birth during that period

• 1700 infants (5.8% vertical

transmission rate) were born with HCV infection/year

Ann Intern Med. 2017;166(11):775-782

Women in Whom Prenatal Screening for HCV is Recommended

• Women who ever injected illegal drugs (even once)
• Users of intranasal illicit drugs
• Women ever on long-term hemodialysis
• Women with percutaneous/parenteral exposures in unregulated setting (eg, tattoos

received outside of licensed parlors or medical procedures done in settings without strict infection control policies)

• Recipients of transfusions or organ transplants before July 1992 and recipients of

clotting factor concentrates produced before 1987

• Recipients of blood products from donor who later tested positive for HCV
• Women with history of incarceration
• Women seeking evaluation or care for sexually transmitted infection, including HIV
• Women with unexplained chronic liver disease (including persistently elevated ALT)

American College of Obstetricians and Gynecologists. Viral hepatitis in pregnancy. Practice bulletin no. 86. Obstet Gynecol 2007;110:941-55.

Screening Tests for HCV

ELISA Screening Tests

• Serologic assays to detect circulating HCV

antibodies

• Sensitivity (97%-100%)
• Positive predictive value

– 95% with risk factors + elevated ALT – 50% without risk factors + normal ALT

• False-positive results

– More likely in patients with low risk of HCV infection

• False-negative results

– More likely in severely immunocompromised patients HCV RNA Assays

• When to test?

– If anti-HCV Ab test result is positive – If antiviral treatment is being considered – If unexplained liver disease and anti- HCV Ab test result is negative and person is immunocompromised – If acute HCV infection is suspected

• 1. AASLD and IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/full-report-view. Accessed April 18, 2017.
• 2. Smith BD et al. MMWR Recomm Rep. 2012;61:1-32.
• 3. Moyer VA et al. Ann Intern Med. 2013;159:349-357.
• 4. World Health Organization, April 2014. www.who.int.

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Effects of HCV in Pregnancy

Gervais A, Bacq Y, Bernuau J, et al. J Hepatol 2000;32:293-9

Intrahepatic Cholestasis of Pregnancy

Wijarnpreecha K, Thongprayoon C, Sanguankeo A, Upala S, Ungprasert P, Cheungpasitporn W. Hepatitis C infection and intrahepatic cholestasis of pregnancy: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2017;41:39-45.

higher risk of ICP in HCV+ pregnant women increased risk of later HCV diagnosis in ICP patients

Pregnancy complications associated with HCV

• Washington state birth cohort, 2003-2005

– HCV-positive mothers with excess weight gain also had a greater risk of gestational diabetes (OR, 2.51; 95% CI, 1.04, 6.03) – Compared with the drug-using cohort, NICU admission and the need for assisted ventilation remained associated with HCV

Pergam SA, et al. Pregnancy complications associated with hepatitis C: data from a 2003-2005 Washington state birth cohort. Am J Obstet Gynecol 2008;199:38.e1-9

Outcome OR 95% CI Low birthweight 2.17 1.24 - 3.80 Small for gestational age 1.46 1.00 - 2.13 Need assisted ventilation 2.37 1.46 - 3.85 Require NICU admission 2.91 1.86 - 4.55

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Meta-analysis of infants outcomes born from HCV-positive women

Odds of A, low birthweight and B, fetal growth restriction

Huang Q, Hang L, Zhong M, Gao Y, Luo M, Yu Y. Maternal HCV infection is associated with intrauterine fetal growth disturbance. Medicine (Baltimore) 2016;95:1-7.

Low Birth Weight Intrauterine Fetal Growth Restriction

Adjustments: age, parity, smoking, alcohol, drugs, HBV/HIV, preeclampsia

Methods to Reduce Maternal-Fetal Transmission

Recommendation Rationale Cesarean delivery should not be performed solely for the indication of hepatitis C (1B) The exact timing of vertical transmission is unknown Elective Caesarean section does not appear to be preventive [1, 2] If invasive prenatal diagnostic testing is requested, risk is low but data is limited; amniocentesis is recommended

• ver chorionic villus sampling (2C)
• No data on chorionic sampling available
• Only a few series discuss amniocentesis in HCV+

pregnant women

• Variations in design prevent meta-analysis [3-6]

Avoid internal fetal monitoring, prolonged rupture of membranes, and episiotomy in managing labor to the extent possible (1B) Inadequate data regarding transmission risk with expectant management of preterm, prolonged rupture of membranes [7, 8] Providers should not discourage breast-feeding (CDC discourages if nipples are bleeding or cracked) (1A) Breast-feeding does not appear to affect the risk of vertical transmission of HCV (systematic review) [9] DAA regimens only in clinical trials or treatment be deferred to the postpartum period (1C) New drugs have shown risk category B (animal studies) DAAs not currently approved for use in pregnancy

1) Br J Obstet Gynaecol 2001;108:371–7. 2) Cochrane Database Syst Rev. 2006; 4: CD005546. 3) J Hepatol 1999;31:416–20. 4) Gastroenterology 2001;(Suppl A):A–366. 5) Gastroenterol Biol Clin 1998;22:A179. 6) Hepatology 2001;33:1341–42. 7) J Infect Dis. 2005; 192: 1880. 8) J Viral Hepat. 1997; 4: 395–409. 9) Ann Intern Med. 2013; 158: 109–113

Principles of Medical Management of HCV

• Alcohol has been associated with progression of liver disease (even in modest use)

– Patients with HCV, including pregnant women, should be counseled to abstain from alcohol

• For patients with HCV who have normal hepatic function, dose adjustments in most prescription and
• ver-the-counter medications are not required
• Patients can take acetaminophen, set to a lower max dose of 2 g/day (rather than 4 g/day for the

general population)

• Routine serial laboratory surveillance of liver function or serial viral load assessment during

pregnancy in HCV-positive women is generally not recommended

• Any woman diagnosed with HCV infection during pregnancy should be referred to a hepatologist or

infectious disease specialist experienced in hepatitis

• Infants born to HCV-positive women should be screened for anti-HCV antibodies >18 months of age
• r for HCV RNA on 2 occasions in infants >1 month of age

Hughes et al. Hepatitis C in pregnancy: screening, treatment, and management.

• AJOG. Nov 2017. Volume 217, Issue 5, Pages B2–B12

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Distribution of HCV Genotypes in the United States1

Germer JJ et al. J Clin Microbiol. 2011;49:3040-3043.

HCV gen 1, 2, and 3 are the most prevalent in the US, representing >98% of all infections.

HCV Therapeutics Timeline

1995 2000 2010 2005 2016 1989 HCV identified Consensus IFN IFN a-2a IFN a-2b + RBV Peg-IFNa-2b Peg-IFNa-2a HCV replicons In vitro HCV replication Peg-IFNa-2a in HCV/HIV IFN a-2b BOC TPV IFN-free GT1 DAA regimens Sofosbuvir Simeprevir (US) Daclatasvir (EU)

IFN-free Treatment Options in 2018 (FDA Approved)

RBV SOF/ LDV SOF RBV OBV/ PTV/r DSV SMV SOF SOF DCV GZR/ EBR SOF/VEL VOX SOF/ VEL

GLE/PIB GLE/PIB GLE/PIB

HCV Life Cycle Presents Multiple Targets for Direct Acting Antiviral Drugs

NS5A: nonstructural protein 5A Manns MP et al. Nat Rev Drug Discov. 2007;6:991-1000

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FDA Approved Direct-Acting Antiviral Agents From Multiple Classes

3’UTR 5’UTR Core E1 E2 NS2

NS4B

NS3 NS5A NS5B p7 Ribavirin Polymerase Daclatasvir (DCV) Ledipasvir (LDV) Ombitasvir (OMV) Elbasvir (EBR) Velpatasvir (VEL) Pibrentasvir (PIB) Sofosbuvir (SOF) Dasabuvir (DSV) NS5B NUC Inhibitors NS5A Inhibitors NS5B Non-NUC Inhibitors Boceprevir (BOC) Telaprevir (TVR) Simeprevir (SMV) Paritaprevir (PTV)/ Grazoprevir (GZR) Glecaprevir (GLE) Voxilaprevir (GLE) NS3 Protease Inhibitors Protease 4A

Resolved Stable Slowly Progressive Transplant/Death

~20% ~15% ~85% ~3%-4%/yr ~80% ~75% ~ 20-year progression rate may be accelerated with HIV, HBV, alcohol, and steatosis1,2

Exposure

(Acute Phase)

Chronic Cirrhosis

~4%/yr ~6%/yr

ESLD HCC

10 20 30

Time (yrs)

5-year survival in patients with HCC is <5%* ESLD: end-stage liver disease

*NIH Consens Statement. June 10-12, 2002;19(3):1-46. NIH Consens Statement. March 24-26, 1997;15(3):1-41.

• 1. Di Bisceglie AM. Hepatology. 2000;31(4):1014-1018. 2. Bialek SR, Terrault NA. Clin Liver Dis. 2006;10(4):697-715.

Natural History of HCV Infection The Benefit of an SVR (Sustained Virologic Response – Cure)

530 patients with advanced fibrosis treated for HCV (36% SVR)

van der Meer AJ. JAMA 2012.

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SVR Decreases Mortality to that

• f the General Population

van der Meer AJ. JAMA 2014.

Goal of HCV Therapy1,a

The goal of treatment of HCV-infected persons is to reduce all- cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by a sustained virologic response (SVR).

aRating: Class I, Level A.

• 1. AASLD/IDSA. HCV Guidelines. www.hcvguidelines.org. Accessed April 18, 2017.

When and in Whom to Initiate HCV Therapy1,a

Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Patients with short life expectancies owing to liver disease should be managed in consultation with an expert.

aRating: Class I, Level A.

• 1. AASLD/IDSA. HCV Guidelines. www.hcvguidelines.org. Accessed April 18, 2017.

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Assessing Readiness for HCV Treatment: PREP-C Cost of FDA Approved Regimens

Regimen Duration $$$ (in US) SOF + PR sofosbuvir + PR* 12 weeks $94,500 SOF + Riba sofosbuvir 12 weeks $91,500 SOF + SMV simeprevir + sofosbuvir 12 weeks $150,000 SOF/LDV ledipasvir/sofosbuvir 12 weeks $94,500 PTV/r/OBV + DSV paritaprevir/ritonavir/ombitasvir+ dasabuvir 12 weeks $90,900 EBR/GZR elbasvir/grazoprevir 12 weeks $54,000 SOF/VEL sofosbuvir/velpatasvir 12 weeks $74,760 GLE/PIB glecaprevir/pibrentasvir 8 weeks $26,400 SOF/VEL/VOX sofosbuvir/velpatarvir/voxilaprevir 12 weeks $74,760 HIV ART many choices 35 years ~$20,000/year PR – peginterferon and ribavirin

VA: > 92 000 HCV-infected veterans since Jan 14, with cure rates > 90%; 51 000 veterans remain

Number of veterans with HCV infection in VA care requiring HCV antiviral treatment over time Effect of availability of HCV drug funding on the number of HCV treatment regimens started in the U.S. Department of Veterans Affairs / week

Belperio PS, Chartier M, Ross DB, Alaigh P, Shulkin D. Curing Hepatitis C Virus Infection: Best Practices From the U.S. Department of Veterans Affairs. Ann Intern Med. 2017;167:499–504

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HCV Elimination in the US

ELISA: enzyme-linked immunosorbent assay.

Thank You! Questions?