Hepatitis C infection in children and adolescents NASPGHAN.pptx

The 2022 NASPGHAN update provides guidelines for the management of hepatitis C infection in children and adolescents.

1. Hepatitis C
Virus Infection
in Children and
Adolescents

2. An Introduction to Hepatitis C in Children

Hepatitis C virus was discovered in 1989, and the
evolution of understanding of the virology led
relatively rapidly to the development of highly
effective treatments, which were urgently needed
given that HCV was a leading cause of liver
disease leading to liver transplant and/or liver
cancer in adults.

3. An Introduction to Hepatitis C in Children

Our knowledge of HCV infection in children has
exploded, motivating testing of these treatments in the
pediatric age group.

4. An Introduction to Hepatitis C in Children

This knowledge motivated NASPGHAN Hepatology
experts to develop this educational program to cover
important aspects of these discoveries, which we hope
will be widely utilized by multiple types of practitioners
— not only pediatric gastroenterologists but pediatric ID
specialists, pediatricians, family practitioners,
obstetricians, and nurse practitioners.

5. COURSE DIRECTORS

Kathleen B. Schwarz, MD
Rady Children’s Hospital,
University of California San Diego

Yen H. Pham MD
Texas Children’s Hospital,
Baylor College of Medicine

CME Reviewer
Nadia Ovchinsky, MD, MBA
Children’s Hospital at Montefiore

FACULTY

Amber Hildreth, DO

Rady Children’s Hospital,
University of California San Diego

William F. Balistreri, MD

Cincinnati Children’s Hospital Medical Center

Regino P. Gonzalez-Peralta, MD
AdventHealth for Children and
AdventHealth Transplant Institute

Daniel H. Leung, MD
Texas Children’s Hospital, Baylor College of Medicine

6. Faculty Disclosure

Kathleen B. Schwarz
Yen H. Pham.
William F. Balistreri

Regino P. Gonzalez-Peralta

Amber Hildreth

DanielH. Leung

Nadia Ovchinsky
Margaret Stallings

Research fundingand consulting: Gilead
Research funding: Alexion, Gilead, Target
Research funding: Gilead, Abbvie, Merck

Research funding: Gilead, Abbvie, Merck, Mirum
‚Advisory Board: Alexion
Drug Safety Board: Orphalan, Albireo

Nothingto disclose

Research funding: Abbvie, Gilead, Mirum
Data Monitoring Committee: Merck

Nothing to disclose
Nothing to disclose

7. Virology

8. HCV: The Virus

Cae Es =

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10. NASPGHAN
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Entry

* Glycosaminoglycans, Lipoprotein receptors
+ CD81
* Scavenger receptortype B class 1 protein

. Uncoating genomes

, URNA sa BA

Assembly
ED

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11. Translation
+ 5’UTR: IRES
* Replication complex (web)
Uncoating + Large polyprotein
= (+) RNA + Posttranslational Processing
+ Structural: host proteases

) Replication
) complex

Endoplasmic
retiou um

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N ; NASPGHAN
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12. NASPGHAN
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HoV

Transcription

+ Viral (+) sense RNA serves as

template for (-) synthesis

* The (-) RNA in turn serves as
template for progeny (+) strand

Translation

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‘complex

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rerum

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ww

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13. Release
+ Exocytosis Release

urn
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14. Replication S
complex ww

Endoplasmic
retiouum

Adapted from Racanelli 2003

NASPGHAN NASPGHAN
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15. NASPGHAN
FOUNDATION Smith DB, et al. Hepate

014;59(1):318-27.

16. [Most common: GT 1

United States |
GT 1: 75%
GT 2: 12%
:10%

HCV genotype proportion
E

Na”. NS ©

Petruzziello A, et al. World J Gastroenterol 2016;22(34):7824-40.

17. GT1
« Higher HCV RNA levels
Less Responsive to IFN
+ Severe disease

GT1, GT4

+ Insulin resistance

GT3

« Steatosis

NA” + 6 ©

THAN Gower E, et al. J Hepatol. 2014;61(1):545-57. Messina JP, et al. Hepatol. 2015;61(1):77-87 > 4

FOUNDATION Petruzziello A, et al. World J Gastroenterol2016;22(34):7824-40.

18. HCV Heterogeneity: Quasispecies

HCV E2 Bo
SS
Ú
——
ze

19. Natural History & Presentation

20. Pattern of Virologic, Biochemical and Serologic
Events Post Perinatal Infection

E]
E
a
E
£
3
El
=
<

0 1 23 4 5
Months:
Time after Perinatal Exposure

Squires JE and Balistreri WF. Hepatology Commun. 2017;

21. Viral Clearance

« 25-40% of children with perinatal transmission may undergo
spontaneous viral clearance
+ Usually occurs by age 2
* 6-12% of those with chronic HCV infection may clear before
reaching adulthood

* Recurrence of viremia has been reported in a child who had
previously seroconverted, indicating longer term follow up
may be warranted even in patients who achieve clearance

22. Factors Associated with Viral Clearance

+ Genotype 3

« Higher ALT levels in the
first 2 years of life

+ Host IFNL3 (formerly IL-
28B) rs12979860 single
nucleotide
polymorphism

23. Factors Associated with More Severe
Clinical Disease

+ Obesity

* Survivors of childhood cancer

* Congenital anemias requiring transfusions
* HIV coinfection

* HBV coinfection

* Intravenous drug use

* Alcohol use

* Homeless adolescents (risky behaviors and poor access to
medical care

* Incarcerated adolescents

24. Chronic HCV in Children and Adolescents

« Liver disease typically mild in those who fail to clear the virus
in absence of additional risk factors

+ Complications from advanced disease such as portal
hypertension, ascites, variceal bleeding, hepatocellular
carcinoma uncommon but have been reported

« Liver transplant rarely performed in children and adolescents
compared to adult population

25. Clinical Signs and Symptoms

« Majority of children are asymptomatic
+ Most children will have either intermittent or persistent liver
enzyme elevations
+ No correlation between degree of liver enzyme elevation and
histologic severity
+ Hepatomegaly was found in 10% of children in one study,
which correlated to higher ALT values

« Extrahepatic manifestations are rare in children

26. Liver Histology

- Liver biopsy not indicated in most patients, but may be done
when an alternative or secondary diagnosis being considered

+ Peds-C Trial

* Minimal inflammation 42%

« Mild inflammation 17%

* Moderate Inflammation 38%

« Severe inflammation 3%

« 2 of 121 patients with cirrhosis (both obese)

27. Liver Histology

A: Severe chronic hepatitis with
extensive interface hepatitis and
widespread parenchymal inflammation

B: Chronic HCV with steatosis, fat
replacing <1/3 liver tissue. Portal area
with chronic inflammation noted at the
bottom of the field

28. DAAs Improves Graft Survival in
Adult Liver Recipients

29. Epidemiology

30. A Global Issue

31. Worldwide Challenges:
The Quest for Therapeutics and Vaccines

32. A

HCV RNA+

0% to < 0.6% A
0.6% to < 0.8% 2%
E 0.8% to < 1.3% P
E 1.3% to < 2.9%
E 29% to <67%
A

NASPGHAN

33. Epidemiology: HCV Infection in Children
and Adolescents

« Published prevalence rates:
+ 0.05-0.36% in the USA and Europe
+ 1.8-5.8% in other developing countries
+ However, suboptimal ascertainment practices result in
underestimates of true prevalence

* Identified infected children reflect only a small fraction of
expected cases

34. > Global prevalence of hepatitis C virus in children in 2018:
| a modelling study
| Jonathan Schmelzer, Ellen Dugan Sarah Blach, Samantha Coleman, Zongzhen Cai Mindi DePaola, Chris Estes, Ivane Gamkrelidze,
Kathryn rae, Sh Ma, Shana Montoya, Devin azo Shar Karyn Rozas here Sra Robbie Sct, Homie Razo
Mand Hardy Syed

Summary

Background Hepatitis C virus (HCV) prevalence estimates for adults and high-risk groups have been widely published,
but the disease burden in children is poorly understood. Directacting antiviral drugs, which are considered to be
highly effective curative therapies for HCV, are now approved for paediatric patients as young as 3 years. Reliable
prevalence estimates for this population are needed to inform scale-up of treatment and national strategies. This
analysis combines past modelling and epidemiological work in 104 countries and territories to estimate global HCV
prevalence in children in 2018.

‘Methods In this modelling study, a comprehensive literature review for articles published between Jan 1, 2000, and
March 31, 2019, was used to determine historical HCV prevalence estimates in children in all 249 countries and
territories of the world. We identified published HCV prevalence estimates for children aged 0-18 years who are not
at high risk of HCV infection in 39 countries and territories and inputted them into dynamic Markov disease-burden
‘models to estimate viraemic HCV prevalence in 2018. For 25 of them, which had complete data, available information
on HCV prevalence in children was used to build regression models to predict paediatric prevalence in an additional
65 countries and territories that had country-specific or territory-specific data about predictors only. Regression
models were created for each 5-year paediatric age cohort from 0 to 19 years, considering several predictor variables.
‘The data and forecasts from the 104 countries and territories for which data were available were used to calculate
HCY prevalence by Global Burden of Disease region, which was then applied to the remaining 145 countries and
territories to generate a global estimate.

NASPGHAN PASPA

FOUNDATION Schmelzer MPH, et al. Lancet Gastroenterol Hepatol. 2020;5(4):374-392.

35. Viraemic prevalence (%),
ages 0-18 years

No data
Bo.00t0<0.07
Bo07t0<0.13
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Schmelzer MPH, et al. Lancet Gastroenterol Hepatol. 2020;5(4):374-392.

36. Epidemiology

+ HCV prevalence in adults is the primary driver of HCV
infection in children:

« Association between prevalence in adults and prevalence in
children aged 5-19 years of age

+ Prevalence in women of childbearing age - strongest predictor of
HCV in children under 4 years of age

+ Proportion of HCV infections in people who inject drugs
significantly associated with HCV prevalence in children aged 15-
19 years of age

37. Tests Available

«1. Anti-HCV (antibody to HCV)

°2. HCV RNA:
* Qualitative
(Positive or Negative)

* Quantitative
(Detectable viral load in log of IU/mL)

38. Recommended Screening Sequence

{No HCV antibody detected No current HCY infection

- + si
Additional testing as appropriate? { ümweare |

For persons who might have been exposed to HCV withinthe past months, testing for HCV ANA or fleur uptestingfor HCV antibody ls recommended. For persons who are
immunccompromises, testing for HCV RNA can be consideres

Rapest HOV RNA testing ifthe persontested iz suspecte ta have had HCV exposure withinthe posts months orhos cliicalevidenes of HC disease, orifthere is cancernregareing
‘the handlingorstorageofthe test specimen

FO Bare N Ptss/Aumedegov/hepatiis/hv/adte/hev How.dt

39. Estimating Prevalence of Hepatitis C
Virus Infection in the United States,

S adults:

+ “1.7% (“4.1 million) Anti-HCV-positive

NASPGHAN minis d
FOUNDATION Hofmeister MG, et al. Hepatol. 2019;69(3):1020-31

40. 3,000

1,000 4

Reported cases (relative #)

NASPGHAN
FOUNDATION

[El Mates
Ml Females

| li

Age Ws 3)

A 32 36 40 4
=

Ryerson AB, et al. MMWR. 2020;69(14):399-4040.

72 76 80 84 88 92 96

enemy

41. Reported Cases Acute Hepatitis C:
United States, 2002-2017

Age group, y

m 0-19

+ 20-29
30-39

ae E 4—
Zn

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

ASPGHAI
FOUNDATION

Price CP and Brandman D. JAMA Intern Med. 2020;180(5):637-639.

42. JAMA | US Preventive Services Task Force | RECOMMENDATION STATEMENT
Screening for Hepatitis C Virus Infection in Adolescents and Adults
US Preventive Services Task Force Recommendation Statement

US Preventive Servic

* Two new recommendations:
ede + HCV screening at least once in a lifetime
À theUSandal
more deaths tl
Cases of acute
because of ind

for all adults aged >18 years

OBJECTIVE To update its 2013 recommendation, the USPSTF commissioned a review of the
M evidence on screening for HCV infection in adolescents and adults.

NASPGHAN
FOUNDATION USPSTF. JAMA. 2020;323(10):970-75.

NASPGHAN )

43. JAMA | US Preventive Services Task Force | RECOMMENDATION STATEMENT

Screening for Hepatitis C Virus Infection in Adolesceris and Adults
US Preventive Services Task Force Reco atement

US Preventive Se:

Ina ne Hi

the US and al Jeff; aged >18 years
more deaths t] ae
H aning for all pregnant women

Cases of acute
because of ind

OBJECTIVE To update its 2013 recommendation, the USPSTF commissioned a review of the
evidence on screening for HCV infection in adolescents and adults.

NASPGHAN NASPGHAN Y)
FOUNDATION ANEP >

44. Hepatitis C in Injection-Drug Users — A Hidden Danger
of the Opioid Epidemic

T. Jake Liang, M.D., and John W. Ward, M.D.
| uch has been written about the escalating the 1990s, then remained stable
| crisis of opioid-overdose deaths in the for years. Since 2009, however, the
s s _ A number of new HCV cases has ris-
United States and its mounting social and n dramatical

“The growing number of wom
childbearing age with HCV increased number

»

of

NASPGHAN NASPGHAN )
FOUNDATION Liang TJ and Ward JW. N Engl Med. 2018;378:1169-71.

45. NASPGHAN NASPGHAN J)
FOUNDATION DER )):1455-61

46. Epidemiology: HCV Infections in Children
and Adolescents

« Historically, HCV was considered a transfusion-related
disease

¢ With current blood-bank screening practices,
mother-to-infant transmission during the perinatal period is
the most common mode of acquisition

47. ¡Hepatitis C Testing Among Perinatally
Exposed Infants

Susan M. Lopata, MD,” Elizabeth McNeer, MS,“* Judith A. Dudley, BS,* Carolyn Wester, MD, MPH,‘ William 0. Cooper, MD, MPH,
James G. Carlucci, MD, MPH,** Claudia M. Espinosa, MD, MSch,” William Dupont, PhD,** Stephen W. Patrick, MD, MPH, MS*

uno: Hepatitis C virus (HCV) prevalence doubled among pregnant women from
2009 to 2014, reaching 3.4 per 1000 births nationwide. Infants exposed to HCV may
acquire HCV by vertical transmission. National guidelines recommend that infants
exposed b
being fd
tested a
testing.

75% of exposed infants Ferencesiin
for HCV in Tennessee

Tenness > a for infants
born between January 1, 2005, and December 31, 2014. Infants were followed until 2 years
old. Multilevel logistic regression was used to assess the association of HCV testing and
hospital- and patient-level characteristics.

NASPGHAN NASPGHAN )
FOUNDATION Lopata SM, et al. Pediatrics. 2020;145(3):e20192482.

48. Clinical Infectious Diseases

MAJOR ARTICLE

Cost-Effectiveness of One-Time Hepatitis C Screening
Strategies Among Adolescents and Young Adults in
Primary Care Settings

Sabrina A. Assoumou.'? Abrlana Tasillo Jarod A. Left? Bruce R. Schackman, Mark Lynn Dralnon!..* €. Robert Horsburgh.'* M. Anita Barry Craig
Regis,” Arthur Y. Kim. Alison Marshall,”"*" Shee! Saxena," Peter ©. Smith,

wi England. Jamaica iain, "south Boston Community Hesith Conte. and "Department of Mediein.

Methods. We p. and in-
cremental cost-efff . . . n (Er
health centers. Str. =| Fdered by
physician vs by co] (PSA) to

ompared to tar;
by $80 and discounted QALYs by 0.0013 per person. Across all strategies, rapid testing provided higher QALYs at a lower cost per
QALY gained and was always preferred. Counselor-initiated routine rapid testing was associated with an ICER of $71000/Q.
gained. Results were sensitive to offer and result receipt rates. Counselor-initiated routine rapid testing was cost-effective (I

FOU N DATION Assoumou SA, et al. Clin Infect Dis. 2020:70(7);1388-96.

49. Prevention

50. e en o
m (1
Horizontal Transmission

RRA TA ht hs

NASPGHAN NASPGHAN)
FOUNDATION -

51. Risk Factors for Possible Risk Factors for Factors Not Associated

Transmission Transmission with Transmission
+ HCV viremia + Invasive prenatal + Mode of delivery
testing
* HIV co-infection + Prolonged rupture of + Breastfeeding (but
membranes should abstain when
nipples are cracked or
bleeding)

+ Maternal IV drug use + Obstetric procedures

NASPGHAN
FOUNDATION

52. Mother-to-Child: Established Risk Factors

+ HCV Viremia
+ Current Strategy: identify and treat prior to conception
+ Avoid pregnancy > 6months after ribavirin-containing regimen

+ No antiviral therapy approved during pregnancy to prevent
transmission

* HIV Co-Infection

« 2-fold increased risk (10.8% vs. 5.8%)

+ HIV-mediated immunosuppression = higher HCV viral load
* Maternal IV Drug Use

+ Odds ratio 1.5

53. Ledipasvir plus sofosbuvir in pregnant women with
hepatitis C virus infection: a phase 1 pharmacokinetic study

Catherine A Chappell, Kimberly K Scarsi, Brian Kirby, Vithika Suri, Anuj Gaggar, Debra L Bogen, Ingrid $ Macio, Leslie A Meyn, Katherine E Bunge,
Elizabeth E Krans, Sharon L Hillier

Findings From Oct 1, 2016, to Sept 30, 2018, 29 pregnant women were screened and nine (3196) were enrolled. Eight
(89%) women were included in the primary analysis. Ledipasvir and sofosbuvir exposures were similar in the
pregnant women versus the non-pregnant reference group (geometric mean ratio of AUC,, ledipasvir 89-3% [90% CI
68-7-116-1); sofosbuvir 91-1% [78-0-106-3)).

Interpretation Ledipasvir-sofosbuvir was safe and effective without clinically meaningful differences in drug exposure
among pregnant versus non-pregnant women.

Funding National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human
Development, the National Institutes of Health Office of Research on Women's Health, and Gilead Sciences.

NASPGHAN ny
FOUNDATION re ner CA STH tee ee 2070 820008

54. Ledipasvir plus Sofosbuvir in Pregnant Women
with Hepatitis C Virus Infection

Figure 3: HCV viral response to
ledipasvir-sofosbuvir during
pregnancy

Data stated below the chart are
median (range). PK-1 visit was
between 10 and 21 days after
treatment initiation. PK-2 visit was
between 32 and 47 days after
treatment initiation. PK-3 visit was
between 59 and 74 days after
treatment initiation. HCV=hepatitis
C virus. PK-1=first pharmacokinetic
visit. PK-2=second pharmacokinetic
visit. PK-3=third pharmacokinetic
visit. SVR12=sustained virological

response 12 weeks after Sreiag Emmen ARAS vay
completion of treatment. 57(52-65) 5715069) 1(0 (0-2) 000) von)

Participant number

8

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FOUNDATION

55. Treatment with DAAs during pregnancy

FOUNDATION Kushner T and Reau N. Hepatol. 2021:74(3)

56. Mother-to-Child: Possible Risk Factors

* Invasive prenatal testing
+ Theoretical, limited data have not suggested clear risk with
amniocentesis
+ No data on chorionic villus sampling (CVS)
+ Amniocentesis suggested over CVS, if needed

57. Mother-to-Child: Possible Risk Factors

« Prolonged rupture of membranes
+ ROM for > 6 hours identified as a risk factor in several studies
+ Adjusted odds ratio 9.3 [95% confidence interval 1.5-180]

58. Mother-to-Child: Possible Risk Factors

+ Obstetric procedures
« Internal fetal monitoring
* Odds ratio 6.7 [95% Cl, 1.1-35.9]

+ Recommendation: minimize
duration of fetal exposure to
maternal fluids and blood, avoid
invasive procedures

59. Mother-to-Child: NOT Risk Factors

+ HCV Genotype

« Mode of Delivery
+ Cesarian delivery not advised, unless indicated for other reasons.
+ No significant difference in HCV transmission among HIV-neg
women with CS vs. vaginal delivery
+ For HIV co-infected mothers, recommendations regarding mode of
delivery depend on status of HIV infection at time of delivery

Mazza, et al. J Med Virol, 199) ‘Ann Intern Med. 2012;158:109-13.

60. Mother-to-Child: NOT Risk Factors

+ Breastfeeding:
+ HCV RNA detectable in colostrum

+ Acquisition of HCV via breastfeeding has NOT been
documented

« Breast milk may inhibit HCV infectivity through disruption of
viral envelope
+ Likely inactivation of virus by acidity in stomach
« Abstain if nipples cracked or bleeding

61. Horizontal Transmission Prevention

+ HCV is not transmitted by casual contact

« Not a risk to other children

« No restrictions in school, sports, and
athletic activities

* Discrimination and stigmatization in school
and child-care settings A

+ Families should not be forced to disclose a
child's HCV infection status, to avoid mai
discrimination and stigmatization

These things do not spread Hep C

Sneezing &
Coughing

¡0!

Sharing Food / drink

62. Horizontal Transmission Prevention

+ Universal precautions at school and
home

« Avoid blood exposure (sharing razors,
toothbrushes, nail clippers, etc.)

* Use gloves and dilute bleach to clean
up blood

63. Horizontal Transmission Prevention

« Adolescents with HCV
+ Avoid high-risk behaviors:
+ Self-tattooing, self-piercing with shared needles
+ IV drugs and intranasal cocaine because of instrument
sharing
+ Risk of sexual transmission very low/rare, except
among HIV-infected men who have unprotected
sex with men

+ Encourage barrier precautions in +HIV, multiple
partners, or STIs

64. Treatment

65. Evolution of HCV Therapy

66. Who Should be Treated?

THEN

+ Elevation of liver
transaminases

NOW

« At least 3 years of age
+ HCV viremia

¢ Fibrosis on liver biopsy *Test for HBV co-infection

« Personal or family history
of early cirrhosis or HCC

67. Direct-Acting Antiviral for HCV Infection in Children

“tl

Prog tle veu ©

Replication www

; ron

Assembly

Nucleus

FOUNDATION Walker and Watkins. 2018

68. HCV Genomic RNA

HCV genomic RNA

S'UTR NY y QU 3 UTR
cov) ex JER) | na) is] wat) a) non] neo]
IL J

T T
Structural Proteins Non-structural Proteins

\ Vist PNA Viral Replication Complex
F iras (+) RIVA

NS3/4 Protease Inhibitors
-Paritaprevir

-Glecaprevir

NSSB RNA Polymerase Inhibitors
-Sofosbuvir
Core Protein NSSA Inhibitors -Dasabuvir
-Ledipasvir
-Ombitasvir
-Pibrentasvir

ASPGHAI

2G
FOUNDATION Leung DH, et al. JPGN. 2020;71(3):407-17.

69. TABLE 2

Study, year

ting antivirals studied in children with chronic hepatitis C

DAAs Age (yo) HCV GT

Sample
size

SVRI2

Most Common AE

SAE

Balistreri et al,
2016 (136)

Wirth et al,
2017 (137)

Murray et al,
2018 (138)

Leung et al,
2018 (139)

Rosenthal et al,
2019 (140)

‘Schwarz et al,
2019 (141)

Jonas et al,
2019 (142)

ISPGHAL
FOUNDATION

‘shane 12-17 1 (and b)
mg/400 mg)

BER“ mg) and 12-17 2 and 3
ribavirin (weight-based)

1,3, and 4
15 mg/200 mg) au
ribavirin (weight-based)

ritonavir + dasabuvir +

ribavirin
and ribavirin

‘weight based) O

Land 4

12-17 1,2,3,0r4

Leung DH, et al. JPGN. 2020;71(3):407-17.

100

2

92

98%

Headache (27%), diarrhea (14%),
fatigue (13%)

Nausea (27%), headache (23%)

Headache (18%), pyrexia (17%)

Headache (21%), fatigue (18%),
nasopharyngitis (13%)

6-11 y 3-5 yr
Vomiting (32%), — Vomiting (46%),
headache (29%) diarrhea (39%)
Vomiting (24%),
cough (21%),
pyrexia (21%)
Nasopharyngitis (26%)
URI (19%)

None

None

One case
(tooth abscess),
not related to
study treatment

None

RBV overdose

70. FDA- Approved DAA’s for Children with HCV

All genotypes
« Glecaprevir and pibrentasvir 40 mg
(New oral pellets formulation and expanded to > 3 years of age June 2021)

Children 3 to <12 years:
* <20 kg: Oral pellets: Oral: Glecaprevir 150 mg/pibrentasvir 60 mg once daily
* 20 to <30 kg: Oral pellets: Oral: Glecaprevir 200 mg/pibrentasvir 80 mg once daily
+ 30 to <45 kg: Oral pellets: Oral: Glecaprevir 250 mg/pibrentasvir 100 mg once daily
+ 245 kg: Tablets, Oral pellets: Oral: Glecaprevir 300 mg/pibrentasvir 120 mg once daily

+ Children >12 years and Adolescents: Tablets, Oral pellets: Oral: Glecaprevir 300
mg/pibrentasvir 120 mg once daily

+ Duration 8, 12 or 16 weeks dependent on genotype, previous treatment, hepatic compensation, or
transplant status

71. FDA Approved DAA’s for Children with HCV

« All genotypes
+ Sofosbuvir (SOF) / velpatasvir (VEL) once daily for 12 weeks

(New oral pellets formulation and expanded to > 3 years of age June 2021)
* 23 years of age and230kg _ Tablets, oral pellets: 400 mg / 100 mg

+ 23 years of age and 17-30 kg _ Tablets, oral pellets: 200 mg / 50 mg

* >3 years of age and<17kg _ Oral pellets: 150 mg / 37.5 mg

72. FDA Approved DAA’s for Children with HCV

« For genotypes 1, 4, 5, or 6
* Ledipasvir \ sofosbuvir once daily for 12 weeks *

* 212 years of age or >35kg oral pellets, tablets: 90 mg /400 mg QD
(April 2017)

T

+ 23 years of age and<17 kg _ oral pellets 33.75 mg /150 mg QD
(September 2019)

+ 23 years of age 17-35 kg _ oral pellets, tablets 45 mg /200 mg QD
(September 2019)

* Also approvedin Canada + Also approvedin Mexico

73. Safe, Simple, Swift, and Successful
« Safe and highly effective

* The promise of a once-daily, patient tailored (i.e. HIV co-
infection, renal insufficiency, with or without cirrhosis),

single pill treatment with a >95% cure and minimal side
effects for children is now available.

mn — El

74. Barriers to Cure with Approved DAA’s
in Children with HCV

* Cost $$
+ Medical restrictions

+ Paperwork/Appeals

« Adherence/Palatability

75. The Initial Sticker Shock of Treatment

* Can cost between $26,000-75,000 cash
for a 12-week treatment.

«In some cases, nearly $1,000 per pill.

» Actual cost paid for the medications
may be significantly lower. Patient
assistance and support programs
available as low as $5 per co-pay with
commercial insurance.

76. current FDA approved) > a

Discounted costs, outcomes, and cost-

regimens, as welllas those in dere cx tes ki ai

ation in

clinical trials, adolescent patients with chronic HCV infection
Treatment Total QALYS/ Totalcost/ ICER- AS/
Strategies by DAA person person AQALYS

Base case analysis: treatment with DAMS currently FDA approved for children
‘SOF/LDV or SOFRBV

Early treatment (12-17) 19.34 $216390 $26 802
Deferred treatment (=18) 18.20 188135

‘Scenario analysis: treatment with pangenotypic DAAS

GLEPIB

Early treatment (12-17) 19.32 9343 $10088
Deferred treatment (=18) 18.24 $87 107

SOFNEL

Early treatment (12-17) 19.32 $177697 — s20604
Deferred treatment (=18) 18.21 $154748

¡ASPGHAN ED
FOUNDATION Nguyen J, et a. J Pediatr 2019;207:90-6.

77. DDA’s Appear to be Cost-Effective in Children
Down to 6 Years of Age

* Incremental cost effectiveness of early treatment of young
children was $12,690 per QALY gained after 20 years, which is
considered cost-effective ($50 000 per QALY is a conservative
threshold) compared with deferred treatment until adulthood.

+ Cirrhosis, hepatocellular carcinoma, death

+ DAA therapy is not only cost-effective in children as young as
6 years of age but medical decisions for this treatment may also
be based on
a) Impairment on quality of life
b) Psychosocial health
c) Cognitive functioning

78. WA
OR tl sl [\
7 CES
N EB nr
m
NM “A a
8 E:
AK
> =
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FOUNDATION

ASA)

79. Insurance Plans Restrictions or Peer to Peer

* Controlling drug costs by placing restrictions on access to
DAAs that focus on (varies by state)
+ Fibrosis severity
* Liver biopsy
+ Fibroscan®
+ FibroTest
+ Sobriety (any positive drug test is a failure)
« Type of prescriber

+ Prior authorization paperwork with required labs at specific
intervals and specific forms

80. Palatability

+ An important cause of lack of SVR in
children

81. Conclusions

* Treatment should be considered and offered to all children with
chronic HCV as early as 3 years of age

* Dosing is specific to age, Gan e, weight, prior treatment status,
presence/absence of cirrhosis, HIV, or renal disease

+ DAA’s are highly effective, cost-effective and safe, but may not be
palatable for younger children.

+ We must strongly advocate for and learn how to access FDA-
aD DAA combination therapies for all children infected with

82. HIV / HCV Co-Infection
in Children

83. An estimated 36.7 million people are living with HIV globally

Of these, about
2.3 million
have past or
present HCV
infection*

drugs

lion with HIV infection are chi

‘<15 years of age = proportion with eo

“Evidence of HCV antibodies, anti-HCV positive 2
infection unknown

Avert) save org

NASPGHAN PDP)
FOUNDATION htpps://apps.who.int. Global Hepatitis Report. 2017.

84. North America |
1535
(14821598)

The Caribbean
25.44 (2135-2953)

Dan Centraland
10-60% South America
CHE 1489
CS (0412-1566)
m:150

Bata of H Vin MSM collected
bot prevalence not reported
ED NoHIY prevalence data for
MSM identified between 2007-12
BNodsta

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FOUNDATION

Westemand
central Europe
63
(531-696)

svt
y
Y
Sub Saharan
‘ia

v3
163-1892)

Beyrer C, et al. Lancet. 2012;380(9839):367-77.

south and south
1474 1408

east Asia
523(488-558)

AN

Oceania
441
1600581)

” +

nine 4

85. WHO European Region HIV/HCV
Co-Infection Prevalence

-Itis estimated that 4-5 million people living with HIV
(PLHIV) are co-infected with HCV around the world

¢ Prevalence of HCV infection in individuals with HIB in
the region is very high

+ Highest rates in Eastern Europe
» Averaging 40% and reaching 50-90% in urban areas

86. WHO European Region HIV/HCV
Co-Infection Prevalence

* 20-40% in Belarus, the Czech Republic and the Russian
Federation

* More than 40% in Latvia and Lithuania
* 80% in Estonia and Ukraine

* Central European countries (except the Czech Republic and
Poland) HCV co-infection usually lower than 5%

« Prevalence rates higher in areas of high injection drug use

87. LA

V

YE HCV viral load

N

Antiviral
Pro-inflammatory
| Regulatory

?Reduces regulatory \_
response
(increased pathology)

x

HIV

an P and Kim A. PLoS Med. 2007:4(10):e240.

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FOUNDATION

Kleneı

"ie, ee

P-

À

Reduces antiviral
response
(increased load)

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88. Why is HIV/HCV Co-Infection Important?

Compared to HIV-uninfected individuals,
those with HIV have:
* Greater susceptibility to mucosal transmission
* Higher rates of chronic disease

* Accelerated rate of fibrosis, higher rates of
cirrhosis — even in current HIV treatment era

* Higher rates of decompensation and higher
liver-related mortality

89. Major Clinical Impact of HIV on HCV and
Immunological Correlates

Key Clinical Observation Immunologic Correlates

+ Increased persistence rate + Reduced acute T cell responses

+ Increased recurrence rate + Reduced post-acute T cell responses
+ Increased viral load + Reduced steady state CD4+ and

CD8+ T cell responses
+ Reduced HCV treatment responses P
. . . + Increased virus load (consequence
* Increased liver fibrosis of reduce T cell responses?)

+ Increased viral load? Reduced
regulatory response TEE
profibrotic cytokines, e.g. TGFB

90. NASPGHAN
FOUNDATION

ANTIRETROVIRAL
DRUGS.

|

DIRECT ROLE OF VIRUS

HIV Hcv
Za nee.

1

VIRAL-MEDIATED
‘CHRONIC
INFLAMMATION AND
IMMUNE DEFICIT.

|

mitochondrial —Tryglicerid accumulation in hepatocytes ‘Adipocytes
nu - Inhibition of VLDL assembly dysfunction
<——— [ADIPORINES

L

“+

+ insulin and glucose

accumulation

|

(STEATOSIS)

I

HSCs proliferation

Foros

Mastroianni CM, et al.

ET
f

Int Mol Sci. 2014;15(6):9184-208.

Adiponectin
À body tat and} insutin sensitivity

110
= À cana na

+ resistin
tus

- À activation HSCS
t Leptin

Lore

Ps

91. Natural History of HCV/HIV Co-Infection in Children

+ 131 of 179 on antiretroviral therapy had undetectable HIV RNA
+ 42% had hepatomegaly

+ 55% had elevated liver enzymes

* 12/97 had > 9kPa on transient elastography

* 6/17 liver biopsies showed bridging fibrosis and
one showed cirrhosis

92. HCV Treatment in Children and Young Adults
with HIV/HCV Co-Infection in Europe

Untreated— Unknown outcome Treatment failure MM SVR24

73 4 36 18 43

101 Children treated with
peg/ribavirin and followed up 24
weeks post discontinuation of
treatment

Gra
3
21

ISPGHAI
FOUNDATION Turkova A, et al. J Viru:

93. Prevalence and Predictors of Liver Disease in
HIV-Infected Children and Adolescents

p<0.0001 p<0.0001 p= 0.0005 p=0.42 P = 0.0006

| | | mi Mm.

iver disease ALT>ULN AST>ULN Bilirubin >ULN GGTP>ULN

M Total (n=79) ii No coinfection (n=71) 14 With coinfection (n=8)

L
FOUNDATION

94. NASPGHAN

FOUNDATION todd Brown. 18% CRO! Conference on Retroviruses and Opportunistic Infections. 2011 Feb 27-Mar 2:Boston, MA.

BACKGRO!

Q HIV and HCV infections are each associated with reduced bone density

A Coinfection might exacerbate bone loss and increase fracture risk
Below is a model for mechanisms for low bone density and fracture:
Antiretroviral
Therapy

HIV—+ |? Cytokines:
TNF-a

Chronic HCV=—+ |: Interleukin-1 |
sinterieukin-s | * (Reduced un Fracture
4 BMD

— Hypogonadism 7

Progressive
Liver
Dysfunction

—> 4 25-0H vitamin D /

+ Insulin-like

growth factor.) > Y osteoblasts

— | osteoprotegrin ——————> 7 osteoclasts

ney

95. Take Home Messages

* HIV co-infection with HCV in children hastens morbidity and
mortality

* But, no data yet on the use of DAA’s for co-infected children

» Hopefully prognosis will improve for co-infected pediatric
subjects just as it has for HCV mono-infection and HIV
mono-infection

96. Stigma in Children with HCV

97. What is Stigma?

“Stigma is a negative attitude held by society that discredits a
person or group because of a particular attribute, such as an
illness - often related to a lack of understanding about the
disease or illness, in particular transmission, for example
where it is believed the illness is self-inflicted as a result of
lifestyle choices.”

98. What is Discrimination?

“Discrimination is the behavioral consequence of stigma and it
means treating an individual unfairly or unjustly because they
have certain characteristics.”

99. Determinants of Stigma Among Patients with
Hepatitis C Infection

« Three statements validated for assessment of stigma
in adults with HCV — no validated tools yet for
assessment of stigma in children with HCV

+ “People have physically backed away from me when they
learn | have HCV”

+ “Some people act as though it's my fault | have HCV”

« “| have stopped socializing with some people because of
their reactions to my having HCV”

100. PubMed Search for Stigma and Children with
HCV; January 2021

« Of the 12 resulted no articles specifically addressed the topic

« Two references with stigma in the title were in Russian

* Bullying, internalized hepatitis (Hepatitis C virus) stigma, and
self-esteem: Does spirituality curtail the relationship in the
workplace (Noor, et a/).

* Therefore, great need for pediatric studies!!

101. Conflicting Data on the Effect of HCV on HRQOL
in Children (U.S.A.)

* PEDS C study of 114 children at entry to clinical trial. Little impact
of HCV on Health-Related Quality of Life (HRQOL) of children,
while HRQOL may reflect negative stigma but stigma per se not
studied!

* HRQOL scores for the study sample did not differ significantly
from the normative sample, including the self-esteem scores.

+ However, two of the scaled scores, General Health Perceptions
(p<0.0001) and Parent Impact-Emotional (p<0.0001), were
significantly lower in the study sample than in the normative
sample. CHQ scores did not vary significantly based on the
caregiver’s own HCV status.

102. Short Form-36 Scores for HCV-Infected Mothers
vs. Non-Infected Caregivers

« SF-36 scaled scores (mean + s.d.) for 43 HCV-infected
mothers who transmitted virus to the enrolled child versus

67 non-infected caregivers

SF-36 Domain HCV-Infected Mothers Non-Infected Caregivers
86 +23
8/224"
80424
ET Ve
63 +20

TT 21,

Physical Functioning

Role-Physical

Bodily Pain

* p<0.006

[Social Functioning
Role Emotional

Mental Health

103. Demographic Characters of HCV Infected and
Control Groups

Cases Control Test of significance

11.43 +33 11.62 = 3.38 1=0.40 p=.68
n(%) n(%)

52 (51.0) 40 (39.2) 122285 p= 09

50 (49.0) 62 (608)

48 (47.1) 60 (58.8) 72528 p=.09
54 (529) 42412)

Years of education
Median (min-max) 6.0 (1.0-12.0) 8.0 (1.0-12.0) 220.33 p=74

Family history of psychiatric disorders
Negative 95 (93.1) 90 (88.2)
Positive 7(69) 12118)

Note. 7?= Chi-square test; z = Mann-Whitney test; t=Student ¢ test.
*p high statistically significant <.001.

Ibrahim IMA, etal. Clin Child Psychol Psychiatry. 2021;26(2):381-92.

104. Comparison of IQ, Depression and Anxiety
Scores Between Cases and Controls

Cases

Control Test of

n=102

significance
n=102

Mean + SD

Mean + SD

Verbal 1Q

Performance IQ

Total IQ

100.28 + 22.61
72.31 +21.76

87.79 + 20.1

Depression 14.34 + 5.87

Anxiety

28.66 + 7.78

102.36 + 13.91
94.87 + 16.49
97.4 + 10.04
7.18+3.7

1833 +96

Note. t=Student t test.
“High statistically significant.

PGA!
FOUNDATION

Ibrahim IMA, etal. Clin Child Psychol Psychiatry. 2021;26(2):381-92.

105. Psychatricdisordersin control group
Psychatric disorders in cases

ano psychiatie mo psychiatrie
disorder disorder
Me depression
ao
Ge conduct
érshymia
span

NASPGHAN ny
FOUNDATION Ibrahim IMA, etal. Clin Child Psychol Psychiatry. 2021;26(2):381-92.

106. 6 FACTORS AFFECTING ATTENDANCE FOR HEPATITIS € CARE

Individuals Providers

KNOWLEDGE

COMPETING
STIGMA GAPS/
PRIORITIES HEALTH LITERACY
nebenan
FOUNDATION https://hepatitiseducation.ca.

is C Disease Course, SRN Nursing

The System

ACCESSTO
SERVICES

NASPGHAN)

107. NASPGHAN WASPGHAN)
FOUNDATION Niebel M. Lancet Gastroenterol & Hepatol, 2017;2(10):P705. a

108. How do WE Eliminate the Stigma
of HCV in Children

* Recognize it does exist for the child
and family

* Respect privacy and the right of non-
disclosure

* Model successful campaigns used for
children with HIV

* Diagnose, treat and eliminate HCV in
children!

109. Summary: Hepatitis C in Children

* Careful description of the molecular virology of hepatitis C
virus led to highly effective direct acting antiviral agents.

¢ Natural history studies have revealed that subtle signs of
liver disease such as fatigue are common and often indicate
progression to fibrotic liver disease suggesting treatment
should be universal.

110. Summary: Hepatitis C in Children

« The opioid epidemic has led to a dramatic increase in
newborns with HCV. Prevention by screening these mothers
is key.

+ HIV/HCV infection has a worrisome natural history

« While it is difficult to study stigma in children with HCV it
exists

« We need to marshal a major team effort to screen high risk
infants and children so as to treat all infected individuals and
eradicate HCV!