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“Progress Towards Elimination-Specific Populations”

Children & Pregnant Women

Manal H. El-SayedProfessor of PediatricsAin Shams University

National Committee for Control of Viral Hepatitis

International HepElimination 2nd-3rd December 2016

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Disclosure of speaker interest

Travel to international meetings in the last two years has been supported by pharma (Abbvie, Gilead and Quadri-Pharma)

Member of Advisory board of Perspectum-Liver Multiscan

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•Overview

• Epidemiology

•Hepatitis in the childbearing age and childhood

•Diagnostic challenges

•Management

2nd Dec 2016

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• Infection is mostly asymptomatic

• Children do not undergo biochemical testing or donate

blood

• Many children with HCV have normal ALT values

• Risk factors are not known or sought by care-providers

• Extrahepatic manifestations are rare

• Pediatricians do not consider HCV infection

Diagnosis

2nd Dec 2016 BURDEN LARGELY UNKNOWN

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El-Sayed and Razavi, Global Estimate of HCV Infection in The Pediatric and Adolescent Population , (2015). P1263. J Hepatol;62:S831–S832.2nd Dec 2016

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•

El-Sayed and Razavi, Global Estimate of HCVInfection in The Pediatric and Adolescent Population , (2015). P1263. J Hepatol;62:S831–S832.

-Viremic prevalence was lowest in

“high income countries”

at 0.3% (0.03-0.5%) and

highest in “low income countries”

at 0.6% (0.1-1.0%).

-There are 6.6 (6.1-11.6) million

viremic infections.

2nd Dec 2016

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2.5 %CLA World Factbook 2012CDC NVSR 2012US Census

• Worldwide population ~7.5 Billion

• Worldwide births 131.6 million/yr

• US population 2012: 314,353,063

• US Births 2010: 3,999,38 6

• Assume 5.6%-7% Transmission:

FertilityRates

• ~160 million currently HCV+ve

• ~3 million/yr will become HCV+ve

• ~5 million HCV+ve

• ~94,000 infants born of HCV+ve mothers/yr

• ~5,200-7,500 new HCV-infected children/yr

2nd Dec 2016

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• 31,000 (0.179%) of 6-11 yrs & 101,000 (0.39%) of 12-19 yrs are anti-HCV +ve.

• CHC estimated: 23-46,000 children in US (6,600 in Canada)

• CHC acquired in childhood is associated with 26-fold increased risk of liver-related deaths

• The most common route of acquiring HCV is vertical transmission

• Pediatric HCV associated with 10 yrs costs of 199 – 336 million USD

National Health and Nutrition Examination Survey III

2nd Dec 2016

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• According to CDC, during 2011–2014, increased HCV detection among women of childbearing age & children aged ≤2 years were observed in the US and Kentucky (22%and 14%, nationally; >200% and 151%, Kentucky).

• During same period, birth certificate data showed the proportion of infants born to HCV-infected mothers increased 68% nationally and 124% in Kentucky.

Implications for public health practice?

• Increased HCV testing of pregnant women, testing

guidelines for children born to HCV-infected women,

and perinatal HCV case definition might improve

early identification and subsequent linkage of

mother and infant to care and treatment to prevent

HCV-related sequelae.

2nd Dec 2016 MMWR / July 22, 2016 / Vol. 65 / No. 28

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2nd Dec 2016

• Extravillous cytotrophoblasts join a column at the tips of the anchoring villi and invade the uterine wall.• Syncytiotrophoblasts that cover floating villimediate passive transfer of IgG from maternal blood to the fetus. • HCV transmission to the fetus could occur through viral transcytosis across trophoblast cells, could be mediated by “HCV receptors” expressed at the surface of placental cells, or could result from direct or indirectinjury that compromise the integrity of the placental barrier.

Le Campion, et al, Viruses; 4, 3531-3550; 2012

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HBV and HCV

Preterm birth

Low birth weight

Premature rupture of membranes

Gestational diabetes

Possible small increase in congenital

anomalies

HCV

Cholestasis of pregnancy

NICU admission

Neonatal abstinence syndrome

2nd Dec 2016

Dunkelberg et al, J Perinatol; 34(12):882-91, 2016.Benova et al, Clin Infect Dis;59:765-73, 2014.Kanninen et al, Hepatology; 62:1656-8, 2015

Pregnancy outcomes with HBV and HCV

• Pregnancy in patients with chronic HBV or HCV is associated with MTCT and may be associated with increased maternal and fetal complications.

• HCV vertical transmission occurs in 5.8% (95% confidence interval= 4.2%–7.8%) of infants born towomen who are infected only with HCV and in up to twice as many infants born to women who are also infected with “HIV” or who have “high HCV viral Loads”.

Dunkelberg et al, J Perinatol; 34(12):882-91, 2016

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2nd Dec 2016

• HBV:

- Neonatal “vaccination” and “immunoprophylaxis”, “antiviral agents” such as TDF or telbivudine during pregnancy beginning at 32 wks of gestation is safe and effective in preventing MTCT.

• HCV:

- In the absence of a vaccine for HCV, we need to improve HCV risk screening, including children born to HCV-infected mothers

- No therapeutic agents are yet available or recommended to decrease the risk of MTCT of HCV, which remains 3 to 10%.

- HCV MTCT can be minimized by avoiding *fetal scalp electrodes and *birth trauma whenever possible.

- Young women with HCV should be referred for treatment post delivery, and neonates should be closely followed to rule out infection.

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2nd Dec 2016

• 200 mothers HBeAg +ve & HBV DNA >200,000 IU/ml. • Subjects randomised to usual care or TDF (300 mg/day)

from 30-32 wks gestation. • All infants received immunoprophylaxis• Maternal & infant safety profiles were similar • After the discontinuation of TDF, ALT elevations >ULN occurred more frequent in TDF group than control group (45% [44 of 97 women] vs. 30% [30 of 100], P = 0.03).

Conclusion: In a cohort of HBeAg+ve mothers with an HBV DNA >200,000 IU/ml during the 3rd trimester, the rate of MTCT was lower among those who received TDF therapy than among those who received usual care.

Pan et al, NEJM; 374;24, 2016

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• Infection is mostly asymptomatic

• Children do not undergo biochemical testing or donate

blood

• Many children with HCV have normal ALT values

• Risk factors are not known or sought by care-providers

• Extrahepatic manifestations are rare

• Pediatricians do not consider HCV infection

Diagnosis

2nd Dec 2016

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0-14 years: 32.1% (male 14,272,494/female 13,639,550) 15-24 years: 17.8% (male 7,913,351/female 7,536,925) Rate of births: 23.35 births/1,000 population

• More than 100,000 < 15 yearsmay be chronically infected with HCV

• >10,000 are born yearly with HCV(DHS survey 2015: 7% HCV viremiaamong the Egyptian population (15-59 years)

2nd Dec 2016

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• Recurrent blood or blood product transfusion or multiple

invasive procedures

• Children born to HCV-infected mothers

• Children with an infected house-hold member

• Adolescents with high risk behavior (illicit drug use)2nd Dec 2016

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• Perinatal HCV in 1,863 mother-infant pairs in rural Egyptian villages.

• 15.7% and 10.9% of pregnant women were anti-HCV and HCV-RNA +verespectively.

• Among 329 infants born of these mothers, 33 (10.0%) WERE +ve for both anti-HCV and HCV-RNA 2 months following birth.

Shebl et al, J Med Virol, 2009

• Incidence of community-acquired infection in children in 3 Egyptian villages.

• 2852 uninfected infants were prospectively followed, the incidence was3.8/1000 PY during infancy and for the 1-5-years age group.

Saleh et al, Trans R Soc Trop Med Hyg. 2010

2nd Dec 2016

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• 1042 children 1-9 years were screened, asymptomatic HCV infection was detectable in 2.02% Egyptian children. (El-Raziky et al, WJG 2007)

• HCV intrafamilial clustering was reported more from sibling-sibling (31%) and to a lesser extent from mother-child (23%), Father-child (12%) or husband-wife (6%) (Plancoulaine et al, 2008)

• 500 children, age between 6 and 15 years, were selected from 10 schools in Alexandria, Egypt. HCV seroprevalence was 5.8%, with HCV viraemia in 75% of the studied children

(Barakat and El-Bashir, J Viral Hepat, 2011)

2nd Dec 2016

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• MOH Survey 2009: prevalence of HCV for 3678 Egyptian children from 1-15 years old in 8 representative Governorates.

• The prevalence for HCV was 0.5%

• HCV infection was higher among rural than urban residents (0.5%

compared with 0.2%). Males are also more affected (0.5%) than

females ( 0.3%).

• DHS survey 2015: prevalence of 0.2-0.5% between ages 0 and 15 yrs

2nd Dec 2016

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• > 20 Egyptian studies ; 1993 through 2011 (mostly thalassemics)

• Maximum no studied <100

• Anti-HCV in 55-90% in early studies

• HCV-RNA dropped to 23-50% in later studies

• One study showed decreased prevalence after 1993

• One study showed increased infection (15%) in neonates after exchange

transfusionKhalifa et al, J Trop Med Hyg, 1993Mansour et al, Hematol Oncol Stem Cell Therap, 2012El-Sayed et al, Egypt J Hematol, 2014Mahmoud et al, Adv Hematol, 20162nd Dec 2016

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Three year prospective survey:

• Among 92 children receiving chemotherapy 62% were anti-HCV &/or HCV-RNA +ve (80% genotype 4) (El-Sayed et al, Hematol J 2003)

• Prevalence and incidence is still high (high reservoir and burden of disease in an immune-suppressed population)

2nd Dec 2016

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P value

Hematological

malignancies

n=51 n(%)

Hematological

disorders

n=49 n(%)Characteristics

0.00240(78.4)21(43.8)History of HBV vaccination

<0.00059(17.6)40(81.6)Anti-HCV Ab +ve

0.01212(23.5)24(49.0)HCV RT-PCR +ve

0.2326(52.0)**19(38.8)HBsAg +ve*

0.114(7.8)0(0.0)HBV PCR (s region) +ve

0.4120(39.2)***15(30.6)HBV PCR (c region) +ve

* HBV anticore IgM was negative in all patients.** 2 of those patients were also HBVeAg

positive *** One patient only was positive for HBV PCR (x region)Said et al, Liver International, 2009Said et al, Liver International, 20092nd Dec 2016

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• Infections acquired during infancy are more likely to spontaneously resolve and fibrosis of the liver tends to increase with age suggesting slow progressive histologic injury.

• 50% acquiring HCV in early childhood are expected to clear the virus before the age of six.

• HIV co-infection: increases the risk of vertical transmission (up to 25%) and progression of liver disease.

• Co-morbidities: including siderosis, cancer chemotherapy among others increase the risk of progression of liver disease.

2nd Dec 2016

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• 32/36 patients underwent liver biopsy, macrovesicular hepatic steatosis associated with chronic hepatitis C was documented in 10 children (31.3%).

• BMI was higher (P ≤ 0.05) and apo-B was lower in steatotic (P ≤ 0.05) than non-steatotic HCV-infected children.

• ALT and apo-B were independent predictors for hepatic steatosis(P<0.001, and <0.05, respectively).

• Worse response to Peg-interferon alpha 2-b plus ribavrin treatment for HCV was reported among children with steatosis (P < .001).

Al-Tawil et al, Pediatr Hematol Oncol, 20152nd Dec 2016

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• Higher SVR rate in older studies using conventional IFN

• Cost advantage using weight- and BSA-based dosing

• Relative absence of co-morbid factors

• Benefits of eradicating HCV before risky behaviors associated with transmission

• Better tolerance of medications (?)

• Excellent compliance with treatment

• Treat Children with co-morbidities to prevent relentless progression of liver disease

2nd Dec 2016

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• Children better candidates

• Avoid disease progression

• Remove social stigma

• School performance and fatigue

• Extrahepatic manifestations and co-morbidities

• Decrease HCV burden and avoid transmission (CasP)-Curing a patient saves ~ US$ 10,000 for the next 15 years Preventing

a case saves ~ US$ 20,000 for the next 40 years.

Treatment

Estes C, et al. Alim. Pharm. Ther. 20152nd Dec 2016

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• ”

• Active neuoropsychiatric disorder

• Pregnancy

• Decompensated liver disease

• Autoimmune diseases

• Renal dysfunction

• Active cancer

• Hemoglobinopathy

• Hemosiderosis

Infants-Young childrenNeurological toxicitySpontaneous viral clearance

2nd Dec 2016

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• Avoid Transmission to Others– Avoid sharing of razors, toothbrushes, nail clippers

– Blood precautions after injuries

– Avoid sharing Hijab Pins

• Delay Progression of Liver Disease– Hepatitis A and (Hepatitis B) immunizations

• Do not exclude children from work, school, play, child-care or other settings based on HCV infection status

• Tell the school nurse???

• Nutrition and Exercise recommendations

2nd Dec 2016

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• Recruiting: Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children With Genotype 2 or 3 Chronic HCV Infection

• Condition: HCV Infection

• Interventions: Drug: SOF (oral tablets);

Drug: RBV;

Drug: SOF (oral granules)

• Recruiting: Safety and Efficacy of Ledipasvir/ Sofosbuvir Fixed Dose Combination +/-Ribavirin in Adolescents and Children With Chronic HCV-Infection G1

• Condition: HCV Infection

• Interventions: Drug: LDV/SOF; Drug: Placebo to match LDV/SOF; Drug: RBV

• Results: 96-100% EOT response naïve, experienced +/- cirrhosis

* IRB approval for SOF/LED trial in children under chemotherapy in Egypt2nd Dec 2016

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• Prevention of Vertical transmission for HBV and HCV (screenng all pregnant women)

• Early treatment of women in childbearing age

• POC diagnostic tests

• Early treatment of children (consider extrahepatic manifestations, Psychiatric disorders and neuro-congnitive dysfunction…...)

• Pediatric clinical trials results won’t be available before 2018/2019

• Stigma

• Compliance to and adherence to HBV therapy long term by adolescents (substance abuse, disruptive behavior….etc)

• The availability economics of manufacturing Pediatric formulations

• Access of children in low and LMIC to prevention and treatment

2nd Dec 2016

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• The NCCVH members and chair: Prof Wahid Doss

• The Egyptian Liver Care Society board members and chair: MrsYosryia Sawiris

• Sawiris Foundation

• CIB Foundation

• WHO, US-CDC & Pasteur Institute (development of national prevention plan)

• Pediatric Departments at: AinShams University, National Liver Institutes in Cairo and Menoufia, Cairo University, Alexandria University, Mansoura University, Minia and Assiut Universities.

• Pediatric Oncology and Virology Departments at the National Cancer Institute and 57357 Hospital.

• My patients and their families

2nd Dec 2016