# Presentation: 710530

## Hepatitis C in Children

## Prevalence of Anti-HCV by Age (U.S.)

- Alter MJ, NEJM, 1999:341:556

## Proportion of Anti-HCV Seropositive Subjects in Pediatric Age Groups (U.S.)

- Alter MJ, NEJM, 1999:341:556

## Children at Risk for HCV Infection

- Recurrent blood or blood product transfusion
- hemophilia (80-95%), thalassemia (60-75%)
- Blood or blood product transfusion prior to 1992
- ALL (4-9%), cardiac surgery (4-5%), orthopedic surgery, NICU care
- Adolescents with “high-risk” behaviors
- Children born to HCV-infected women

## Low Seroprevalence of Anti-HCV in Urban Adolescents

- 869 subjects from Adolescent Clinic or a high-school based clinic
- 3.2% (22/669) repeatedly anti-HBc seropositive
- 1 (0.1%) anti-HCV seropositive

- Jonas MM, J Pediatr 1997;131:314

## Frequency of Perinatal HCV Transmission

## Perinatal HCV Transmission

- 266 infants born to HCV RNA + women (all infants anti-HCV +)

- Birth (cord blood)	HCV RNA +			HCV RNA -
- 			       18				       248

- Age 4 months	     HCV RNA -	HCV RNA +	      HCV RNA -
- 			16		   2+6 = 8*		242

- Conte D, Hepatology 2000;31:751

- * remained infected at 18 months

## Risk Factors for Perinatal HCV Transmission

- HIV coinfection
- associated with increased HCV viremia
- not necessarily with HIV co-transmission
- Prolonged rupture of membranes
- > 6 hours [Mast E; Antiviral Therapy 2000; 5 (Suppl): 54]
- Internal fetal monitoring [Mast E]
- Mode of delivery not a demonstrable risk in most studies

## Perinatal HCV Transmission fromHIV Coinfected Women

## Perinatal HCV TransmissionOccurs Peripartum

- 441 mother-child pairs in the UK and Ireland
- Overall perinatal transmission rate 6.7%
- 3.8 times higher transmission from HIV coinfected women (no concurrent HIV transmission)
- Negative PCR common in infected newborns
- Mode of Delivery
- Vaginal		    7.7%
- Emergency C/S	     5.9%
- Elective C/S            0%        adjusted OR 0 (0-0.87)

- Gibb DM, Lancet 2000;356:904

- Early rupture of membranes

## Current Recommendations regarding Perinatal HCV Transmission

- Universal testing of pregnant women is not indicated (yet) - targeted testing is recommended
- Elective C/S to prevent HCV transmission is not recommended - avoid internal fetal monitoring or prolonged ROM?
- Breast feeding is not contraindicated
- Testing infants of HCV infected women after 15 months of age for anti-HCV is recommended

## Clinical Features of HCV Infectionin Children

- Acute infection is rarely symptomatic
- Chronic infection is rarely symptomatic
- chronic fatigue may be difficult to assess
- extrahepatic manifestations are much less common than in adults

## Natural History of HCV Infectionin Children - Critical Issues

- What is the rate of progression of liver disease?
- Does fibrosis progress linearly?
- What are the risk factors for progression during childhood?
- What is the role of underlying disease? Mode of acquisition?
- Most natural history studies thus far are cross-sectional cohort studies; prospective studies go out only a few years - is this enough?

## Natural History of Transfusion-Acquired HCV in Children

## HCV Infection Among Survivors of Childhood Cancer

- 1456 transfused/deceased                  1521 transfused/survivors
-     12/346 (3.5%)	     HCV infected	    77 (6.6%)

- 1 death from liver failure			35 have undergone liver bx
-     (9 years after rx)

- 2 deaths from HCC				80% chronic hepatitis
-    (25 and 27 years after rx)			71% fibrosis
- 						 9%  cirrhosis
- 						(9.6, 20, 27 yr after rx)

- Strickland DK, Blood 2000;95:3065

## Natural History of Perinatally Acquired HCV in Children

- Sasaki, 1997:    3/15 at risk infants HCV RNA positive in first month
-                               	 only 1/15 infected at 16 months

- Palomba, 1996:  7 HCV-infected infants born of HCV/HIV coinfected women  all remained infected after 26-90 months

- Bortolotti, 1997:  10 HCV-infected infants followed for 12-48 months
- 		      	 8/10 remained infected

- Anecdotes:  	2 perinatally-infected children developed cirrhosis by
- 		    age 11, 13 years
- 	        	3 perinatally-infected children with decompensated cirrhosis
- 		    at 4, 6, 11 years - 2 born to HCV/HIV coinfected women

- Zuccotti, 2000:   11 HCV-infected infants followed for 42-144 months 
- 		       	 10/11 remained infected:

## Comparison of Histopathologic Features of HCV Infection - Adults and Children

## Histopathologic Features of HCV Infection in Children

- The features are generally the same as seen in adults - suggesting the same disease and pathogenesis
- There is an association between extent of fibrosis and age and duration of infection

## Natural History of HCV Infection in Children - Summary

- May be different in children infected by transfusion vs those infected perinatally
- May be different according to underlying disease for which transfusion was indicated
- Benign in the first 20 - 25 years in most instances; a few have aggressive disease
- Not known in the 3rd decade and beyond

## HCV in ChildhoodGoals of Therapy

- Sustained normalization of ALT
- Sustained virologic response
- Improvement in hepatic histology
- Decrease risk of cirrhosis
- Decrease risk of HCC

## Treatment of HCV Infection in ChildrenInterferon Monotherapy

- No large, randomized, controlled trials
- Heterogeneous patient groups
- Different dosages and types of interferon
- Different lengths of treatment

## Interferon Monotherapy Trialsin Children

- * includes some of the same patients

## Interferon Monotherapy in ChildrenA Meta-analysis

- 11 manuscripts and 3 abstracts
- 270 treated children, 37 controls
- One of the controls cleared HCV RNA
- SVR in treated subjects 35% (0-73%)
- 26% in genotype 1
- 70% in genotype non-1
- Few controls, heterogeneous rx, publication bias

- Jacobson KR, JPGN 2000;S123

## Interferon MonotherapyGreater Efficacy in Children?

- Younger age
- Earlier stage of liver disease
- Different modes of acquisition
- Higher relative interferon dose
- Lack of co-morbid factors
- Artifact

## IFN Side Effects in Children

- Flu-like illness
- Neutropenia
- Weight loss / failure to gain weight
- Irritability, poor school performance, behavior disturbance
- Seizures, lower seizure threshold
- Spastic diplegia (infants)
- Long-term?

## Ribavirin Toxicity

- Hemolytic anemia
- most common in the first weeks
- stabilizes thereafter
- usually < 2 g drop in hemoglobin
- reversible, dose dependent
- Teratogenic, male and female
- Mutagenic in animal models

## Rebetron Pediatric ClinicalTrials

- Phase I Dose Finding Study (Complete)
- 48 weeks treatment, 24 weeks follow up
- Intron A 3 MIU/m TIW & Rebetol 8,12,15 mg/kg/day
- Dose of 15mg/kg/day selected for phase III
- 61 children age 5 to 16 enrolled
- 57 naïve/4 relapse
- Phase III Open Label Study (Ongoing)
- 48 weeks treatment, 24 weeks follow up
- Intron A 3 MIU/m2 TIW & Rebetol 15 mg/kg/day
- 105 children age 3 to 16 enrolled
- naïve only

## Combination Therapy for Childhood HCV - Safety (Phase 1)

- Types of AEs observed similar to those seen in adults
- 2 of the 61 patients (3%) discontinued due to AEs
- 7 of the 61 patients (11%) required dose modification due to AEs

## Phase I Clinical TrialSustained Virologic Response

- Interferon-alfa 2b 3 MU/m2 thrice weekly plus

- *1 nonresponder GT4

## HCV in ChildhoodTherapeutic Considerations

- The long-term natural history is still not completely known - benign in  most?  Aggressive in some.
- Which children should be treated?
- Use same criteria as for adults
- None - no DBRCT’s
- All - short duration, mild liver disease, more likely to respond?