Treatment of HCV in Children

Maureen M. Jonas, MD Center for Childhood Liver Disease

Disclosures

• Merck: research support • Roche: research support • BMS: research support • Gilead: consultant (DSMB) • Novartis: consultant

• I will talk briefly about off-label use of

pharmaceutical agents in children

The Pediatric “Final Rule” • FDA Modernization Act (FDAMA) 1997

– Established financial incentives for inclusion of children (6 months exclusivity extension)

• Pediatric Rule of FDA in 1998 – Applications for new active ingredient, indication, dosage form,

dosage regimen, route administration – required pediatric assessments

– Not enforceable, not a “law” (suspended by court order October 2002)

• “Children’s Health Act” enacted in 2000 – Requires that all research involving children that is conducted,

supported, or regulated by HHS be in compliance with HHS regulations providing additional protections for children involved as subjects of research

• FDA initiated other measures in 2001 with specific pediatric ethical considerations

The Pediatric “Final Rule”

• An “interim” Rule was passed into law in April 2001 (66 FR 20589)

• Best Pharmaceutical Practices for Children Act – 2002 and 2007 – reaffirmed exclusivity

• Pediatric Research Equity Act of 2007 • Patient Protection and Affordable Care Act –

2010 – re-affirmed pediatrics as special population and extended pediatric exclusivity to biological products

Per year post-2001 2001 Low High

Drugs and Biological Products 264 561 637

Medical Devices 170 305 572 Foods and Food Additives:

Infant Formula 5 5 15 Food Additives 1 1 3 Total IRB Reviews per year 440 872 1,227

Total IRB Costs per year (annual reviews)

$33,000 $79,817 $112,357

Estimated Number of IRB Reviews per Year for Clinical Investigations in Children

The Pediatric “Final Rule” • Increases in enrollment of children in clinical

investigations • Amendment and finalization passed in February

2013, effective March 28, 2013 – Adopted the safeguards described in previous FDA

reports and recommendations – Included drugs, biologicals, medical devices, foods

including dietary supplements, infant formulas, etc. – Modified definitions (“guardian” “permission”), clarify

levels of risk – Defined specific conditions under which placebo-

controlled trials may be appropriate in children

Boston Children’s Hospital Each protocol undergoes 2 separate reviews 1. Scientific review

– Even an industry-sponsored multicenter trial

2. Human Subjects Protection review – Special pediatric considerations – Privacy issues – medical conditions, pregnancy

testing and results

HCV Case 1

• 4 year old girl • Adopted from Ukraine orphanage • Asymptomatic • ALT 74 • Genotype 1b • Liver biopsy: grade 2, stage 3

HCV Case 2

• 9 year old boy • Mother treated for HCV • ADHD on Ritalin • ALT 24 • Genotype 2a • Liver biopsy: grade 1, stage 1

HCV Case 3

• 14 year old girl • Newly diagnosed ulcerative colitis • ALT 98 • ANA positive • HCV genotype 1a • Liver biopsy: chronic lymphoplasmacytic

hepatitis and findings of PSC

Hepatitis C Virus Infection Prevalence by Age

0

1.0

2.0

3.0

4.0

5.0

< 11 11-19 20-29 30-39 40-49 50-59 60-69 ≥ 70

Age Group

Anti-

HCV

Posi

tive

(%)

Alter MJ, et al. N Eng J Med. 1999;341:556-562.

Hepatitis C in children in Florida - 2008

18,251,243

4,040,238 children

12,155 Expected HCV infected children

Year Cases Reported

2000-6 1,167

2007 318

2008 270

Total 1755 (14.4%)

∼12% of identified children receiving care

Delgado-Borrego, A.et al. J Pediatr 2012:161:915-21

Proportion of HCV-Infected Children Identified by State

Natural History of Hepatitis C

Acute infection

Chronic infection develops in 80%

Chronic hepatitis

Cirrhosis develops in 20%

Risk of carcinoma 1-4% per year

> 30 years

≤ 20 years

Female sex, young age at infection

Alcohol use, coinfection

Rate

of P

rogr

essio

n

Acute HCV in children

• Rarely recognized • Known exposure (IV drugs) • No studies specifically with children • Some spontaneous resolution • Consider treatment within 2 to 3 months of

known exposure

HCV in Children Rationale to Treat during Childhood

• Higher SVR rate in older studies using conventional IFN

• Cost advantage using weight-based and BSA-based dosing

• Relative absence of comorbid factors • Benefits of eradicating HCV before risky behaviors

associated with transmission • Better tolerance of medications • Excellent compliance with treatment

HCV in Children PEG-IFN alfa2b Pediatric Trial

107 Treatment Naïve Children 3 to 17 years of age

PEG α2b 1.5 mcg/kg/week ribavirin 15 mg/kg/day

GT 1, 4 GT 3, HVL*

GT 2 GT 3, LVL

48 weeks 24 weeks

*HVL: >600,000 IU/ml Wirth S et al. J Hepatology 2010;52(4):501-507

HCV in Children -2010 PEG-IFN alfa2b Pediatric Trial

GT 1, 4 GT 3 HVL

GT 2 GT 3 LVL

55% SVR 96% SVR

Wirth S et al. J Hepatology 2010;52(4):501-507

HCV in Children -treatment

• Peginterferon-alfa2b and ribavirin licensed for use in children as young as 3 years of age in 2010

Hepatitis C in Children – PEDS-C

• PEDS-C (peginterferon-alfa2a ± ribavirin) begun in 2004, completed in 2010 – 119 children screened, 114 treated

• Baseline histology data* – Inflammation moderate in 38%, severe in 3% – 2 with cirrhosis, 5 had bridging fibrosis – Correlation of duration of infection and steatosis

with fibrosis

*Goodman Z et al. Hepatology 2008;47:836-43

PEDS-C Efficacy and Safety Results

SVR rate (%)

PEG + riba N = 55

PEG alone N = 59

Overall 53 21

GT 1 47 18

GT non-1 80 36

Schwarz et al. Hepatology 2008;48:418A Schwarz et al. Gastroenterology 2011;140:450-8

HCV in Children - PEDS-C Safety

Three major safety concerns at the outset – Depression, behavior changes, cognitive

changes – Neutropenia and infection – Changes in BMI, body composition, and growth

(pediatric-specific)

PEG-IFN has minimal effect on QOL, behavior and cognitive outcomes in children

• 114 children 5-17 years of age • Standardized assessments at baseline, after 24 and 48

weeks of treatment, 6 months, 1 and 2 years after treatment

• At week 24, mean physical QOL scores declined but remained normal

• 3 children had increase in depression symptoms • At week 48, no significant effects observed • Majority of children experienced no clinically

significant change in QOL, behavioral adjustment, depression or cognitive functioning during or after treatment

Rodrigue JR et al. Hepatology 2011;53(5):1468-75

PEDS-C Neutropenia

Neutropenia incidence: • ANC 500 to < 750 in 33% • ANC 250 to < 500 in 7% • ANC < 250 in 0% (obligate dose reductions) • No difference in rate of infection in subjects

with neutropenia • No clear effect of dose reduction on SVR rate

PEDS-C: Changes in WAZ, HAZ and BMIZ (48 week treatment group)

Jonas et al. Hepatology 2012;56:523-31

PEDS-C: changes in body composition

PEG-IFN in children: Ophthalmologic complications

• 114 children in PEDS-C • Eye exams at baseline and after 24 (N=110) and

48 (N=103) weeks of treatment • 2 documented and 1 possible eye complication:

– 1 ischemic retinopathy (cotton-wool spots) at week 24; treatment discontinued, resolution by 6 weeks

– 1 uveitis at week 48; topical prednisone and cyclopentylate, poor compliance, no vision change but synechiae persisted

– 1 transient (< 4 hr) monocular blindness at week 36, PI not notified until week 43, treatment discontinued, exam normal

Narkewicz MR et al. J Pediatr Gastroenterol Nutr 2010;51:183-6

PegIFN and ribavirin trials in children Wirth et al

2005 Wirth et al 2010

Schwarz et al 2011 Sokal et al 2010

N 62 107 114 after exclusions 65 Age 2-17 3-17 5-17 6-17 % with cirrhosis 0 0 2 (excluded) 0 peginterferon (weekly) alfa-2b 1.5 µg/kg alfa-2b 60 µg/m2 alfa-2a 180 µg/1.73m2 alfa-2a 100 µg/m2 ribavirin (daily) 15 mg/kg 15 mg/kg none or 15 mg/kg 15 mg/kg Duration (weeks) GT 2 or 3 24 or 48 24 or 48 48 24 GT 1, other 48 48 48 48

SVR (%) GT 2 or 3 100 93 80 (comb rx) 94 GT 1, other 48 54.5 47 (comb rx) 57 Adverse Events neutropenia (%) 83 33 27 17 abnormal TSH 10.3 23 NR 11 Weight loss (%) 19.7 19 (see figures) none Growth disturbance (%) NR 70 33 none

Aggregate SVR by Treatment

Hu J, et al. Treatment of hepatitis C in children: a systematic review. PLoS One 2010;5(7): e11542

IFN (122/342) PEG-IFN(6/14) IFN+riba (109/233) PEG-IFN+riba (341/493)

HCV in Children- PEG/riba Systematic Review and Meta-analysis

• 8 trials met inclusion criteria (φ = 0.94) (N=438) • 58% subjects (95% CI 53-64%) achieved SVR,

rates higher GT 2/3 than 1/4 • Discontinuation for AE: 4% • Discontinuation for viral breakthrough: 4% • Discontinuation for lack of response: 15% • Relapse 7%

Druyts et al. Clinical Infectious Diseases, published on-line December 27, 2012

HCV in Children- PEG/riba Systematic Review and Meta-analysis

• Anemia: 11% • Neutropenia: 32% • Thrombocytopenia: 5% • Alopecia: 13% • Pruritus: 10%

• Conclusion: PEG-IFN/RBV combination is safe

and effective treatment for HCV in children and adolescents

Influence of BMI on Outcome of Pediatric HCV Treatment

• Retrospective study of 123 children treated at Boston Children’s Hospital between 1998 and 2007

• Difference in BMI percentiles (P=0.04) – Responders: 50th ± 6.5 – Non-responders: 70th ± 7.4

• One SD (z score unit) increase in BMI associated with 12% decrease in likelihood of SVR in multivariate model

Delgado-Borrego A. JPGN 2010;51:191-7

Influence of BMI on Outcome of Pediatric HCV Treatment

Delgado-Borrego A. JPGN 2010;51:191-7

Chronic viral hepatitis in Children: Use of CAM

• Cross-sectional study in 68 children at single site • 46% of families reported using CAM at least once • 31% used CAM monthly or more frequently • Typically herbals and dietary supplements • Use of CAM independently associated with

current or previous use of antivirals • Rate of physician non-disclosure regarding use of

CAM: > 60%

Erlichman et al. J Pediatr Gastroenterol Nutr 2010; 50:417-21

Pediatric HCV – IL28b Genotype

• Favorable IL28b genotype associated with more spontaneous clearance of perinatal HCV infection (Ruiz-Extremera, Hepatology 2011;53:1830-8)

• Role of IL28b genotype in treatment response not yet defined (being analyzed in PEDS-C cohort)

HCV in Children DAA agents in Children

• Clinical trials have begun – boceprevir – suspended by FDA – telaprevir

• Newer agents? – Trials under discussion

Opportunities for HCV Therapy in Children

• Excellent compliance • Cirrhosis less common • Fewer co-morbidities

– Obesity – Renal disease – Cardiovascular disease

• Fewer concomitant medications • Close follow up

Challenges to Development of HCV Therapy in Children

• Case detection • Patient selection for treatment • Stigmatization • Pk studies (especially single-dose studies) • Safety concerns (longer follow up needed)

– Direct drug toxicity – Effects on growth

• Rapid drug development combined with long lag times to develop pediatric protocols → rapid “irrelevance” of pediatric studies

HCV in Children Wish List

• Elucidation of the mechanisms and risk factors for perinatal transmission

• Effective strategy to prevent perinatal transmission

• Availability of safe treatment (non-IFN based) • Safe and effective vaccine

PEDIATRIC