treatment of hcv in special populations -...
TRANSCRIPT
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
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
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
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