Keywords
elimination of HCV - chronic hepatitis C - children and adolescents - direct-acting
antivirals
Hepatitis C virus (HCV) infection is a major global public health concern.[1] In 2016, there were an estimated 71 million people living with chronic HCV infection
worldwide.[2]
[3] This is in addition to approximately 1.75 million new infections per year.[2] With the advent of direct-acting antivirals (DAAs) in 2013 and the prospect of increasing
numbers of cured HCV patients, the World Health Organization (WHO) global health sector
strategy on viral hepatitis (2016–2021) defined targets and actions for countries
to achieve the goal of eliminating hepatitis C as a major public health threat by
2030.[4] Achieving the elimination goal, however, necessitates a mass scale-up of testing
and treatment in both adults and children particularly in the settings with the highest
burden of disease. In most countries, the prevalence and burden of HCV infection and
its impact on morbidity and the mortality in children and adolescents are essentially
unknown. Only one systematic review since 2015 has addressed the prevalence of pediatric
HCV infection, with an estimated global prevalence of 0.13% corresponding to 3.26
million (95% confidence interval [CI]: 2.07–3.90) viremic children.[5]
[6]
HCV infection infrequently contributes to morbidity during childhood, but the majority
of infected children develop chronic HCV, with a lifetime risk of serious liver disease.
Cirrhosis is reported in around 1 to 2% of chronically infected adolescents and children,
including decompensation[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] and a few case reports of hepatocellular carcinoma.[15] In children and adolescents, comorbidities such as hematological diseases with iron
overload, obesity, cancer, and viral coinfections (HIV and hepatitis B virus [HBV])
can also accelerate the development of hepatic fibrosis.[11]
[12]
[13] Moreover, studies have indicated that HCV affects childhood quality of life and
behavior, neurocognitive function has been shown to be affected, and families report
increased stress that affects family well-being.[16]
[17] Little attention has been paid to testing, treatment, and preventive strategies
among children and adolescents compared with adults, in part, because until 2017,
none of the DAA regimens had been approved for use in people younger than 18 years,
and there were major gaps in the evidence to guide pediatric management practices
and policies.[18] Although children under 15 years of age represent an average of 25.8% of the global
population, ranging between approximately 15% in the most developed countries to more
than 40% in the least developed low-income countries,[19] and some 1.2 billion adolescents aged 10 to 19 years today make up 16% of the world's
population,[20] very few national viral hepatitis policies addressed this vulnerable population
in their testing, treatment, and preventive strategies. This is despite the high socioeconomic
benefits from investing in adolescents' health. It was documented in one study that
improving the physical, sexual, and mental health of adolescents aged 10 to 19 years
could bring a 10-fold economic benefit.[21]
Vertical transmission is currently the most important source of pediatric HCV infection,
particularly in high-income countries. A retrospective cohort study of pregnant women
who delivered between 2006 and 2014 showed that 70% of HCV-exposed infants were not
screened or followed-up and therefore were missed.[22] Furthermore, children whose mothers or other family members are living with HCV
are at an increased risk since the virus can be transmitted through other routes as
household contacts.
On the other hand, adolescents remain a vulnerable population for new HCV infections
globally with the increasing numbers of injection drug users, young age pregnancies,
migration, and displaced populations from conflict zones exposed to violence with
no health care coverage or support. More than half of all adolescents globally live
in Asia, whereas Sub-Saharan Africa is the region where adolescents make up the greatest
proportion of the population, with nearly 23% of the region's population.[20] Despite the overall progress in improving access to DAA in the adult population
with the availability of affordable generic medicines, many vulnerable groups are
being left behind, and particularly children and adolescents in low-resource settings
are at a risk.
Elimination of Hepatitis C Virus in Children
Elimination of Hepatitis C Virus in Children
Elimination of HCV infection is defined by the WHO Global Health sector strategy as
an 80% reduction in new HCV infections and a 65% reduction in HCV mortality by 2030.[4] It is debated that elimination without the availability of a vaccine has never been
attained for any infectious disease.[23] Elimination of viral hepatitis will require a shifting emphasis from a focus on
individual patients to a focus on a coordinated public health approach to interruption
of transmission and infection through prevention and treatment.[1] In the presence of highly effective and safe DAA, the goal should be to reduce the
disease burden in every country that requires enhanced rates of diagnosis and treatment,
as well as strategies to prevent new infections. Some countries, including Australia,
Egypt, Georgia, Iceland among others, have already undertaken broad elimination efforts
aimed at the general population.[24] One of the major gaps in the response to the HCV epidemic, however, remains the
lack of reliable epidemiological data in many countries and regions. Data gaps are
considerable in some subpopulations including the pediatric population, where there
is also lack of awareness regarding the infection. Diagnosis of HCV in children and
therefore access to screening is quite challenging due to the asymptomatic nature
of the disease and the lack of liver enzyme elevations.[25] In addition, in countries with low prevalence rates of HCV, the prevalence in infants
and children would be quite low, and investments in case finding would be a barrier
to identification of infected children. Therefore, risk stratification according to
individual country prevalence is important to better define screening policies and
ensure access to diagnosis in infants, children, and adolescents. A recent study has
shown that in generalized epidemics, the number of tests needed to identify a chronic
HCV infection was 2.5 for persons who inject drugs, 2.4 for populations with liver
conditions, 2.7 for populations with high-risk health care exposures, and 14.2 for
general populations. However, in concentrated epidemics corresponding numbers were
2.8, 8.6, 5.1, and 222.2, respectively. Program expansion path curves demonstrated
major gains in program efficiency by targeting specific populations. The study concluded
that testing strategies can be much more efficient through population prioritization
by risk of exposure.[26]
Despite the most recent U.S. Food and Drug Administration (FDA) approval of DAA in
children aged 3 years and above (September 2019) and approval for ages 12 years and
above since April 2017, access to treatment is still a major concern driven by the
prohibitive prices of DAA in some countries and the lack of policies and strategies
addressing linkage to care and elimination in the pediatric population. Adolescents
also face particular challenges in terms of access to and quality of care, as they
have special needs (including for confidentiality) and may not be reached by mechanisms
aimed at children and adults.[27] Furthermore, in countries with the highest burden of HCV in children and with generic
medicines available for use in macroelimination in the adult population, the economics
of producing pediatric formulations can be a barrier to access in the younger age
groups, particularly in the absence of informing epidemiological data. To date, Egypt
is the only country addressing access to the HCV cascade of care on a nationwide basis,
with inclusion of school children, 12 years and above and/or weighing more than 35 kg,
in a test-and-treat program fully funded by the state and national insurance service.
A suggested simplified cascade of care for hepatitis C macro- and micro-elimination
in children and adolescents is shown in [Fig. 1].
Fig. 1 Simplified cascade of care for micro- and macroelimination of HCV in children and
adolescents. HCV, hepatitis C virus; PHP, primary health care physicians; HCWs, health
care workers; POC, point of care; HCF, health care facilities; DAA, direct-acting
antivirals; SVR, sustained virological response.
Microelimination in Children and Adolescents
Microelimination in Children and Adolescents
Elimination of hepatitis C in children and adolescents at high risk of infection is
complicated by multiple factors including the large size of the population, consenting
age, accessibility to health care services, and cost of implementation. A suggested
practical approach is breaking down national elimination goals into smaller goals
for individual population segments, for which treatment and prevention interventions
can be delivered more quickly and efficiently using targeted methods, a concept known
as “microelimination.”[24] Pursuing the microelimination of HCV approach in the pediatric population means
achieving the WHO targets in those at the highest risk of infection (e.g., children
infected through mother-to-child transmission or intrafamilial transmission, injecting
drug users, those acquiring infection in juvenile penitentiaries and hospital settings,
those with inherited blood disorders [IBDs], those coinfected by HIV, migrants, and
refugees, among others). Those marginalized subpopulations would benefit most from
the microelimination approach, and targeted programs can be designed and tailored
to improve access to diagnosis and linkage to care.
Injection Drug Use and Mother-to-Child Transmission
One of the most important consequences of the opioid epidemic has been the rise in
HCV infection among persons in the reproductive age group who inject drugs,[28]
[29] including pregnant women. Although mother-to-child transmission is recognized as
a key source of HCV infection in children,[30] there are recent concerns of increasing horizontal transmission in adolescents through
injecting drug use.[31] Intravenous drug administration is a significant and increasingly common route of
HCV infection in adolescents and young adults.[32] This has recently been documented in a United Kingdom study demonstrating that in
adolescents, HCV infection is transmitted by intravenous drug use in 53%, blood products
in 24%, and perinatally in 11%.[33] Other modes of transmission including nosocomial transmissions, percutaneous exposure
to blood, and unsafe medical interventions, however, continue to be key risk factors
in addition to certain practices such as tattooing and circumcision in resource-limited
settings.[34]
In the context of developing microelimination strategies targeting children in specific
settings, it may be advisable to consider the possible role of universal screening
of pregnant women in those settings. It is noteworthy that teen pregnancy is becoming
a global challenge, affecting rich and poor countries alike, but birth rates are highest
in resource-poor settings. In Sub-Saharan Africa, the adolescent birth rate is more
than twice the global average.[35] Child marriage is reportedly on the rise for girls in Syria and among Syrian refugee
populations, believing marriage will protect them and also ease financial burdens
on the family.[36]
Although the risk of vertical transmission of HCV is relatively low (5.8% [4.2–7.8%])[31] compared with HBV, the public health implications are considerable. Among HIV–HCV
coinfected women, the risk of transmission is much higher and estimated to be 10.8%
(7.6–15.2%).[30] Unfortunately, most of those HCV infected infants and children are not diagnosed
or followed up. The numbers of children with chronic HCV infection will surpass those
suffering from chronic HBV given the lack of prevention and control programs for pregnant
women and women in child-bearing age with HCV infection and the absence of public
health approaches for case definition and management of expectant mothers or children.
It is noteworthy that globally, the estimated number of women in child-bearing age
(15–44 years) who are HCV viremic is 13.0 million, with 28 countries responsible for
80% of the infections.[6] In the United States, the HCV incidence has increased 294% nationally from 2010
to 2015; acute cases of HCV largely attributed to injection drug use.[37] A recent report projected nearly 29,000 women with HCV infection giving birth every
year, resulting in almost 1,700 infected infants.[38] The authors noted, though, that only 200 infections in children aged 2 to 13 years
are being reported to public health surveillance each year. Continued efforts to ensure
that pregnant women have access to transmission prevention services are critical.
Suppressing viremia during pregnancy would be expected to prevent HCV transmission.
Nonetheless, the newer DAA agents lack sufficient safety data for use during pregnancy,[39] and pregnancy is currently a contraindication to treatment despite the AASLD/IDSA
guidelines' recommendation for universal screening of pregnant women.[40] Data on DAA in this population are limited to three abstracts on either intentional
or accidental exposure during pregnancy in a small number of women.[41]
[42]
[43] Two studies reported the use of sofosbuvir/ledipasvir during pregnancy. One study
from India included HCV-infected pregnant women who requested treatment during their
second or third trimesters to prevent vertical transmission (n = 15).[41] The other is a phase I trial of sofosbuvir/ledipasvir starting during the second
trimester of pregnancy (n = 8) from the United States.[42] The only data available on a pangenotypic combination is a study from Egypt on accidental
sofosbuvir/daclatasvir exposure around the time of conception (n = 7), all of whom discontinued treatment before week 9 of gestation. No adverse birth
outcomes were reported, but one infant tested HCV positive at 18 months with low viremia.[43] There are currently no recommendations for the treatment of HCV with DAAs during
pregnancy and breastfeeding due to the paucity of sufficient safety data. Ideally,
a pan-genotypic, safe, and effective DAA combination would be available to all HCV-pregnant
women living with HCV diagnosed by a (cost-effective) universal screening program.[44]
Hepatitis C testing should be ordered at all routine clinic visits, such as antenatal
checks and well-child and vaccination appointments to ensure that those diagnosed
receive appropriate treatment. Obstetricians may play a key role by implementing universal
testing for HCV in pregnant women, thereby enhancing the health of mothers and identifying
children at risk. This is in addition to integration with HIV, HBV, and syphilis testing
during pregnancy. In the meantime, early diagnosis and treatment of HCV infection
in adolescent girls should be considered during their routine checkup or vaccination
visits. A unique opportunity, particularly in high-income countries, would be during
the routine HPV vaccination recommended by the advisory committee for immunization
practices at the age of 11 or 12 years (occasionally starting at age 9 years of age).[45]
It is also important to consider that harm reduction policies, decriminalization,
safe-use education campaigns, and removal of stigma related to injecting drug use
in adolescents represent an important component for supporting the vulnerable youth
and linking them to care. An outreach HCV test-and-treat program is required to engage
adolescents receiving harm reduction and needle syringe exchange services. Concerted
efforts are needed to increase the evidence base on interventions that aim to reduce
the high burden of HCV in adolescents who inject drugs.
Refugees and Migrants
Given the growing size of the youth population in the conflict region, as well as
migrants and refugees, viral hepatitis needs to be addressed, diagnosed, and managed
at an early age. This would prevent complications and transmission of infection and
fulfill the WHO's 2030 elimination goal.
Refugees and migrants are marginalized due to risk factors such as HCV prevalence
in their country of origin, countries visited during their journey as migrants, and
the conditions they experienced during migration; immigrants and refugees are at an
elevated risk of being infected with HCV as well as having other health problems.[46] Migrants often remain unidentified and thus untreated. According to a 2015 review,
anti-HCV prevalence among migrants is 1.9% overall, with higher rates associated with
region of origin, particularly Eastern Europe, Asia, and Sub-Saharan Africa.[47] Today, there are more than 50 million displaced children who need protection, of
whom 28 million have been displaced due to wars and extreme poverty. This figure includes
the millions of children attempting to flee from the internal strife affecting a dozen
countries including Syria, Iraq, Yemen, and South Sudan. The number of children who
are suffering due to the conflict and instability in Syria and Iraq alone have reached
14 million.[48] The total number of HCV-infected children projected in the MENA (Middle East North
African) region from verified models is approximately 820,000 out of a population
of more than 160 million children below the age of 15 years, with an average infection
rate of 0.42%.[6] This is in addition to an estimated > 1.6 million HCV-infected women in child-bearing
age of > 96 million in the region with an average prevalence rate of 1.45%.[6] Regional civil wars, displaced children, health insurance policies, and inequitable
insurance coverage are many regional challenges that would impede elimination efforts
in this population group.
The WHO recommends screening persons originating from countries with an intermediate
(≥ 2%) and high (≥ 5%) HCV prevalence.[49] Migrants and refugees face multiple hurdles in accessing healthcare services, resulting
in gaps along all steps of the HCV care continuum. HCV screening uptake and linkage
to care, however, can be improved in this population by implementing decentralized
community-based screening strategies and working with community-based organizations
to overcome cultural and language barriers,[50]
[51]
[52]
[53]
[54] or using multidisease testing approaches, whereby HCV testing is offered as a blood
test alongside HBV, HIV, and latent tuberculosis.[55] A randomized controlled trial compared integrated point-of-care testing for HCV,
HBV, and HIV in primary care among migrants with individual serological testing and
found that testing uptake (98 vs. 62%) and linkage to care (90 vs. 83%) were higher
among point-of-care testing.[56] In addition, it will be necessary to develop screening guidelines and ensure universal
access to health care to enhance uptake along the entire HCV cascade of care.
Inherited Blood Disorders
Chronic infection with the HCV has long been the dominant complication of substitution
therapy in patients with IBDs and the cause of anticipated death due to end-stage
liver disease.[57] In industrialized countries, HCV transmission through blood transfusions has been
virtually eliminated. In contrast, the blood supply in many low-income countries is
poorly controlled. Poor quality screening of blood products in transfusion centers,
among other iatrogenic routes, account for the majority of new HCV infections in resource-limited
countries.[34] Blood transfusion safety is still a concern, especially in low- and middle-income
countries, where the prevalence of transfusion-transmissible infections among blood
donors is high, but quality and coverage of blood screening is inadequate. The 2016
WHO Global Status Report on Blood Safety and Availability reported that in low- and
middle-income countries, up to 67% of all transfusions are for children under the
age of 5 years.[58] A spontaneous HCV clearance rate of 28 to 42%, however, has been reported among
thalassemic and hemophilic patients in the West.[59]
[60]
The prevalence of anti-HCV seropositivity among thalassemia patients has been reported
to be 2.7 to 97% across countries in an early report.[61] In the West, cohorts of HCV infected thalassemic patients are mainly comprise adults,
of whom 80% acquired the infection before 1990,[62] whereas in the Middle East and Asia, the same is true for many children or young
adults (10–40% of all patients) who acquired the infection in the last decades, resulting
in the development of chronic liver disease.[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
DAA treatment of hepatitis C as part of a microelimination program targeting IBD is
an effective intervention aiming to prevent transmission of HCV in the general population.[46] Many recent studies suggest that individuals with IBD may safely and successfully
be treated for HCV with the DAA therapy.[71] In five recent studies investigating the DAA treatment in 254 hemophiliacs and von
Willebrand disease patients, of whom 51 were cirrhotic, 243 were cured of hepatitis
C.[71]
[72]
[73]
[74]
[75] Other reports in thalassemic patients documented cure of 401 out of the 420 recruited
patients with various genotypes and degrees of fibrosis.[76]
[77]
[78]
[79] The average success HCV cure rate in patients with IBD was 95% in published studies.
The current European Association for the Study of the Liver Clinical Practice Guidelines
recommend interferon-free regimens for the treatment of HCV infection in patients
with hemoglobinopathies, as DAA have provided > 90% rates of cure, irrespective of
HCV genotype or history of previous antiviral therapy.[80] The use of DAA in the treatment of HCV-infected children and adolescents with IBD
should be implemented for microelimination in this population, particularly in resource-limited
settings with high prevalence rates. This approach would prevent horizontal and nosocomial
transmissions in this high-risk population and avert early liver-related morbidity
and mortality.
Evidence on the Use of DAA for Adolescents and Children with Chronic HCV Infection
Evidence on the Use of DAA for Adolescents and Children with Chronic HCV Infection
The drug regimens currently approved for use in adolescents and children with chronic
HCV infection by the FDA are summarized in [Table 1]. [Table 2] reports the ongoing pediatric trials with the second-generation DAA regimens.
Table 1
Age and genotypic indications provided by the U.S Food and Drug Administration on
the use of the direct-acting antiviral regimens approved for the treatment of chronic
hepatitis C virus infection in adolescents and children
|
Regimen
|
GT and duration of treatment
|
Formulations
|
Doses by age
|
|
Sofosbuvir/ledipasvir
|
GT 1, 4, 5, 6: 12 wk
GT 1, treatment-experienced (IFN-based therapy) or cirrhosis: 24 wk
|
Tablet (FDC) 400/90 mg
Tablet (FDC) 100/22.5 mg
Packet of granules 50/11.25 mg
|
12–17 y or weighing ≥ 35 kg: 400/90 mg/d
6–11 y: 200/45 mg/d
3–5 y: 200/45 mg/d if ≥ 17 kg; 150/33.75 mg/d if < 17 kg
|
|
Sofosbuvir + ribavirin
|
GT 2: 12 wk
GT 3: 24 wk
|
Sofosbuvir
Tablet 400 mg
Tablet 100 mg
Capsules 50 mg (granules)
|
Sofosbuvir
12–17 y or weighing ≥ 35 kg: 400 mg/d
6–11 y: 200 mg/d
3–5 y: 200 if ≥ 17 kg; 150 mg/d if < 17 kg
Ribavirin
15 mg/kg/d in two divided doses
|
|
Glecaprevir/pibrentasvir
|
All GTs: 8 wk
All GTs with cirrhosis: 12 wk
GT 3, treatment-experienced (IFN-based therapy): 16 wk
|
Tablet (FDC) 100/40 mg/day
|
12–17 y or weighing ≥ 45 kg: 300/120 mg/d
|
Abbreviations: FDC, fixed-dose combination; GT, genotype; IFN, interferon.
Table 2
Ongoing pediatric trials with second-generation direct-acting antiviral regimens
|
Drugs
|
Clinicaltrial.gov accession number
|
Main characteristic of the combination
|
|
Sofosbuvir/velpatasvir
|
NCT03022981
|
Pangenotypic regimen
|
|
Glecaprevir/pibrentasvir
|
NCT03067129
|
Pangenotypic regimen; this combination is safe and effective in patients with advanced
renal disease
|
|
Sofosbuvir/velpatasvir/voxilaprevir
|
NCT03820258
|
Pangenotypic regimen for patients who have experienced treatment failure with DAA
therapy; treatment for 8 wk for almost all the patients treated
|
|
Elbasvir/grazoprevir
|
NCT03379506
|
Agents are completely hepatically metabolized, and pharmacokinetic data in adults
showed them to be safe in patients with advanced renal disease including those on
hemodialysis
|
Sofosbuvir/Ledipasvir
The fixed-dose combination of sofosbuvir/ledipasvir is approved by the FDA for the
treatment of children and adolescents (3–17 years of age) with chronic HCV genotype
1, 4, 5, or 6 infection ([Table 1]).[40]
[81]
[82]
A large phase II and III, open-label, multicenter, multicohort study evaluated the
safety and the efficacy of sofosbuvir (a potent NS5B polymerase inhibitor) and ledipasvir
(an NS5A inhibitor).[83]
[84]
[85]
Adolescents
Sofosbuvir and ledipasvir were used for 12 weeks ([Table 3]).[85] The first 10 adolescents underwent separate intensive pharmacokinetic evaluations
of the concentrations of sofosbuvir and ledipasvir. The adult dosing resulted in comparable
plasma exposures in adolescents than those found in phase II and III clinical trials
in adults with chronic hepatitis C (CHC). The efficacy of the combination was high
(SVR12 [sustained virological response at week 12 posttreatment] 98%, intention-to-treat
analysis). Of the 100 patients who initiated treatment, 99 completed and 1 discontinued
the treatment, and of those who completed the treatment, 1 did not attend the posttreatment
follow-up visits after having achieved end of treatment response. The efficacy was
similar among treatment-naïve (78/80; SVR12: 98%; 95% CI: 91–100%) and treatment-experienced
patients (20/20; SVR12: 100%; 95% CI: 83–99%). The only patient with cirrhosis was
treatment-naïve, received 12 weeks of therapy, and achieved SVR12. The treatment was
well tolerated. No serious or grade 3/4 adverse event was reported, and no patient
discontinued treatment due to an adverse event.[85]
Table 3
Summary of the pediatric studies on different combinations of direct-acting antivirals
|
Drug regimen
|
Age range (years)
|
Sample size
|
Genotype(s)
|
Drug doses
|
Number of patients with SVR12 (%)
|
|
Sofosbuvir/ledipasvir
|
12–17[85]
|
100
|
1
|
400/90 mg
|
98/100 (98%)
|
|
6–11[83]
|
92
|
1, 3, 4
|
200/45 mg
|
91/92 (99%)
|
|
3–5[84]
|
34
|
1, 4
|
if ≥17 kg: 200/45 mg
if <17 kg: 150/33.75 mg
|
33/34 (97%)
|
|
Sofosbuvir plus ribavirin
|
12–17[94]
|
52
|
2, 3
|
Sofosbuvir 400 mg
Ribavirin 15 mg/kg in two divided doses
|
51/52 (98%)
|
|
3–11[95]
|
54
|
2, 3
|
Sofosbuvir
6–11 years: 200 mg
3–5 y: 200 mg if ≥ 17 kg; 150 mg if < 17 kg
Ribavirin 15 mg/kg in two divided doses
|
53/54 (98%)
|
|
Glecaprevir/pibrentasvir
|
12–17[98]
|
47
|
1, 2, 3, 4
|
300/120 mg
|
47/47 (100)
|
|
Ombitasvir/paritaprevir/ritonavir
±dasabuvir
±ribavirin
|
12–17[97]
|
38
|
1, 4
|
25 mg/150 mg/100 mg once daily
Dasabuvir 250 mg twice daily
Ribavirin 15 mg/kg in two divided doses
|
38/38 (100)
|
|
Sofosbuvir plus daclatasvir
|
15–17[99]
|
13
|
4
|
Sofosbuvir 200 mg
Daclatasvir 60 mg
|
13/13 (100%)
|
|
13–17[103]
|
10
|
4
|
10/10 (100)
|
|
12–17[100]
|
30
|
4
|
29/29 (100)
|
|
8–17[102]
|
40
|
1, 4
|
39/39 (100)
|
|
7–13[101]
|
14
|
3
|
14/14 (100)
|
Abbreviation: SVR12, sustained virological response at week 12 posttreatment.
Children Younger Than 12 Years
Results of the same association are available for children aged 6 to 11 years[83] and for those aged 3 to 5 years ([Table 3]).[84] Treatment duration was 12 weeks for all except one patient with HCV genotype 1 infection
who was treatment-experienced and cirrhotic and two patients with HCV genotype 3 infection
who received 24 weeks of therapy.[2] The pharmacokinetic analyses showed that the “half strength” dosing resulted in
plasma concentration generally within the range of those observed in adults.[86] Ninety-nine percent (91/92; 95% CI: 94–100%) of the children achieved SVR12. One
cirrhotic patient with HCV genotype 1a relapsed at follow-up week 4 visit. The treatment
was well tolerated; no grade 3/4 adverse event was reported, and no patient discontinued
the treatment due to an adverse event. One serious adverse event (a dental abscess
with abdominal pain and gastroenteritis) was reported that was not considered drug-related.[83]
Of the children, 99% between 3 and 5 years treated with weight-based doses of combined
ledipasvir-sofosbuvir as granules achieved SVR12 (33/34; 95% CI: 85–100%). The only
patient who did not achieve SVR12 was 3 years old and discontinued treatment after
5 days due to “abnormal drug taste.” The treatment was well tolerated; no grade 3/4
adverse event was reported, and no patient discontinued the treatment due to an adverse
event.[84]
Real-World Data
The results of the registration study have been recently confirmed in several real-word
studies using the same drug doses and treatment durations.[87]
[88]
[89]
[90] Three different studies recently reported the efficacy and safety of sofosbuvir/ledipasvir
used for 8 weeks of treatment in adolescents with chronic HCV infection. Eight weeks
of treatment resulted in comparable efficacy and safety independently of HCV genotype.[91]
[92]
[93]
Sofosbuvir and Ribavirin
The combination of sofosbuvir and ribavirin is approved by the FDA for the treatment
of children and adolescents (3–17 years of age) with chronic HCV genotypes 2 or 3
infection ([Table 1]). The recommended treatment duration is 12 weeks for genotype 2 and 24 weeks for
genotype 3.[40]
[81]
[82] A large phase II and III, open-label, multicenter, multicohort, single-arm study
evaluated the safety and the efficacy of sofosbuvir and ribavirin.[94]
[95]
Adolescents
Sofosbuvir and ribavirin were used for adolescents (aged between 12 and 17 years or
weighing more than 35 kg) with chronic HCV genotype 2 or 3 infection for 12 or 24
weeks, respectively ([Table 3]).[94] Pharmacokinetic evaluations of the concentrations of sofosbuvir showed that 400 mg
per day provided plasma exposures comparable with those observed in adults from phase
II and III studies. The combination showed high efficacy and a good safety profile,
and SVR12 was 98% (95% CI: 90–100%; intention-to-treat analysis) overall, 100% (95%
CI: 75–100%) for genotype 2, and 97% (95% CI: 87–100%) for genotype 3. All the nine
treatment-experienced patients achieved SVR12 (100%; 95% CI: 66–100%). The single
patient who did not achieve SVR12 achieved end of treatment response and SVR4 (HCV
RNA negative 4 weeks after the end of treatment) and then was lost to follow-up. Treatment
was well tolerated. No serious or grade 3/4 adverse event related to the study drug
was reported, and no patient discontinued treatment due to an adverse event.
Children Younger Than 12 Years
Results of the same association are available for 41 children aged 6 to 11 years and
for 13 children aged 3 to 5 years ([Table 3]).[95] The pharmacokinetic analyses conducted in each age group confirmed the appropriateness
of sofosbuvir doses. Of the children, 98% (53/54; 95% CI: 90–100%) achieved SVR12.
The only patient who did not achieve SVR12 was 4 years old and discontinued treatment
after 3 days due to “abnormal drug taste.” The treatment was well tolerated; no grade
3/4 adverse event was reported. One serious adverse event (a 3-year-old patient with
accidental ribavirin overdose requiring hospitalization for monitoring) was reported.
This child completed treatment and achieved SVR12.[95]
Real-World Data
The results of the sofosbuvir and ribavirin registration study have been confirmed
in an open-labeled uncontrolled study from Pakistan. In this study, 35 children with
a mean age of 10.24 ± 2.80 years were enrolled and treated for 24 weeks to determine
the safety and efficacy of sofosbuvir and ribavirin.[96] Interestingly, 27 (77.1%) were infected by HCV genotype 3 and 6 (17.1%; two untypeable)
by genotype 1. SVR12 was achieved by all the patients with genotype 1 infection and
by 26/27 (96.3%) of those with HCV genotype 3. The treatment was well tolerated in
most patients. No serious adverse event was reported. Headache was observed in eight
children (22.86%). One patient stopped the therapy at treatment week 8 for severe
headache and achieved SVR12, and constipation was observed in one patient.
Ombitasvir/Paritaprevir/Ritonavir ± Dasabuvir ± Ribavirin
The combination of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, with
or without ribavirin is not yet approved for the treatment of children and adolescents
with chronic HCV infection.
The ZIRCON open-label, multicenter study (NCT 02486406) is currently exploring the
safety and efficacy of this association in children aged 3 to 17 years, with HCV genotype
1 or 4 infection, treatment-naive and treatment-experienced, with or without compensated
cirrhosis. In this study, the fixed-dose combination of ombitasvir/paritaprevir/ritonavir
was used with dasabuvir for patients with genotype 1 infection and with ribavirin
for those with genotype 1a and 4 infections. The duration of treatment was 12 weeks
for all the patients enrolled except for those with genotype 1a infection or with
compensated cirrhosis who were treated for 24 weeks. Preliminary results were presented
for the 12- to 17-year age cohort.[97]
Adolescents
Thirty-eight adolescents were enrolled in this study.[97] Pharmacokinetic evaluations showed that the exposures to the four drugs in the 12
adolescents studied were comparable with exposures seen in adults. The combination
showed excellent efficacy and a good safety profile. SVR12 was 100% and therefore
independent of genotype, treatment history, and stage of liver disease. No adverse
event led to discontinuation of study drugs.
Glecaprevir/Pibrentasvir
The combination of glecaprevir/pibrentasvir is approved by the FDA for the treatment
of adolescents with chronic HCV infection ([Table 1]).
The DORA open-label, multicenter study is currently exploring the safety and efficacy
of this association in children aged 3 to 17 years, independently of HCV genotype,
treatment-naive and treatment-experienced, with or without compensated cirrhosis.
In this study the duration of treatment with the fixed-dose combination of glecaprevir/pibrentasvir
was 8 weeks for all the patients enrolled except for those with compensated cirrhosis
who were treated for 12 weeks and those treatment-experienced with HCV genotype 3
infection who were treated for 16 weeks. Preliminary results were presented for the
12 to 17 age cohort.[98]
Adolescents
Forty-seven adolescents were enrolled in this study ([Table 3]). Pharmacokinetic evaluations showed that the exposures to the adult dose were comparable
with exposures seen in adults. SVR12 was 100%. No patients had virological nonresponse,
breakthrough or relapse. Treatment was well tolerated. No serious adverse event was
reported and no patient discontinued treatment due to an adverse event.[98]
Sofosbuvir + Daclatasvir ± Ribavirin
The combination of sofosbuvir + daclatasvir with or without ribavirin is not approved
for the treatment of children and adolescents with chronic HCV infection.
In 2017, for the first time, the preliminary results of an Egyptian study on the use
of sofosbuvir 400 mg and daclatasvir 60 mg once daily have been presented ([Table 3]).[99] Thirteen adolescents aged between 15 and 17 years with HCV genotype 4 infection
received 12 weeks of treatment. Ribavirin was used in the four patients with cirrhosis,
and SVR 12 was 100%. No serious adverse event was reported, whereas mild adverse events
were noted in the form of mild headache, dizziness, itching, and ribavirin-induced
hemoglobin reduction (< 1 g/dL). The adult dosing resulted in comparable plasma exposures
in adolescents than those found in phase II and III clinical trials in adults with
CHC (unpublished data, Manal H. El-Sayed, MD, PhD, 2019). Following this study, many
others confirmed the efficacy and the safety of this combination for adolescents and
children.[100]
[101]
[102]
A recent pilot study explored the efficacy of a shortened 8-week duration of sofosbuvir
and daclatasvir in a cohort of 10 consecutive adolescents. All patients (10/10 (100%
(CI: 72.25–100%) achieved SRV with good tolerability and no serious adverse events.[103]
Challenges toward the Elimination of HCV in Children
Challenges toward the Elimination of HCV in Children
To achieve WHO's elimination goal and targets by 2030, it is pivotal to understand
the current challenges associated with HCV elimination worldwide and undertake strategic
efforts to overcome these challenges.
In the absence of a vaccine, HCV treatment is central to infection control. An HCV
vaccine would be an important public health tool to interrupt and control HCV spread
and to protect high-risk populations such as people who inject drugs. The first prophylactic
randomized, placebo-controlled, phase I/II trial (NCT01436357) of a prime-boost vaccine
to prevent chronic HCV infection in an at-risk population demonstrated the feasibility
of conducting rigorous vaccine research in people who inject drugs. The regimen elicited
robust immune responses without evident safety concerns but did not provide protection
against chronic HCV infection.[104]
In recent years, the new DAA combinations have revolutionized the treatment of CHC
globally. These treatments have excellent efficacy and safety in both adults and children,
with more than 95% SVR rates. The few side effects and the short treatment durations
(as short as 8 weeks) have dramatically improved patient adherence relative to the
previous standard of care: pegylated interferon and ribavirin. Although an increasing
number of DAA have gained approval for adults since 2011 worldwide, the expansion
of DAA treatment to adolescents and children and access to DAA for these populations
remains slow and limited due to various factors. First, the degree of awareness regarding
chronic HCV infection in children and adolescents is low. Chronic HCV infection in
childhood has usually and inappropriately been considered a mild disease. The outcome
of the infection beyond the pediatric age, as well as the social stigma related to
the infection and the burden of the extrahepatic manifestations, has never been adequately
evaluated. Overall, the need for general proactive screening, as well as through the
use of simple, adolescent-friendly testing, is underperceived. Poor linkage to care
is a key barrier to treatment for adults as well as for adolescents and children.
Newer and further highly effective, safe, and simple treatment options are required
to increase the treatment uptake in the HCV pediatric population. The pangenotypic
regimen sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir
can simplify the treatment and satisfy the clinically unmet needs in patients with
cirrhosis and prior treatment failure. However, DAA regimens are still largely unaffordable
to many patients worldwide. Wider medical reimbursement coverage is therefore needed
to improve the affordability of DAA regimens, which will enhance treatment uptake.
Global efforts are underway to accelerate the development and introduction of pediatric
formulations.[105] These efforts rely on coordinated and well-funded actions by policy-makers, researchers,
industry, regulators, and other relevant stakeholders.[18]
Children and adolescents need to be included in a country's age-stratified national
population-based serosurveys and should be part of the global, regional, and national
data reporting systems and strategies for control of viral hepatitis. Moreover, long-term
follow-up data systems are required to monitor the progression of liver disease in
children. Integration of HCV with other childhood infectious disease surveillance
health information systems can also capture new infections and identify risk factors,
therefore guiding national and preventive strategies. It is critical to simplify the
cascade of diagnosis and assessment through point-of-care test and treat programs
with noninvasive assessment to stage liver disease. This would increase the number
of diagnosed and treated children and adolescents particularly in the high-risk populations.
While actively engaging adolescents, preventive interventions can be delivered in
educational settings, which provide an opportune platform to deliver information relating
to HCV and the behaviors linked to the transmission of infection. With the fast-growing
newer technologies and communication systems, innovations can be tailored for delivery
of the services to children and adolescents and improve access to care and treatment.
This requires key stakeholders collaboration across different sectors including governments,
research institutes, HCV associations and consortia, media, information and technology
experts, civil society, and pharmaceutical companies, as well as pediatric and obstetric
health care professionals to integrate all resources to combat and eliminate HCV.
International collaborative efforts are required for the development of robust HCV
data registries on diagnosed, treated, and cured children and adolescents. Models
of care in this key population particularly in high burden settings can guide global
and national policies and practices on prevention, diagnosis, and linkage to treatment.
Elimination of HCV can eventually be achieved with the global commitment for universal
health coverage through integrated policies and programs leaving no one behind.
