The US Food and Drug Administration (FDA) on 7 April
approved the first direct-acting antivirals for the treatment of chronic
hepatitis C virus (HCV) infection in adolescents aged 12 to 17 years. Sofosbuvir/ledipasvir (Harvoni) is now indicated for
adolescents with HCV genotypes 1, 4, 5 or 6, while sofosbuvir (Sovaldi) plus ribavirin is approved for
those with genotypes 2 or 3.
"These approvals will help
change the landscape for HCV treatment by addressing an unmet need in children
and adolescents," Edward Cox, MD, director of the FDA's Office of
Antimicrobial Products, said in an FDA press release.
New medications are typically
first tested and approved for adults, with paediatric approval following some
time later. While hepatitis C is not common among children and adolescents
compared to older age groups, experts estimate that 23,000 to 46,000 have HCV,
mostly attributable to mother-to-child transmission. Until now these young
people have had no approved options other than interferon-based therapy, which
is poorly tolerated and less effective than the new direct-acting antivirals.
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
Gilead Science's HCV polymerase inhibitor sofosbuvir was one of the first direct-acting antivirals
that could be used without interferon, FDA-approved for adults in December
2013. The all-in-one combination pill Harvoni,
containing sofosbuvir and the HCV NS5A inhibitor ledipasvir, was FDA-approved
in December 2014 for genotypes 1, 4, 5 and 6; ledipasvir does not work against
genotypes 2 or 3. The new pangenotypic combination pill Epclusa (sofosbuvir/velpatasvir) pill, which works against all
types of HCV, was FDA-approved in June 2016.
Both supplemental approvals cover paediatric patients
aged 12 to 17 years (after which the adult approval kicks in) and weighing at least 35 kilograms, without liver cirrhosis or with
compensated cirrhosis. Adolescents use the same Harvoni and Sovaldi doses as adults; ribavirin doses are adjusted based on
Adolescents with HIV/HCV co-infection can use
the same regimens, taking into consideration potential interactions with
antiretroviral drugs. Harvoni and Sovaldi can lead to hepatitis B virus (HBV)
reactivation in people with HBV/HCV co-infection. The FDA cautioned that the safety
and efficacy of Harvoni and Sovaldi have not been established in
children under 12 years old or weighing less than 35kg.
The supplemental approval of Harvoni was supported by data
from Gilead's Study 1116, an open-label clinical trial of 100 participants aged 12-17 with HCV genotype 1, with or
without liver cirrhosis. They received 400/90mg sofosbuvir/ledipasvir once daily
for 12 weeks; there was no placebo arm.
As reported at last year's EASL International Liver
Congress, 97% achieved sustained
virological response, or continued undetectable HCV RNA at 12 weeks
post-treatment (SVR12); a Gilead press release gave the final cure rate as 98%. There
were no virological failures or relapses – those without SVR12 were lost to
follow-up and also may have been cured. Adverse events
were similar to those seen in adult studies, with headache and fatigue being
Supplemental approval of sofosbuvir plus ribavirin was
supported by data from Gilead's Study 1112, an open-label trial of 50
adolescents aged 12-17 with or without cirrhosis.
Those with genotype 2 received 400mg once-daily sofosbuvir plus ribavirin for
12 weeks, while those with genotype 3 extended treatment to 24 weeks. All
people with genotype 2 and 97% of people with genotype 3 were cured. Again, adverse
events were similar to those seen in adults; despite using ribavirin, none
The cure rate in the sofosbuvir/ledipasvir trial was
similar to those seen in adult studies, while the adolescent cure rate for
sofosbuvir plus ribavirin was somewhat higher. Although adolescents with
cirrhosis were allowed in these studies, almost all were non-cirrhotic or had
unknown cirrhosis status, which is a predictor of better treatment response
with this regimen.
Sofosbuvir/ledipasvir is a recommended treatment
option for adults with genotype 1. However, the latest AASLD/IDSA HCV
treatment guidelines no longer recommend
sofosbuvir plus ribavirin alone for genotypes 2 or 3, favouring the more
effective sofosbuvir/velpatasvir or sofosbuvir plus daclatasvir (Daklinza) combinations.