Study of DAA Treatment for Children and Adolescents With Active HCV Infection in Cambodia

Non-comparative multicenter pilot therapeutic prospective study conducted in Phnom Penh, Siem Reap and Battambang province and divided in 2 phases:

Screening phase:

First, all children aged more than 6 years old and adolescents under 18 years old will be screened for HCV infection using Bioline HCV rapid test in several pediatric populations in Phnom Penh, Siem Reap and Battambang including children born from HIV/HCV co-infected women followed in OI/ART sites or born from HCV mono-infected women.

HCV RNA will be performed in case of HCV rapid test positivity. A case-control study will be performed to evaluate the risk factors associated to HCV acquisition. Cases will be defined as children with positive HCV RDT and controls as children with negative HCV RDT. Four controls will be randomly selected for one case.

Therapeutic phase:

Children and adolescents confirmed with active HCV infection (positive HCV RNA) during the first phase will be referred to a specific consultation in Kantha Bopha hospital in Phnom Penh, Jayavarman VII hospital in Siem Reap, National Pediatric Hospital and Battambang provincial hospital for treatment after evaluation of liver disease. Patients with a weight > 25 kg will be treated with a sofosbuvir/daclatasvir combination for 12 weeks with adult dose (400/60 mg), children with a weight between 14 and 25 kg will be treated with the same sofosbuvir/daclatasvir combination with the half adult dose (200/30 mg) for 12 weeks. For all children and adolescents, residual plasma concentrations (trough concentrations) of the drugs will be assessed after 2 weeks of treatment. For the first 20 children and adolescents included (10 children weighing between 14 and 25 kg and 10 weighing more than 25 kg), whatever their HIV status and ARV treatment, a complete pharmacokinetic analysis will be performed prior to drug administration and +1h, +2h, +6h and +10h after drugs intake. A non-compartimental analysis using Phoenix WinNonlin 8.1 (Certara, Princeton, NJ, USA) will be performed to estimate the pharmacokinetic parameters of sofosbuvir, GS-331007 and daclatasvir. Maximal concentration (Cmax), trough concentration at steady state (Ct), minimal concentration (Cmin) and the time required to reach Cmax (Tmax) are the observed parameters. The area under the curve (AUCtau) will be estimated by the linear up log down trapezoidal method using the predose concentration as 24-hour postdose concentrations.

Inclusion criteria

Screening phase Inclusion criteria

• Aged ≥ 6 years old with weight ≥ 14 kg
• Aged <18 years old
• Informed consent obtained with information sheet given and explained before the inclusion visit, the consent form signed by at least one of the 2 parents or legal guardians and oral assent collected if the child ≥ 13 years old, at the latest the day of the inclusion

Non-inclusion criteria

• Any concomitant medical condition that, according to the clinical site investigator, would contraindicate the HCV screening

Therapeutic phase Inclusion criteria

• Aged ≥ 6 years old with weight ≥ 14 kg
• Aged < 18 years old
• HCV RNA detectable
• HCV treatment naive
• In case of HIV coinfection,

• HIV-1 infection confirmed according to Cambodian screening policies
• On ART for more than 6 months
• CD4 cell-count> 100 cells/μL and > 15% and HIV viral load < 1000 copies/mL at inclusion visit
• Informed consent obtained with information sheet given and explained before the inclusion visit and the consent form signed by at least one of the 2 parents and oral assent collected if the child ≥ 13 years old, before any sample or drug administration corresponding to the therapeutic phase.

Non-inclusion Criteria:

• Suspicion of evidence of hepato-cellular carcinoma (HCC) or any other neoplasia
• Decompensated cirrhosis
• Co-infection with HBV (positive HBsAg)
• Advanced/terminal renal disease defined as serum creatinine clearance < 30 mL/min
• Active tuberculosis under treatment
• In case of HIV coinfection,

• Repeated ART failures and impossibility of prescription of an effective ART regimen
• Active opportunistic infection (OI)
• Current pregnancy or breast feeding
• Use of any drug known to interact with Sofosbuvir or Daclatasvir and for which temporary cessation or dose modification would be impossible
• Any concomitant medical condition that, according to the clinical site investigator, would contraindicate participation in the study
• Concurrent participation in any other clinical trial without written agreement of the two study investigators