What Is Known/What Is New
What Is Known
- Dual sofosbuvir/daclatasvir therapy is currently an option for the treatment of chronic hepatitis C (all genotypes) in adults; however, it is still not considered for patients younger than 18 years old.
- What Is New
- This study demonstrated that this combination is safe and efficacious in the treatment of chronic HCV genotype-4 in adolescent patients from 12 to 17 years old, with high tolerability, no serious adverse effects and no treatment failures.
- These results could incite other studies on different populations and genotypes in a way to establish numerous cost-effective, pan-genotypic options for the treatment of chronic HCV in pediatric age groups.
The use of the fixed dose combination of sofosbuvir (SOF; 400 mg)/ledipasvir (LDV; 90 mg) has been approved recently by both the United States Food and Drug Administration (FDA) and The European Medicines Agency for the treatment of chronic hepatitis C virus (HCV), genotypes 1, 4, 5, or 6 infections in adolescents, 12 years old and above or weighing at least 35 kg (1).
Subsequently, the American Association for the study of Liver Disease (AASLD) has recommended, in its last updated guidelines, the use of SOF/LDV, for the treatment of chronic HCV, in adolescent patients (12 years and above or weighing at least 35 kgkilograms), with the same adult daily dose. The recommended duration for genotype 4, 5, or 6 is fixed 12 weeks for both treatment-naïve or treatment-experienced, without or with compensated cirrhosis. For the treatment of genotype 1 infection, the recommended durations are either 12 weeks (for treatment-naïve/experienced, without cirrhosis or treatment-naïve with compensated cirrhosis) or 24 weeks for treatment-experienced with compensated cirrhosis (2). This has also been endorsed by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition in its recently released updated position paper on treatment of chronic HCV in children (3).
Dual SOF/DCV therapy is currently recommended by the European Association for Study of Liver (EASL) as an option for the treatment of chronic HCV (all genotypes) in adults; however, it is still not considered for the treatment of patients younger than 18 years old (4).
In a developing country like Egypt with the highest prevalence of chronic HCV infections and a very ambitious governmental mass HCV screening and treatment program, adopting the world health organization (WHO) initiative, to eliminate viral hepatitis by the year 2030; very economic yet cost-effective strategies are fundamental to assure sustainability, continuity, and effectiveness of the program. This necessitates that health policy makers in Egypt would adapt the international guidelines for management of chronic HCV in a way to diminish burdens and costs of the needed investigations and drugs to the minimal cost effective levels for each particular situation. Availability of low-cost, generic, pan-genotypic drugs was estimated to be the most cost-effective strategy that enables the government to pursue its ambitious program through the great reduction not only in drug budgets but also in the need of the highly costly HCV genotyping test, which is available only in few highly sophisticated labs.
We conducted this study to investigate the safety and efficacy of the dual SOF/DCV therapy in Egyptian adolescent patients with chronic HCV infection.
PATIENTS AND METHODS
Study Design and Setting
The study had been conducted according to a prospective, single cohort, open-label, multicenter study design in an outpatient setting.
Consecutive male or female adolescent patients, between 12 and 17 years old, who presented to 4 medical sites 2 in Alexandria and 2 in Cairo, Egypt and had a diagnosis of chronic hepatitis C were screened for inclusion. Key exclusion criteria were: pregnancy or lactation; concurrent other causes of hepatitis or HIV virus infection; active schistosomiasis; Child-Pugh score >6; alanine or aspartate aminotransferase >7 times the upper limit of normal, albumin <2.8 g/dL; international normalized ratio >2.3; transient elastography (by FibroScan) result of more than 12.5 kPa at screening and/or an aspartate aminotransferase to platelet ratio index (APRI) of more than 2; platelet count less than 50 × 109 /L; severe anemia (hemoglobin grade 3 or higher (<8 g/dL)); any malignancy; Alfa-fetoprotein (AFP) level above 200 ng/mL; critically ill or more than slight limitation of activity; unwilling to participate or to sign the informed consent.
The study protocol was reviewed and approved by the Research Ethics Committee of Faculty of Medicine, Alexandria University (IRB00007555) according to the Declaration of Helsinki. All subjects and their parents/guardians signed the informed consents before the start of the study interventions.
Starting from February 21, 2017, adolescent patients presenting, with chronic HCV infection, to 2 outpatient clinics in Alexandria and 2 in Cairo, Egypt were subjected to full screening for eligibility criteria. The first 30 consecutive patients who fulfilled all eligibility criteria were included in this study as a single treatment group.
During the screening/baseline visit (week 0) and all other study visits (week 2, week 4, week 12), end of treatment (EOT), and week 24 (12 weeks after EOT), all patients were subjected to full physical examination and investigations including the complete blood count (CBC), serum bilirubin, serum albumin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), prothrombin time (PT), serum creatinine, and ultrasonographic abdominal scan.
The serum HCV-RNA level (virus load) was tested using the Polymerase Chain Reaction (PCR) quantitative measurements by COBAS Amplicor 2.0, Roche Molecular Diagnostics, Pleasanton, CA (lower limit of detection of 10 IU/mL) during the screening visit and all the study visits. While tests to exclude pregnancy, active schistosomiasis, hepatitis B, HIV and autoimmune hepatitis as well as the test for genotyping “if not known” using GEN-C 2.0 Reverse Hybridization Strip Assay (Nuclear Laser Medicine, Settala, Italy) were done only at the screening visits. Liver biopsy and/or Transient Elastography by FibroScan (Echosens, Paris, France) were performed at screening visit to exclude patients with liver cirrhosis (F4 or more than 12.5 kPa by FibroScan) and to have an estimate for the stage of fibrosis at baseline.
All patients were interrogated throughout the study for any adverse events and were requested to call by phone or visit at any unscheduled time for reporting any adverse event or query.
All patients were subjected to a dual therapy in the form of a weight-based daily doses of SOF (Grateziano) with daclatasvir (DCV; generic products produced by European Egyptian Pharmaceutical Industries, a company of Pharco Corporation, Alexandria, Egypt) for 12 weeks duration. Both drugs had demonstrated bioequivalence to the reference brands by pharmacokinetic/bioequivalence studies conducted in internationally accredited bioequivalence research centers (5). The daily dose of SFO 400 or 200 mg tablets was based on body weight categories corresponding to the adult dose of approximately 400 mg/1.7 m2 body surface area after correcting for the variation of (surface area to weight ratios [km factor]) between adults (km factor = 37 kg/m2) down to children (km factor = 25 kg/m2). The calculated doses were approximated for each body weight category (for body weight from 20 to to 30 kg, the dose is 200 mg daily; >30–40 kg, 300 mg daily; >40 kg/adults, 400 mg once daily). Similarly, DCV 60 or 30 mg tablets was given on a daily dose based on body weight categories corresponding approximately to 60 mg/1.7 m2 body surface area (from 20 to 30 kg: 30 mg once daily; >30–40 kg: 45 mg once daily; and >40 kg: 60 mg once daily).
The primary outcome of the trial was the proportion of patients achieving sustained virologic response 12 (SVR12) defined as serum HCV RNA below lower level of quantification at week 12 after EOT) both on intention to treat (ITT) basis and per-protocol basis.
Treatment virologic failure was defined as either: on-treatment virologic failure defined as the failure to reach a virus load (VL) less than the lower limit of quantification (LLOQ) by the EOT, or a confirmed rise of VL above the LLOQ after being below the limit; or posttreatment failure (relapse) defined as detectable HCV RNA in the serum within 12 weeks after the EOT with HCV RNA concentration below LLOQ.
Treatment-emergent adverse event (TEAE) was defined as any adverse event reported by patients or observed by investigators during the study visits or any deviation from a baseline normal laboratory test, occurring after administration of the first dose of study drugs until 30 days after the last dose. All TEAEs were reported using the Medical Dictionary for Regulatory Activities version 19 (MedDRA v.19) lowest level and preferred terms. TEAEs deemed to have certain, probable or possible causality category according to Uppsala Monitoring Center (UMC) causality categorization were considered in analysis for incidence rate in an ITT basis and graded according to seriousness (serious/nonserious) and severity using the Common Terminology Criteria for Adverse Events v3.0.
We presented our qualitative data as counts, proportions or percentage with the CI using Wilson Score Interval Method. For quantitative data, descriptive statistics are the arithmetic mean, the standard deviation, the median, and the 95% CI whenever found appropriate.
Thirty eligible patients were included in the study and received their treatment with dual SOF/DCV. During the whole period of the study, only 1 patient was lost to follow-up. His results have been included in the ITT analysis as not achieving SVR12. (Flowchart: Supplemental Figure 1, Supplemental Digital Content 1, http://links.lww.com/MPG/B328).
The demographic and some baseline characteristics are presented in Supplemental Table 1 (Supplemental Digital Content 2, http://links.lww.com/MPG/B329).
By the end of week 4, all patients 30 of 30 (100%; 95% CI 88.7%–100%) achieved rapid virologic response (RVR; defined as serum HCV RNA below the level of quantification at week 4). Serum HCV-RNA levels, measured by PCR for all patients, at the EOT response (ETR) were all negative and reported as target not detected (TND) with 100% (95% CI 88.7%–100%) EOT virologic response rate.
The ITT SVR12 rate was 29 of 30 (96.7%; 95% CI 83.3%–99.4%). No treatment failure was reported. The only patient who did not achieve SVR12 was lost to follow-up after showing viral negativity at the 12th week (EOT) visit, whereas all the remaining 29 patients (100%, 95% CI 88.3%–100%) who completed the full protocol and follow-up visits achieved SVR12.
The virus load presented in mean log10 of the HCV RNA values showed marked reduction from the mean baseline value to be negative throughout from week 4 (Fig. 1).
Serum alanine and aspartate aminotransferase enzymes (ALT and AST) showed marked reduction towards full normalization in all patients at the end of the study (Figs. 2 and 3).
No fatalities or serious adverse events were reported during the period of the study. Only 8 from our patients reported 15 nonserious treatment-emergent adverse events throughout the study with causality assessment reports as possible or above. These events included nausea reported by 3 patients, abdominal pain reported by 3 patients, fatigue reported by 4 patients, headache by 3 patients, and pruritus or skin rash by 2 patients. All were mild-to-moderate (≤grade 2) in severity (Supplemental Table 2, Supplemental Digital Content 3, http://links.lww.com/MPG/B330).
No significant changes in hemoglobin levels or any other hematological parameters from normal ranges were observed throughout the study. Figure 4 and Supplemental Figure 2 (Supplemental Digital Content 4, http://links.lww.com/MPG/B331) show both hemoglobin (g/dl) and platelet count changes.
The same was applied to serum creatinine level as an indicator of kidney function, which showed no significant difference from normal range throughout the study (Supplemental Figure 3, Supplemental Digital Content 5, http://links.lww.com/MPG/B332).
Our study is one of the earliest studies conducted on a pediatric age group using the dual combination SFO/DCV. Our results demonstrated that this combination is safe and efficacious in the treatment of adolescents from 12 to 17 years old, with high tolerability, no serious adverse effects and no treatment virologic failures. The SVR12 rate by ITT analysis was 29 of 30 (96.7%; 95% CI 83.3%–99.4%). The only patient who did not achieve SVR12 was lost to follow-up after showing viral negativity at the EOT visit. Normalization of liver enzymes and no adverse effects on hematological or kidney functions were demonstrated in our study results.
We had published earlier the results of our small pilot study on 10 adolescent patients who all achieved SVR12 after dual SOF/DCV therapy with, shortened 8-week course based on achieving undetectable serum HCV RNA at week 2 (very RVR [vRVR]) as a qualifier (6).
Whereas, El-Sayed et al had presented their poster in the international liver congress 2017, reporting the results of 13 adolescents between 15 and 17 years old with chronic HCV infection who had been treated with adult dose of SOF/DCV combination alone for noncirrhotic patients, and with added weight-based ribavirin for cirrhotics, for 12 weeks. All the 13 patients completed the full protocol with good tolerability and showed SVR12 rate of 13 of 13 (100%) (7).
Also, Abdel Ghaffar et al had presented their poster in the AASLD Liver Meeting 2017, reporting the interim results of a cohort of adolescent patients treated with the same dual therapy (SOF/DCV) for 12 weeks. All the 22 patients (100%), for whom the posttreatment follow-up data was available at the time of presentation, achieved SVR12 with good tolerability and no serious adverse events (8).
Despite the availability of so many “Interferon and Ribavirin free” treatment regimens recommended in guidelines for the treatment of chronic HCV-infected adults, yet, so far, there is only one option (SOF/LDV) recommended in guidelines for those below 18 years old excluding genotypes 2 and 3 (2,3). More options, that can cover all genotypes, with reasonable costs, are highly needed for pediatric age groups. That is in-order to assure the sustainability and effectiveness of the global elimination programs, if the world is committed to reach the goal of the WHO initiative to eliminate viral hepatitis by the year 2030.
We acknowledge the uncontrolled, non-blinded study design and the small sample size as the main limitations in our study. However, our study could be regarded as a foundation to encourage other investigators to conduct investigator-initiated studies on pediatric age groups in other populations, with different genotypes, particularly on those infected with genotypes 2 and 3 who are being currently still treated with a ribavirin-based treatment (SFO/ribavirin) combination (2,3).
In summary, SFO/DCV combined therapy could be a safe and effective treatment in adolescent patients 12 to 17 years old with chronic HCV genotype 4 infections. Being a pan-genotypic combination, these preliminary results could incite other studies on different other populations, infected with different genotypes in a way to establish numerous cost-effective options in the treatment of chronic HCV in pediatric age groups.
1. FDA News Release. FDA approves two hepatitis C drugs for pediatric patients. FDA Web site. Available at: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm551407.htm
. Published April 7, 2017. (Accessed January 2, 2018).
2. AASLD-IDSA. HCV in children. Recommendations for testing, managing, and treating hepatitis C. Available at: http://www.hcvguidelines.org/full-report/hcv-testing-and-linkage-care
. (Accessed January 30, 2018).
3. Indolfi G, Hierro L, Dezsofi A, et al. Treatment of chronic hepatitis C virus infection in children. A position paper by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr
4. European Association for the Study of the Liver. Electronic address: [email protected]
EASL recommendations on treatment of Hepatitis C 2016. J Hepatol
5. Hill AM, Tahat L, Mohammed MK, et al. Bioequivalent pharmacokinetics for generic and originator hepatitis C direct acting antivirals: Poster Presented at AASLD - The Liver Meeting 2017, Abstract # 1078. Hepatology
2017; 66 (S1):577A.
6. El-Shabrawi M, Abdo AM, El-Khayat H, et al. Shortened 8 weeks course of dual sofosbuvir
/daclatasvir therapy in adolescent patients, with chronic hepatitis C infection. J Pediatr Gastroenterol Nutr
7. El-Sayed M, Hassany M, Asem N. A pilot study for safety and efficacy of 12 weeks sofosbuvir
plus daclatasvir with or without ribavirin in Egyptian adolescents with chronic hepatitis C virus infection: Poster Presented at EASL-ILC 2017, Abstract # THU-412. J Hepatol
2017; 66:S178Available at: http://www.journal-of-hepatology.eu/article/S0168-8278(17)30642-6/fulltext
. (Accessed January 30, 2018).
8. Abdel Ghaffar T, El-Naghi S, Abdel-Gawad M, et al. The safety and efficacy of sofosbuvir
& daclatasvir combined therapy for treatment of Egyptian children and adolescents with chronic hepatitis C (HCV)-genotype 4: interim results: Poster presented at AASLD - The Liver Meeting 2017, Abstract # LB-20. Hepatology
(Accessed January 30, 2018).