Abstract
Background:
12-week sofosbuvir/ledipasvir combination is approved for the treatment of HCV genotype 4.Objectives:
The study aimed to evaluate the safety and efficacy of generic sofosbuvir/ledipasvir for 8 and 12 weeks in easy to treat patients infected with the hepatitis C virus (HCV) genotype 4.Methods:
In this prospective randomized study, 40 naïve non-cirrhotic easy to treat patients were randomized to receive 8 or 12 weeks (groups 1 and 2, respectively) of generic ledipasvir/sofosbuvir (MPIviropack-Plus provided by Marcyrl Pharmaceutical Industries). A simple randomization was done using computer-generated random numbers by Microsoft Excel. The primary endpoint was the sustained virological response 12 weeks post-treatment (SVR12).Results:
There was no significant difference between the two groups of 8 and 12 weeks of therapy in pre-treatment demographics, laboratory parameters, and viral load. A more significant reduction in liver enzymes was noticed in group 2. No adverse events were recorded. SVR12 was 100% with 8 weeks of generic sofosbuvir/ledipasvir and 95% with 12 weeks of the same regimen.Conclusions:
Generic sofosbuvir/ledipasvir for 8 weeks is highly effective with a high rate of SVR12 among naïve non-cirrhotic easy to treat patients with HCV genotype 4 infection. No additional benefit was associated with the extension of the treatment duration to 12 weeks.Keywords
1. Background
In Egypt, the seroprevalence of hepatitis C virus (HCV) infection declined from about 15% in 2008 to 6.3% in 2015 among the studied population (1), with an overall estimated 30% decrease in the HCV prevalence (2). Genotype 4 is responsible for over 90% of infections and the rest of the infections is due to genotype 1 (3, 4). HCV treatment using combinations of directly acting antiviral (DAA) agents has led to a great increase in the number of patients achieving sustained virological response (SVR) rates, reaching up to 90% - 95% and even higher (5).
The sofosbuvir/ledipasvir (SOF/LDV) combination is available in a two-drug fixed-dose tablet containing sofosbuvir 400 mg and ledipasvir 90 mg. It has been recently approved for the treatment of genotypes 1, 4, 5, and 6 as a once-daily 12-week regimen for treatment of naive non-cirrhotic patients or patients with compensated cirrhosis (Child-Pugh A) (6). The SOF/LDV combination also provided a chance to consider 8 versus 12 weeks of treatment for genotype 1 infected patients with favorable virological and clinical characteristics (7). The most common adverse events reported with SOF/LDV combination were a headache and fatigue (6).
The use of low-cost generic DAAs was adopted by some countries due to the very high cost of branded versions. Their use was proved a feasible and economical alternative with comparable high SVR12 rates (8, 9).
The “global health sector strategy on viral hepatitis, 2016 - 2021” was recently formulated by The World Health Organization and determined service coverage goals to eliminate hepatitis C infection. This would be achieved through scaling-up of hepatitis C diagnosis and treatment by 2030 for a coverage of 90% and 80%, respectively, and an 80% decrease in incidence (10).
The National Committee for Control of Viral Hepatitis (NCCVH) in Egypt has started a mass therapeutic program (10) with sofosbuvir-based drug combinations since October 2014 with chronological changes in the used drugs (11-13). Generic DAAs have been used in the Egyptian national treatment program since October 2015 (14). Egypt is on the road to elimination of HCV. It is one of the only ten countries wherein, patients achieving SVR are 5 times more than patients with new infections (15).
2. Objectives
The objective of the current study was to assess the safety and efficacy of generic SOF/LDV combination therapy for eight versus 12 weeks in naïve, non-cirrhotic, easy to treat Egyptian patients infected with hepatitis C virus (HCV) genotype 4.
3. Methods
This prospective randomized study included 40 Egyptian patients with HCV (genotype 4) infection who were candidates for anti-viral therapy according to the guidelines of the National Committee for Control of Viral Hepatitis (NCCVH) (16) during the period of recruitment (from February 2017 to July 2017). This study was based on a purposive sampling. Patients were randomly divided into two equal groups by simple randomization using computer-generated random numbers by Microsoft Excel. The person performing HCV polymerase chain reaction at the end of the treatment and 12-week post-treatment did not know if this patient had received 8 or 12 weeks of treatment. The person randomizing the patients did not know what the next treatment duration allocation would be. This study included easy to treat patients (11) who were: adults > 18 years of both sexes, viral load of less than 2.000.000 IU/mL, fibrosis stages (Fo-F1-F2) by fibro-scan, naïve to antiviral therapy, those not having cirrhosis, and those having compensated liver biochemical parameters: serum bilirubin ≤ 1.2 mg/dL, serum albumin ≥ 3.5 g/dL, INR ≤ 1.2, and platelet count ≥ 150 000 cmm.
The exclusion criteria were patients with advanced fibrosis stages (fibrosis stages F3 and F4) by transient elastography, HBV or HIV co-infection, pregnancy or inability to use effective contraception, inadequately controlled DM (HbA1c of more than 9%), hepatic or extrahepatic malignancy, creatinine clearance of less than 30 mL/min, breastfeeding, patients with organ transplant or using immunosuppressive drugs, substance abuse, IV drugs, inhaled drugs, and drug-related liver disease.
The patients received the generic form of SOF/LDV combination under the name of “MPIviropack Plus” provided by Marcyrl Pharmaceutical Industries, Cairo, Egypt, that contained a combination of SOF 400 mg and LDV 90 mg. group 1 (20 patients) received generic SOF/LDV daily fixed dose 400/90 mg for 8 weeks only while group 2 (20 patients) received the same treatment for 12 weeks.
The patients were subjected to baseline and follow-up full history taking and clinical examination with a special emphasis on any complications during or after the end of treatment like fatigue, headache, fever, jaundice, and rash. Routine laboratory and radiological investigations were performed at baseline and at the end of therapy to determine complete blood picture, liver biochemical profile (total serum bilirubin, direct and indirect bilirubin, serum albumin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, prothrombin time, and international normalized ratio (INR)), serum creatinine, alfa-fetoprotein (AFP), and abdominal ultrasonography. In addition, quantitative HCV-RNA was conducted by real-time polymerase chain reaction (PCR) (TaqMan probe) ABI 7900 (Thermo Fisher Scientific, Waltham, USA), before the start of treatment, four weeks after the start of therapy, at the end of therapy, and 12 weeks after the end of therapy.
Transient elastography was performed on all patients before treatment. The cutoff values for liver stiffness measurements expressed in Kpa were used in this study according to De Ledinghen and Vergniol (17) as follows: F0: 0 - 5.4 Kpa, F0 - F1: 5.5 - 5.9 Kpa, F1: 6 - 6.9 Kpa, F1 - F2: 7 - 8.7 Kpa, F2: 8.8 - 9.4 Kpa, F3: 9.5 - 12.4 Kpa, F3 - F4: 12.5 - 14.4 Kpa, and F4: ≥ 14.5 Kpa.
The study was performed in compliance with the ethical principles of the 1964 Declaration of Helsinki (as revised in Brazil 2013) and its later amendments with GCP guidelines. The study protocol, as well as the informed consent, was approved by the research ethics committee of the Institutional Review Board (IRB) of Cairo University (number N-38 - 2016).
3.1. Statistical Methods
Data were coded and entered into SPSS (Statistical Package for the Social Sciences) version 24 software. The data were summarized using mean, standard deviation, median, minimum, and maximum for quantitative data and using frequency (count) and relative frequency (percentage) for categorical data. Comparisons between the two groups were made using unpaired t test for normally distributed quantitative variables while the non-parametric Mann-Whitney test was used for non-normally distributed quantitative variables. For comparison of serial measurements (pretreatment and end of treatment) for each patient, the paired t test was used (18).
For comparing categorical data, the Chi-square (χ2) test was performed. The exact test was used instead when the expected frequency was less than five (19). P values of less than 0.05 were considered statistically significant.
4. Results
The demographic and laboratory features of the two studied groups are shown in Table 1. There was no significant difference between the two groups regarding their age, gender, BMI, baseline liver stiffness or laboratory parameters, and viral load. There were no adverse effects recorded during therapy in any of the treated patients.
| Group 1 (8 Weeks of Generic SOF/LDV) | Group 2 (12 Weeks of Generic SOF/LDV) | P Value | |
|---|---|---|---|
| Gender (male/female) | 10 (50)/10 (50) | 7 (35)/13(65) | 0.337 |
| Age (y) | 37.65 ± 14.25 | 40.60 ± 14.14 | 0.547 |
| BMI | 26.04 ± 3.19 | 27.24 ± 4.79 | 0.414 |
| Liver stiffness KPa | 5.54 ± 1.43 | 5.35 ± 1.51 | 0.547 |
| F0 | 10 (50) | 12 (60) | 0.302 |
| F1 | 4 (20) | 4 (20) | 0.302 |
| F0 - F1 | 3 (15) | 2 (10) | 0.302 |
| F1 - F2 | 3 (15) | 0 (0) | 0.302 |
| F2 | 0 (0) | 2 (10) | 0.302 |
| Diabetes mellitus | 2 (10) | 1 (5) | 1 |
| History of bilharziasis | 2 (10) | 4 (20) | 0.661 |
| White blood cells (103/cmm) | 6.24 ± 1.86 | 6.77 ± 2.17 | 0.414 |
| Hemoglobin (gm/dL) | 13.75 ± 1.81 | 13.10 ±1.63 | 0.240 |
| Platelet count (103/cmm) | 239.75 ± 46.29 | 266.35 ± 57.49 | 0.115 |
| Serum albumin (gm/dL) | 4.46 ± 0.42 | 4.34 ± 0.36 | 0.380 |
| Total bilirubin (mg/dL) | 0.65 ± 0.24 | 0.54 ± 0.21 | 0.139 |
| Direct bilirubin (mg/dL) | 0.21 ± 0.14 | 0.21 ± 0.13 | 0.946 |
| ALT (U/L) | 38.25 ± 12.67 | 41.05 ± 24.81 | 0.656 |
| AST (U/L) | 35.40 ± 9.11 | 35.30 ± 16.05 | 0.981 |
| Serum creatinine (mg/dL) | 0.73 ± 0.18 | 0.75 ± 0.23 | 0.764 |
| INR | 1.03 ± 0.05 | 1.01 ± 0.08 | 0.319 |
| AFP (ng/mL) | 3.62 ± 1.95 | 3.52 ± 1.35 | 0.968 |
| Viral load (IU/mL) | 363094.62 ± 485807.82 | 429048.01 ± 505015.62 | 0.495 |
The follow-up laboratory parameters after treatment revealed no significant change apart from AST and ALT, which showed a significant reduction in the two groups (Table 2). Patients in group 2 who received 12 weeks of therapy showed a more significant reduction in AST and ALT. Regarding the virological response, there were three patients who had positive HCV PCR four weeks after the initiation of therapy, including one patient in group 1 and two patients in group 2. At the end of therapy, all patients in the two groups had negative HCV PCR.
| Group 1 (8 Weeks of Generic SOF/LDV) | Group 2 (12 Weeks of Generic SOF/LDV) | |||||
|---|---|---|---|---|---|---|
| Baseline | 12W After Treatment | P Value | Baseline | 12W After Treatment | P Value | |
| White blood cells (103/cmm) | 6.24 ± 1.86 | 6.83 ± 2.76 | 0.244 | 6.77 ± 2.17 | 6.88 ± 1.84 | 0.710 |
| Hemoglobin (gm/dL) | 13.75 ± 1.81 | 13.50 ± 1.91 | 0.373 | 13.10 ± 1.63 | 12.83 ± 2.05 | 0.192 |
| Platelet count (103/cmm) | 239.75 ± 46.29 | 241.90 ± 38.91 | 0.872 | 266.35 ± 57.49 | 257.60 ± 60.59 | 0.466 |
| Serum albumin (gm/dL) | 4.46 ± 0.42 | 4.31 ± 0.32 | 0.093 | 4.34 ± 0.36 | 4.26 ± 0.36 | 0.297 |
| Total bilirubin (mg/dL) | 0.65 ± 0.24 | 0.67 ± 0.37 | 0.757 | 0.54 ± 0.21 | 0.52 ± 0.17 | 0.532 |
| Direct bilirubin (mg/dL) | 0.21 ± 0.14 | 0.19 ± 0.10 | 0.362 | 0.21 ± 0.13 | .19 ±.09 | 0.373 |
| ALT (U/L) | 38.25 ± 12.67 | 20.90 ± 9.68 | < 0.001 | 41.05 ± 24.81 | 16.13 ± 7.32 | < 0.001 |
| AST (U/L) | 35.40 ± 9.11 | 23.60 ± 8.73 | 0.002 | 35.30 ± 16.05 | 17.67 ± 4.13 | < 0.001 |
| Serum creatinine (mg/dL) | 31.15 ± 12.38 | 27.70 ± 6.11 | 0.233 | 25.70 ± 5.91 | 26.80 ± 7.30 | 0.418 |
| INR | 0.73 ± 0.18 | 0.84 ± 0.16 | 0.102 | 0.75 ±.23 | 0.70 ± 0.17 | 0.302 |
| AFP (IU/mL) | 1.03 ± 0.05 | 1.06 ± 0.11 | 0.379 | 1.01 ± 0.08 | 1.00 ± 0.05 | 0.721 |
SVR 12 was achieved in all patients of group 1 while one patient (5%) in group 2 failed to achieve SVR 12 (Table 3). The patient who failed to achieve SVR was a 45-year-old male patient, with a BMI of 22.4. He was not diabetic, hypertensive, smoker, or alcoholic. His liver stiffness measurement was 4.7 KPa (F0) by fibroscan with a baseline viral load of 5007 IU/mL. His HCV RNA at week 4 of treatment and at the end of treatment was negative. HCV RNA 12 weeks after the end of treatment was 35 000 IU/mL.
| Treatment Response | Group I (n = 20) | Group II (n = 20) |
|---|---|---|
| HCV RNA PCR 4 weeks after treatment initiation (negative/positive) | 19 (95)/1 (5) | 18 (90)/2 (10) |
| End of treatment | 20 (100) | 20 (100) |
| SVR12 | 20 (100) | 19 (95) |
| Non-SVR12 | 0 (0) | 1 (5) |
5. Discussion
Drug price is a considerable obstacle to implementing treatment for chronic hepatitis C with direct-acting antiviral agents (DAAs)-based regimens (20). Gilead and Bristol-Myers Squibb pharmaceutical companies have granted voluntary licenses (VLs) to generic companies to mass produce cheaper generic DAAs that proved to be bioequivalent to the originator drugs. Mass treatment of chronic hepatitis C with generic DAAs at a low cost is the most hopeful approach to reach the ambitious World Health Organization goals for HCV eradication by 2030 (9).
In the present study, the aim was to assess the response of chronic hepatitis C genotype 4 infected patients to treatment with generic SOF/LDV combination and compare the response rates between eight and twelve weeks regimens. 40 patients were included in the study and were randomized into two groups according to the duration of treatment.
The 8-week course of “MPIviropack Plus” treatment costs 2200 L. E while the 12-week regimen costs 3300 L. E. The 8-week regimen would be cheaper particularly for patients with no health insurance who have to buy the drugs by their own. In addition, no added benefit was associated with the extension of the duration of treatment to 12 weeks.
In the present study, patients who received 8 weeks of treatment regimen showed a response rate of 100% that is higher than that previously reported among patients with genotype 4 infection. Shiha et al. (21) reported an SVR12 of 95% (41 of 43 patients) in naïve non-cirrhotic Egyptian patients chronically infected with HCV genotype 4 who received SOF/LDV for 8 weeks while SVR12 was 98% (42 of 43 patients) in patients who received the same regimen for 12 weeks.
Naïve, non-cirrhotic, easy to treat patients in our study showed the SVR12 rates after 8 weeks of treatment with SOF/LDV that was higher than the rates previously reported among genotype 1 patients. Kowdley et al. (22) reported SVR12 rates of 94% with 8 weeks of SOF/LDV, 93% with 8 weeks of LDV-SOF plus ribavirin, and 95% with 12 weeks of LDV-SOF in non-cirrhotic genotype 1 infected patients. Curry et al. (23) reported an SVR rate of 95.3% and there was no statistical difference in SVR rates between patients who received 8 and 12 weeks of SOF/LDV combination therapy irrespective of any clinical or virological parameters. In addition, Buggisch et al. (24) revealed that in the 8-week group, 85.1% of the intention-to-treat and 98.3% of the per-protocol patients achieved SVR12 while in the 12-week group, 85.5% of the ITT and 98.1% of the PP patients achieved SVR12. This may be related to the genotype difference compared to our study and that all of our patients were easy to treat with minimal to mild fibrosis stages.
The 8-week treatment regimen with SOD/LDV was also studied on other genotypes. Nguyen et al. (25) conducted a study on patients chronically infected with HCV genotype 6 without cirrhosis or prior treatment failure, as well as on patients with cirrhosis and/or prior treatment failure. SVR12 rates were 95.0% for the 8-week group and 95.0% for the 12-week group. Gane et al. (26) conducted another study on patients chronically infected with HCV genotype 2 who were naïve and treatment-experienced and revealed SVR12 rates of 96% for 12 weeks and 74% for 8 weeks of SOV/LDV.
Regarding the changes in baseline laboratory data in the studied groups, we found a significant improvement in AST and ALT that could be explained by inflammation regression following treatment. This agrees with different studies that included treatment of different HCV genotypes with DAAs (27-30). On the other hand, there were no significant changes in other laboratory parameters of the patients.
A limitation of our study is the small number of enrolled patients. The sequencing analysis of the virological failure was not done. Thus, no interpretation of the potential NS5A or NS5B resistance-associated substitutions could be made.
In summary, the 8-week treatment regimen of generic SOF/LDV, using two DAAs with distinct viral targets and mechanisms of action, could show a high efficacy in the treatment of naive non-cirrhotic easy to treat chronic HCV genotype 4 infection. For the generalization of the study results to the whole population, there is a need for a high-quality study with large numbers of participants.
References
-
1.
Ministry of Health and Population Cairo-Egypt; El-Zanaty and Associates Cairo-Egypt; The DHS program; ICF international. Egypt health issues survey. Rockville, Maryland, USA: Ministry of Health and ICF International; 2015.
-
2.
Kandeel A, Genedy M, El-Refai S, Funk AL, Fontanet A, Talaat M. The prevalence of hepatitis C virus infection in Egypt 2015: implications for future policy on prevention and treatment. Liver Int. 2017;37(1):45-53. [PubMed ID: 27275625]. [PubMed Central ID: PMC5145777]. https://doi.org/10.1111/liv.13186.
-
3.
Waked I, Doss W, El-Sayed MH, Estes C, Razavi H, Shiha G, et al. The current and future disease burden of chronic hepatitis C virus infection in Egypt. Arab J Gastroenterol. 2014;15(2):45-52. [PubMed ID: 25097045]. https://doi.org/10.1016/j.ajg.2014.04.003.
-
4.
Blach S, Zeuzem S, Manns M, Altraif I, Duberg AS, Muljono DH, et al. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: A modelling study. Lancet Gastroenterol Hepatol. 2017;2(3):161-76. [PubMed ID: 28404132]. https://doi.org/10.1016/S2468-1253(16)30181-9.
-
5.
Childs K, Merritt E, Considine A, Sanchez-Fueyo A, Agarwal K, Martinez-Llordella M, et al. Immunological predictors of nonresponse to directly acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis. Open Forum Infect Dis. 2017;4(2):ofx067. [PubMed ID: 28584852]. [PubMed Central ID: PMC5450903]. https://doi.org/10.1093/ofid/ofx067.
-
6.
European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018. J Hepatol. 2018;69(2):461-511. [PubMed ID: 29650333]. https://doi.org/10.1016/j.jhep.2018.03.026.
-
7.
Terrault NA, Zeuzem S, Di Bisceglie AM, Lim JK, Pockros PJ, Frazier LM, et al. Effectiveness of ledipasvir-sofosbuvir combination in patients with hepatitis C virus infection and factors associated with sustained virologic response. Gastroenterology. 2016;151(6):1131-1140 e5. [PubMed ID: 27565882]. [PubMed Central ID: PMC5300778]. https://doi.org/10.1053/j.gastro.2016.08.004.
-
8.
Hill A, Khwairakpam G, Wang J, Golovin S, Dragunova J, Smith R, et al. High sustained virological response rates using imported generic direct acting antiviral treatment for hepatitis C. J Virus Erad. 2017;3(4):200-3. [PubMed ID: 29057082]. [PubMed Central ID: PMC5632545].
-
9.
Hill A, Tahat L, Mohammed MK, Tayyem RF, Khwairakpam G, Nath S, et al. Bioequivalent pharmacokinetics for generic and originator hepatitis C direct-acting antivirals. J Virus Erad. 2018;4(2):128-31. [PubMed ID: 29682307]. [PubMed Central ID: PMC5892672].
-
10.
World Health Organization. Global health sector strategy on viral hepatitis 2016 – 2021. 2016. Available from: http://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en/.
-
11.
Elsharkawy A, Fouad R, El Akel W, El Raziky M, Hassany M, Shiha G, et al. Sofosbuvir-based treatment regimens: real life results of 14 409 chronic HCV genotype 4 patients in Egypt. Aliment Pharmacol Ther. 2017;45(5):681-7. [PubMed ID: 28070899]. https://doi.org/10.1111/apt.13923.
-
12.
Buti M, Calleja JL, Lens S, Diago M, Ortega E, Crespo J, et al. Simeprevir in combination with sofosbuvir in treatment-naive and -experienced patients with hepatitis C virus genotype 4 infection: a Phase III, open-label, single-arm study (PLUTO). Aliment Pharmacol Ther. 2017;45(3):468-75. [PubMed ID: 27896822]. https://doi.org/10.1111/apt.13883.
-
13.
Eletreby R, Elakel W, Said M, El Kassas M, Seif S, Elbaz T, et al. Real life Egyptian experience of efficacy and safety of Simeprevir/Sofosbuvir therapy in 6211 chronic HCV genotype IV infected patients. Liver Int. 2017;37(4):534-41. [PubMed ID: 27712017]. https://doi.org/10.1111/liv.13266.
-
14.
Doss W. The Egyptian HCV control program, international viral hepatitis elimination (IVHEM) 2017. Amsterdam, Netherlands; 2016. Available from: http://regist2.virology-education.com/2016/IVHEM/04_Doss.pdf.
-
15.
Hill AM, Nath S, Simmons B. The road to elimination of hepatitis C: Analysis of cures versus new infections in 91 countries. J Virus Erad. 2017;3(3):117-23. [PubMed ID: 28758018]. [PubMed Central ID: PMC5518239].
-
16.
El-Akel W, El-Sayed MH, El Kassas M, El-Serafy M, Khairy M, Elsaeed K, et al. National treatment programme of hepatitis C in Egypt: Hepatitis C virus model of care. J Viral Hepat. 2017;24(4):262-7. https://doi.org/10.1111/jvh.12668.
-
17.
De Ledinghen V, Vergniol J. Transient elastography (FibroScan). Gastroenterol Clin Biol. 2008;32(6 Suppl 1):58-67. [PubMed ID: 18973847]. https://doi.org/10.1016/S0399-8320(08)73994-0.
-
18.
Chan YH. Biostatistics 102: Quantitative data--parametric & non-parametric tests. Singapore Med J. 2003;44(8):391-6. [PubMed ID: 14700417].
-
19.
Chan YH. Biostatistics 104: Correlational analysis. Singapore Med J. 2003;44(12):614-9. [PubMed ID: 14770254].
-
20.
Hoofnagle JH, Sherker AH. Therapy for hepatitis C the costs of success. N Engl J Med. 2014;370(16):1552-3. [PubMed ID: 24725236]. https://doi.org/10.1056/NEJMe1401508.
-
21.
Shiha G, Esmat G, Hassany M, Soliman R, Elbasiony M, Fouad R, et al. Ledipasvir/sofosbuvir with or without ribavirin for 8 or 12 weeks for the treatment of HCV genotype 4 infection: results from a randomised phase III study in Egypt. Gut. 2018. [PubMed ID: 29666174]. https://doi.org/10.1136/gutjnl-2017-315906.
-
22.
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-88. [PubMed ID: 24720702]. https://doi.org/10.1056/NEJMoa1402355.
-
23.
Curry MP, Tapper EB, Bacon B, Dieterich D, Flamm SL, Guest L, et al. Effectiveness of 8- or 12-weeks of ledipasvir and sofosbuvir in real-world treatment-naive, genotype 1 hepatitis C infected patients. Aliment Pharmacol Ther. 2017;46(5):540-8. [PubMed ID: 28691377]. https://doi.org/10.1111/apt.14204.
-
24.
Buggisch P, Vermehren J, Mauss S, Gunther R, Schott E, Pathil A, et al. Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C. J Hepatol. 2017. [PubMed ID: 29133244]. https://doi.org/10.1016/j.jhep.2017.11.009.
-
25.
Nguyen MH, Trinh H, Do S, Nguyen T, Nguyen P, Henry L. Open label study of 8 vs. 12 weeks of ledipasvir/sofosbuvir in genotype 6 treatment naive or experienced patients. Am J Gastroenterol. 2017;112(12):1824-31. [PubMed ID: 29087397]. https://doi.org/10.1038/ajg.2017.399.
-
26.
Gane EJ, Hyland RH, Yang Y, Svarovskaia E, Stamm LM, Brainard DM, et al. Efficacy of ledipasvir plus sofosbuvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2 infection. Gastroenterology. 2017;152(6):1366-71. [PubMed ID: 28137593]. https://doi.org/10.1053/j.gastro.2017.01.017.
-
27.
Elsharkawy A, Eletreby R, Fouad R, Soliman Z, Abdallah M, Negm M, et al. Impact of different sofosbuvir based treatment regimens on the biochemical profile of chronic hepatitis C genotype 4 patients. Expert Rev Gastroenterol Hepatol. 2017;11(8):773-8. [PubMed ID: 28480808]. https://doi.org/10.1080/17474124.2017.1326816.
-
28.
Macarthur KL, Smolic R, Smolic MV, Wu CH, Wu GY. Update on the development of anti-viral agents against hepatitis C. J Clin Transl Hepatol. 2013;1(1):9-21. [PubMed ID: 26357602]. [PubMed Central ID: PMC4521270]. https://doi.org/10.14218/JCTH.2013.007XX.
-
29.
Mehrez MI. Fibrosis regression after treatment with daas. Gastroenterol Hepatol Open Access. 2017;7(1). https://doi.org/10.15406/ghoa.2017.07.00223.
-
30.
Shousha HI, Mehassab MK, Mehrez MI, Afifi SA, Elsharkawy M, Hamed M, et al. Non-invasive fibrosis scores and liver stiffness changes in chronic hepatitis C after sofosbuvir-based treatment. Int J Hepatol Gastroenterol. 2017;3(4):85-90.