Prospective Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2017; 23(44): 7899-7905
Published online Nov 28, 2017. doi: 10.3748/wjg.v23.i44.7899
Dramatic response of hepatitis C patients chronically infected with hepatitis C virus genotype 3 to sofosbuvir-based therapies in Punjab, Pakistan: A prospective study
Sajjad Iqbal, Muhammad Haroon Yousuf, Muhammad Iftikhar Yousaf
Sajjad Iqbal, Department of Pathology, Shalamar Hospital, Lahore 54840, Pakistan
Muhammad Haroon Yousuf, Muhammad Iftikhar Yousaf, Department of Gastroenterology and Hepatology, Shalamar Hospital, Lahore 54840, Pakistan
ORCID number: Sajjad Iqbal (orcid.org/0000-0001-7476-7552); Muhammad Haroon Yousuf (orcid.org/0000-0001-5448-0781); Muhammad Iftikhar Yousaf (orcid.org/0000-0002-5099-9022).
Author contributions: Iqbal S designed the study, performed the research, analyzed the data and wrote the paper; Yousuf MH and Yousaf MI treated the patients, collected and analyzed the patient data.
Institutional review board statement: The study was reviewed and approved by the review board of Shalamar Hospital Lahore, Pakistan.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: There was no conflict of interest in this study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sajjad Iqbal, PhD, Department of Pathology, Shalamar Hospital, Shalimar Link road Mughal Pura, Lahore 54840, Pakistan. sajjad.iqbal@sihs.org.pk
Telephone: +92-42-111205205 Fax: +92-42-36823712
Received: June 12, 2017
Peer-review started: July 12, 2017
First decision: August 10, 2017
Revised: September 6, 2017
Accepted: September 13, 2017
Article in press: September 13, 2017
Published online: November 28, 2017

Abstract
AIM

To prospectively evaluate the efficacy of sofobuvir (SOF) in hepatitis C patients infected with hepatitis C virus (HCV) genotype 3 in Pakistan.

METHODS

The present study was performed with the coordination of gastroenterology and pathology departments of Shalamar Hospital Lahore from August 2014 to May 2016. The total number of patients included in this study was 1375 and all of them were infected with HCV genotype 3. On the basis of drug combinations, all the patients were separated into two groups. The first group of patients was treated for 24 wk with SOF (Sovaldi® by Gilead Sciences) plus ribavirin (RBV) [Ribazol® by Getz Pharma Pakistan (PVT) Ltd], while the patients of the second group were treated with SOF + RBV + pegylated-interferon (pegIFN) alfa-2a (Ropegra by Roach) for 12 wk. HCV genotyping and viral load measurement were performed on fully automated Abbott Real-Time PCR system (Abbott m24sp automated nucleic acid extraction system and Abbott m2000rt amplification system; abbott Molecular, Des Plaines, IL, United States). For the assessment of sustained virological response (SVR), all HCV RNA negative patients were followed for 12 weeks after the treatment completion. Any patient with less than 12 IU/mL viral load after 12 wk of treatment completion was considered as a sustained virological responder (SVR-12).

RESULTS

A total of 1375 patients chronically infected with HCV genotype 3 were treated with two drug combinations SOF + RBV and SOF + RBV + pegIFN alfa-2a. On the basis of these drug combinations, patients were divided into two groups (first and second). Overall SVR-12 was excellent in both groups (99.17% and 97.91%). Older patients (> 40 years) of second group showed lower SVR-12 (93.46%) compared to first group older patients (98.79%), while in the younger patients of both groups, the SVR-12 rate was almost the same (99.54% in first group and 99.05% in second group). No such difference regarding SVR-12 rate was seen in males and females of first group patients (99.68% and 98.88%, respectively), while in second group the males were found to be better responders compared to females (98.96% and 95%). The SVR-12 rate in previously treated patients of first group was better (99.34%) than second group (93.70%), while naïve patients of second group were marginally better responders (99.25%) than first group (97.80%). Rapid viral response at week-4 was found to be a very effective predictor for assessing the SVR rate at this stage of therapy in both groups. Headache, anemia and fatigue were common side effects in both groups either treated with SOF + RBV or SOF + RBV + pegIFN alfa-2a, while the overall percentage of the side effects was higher in second group.

CONCLUSION

The remarkable SVR response rate of HCV genotype 3 infected patients to SOF provided a new way to look forward to eliminate hepatitis C from our region.

Key Words: Sofosbuvir, Sustained virological response, Pakistan

Core tip: Previously, hepatitis C was treated with interferon-based therapies. Intolerable side effects, prolonged treatment duration and unsatisfactory response rates were the major droughts of those therapies. The introduction of sofobuvir (SOF) was claimed as a highly responding oral drug for hepatitis C patients, with minimal side effects in different trials; thus, it was important to assess its efficacy in our population. We found an outstanding response rate of SOF in hepatitis C patients infected with genotype 3 of hepatitis C virus. These findings revealed that with SOF we may eliminate hepatitis C from our population.



INTRODUCTION

Approximately 2%-3% of the world’s population (about 170 million) is chronically infected with hepatitis C virus (HCV)[1]. Prevalence of hepatitis C only in Europe and United States was estimated as 0.2%-2%[2,3]. In Pakistan, the situation regarding HCV infection rate was alarming. About 5.5% Pakistani population was infected with HCV; out of those 60%-80% had HCV genotype 3[4-6]. Hepatitis C patients always remain at risk for developing higher stages of disease like decompensated liver cirrhosis or hepatocellular carcinoma (HCC) that need liver transplantation[7-9].

Since the late 1980s, different categories of conventional interferon were known as a “key drug” to treat hepatitis C patient[10]. Although, the addition of RBV and improvement of conventional interferon with pegylation had enhanced the rate of sustained virological response (SVR)[11-13], yet most of the cases remained non-responders or relapsed after the termination of the treatment.

Because of prolonged treatment, adverse side effects and low SVR rates of interferon plus RBV based therapies, there was a need to improve the long-term viral clearance rate with more effective and less side effects containing drug for hepatitis C patients. In recent trials, newly approved drug “Sofosbuvir” drastically improved the SVR rate[14-16]. Sofosbuvir is thought the next milestone in the advancement of medication for hepatitis C[15]. Sofosbuvir is a nucleotide analogue that acts directly on virus and inhibits polymerase coding region NS5B of HCV and is thought to be more effective direct acting antiviral drug. Sofobuvir is also thought that it has rare side effects as compared to different categories of interferon those were associated with a long list of side effects[17-19].

Although some studies from Pakistan especially from province Punjab were reported regarding SOF based therapies response in HCV genotype 3 infected patients[20,21], yet the efficacy of SOF on such a large scale was never evaluated previously in this region. The main objective of the present study was to assess the response and side effects of SOF in hepatitis C patients infected with genotype 3. Additionally, we were also interested to see the influence of patient’s age, gender and baseline viral load on treatment response and to evaluate the association of rapid viral response (RVR) at week-4 with SVR that may help to predict the viral response rate at the earliest stage of the treatment.

MATERIALS AND METHODS
Patients and study design

From August 2014 to May 2016, 1375 patients having chronic infection of HCV genotype 3 were registered at the Department of Gastroenterology in Shalamar Hospital Lahore. Out of these 1375 patients, 885 (64.36%) were either non-responders or relapsers against pegIFN alfa-2a plus RBV and 490 (35.64%) were naive. According to the drug combinations, all the patients were separated into two groups. Patients of the first group were treated with SOF (Sovaldi® by Gilead Sciences) and RBV (Ribazol® by Getz Pharma Pakistan (PVT) Ltd). For the patients of the second group; pegIFN alfa-2a (Ropegra by Roach) was added with SOF + RBV.

Before starting the treatment; baseline characteristics, clinical data and laboratory investigations of all the patients was collected. All the patients included in the present study adults with more than 18 years of age were infected with HCV genotype 3. Out of 1375 patients, 696 (50.62%) were males and 679 (49.38%) were females. HCV genotyping and viral load measurement was performed on fully automated Abbott Real-Time PCR system (Abbott m24sp automated nucleic acid extraction system and Abbott m2000rt amplification system, Abbott Molecular, Des Plaines, IL, United States). Viral load was measured at day-0, week-4 and week-12 of the treatment in the first group and at day-0, week-4 and week-24 in the second group. To evaluate the SVR rate, PCR for HCV RNA was done at week-12 after the termination of treatment. Limit of detection or limit of quantitation was 12 IU/mL on Abbott Real-Time PCR system.

Approved recommendations were followed to treat the patients[22]. The first group was treated for 24 wk with SOF + RBV. For the second group, pegIFN alfa-2a was included with SOF and RBV and treatment duration was reduced to 12 wk. SOF of 400 mg was given as a single pill per day and the dosage of RBV was adjusted according to the patient’s body weight (1000-1200 mg/d). For the second group, additional 180 μg of pegIFN alfa-2a was subcutaneously injected once in a week.

Statistical analysis

Continuous data like age, hemoglobin was expressed as mean ± SD, whereas categorical data was expressed in the form of frequencies, proportion and percentages. A 95%CI was also calculated for various proportions. A P < 0.05 was considered statistically significant. Statistical analysis was performed using Epicalc 2000 software (version 1.2, Brixton Health, United States).

RESULTS

In the present study, 1375 patients, including 50.62% males and 49.38% females with chronic infection of HCV genotype 3 were enrolled. Out of 1375, 35.64% patients were fresh and 64.36% had previous treatment history of pegIFN alfa-2a + RBV (Table 1).

Table 1 Baseline characteristics of the patients.
CharacteristicsValue
Total participants (n)1375
mean age (yr) mean ± SD (range)48 ± 13 (18-65)
Gender
Male696 (50.62%)
Female679 (49.38%)
Treatment history
Treatment naive490 (35.64%)
Treatment experienced885 (64.36%)
Laboratory investigations
Hemoglobin(Hb) (g/dL), mean ± SD (range)12.50 ± 3.50 (7.5-18.3)
Platelets (103/μL), mean ± SD (range)160 ± 76 (50-450)
Creatinine (mg/dL)0.65 ± 0.22 (0.38-1.50)
Mean viral load (106 IU/mL) mean ± SD (range)3.54 ±2.56 (0.01-33.98)
HCV genotype 31375 (100%)

The response of first group patients was 100% (847/847) to SOF + RBV at the end of therapy (ETR). From 847 ETR responders 840 (99.17%) could sustain their response after 12 weeks of the therapy termination and were declared as SVR-12 responders. In the second group, 526 (99.62%) out of 528 patients showed response at the time of treatment completion and 515 (97.91%) out of 526 were able to sustained their response (SVR-12) (Tables 2 and 3).

Table 2 Association of baseline characteristics of the patients with sustained virological response treated with sofosbuvir+ribavirin (First group) n (%).
Baseline characteristics (n = 847)ETR (n = 847), overall ETR = 100%SVR (n = 840), overall SVR = 99.17%Relapse (n = 7), overall relapse rate = 0.83%
Age (yr)
≤ 40 (n = 435)435 (100)433 (99.54)2 (0.46)
> 40 (n = 412)412 (100)407 (98.79)5 (1.21)
Previous antiviral treatment history
Naïve (n = 91)91(100)89 (97.80)2 (2.20)
Treated (n = 756)756 (100)751 (99.34)5 (0.66)
Gender
Male (n = 310)310 (100)309 (99.68)1 (0.32)
Female (n = 537)537 (100)531 (98.88)6 (1.12)
Table 3 Association of baseline characteristics of the patients with sustained virological response treated with sofosbuvir+ribavirin+peg-interferon alfa-2a (Second group) n (%).
Baseline characteristics (n = 528)ETR (n = 526), overall ETR 0.9962SVR (n = 515), overall SVR 0.9791Relapse (n = 11), overall relapse rate = 2.09%
Age (yr)
≤ 40 (n = 419)419 (100)415 (99.05)4 (0.95)
> 40 (n = 109)107 (98.17)100 (93.46)7 (6.54)
Previous antiviral treatment history
Naïve (n = 399)399 (100)396 (99.25)3 (0.75)
Treated (n = 129)127 (98.45)119 (93.70)8 (6.30)
Gender
Male (n = 386)386 (100)382 (98.96)4 (1.04)
Female (n = 142)140 (98.59)133 (95)7 (5)

The rate of relapse cases was higher (6.54%) in old age patients (> 40 years) of the second group as compared to first group’s old age patients (1.21%). In less than 40 years of age from First and second group’s patients the rate of relapse cases was on the lower side (0.46% and 0.95%) (Table 2 and 3). In previously treated patients of the First group, SVR-12 was higher (99.34%) than naïve patients (97.80%) while, in second group, the SVR-12 rate of previously treated patients was lower than naïve (93.70% and 99.25% respectively) (Tables 2 and 3).

Males of both groups were found better responders than females in the present study. In the first group the difference in the response (SVR-12) of males and females was marginal (99.68% and 98.88%, respectively) as compared to second group where the SVR-12 of males and females was examined 98.96% and 95% (Tables 2 and 3).

The SVR-12 rate of the patients from both groups was higher (99.68% and 99.05% respectively) who had less than or equal to 2 MIU/mL of HCV viral load at day-0 than the patients having more than 2 MIU/mL viral load at that stage (97.70% and 96.19% respectively) (Tables 4 and 5). The RVR of the patients (week-4 response) was found very effective predictor to assess the SVR rate at earlier stages of the study. All the patients with HCV RNA negative after four weeks of the treatment (week-4) were also able to sustain their response after 12 weeks of the treatment completion either they belong to first or second group. One patient from the first group (0.19%) and four from the second group (1.05%), who were not able to drop more than two logs of the viral load at the fourth week of the treatment but were negative at the end of treatment, relapsed within 12 wk after the treatment termination. The rate of SVR-12 from both groups was found lower (64.70% from first group and 76.67% from second group) in those patients who were unable to drop more than two logs of viral load at week-4 (Tables 4 and 5).

Table 4 Association of baseline characteristics of the patients with sustained virological response treated with sofosbuvir+ribavirin (First group) n (%).
Time pointViral load (n = 847)ETR (n = 847), overall ETR =100%SVR (n = 840), overall SVR = 99.17%Relapse (n = 7), overall relapse rate = 0.83%
Baseline (d-0)≤ 2 MIU/mL (n = 630)630 (100)628 (99.68)2 (0.32)
> 2 MIU/mL (n = 217)217 (100)212 (97.70)5 (2.30)
RVR (weeks-4)Negative (n = 290)290 (100)290 (100)0 (0)
≥ 2 log drop (n = 540)540 (100)539 (99.81)1 (0.19)
< 2 log drop (n = 17)17 (100)11 (64.70)6 (35.30)
Table 5 Association of baseline characteristics of the patients with sustained virological response treated with sofosbuvir + ribavirin + peg-interferon-alfa-2a (Second group) n (%).
Time pointViral load (n = 528)ETR (n = 526), overall ETR 0.9962SVR (n = 515), overall SVR 0.9791Relapse (n = 11), overall relapse rate = 2.09%
Baseline (d-0)≤ 2 MIU/mL (n = 316)316 (100)313 (99.05)3 (0.95)
> 2 MIU/mL (n = 212)210 (99.06)202 (96.19)8 (3.81)
RVR (weeks-4)Negative (n = 116)116 (100)116 (100)0 (0)
≥ 2 log drop (n = 380)380 (100)376 (98.95)4 (1.05)
< 2 log drop (n = 32)30 (93.75)23 (76.67)7 (23.33)

The most common side effects in the patients of both group were headache, fatigue and anemia. Excluding hashimoto’s thyroiditis, rash, acute psychosis, Bell’s palsy and intracranial hemorrhage the percentage of other side effects was higher in the patients of second group in which pegIFN alfa-2a was included with SOF+RBV as compared to first group patients treated without pegIFN alfa-2a. Three cases of Bell’s palsy from the first group and one from the second group were new findings of the present study. Intracranial hemorrhage (ICH) was also found in two patients of the first group only but not in second group’s patients (Table 6).

Table 6 Side effects (n = 1375) n (%).
Side effectsSOF + RBV (n = 847)SOF + RBV + Peg (n = 528)P value
Headache248 (29.28)198 (37.50)0.083
Fatigue147 (17.36)168 (31.82)0.001
Myalgia38 (4.49)43 (8.14)0.830
Hashimoto's thyroiditis2 (0.23)1 (0.19)0.001
Decreased appetite71 (8.38)89 (16.86)0.179
Rash7 (0.82)3 (0.57)0.001
Thrush23 (2.71)19 (3.60)0.467
Hair loss8 (0.94)59 (11.17)0.781
Aggressiveness29 (3.42)38 (7.20)0.895
Pruritus69 (8.14)57 (10.79)0.959
Insomnia79 (9.32)63 (11.93)0.498
Depression36 (4.25)67 (12.69)0.006
Acute psychosis8 (0.94)3 (0.57)0.776
Hematologic abnormalities
Anemia (< 10 g/dL)238 (28.10)215 (40.72)0.001
Leukocytopenia (< 3 × 103/μL)16 (1.89)61 (11.55)0.001
Thrombocytopenia (< 100 × 103/μL)64 (7.56)72 (13.64)0.188
Bell’s Palsy3 (0.35)1 (0.19)0.628
Intracranial hemorrhage2 (0.23)0 (0)
DISCUSSION

The main purpose of antiviral therapy in hepatitis C is either to eradicate the infection from the patient’s body or to slow down the chances of disease progression to advanced stages like cirrhosis and HCC[23]. Before the introduction of SOF, hepatitis C was treated with interferon and RBV. The response rate of those drugs was not satisfactory. The patient also had to face many side effects of those drugs for a long time due to prolonged therapy durations. The addition of SOF in the antiviral therapy regimen has not only dramatically improved the SVR rate, but has also minimized the side effects[23].

Sofosbuvir is a nucleotide analogue that acts as a NS5B polymerase inhibitor. It has become the key drug to treat the patients of hepatitis C[17-19,24,25]. No virological breakthrough (HCV RNA negative patients at early stages of therapy became again positive during the therapy) was examined so far in the previous studies in which SOF was used as part of drug combinations in hepatitis C patients[24,26]. The same situation was observed in our findings where no virological breakthrough was seen. It confirms the efficacy of SOF based therapies.

The overall SVR-12 rate in first and second group was 99.17% and 97.91% respectively. These findings show that the addition of SOF in drug combinations for hepatitis C patients infected with genotype 3 is more effective as compared to the treatment regimen without SOF as was reported before[22-24]. This is encouraging to eliminate the hepatitis C disease from the Pakistani population where most of the patients are infected with HCV genotype 3[27-29].

Our findings also advocate that 12 wk regimen containing SOF + RBV + pegIFN alfa-2a is equally effective as the 24 wk regimen of SOF + sRBV in HCV genotype 3 patients. It indicates that the pegIFN is still effective if given with SOF based regimen. With the SOF + RBV + pegIFN alfa-2a combination, treatment duration and cost could also be cut down in HCV genotype 3 cases. But, more side effects due to pegIFN as shown in this study may be the major disadvantage.

The patients less than 40 years of age were better responders in both groups as compared to the patients with more than 40 years of age. The better response of younger group patients treated with pegIFN+RBV was also indicated in our[30] and many other previous studies reported from different areas of the world before the introduction of SOF[29,30]. It revealed that younger group patients with hepatitis C are suitable candidates to treat. Intolerance of old age patients (More than 40 years) as compared to young patients (Less than 40 years) against pegIFNs may be a major cause of lower SVR-12 rate in older patients as was also indicated previously[30-32]. It shows that the use of SOF without pegIFN alfa-2a is more effective, especially in old age patients and it may help to manage the hepatitis C patient’s treatment regimen in the future.

The SVR-12 rate of previously treated patients was higher in first group patients (99.34%) than the second group (93.46%). It indicates that six months therapy of SOF + RBV is more effective in previously non-responders or relapsed patients to pegIFN alfa-2a + RBV and infected with HCV genotype 3 as compared to three months therapy of SOF + RBV + pegIFN alfa-2a. On the other hand, SVR-12 rate of naïve patients was on higher side in second group’s patients compared to first group’s patients. It revealed that in naïve patients, treatment could be reduced from six to three months with the addition of pegIFN alfa-2a.

Interestingly, the RVR rate at week-4 was found a good predictor of SVR in both groups. All HCV RNA negative patients at week-4 were also found SVR-12 responders either they belongs to first or second group. The SVR rate of both group patients who were able to drop more than two log viral load at week-4 of the therapy was more satisfactory as compared to those who were unable to drop more than two log viral load at that stage. The effect of baseline (Day-0) viral load was not so significant in the present study.

The overall percentage of side effects was higher in the patients treated with triple therapy regimen (SOF + RBV + pegIFN alfa-2a) as compared to those patients treated with double therapy regimen (SOF + RBV). Headache, fatigue and anemia were the common side effects in all the patients either treated with or without pegIFN alfa-2a. Myalgia, decreased appetite, hair loss, aggression, depression, leukocytopenia and thrombocytopenia were prominently on the higher side in the patients of the second group as compared to first group’s patients. It was also reported previously in RBV and pegIFN alfa-2a treated patients[33].

Severe neuropsychiatric side effects were commonly reported previously in hepatitis C patients treated with pegIFN and RBV[33,34]. Sometimes treatment has to discontinue because of the severity of such adverse side effects. But in newly introduced antiviral drug “SOF’’ the severe neuropsychiatric complications are not much reported so far.

Two cases of intracranial hemorrhage were found only in first group’s patients. Intracranial hemorrhage was also reported before in untreated hepatitis C patients[35,36], but no evidence of ICH with pegIFN plus RBV was seen previously. In our findings ICH may also be due to HCV not because of SOF that needs further studies on a large scale.

In conclusion, SOF (SOVALDI®) based therapy was found safe, effective and well tolerated by the patients infected with HCV genotype 3 in Pakistan. Higher SVR rate of the present study indicates that this is the right time for full blooded attack on HCV to get rid of it permanently from our region. To achieve the target, there is a need of policy under the aegis of the Federal Government to provide drugs on discounted rates or free for non-affording patients.

COMMENTS
Background

In Pakistan about 5.5% population is infected with hepatitis C virus (HCV), out of those 60%-80% has HCV genotype 3. Due to lower response and intolerable side effects of peg-Interferon plus RBV therapy, it was difficult to treat hepatitis C patients in past. In recent trials, the newly introduced oral drug “Sofosbuvir” was claimed for its remarkable response in the chronically infected patients with HCV genotype 2 and 3. It was important to see its efficacy in Pakistani population where most of the patients were infected with HCV genotype 3.

Research frontiers

Outcomes of the present study revealed that the SOF is more effective drug to treat the hepatitis C patients especially infected with genotype 3 of HCV. Sofosbuvir has less side effects and short treatment duration that helps the patient to get relief from hepatitis C in short time. These outcomes are also encouraged to eliminate hepatitis C from Pakistan where most of the population is infected with genotype 3 of HCV.

Innovations and breakthroughs

The novel finding of this study was to find highly responding oral drug (SOF) with low side effects that may help to eradicate hepatitis C from Pakistan where most of the population is infected with HCV genotype 3. Furthermore, we were also able to declare that the use of SOF is equally effective with or without peg-Interferon that may also help to avoid the adverse side effects of peg-Interferon injections. Its better response in all age groups also make easy to the clinician to treat the hepatitis C patients of all age groups.

Applications

The use of this oral drug (SOF) that has a dramatic response rate in hepatitis C patients will help to eliminate hepatitis C from Pakistan. To achieve the target, there is a need for policy under the aegis of the Federal Government to provide free drugs or on discounted rates for non-affording.

Terminology

Scientific terms that have been used in this manuscript are familiar with most readers and have been described comprehensively in different sections of the manuscript.

Peer-review

The authors carried out a prospective study to assess the efficacy and safety of SOF based therapies for the patients with HCV genotype 3. This study is well designed and the results are relevant to clinical practice.

ACKNOWLEDGMENTS

We express our special gratitude to all participants of this study and the entire staff of the Shalamar hospital for their exceptional cooperation.

Footnotes

Manuscript source: Unsolicited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Pakistan

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B, B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Adinolfi IE, Atsukawa M, Khaliq S, Lee HC S- Editor: Wei LJ L- Editor: A E- Editor: Lu YJ

References
1.  Global burden of hepatitis C working group. Global burden of disease (GBD) for hepatitis C. J Clin Pharmacol. 2004;44:20-29.  [PubMed]  [DOI]
2.  Lavanchy D. The global burden of hepatitis C. Liver Int. 2009;29 Suppl 1:74-81.  [PubMed]  [DOI]
3.  Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus infection in Europe. J Hepatol. 2008;48:148-162.  [PubMed]  [DOI]
4.  Attaullah S, Khan S, Ali I. Hepatitis C virus genotypes in Pakistan: a systemic review. Virol J. 2011;8:433.  [PubMed]  [DOI]
5.  Qazi MA, Fayyaz M, Chaudhary GMD, Jamil A, Malik AH, Gardezi AI, Bukhari MH. Hepatitis C virus genotypes in Bahawalpur. Biomedica. 2006;22:51-54.  [PubMed]  [DOI]
6.  Ahmad S, Salati SAA, Mattar EH, Al-Sabban AMH, Hamad AM. Epidemiology of hepatitis C Virus (HCV) infection. Physicians Academy. 2010;4:82-87.  [PubMed]  [DOI]
7.  Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9:331-338.  [PubMed]  [DOI]
8.  Verna EC, Brown RS Jr. Hepatitis C virus and liver transplantation. Clin Liver Dis. 2006;10:919-940.  [PubMed]  [DOI]
9.  El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745-750.  [PubMed]  [DOI]
10.  Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC Jr, Perrillo RP, Carey W, Jacobson IM, Payne J, Dienstag JL; Hepatitis interventional therapy group. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. N Engl J Med. 1989;321:1501-1506.  [PubMed]  [DOI]
11.  McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis interventional therapy group. N Engl J Med. 1998;339:1485-1492.  [PubMed]  [DOI]
12.  Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.  [PubMed]  [DOI]
13.  Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.  [PubMed]  [DOI]
14.  Liu X, Wang Y, Zhang G, Li N, Zhu Q, Chang H, Han Q, Lv Y, Liu Z. Efficacy and safety of sofosbuvir-based therapy for the treatment of chronic hepatitis C in treatment-naïve and treatment-experienced patients. Int J Antimicrob Agents. 2014;44:145-151.  [PubMed]  [DOI]
15.  Steinebrunner N, Sprinzl MF, Zimmermann T, Wörns MA, Zimmerer T, Galle PR, Stremmel W, Eisenbach C, Stein K, Antoni C. Early virological response may predict treatment response in sofosbuvir-based combination therapy of chronic hepatitis c in a multi-center “real-life” cohort. BMC Gastroenterol. 2015;15:97.  [PubMed]  [DOI]
16.  Korean Association for the Study of the Liver. KASL clinical practice guidelines: management of hepatitis C. Clin Mol Hepatol. 2016;22:76-139.  [PubMed]  [DOI]
17.  Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J BioChem. 2010;285:34337-34347.  [PubMed]  [DOI]
18.  Lam AM, Murakami E, Espiritu C, Steuer HM, Niu C, Keilman M, Bao H, Zennou V, Bourne N, Julander JG. PSI-7851, a pronucleotide of beta-D-2’-deoxy-2’-fluoro-2’-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication. Antimicrob Agents Chemother. 2010;54:3187-3196.  [PubMed]  [DOI]
19.  Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368:34-44.  [PubMed]  [DOI]
20.  Akhter TS, Umar M, Khaar HT, Aslam F, Nisar G, Naseer A, Ahmad S, Osama M. Sofosbuvir for the treatment of hepatitis C genotype 3 infected patients in Pakistan. J Ayub Med Coll Abbottabad. 2016;28:S884-S889.  [PubMed]  [DOI]
21.  Wahid B, Saleem K, Ali A, Rafique S, Idrees M. Rising relapse rate in hepatitis C virus type 3a-infected patients against sofosbuvir and ribavirin combination therapy: a Pakistani experience. Eur J Gastroenterol Hepatol. 2017;29:979-980.  [PubMed]  [DOI]
22.  European Association for the Study of the Liver.. EASL recommendations on treatment of hepatitis C 2014. J Hepatol. 2014;61:373-395.  [PubMed]  [DOI]
23.  European Association for Study of Liver.. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2014;60:392-420.  [PubMed]  [DOI]
24.  Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, Schultz M, Davis MN, Kayali Z, Reddy KR. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887.  [PubMed]  [DOI]
25.  Lange CM, Zeuzem S. Perspectives and challenges of interferon-free therapy for chronic hepatitis C. J Hepatol. 2013;58:583-592.  [PubMed]  [DOI]
26.  Lawitz E, Gane EJ. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;369:678-679.  [PubMed]  [DOI]
27.  Khan N, Akmal M, Hayat M, Umar M, Ullah A, Ahmed I, Rahim K, Ali S, Bahadar S, Saleha S. Geographic distribution of hepatitis C virus genotypes in pakistan. Hepat Mon. 2014;14:e20299.  [PubMed]  [DOI]
28.  Iqbal S, Ahmad R, Yousuf MH, Mumtaz A, Amin D, Rasool G, Manzoor A. Assessment of major genotypes and subtypes of Hepatitis C virus. Prof Med J. 2007;14:266-271.  [PubMed]  [DOI]
29.  Idrees M, Riazuddin S. Frequency distribution of hepatitis C virus genotypes in different geographical regions of Pakistan and their possible routes of transmission. BMC Infect Dis. 2008;8:69.  [PubMed]  [DOI]
30.  Iqbal S, Khalil-Ur-Rahman , Sheikh MA, Arshad M. Response of different HCV genotypes to interferon therapy in different age groups of chronic hepatitis-C patients. J Ayub Med Coll Abbottabad. 2014;26:310-315.  [PubMed]  [DOI]
31.  Ismail MH. Prediction of sustained virologic responses to combination therapy of pegylated interferon-α and ribavirin in patients with chronic hepatitis C infection. J Family Community Med. 2013;20:35-40.  [PubMed]  [DOI]
32.  Kau A, Vermehren J, Sarrazin C. Treatment predictors of a sustained virologic response in hepatitis B and C. J Hepatol. 2008;49:634-651.  [PubMed]  [DOI]
33.  Modabbernia A, Poustchi H, Malekzadeh R. Neuropsychiatric and psychosocial issues of patients with hepatitis C infection: a selective literature review. Hepat Mon. 2013;13:e8340.  [PubMed]  [DOI]
34.  Guadagnino V, Trotta MP, Carioti J, Caroleo B, Antinori A; Nocchiero Study Group. Does depression symptomatology affect medication compliance during the first weeks of anti-HCV therapy in intravenous drug users? Dig Liver Dis. 2006;38:119-124.  [PubMed]  [DOI]
35.  Tseng CH, Muo CH, Hsu CY, Kao CH. Increased Risk of intracerebral hemorrhage among patients with hepatitis C virus infection. Medicine (Baltimore). 2015;94:e2132.  [PubMed]  [DOI]
36.  Karibe H, Niizuma H, Ohyama H, Shirane R, Yoshimoto T. Hepatitis C virus (HCV) infection as a risk factor for spontaneous intracerebral hemorrhage: hospital based case-control study. J Clin Neurosci. 2001;8:423-425.  [PubMed]  [DOI]