Host and Viral Factors and Changes in Liver Function Associated with Direct- Acting Antivirals Response in HCV Genotype-4 Patients
Rasha Mohamed Mahmoud Khairy¹, Aya Nabil Gamil, Mahmoud Shokry Mahmoud¹, WafaaKhairy Mohamed Mahdi ¹, Ebtisam Samir Mohamed¹, Noha Anwar Hassuna¹
¹Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Egypt.
*Correspondence to:
Rasha M.M. Khairy
Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia 61511, Egypt
Email: [email protected]
Email: [email protected]; Telephone: +20-106-409-1492 Running title: Host and viral factors and response to DAAs.
Background and Aim: The response to DAAs therapy is attributed to a host of host and viral variables. Hepatitis C eradication is linked to considerable improvements in liver function and fibrosis. Several noninvasive methods for assessing hepatic fibrosis prior to HCV treatment have been developed and validated, all of which have a high level of reliability and clinical utility.
However, their utility in assessing fibrosis progression after HCV eradication with DAAs is currently restricted.
The aim of this study was to investigate into the potential significance of some host and viral characteristics in predicting direct-acting antiviral (DAAs) outcome and to assess changes in hepatic fibrosis and inflammation in chronic Hepatitis C genotype-4 patients treated with DAAs.
Subjects and Methods: A total of 150 CHC patients receivinga 12-week regimen of DAAs (SOF/DAV+RIB)were included in this study. Achieving sustained virologic response at 12weeks post-treatment(SVR12) was the main goal. Blood samples were withdrawn from allsubjects at baseline and 12 weeks after the end of treatment (EOT) for assessing viral load, liver transaminases levels, platelet count and other biochemical profiles in addition to calculating non-invasive biomarkers of liver fibrosis; fibrosis-4 index (FIB-4), Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) score, AST/ALT ratio.Liver stiffness measurement (LSM) by FibroScan was performed prior treatment. Results: SVR to DAAs therapy was significantly correlated with HCV viral load and degree of liver fibrosis. SVR achieved by DAAs therapy was associated with significant improvement of non-invasive biomarkers of fibrosis (FIB-4, APRI score, and AAR) in addition to significant decrease in liver transaminases and elevation of platelet count from baseline compared to 12 weeks EOT (p ˂0.05).
Conclusions:DAAs therapy is associated with significant improvementof liver function and fibrosis.
Introduction
Eradication of the hepatitis C virus (HCV) is a global public health issue. In many regions of the world, HCV is a main cause of chronic hepatitis, cirrhosis, and hepatocellular cancer, as well as a major reason for liver transplantation. (de Oliveria et al., 2009).
Chronic hepatitis C(HCV) infects 71 million people globally, according to the World Health Organization (WHO) (Organization, 2017). Decompensated cirrhosis and hepatocellular carcinoma are among the liver complications that 10–20 percent of people will encounter (Westbrook &
Dusheiko, 2014). Egypt has the world's highest HCV prevalence rate(Esmat et al., 2016). Around 10.4 million Egyptians develop HCV infection, accounting for roughly 13% of global infections (Ahmed et al., 2018). In Egypt, the HCV-4 genotype is the most prevalent, accounting for 94.1 percent of all infections (Kouyoumjian et al., 2018). The World Health Organization established a 2030 deadline for eradicating chronic hepatitis C infection (HCV). Interferon-based regimens were used to treat HCV before 2014, but they had low success rates, long treatment periods, and severe side effects (Yee et al., 2015).New direct-acting antiviral (DAA) medication is more reliable, safer, and well-tolerated than earlier medications, with shorter treatment intervals (typically 12 weeks), but more expensive.(Organization, 2016). However, existing drug regimens can be improved, resistance mutations can be limited, and individual therapy can be promoted. (Bukh, 2016). Treatment predictors are critical for individuals with chronic hepatitis C infection to control their therapy(Jovanovic-Cupic et al., 2018).
HCV replication is inhibited by direct-acting antiviral therapy (DAAs), that target nonstructural proteins of HCV(Pawlotsky, 2014).A sustained virologic response is defined as the lack of detectable HCV RNA 12 weeks following therapy completion (SVR).This is generally referred to as the SVR12, and the aim of therapy is to obtain an SVR12(Burgess et al., 2016). The combination of sofosbuvir and daclatasvir has been proven to increase SVR rates in genotype 1 or 4 individuals who are regarded difficult to treat. In cirrhotic and previously treated individuals, ribavirin increases SVR levels(Ahmed et al., 2018).
Genotype, viral load, age, gender, liver fibrosis level, IL-10 (interleukin-10) and IL28B (interleukin- 28B) polymorphisms, and other baseline host and virus-related parameters have all been linked to treatment outcome in previous studies(Cavalcante & Lyra, 2015; Jovanovic-Cupic et al., 2016, 2018).
On the other hand, IL-10 and IL28B polymorphisms, HCV genotype, high baseline viral load, and previous interferon failure, according to some studies, have no effect on therapeutic results. (Arias et al., 2017).The goal of this study was to investigate some of the host and viral variables that influence DAAs therapeutic response.
Subjects and methods
This study was condcted at Microbiology and Immunology department, Faculty of Medicine, Minia University in the period from February 2017 to January 2019.
150 chronic HCV-infected persons with positive anti-HCV antibodies by ELISA and HCV RNA by
reverse transcriptase polymerase chain reaction (RT-PCR) were enrolled in this study. Before participating in the study, all subjects were given informed consent in accordance with the 1975 Declaration of Helsinki standards. All patients received the new direct-acting antiviral combination (Sofosbuvir + Daclatsvir + Ribavirin)(SOF/DAV+RIB) for 12 weeks.
At baseline and 12 weeks after the end of treatment (EOT), all patients underwent a thorough medical history, complete clinical examination, routine laboratory investigations, and abdominal ultrasound, as well as certain serum methods for fibrosis assessment such as the AST to Platelet Ratio Index (APRI) score, AST/ALT ratio (AAR), and Fibrosis-4 (Fib-4 index). FibroScan was utilised to measure liver stiffness (LSM) before and after treatment in order to assess liver fibrosis.
Before and after therapy, the viral load of the hepatitis C virus RNA (HCV-RNA) was determined using a quantitative polymerase chain reaction (PCR). The lack of detectable HCV RNA 12 weeks after treatment completion is considered a sustained virologic response (SVR12).
Statistical analysis
The data was statistically analysed using SPSS version 24 (Statistical Package for Social Sciences) software. When appropriate, descriptive statistics for parametric quantitative data were calculated using the mean, standard deviation, median (25 percent -75 percentiles), or number (percentage). The Mann—Whitney U-test or the Student's t test were employed to compareindependent samples from two groups in this study.(p-value 0.05) was used to determine the level of significance.
Results
Out of 150 HCV-4 patients, 141 (94%) were responders to (SOF/DAV+RIB) regimen. Only 9 patients were resistant to the treatment (6%)(Figure 1).
Table 1 demonstrates how the study group's laboratory data changed from baseline to 12 weeks after treatment ended (SVR12). The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) both decreased significantly (p-value 0.001). The mean platelet count, on the other hand, increased significantly (p-value 0.05).
Non-invasive fibrosis biomarkers (APRI, FIB-4, and AAR) also demonstrated a substantial reduction 12 weeks after therapy ended (p-value 0.001).
Patients' ages ranged from 32 to 65 years old, with a median of 47 years among responders and 35 to 67 years old, with a median of 59 years among non-responders, with a non-significant correlation (p=0.066, r=0.155) between age and treatment response (outliers were excluded) (Figure 2).
HCV viral load, log EQ/ML, and response to therapy had a significant correlation (p=0.001, r=0.278), with HCV titers ranging from 2.54 to 9.65, with a median of 6.45 (IQR: 4.7-7.5) among responders and from 6.35 to 9.57, with a median of 8.3 (IQR: 7.5-9.5) among non-responders.
(Figure 3).
The stage of liver fibrosis and response to treatment had a significant correlation (p<0.001, r=0.476), with 13.5 percent of sustained virological responders (SVR) belonging to stage 0, 59.6% to stage 1, 24.1 percent to stage 2, and 2.8 percent to stage 3. In the case of non-responders, 100% of the patients
were in stages 2 and 3, with 44.4 percent belonged to stage 2 and 55.6 percent belonged to stage 3 (Figure 4).
Figure 1: response of study group to direct-acting antiviral therapy
Table (1) Changes in some laboratory parameters of the study group at baseline and 12w after EOT
Parameter ALT AST PLT
count
APRI FIB-4 AAR
Baseline 56.0±4.3 54.2±4.2 119.4±
33.06
1.19±
0.24
3.13±
0.75
1.04±
0.18
12 weeks after EOT (SVR12)
33.31 ± 2.56
31.14±2.41 133.3 ± 36.92
0.59±0.13 1.98±0.47 0.69±0.12
Percent of change
− 40.52% − 42.55% 11.67% − 46.23% − 36.86% − 33.88%
p-value 0.001* 0.001* 0.05* 0.001* 0.001* 0.001*
Data were represented as mean ± standard deviation. * Difference is statistically significant (P <
0.05). EOT (End of treatment). PLT (platelet)
SVR; 94
NR; 6
SVR NR
0 10 20 30 40 50 60 70 80 90 100
Figure 2: Correlation between age of patients and response to DAAs therapy
Figure 3: Correlation between HCV viral load and DAAs response
Figure 4: Correlation between degree of liver fibrosis and DAAs response
Discussion
HCV is a main cause of chronic hepatitis, cirrhosis, and hepatocellular cancer, as well as a major reason for liver transplantation worldwide, so those with HCV require adequate antiviral therapy to prevent these complications and minimize mortality(Elgharably et al., 2017).
Previous research have related genotype, viral load, age, gender, liver fibrosis level, and IL28B (interleukin-28B) polymorphisms to therapeutic outcome. Among viral variables, HCV genotype and baseline HCV-RNA levels are major predictors of treatment success (Jovanovic-Cupic et al., 2018).
The goal of this study was to investigate the potential significance of some host and viral characteristics in predicting direct-acting antiviral (DAAs) outcome and to assess changes in hepatic fibrosis and inflammation in chronic Hepatitis C genotype-4 patients treated with DAAs.
This study included 150 CHC patients who were following DAA therapy (SOF/ DAV + RBV). All individuals had blood collected at baseline and 12 weeks after the end of treatment (EOT) to measure liver transaminases, platelet count, and other laboratory prameters, as well as to identify HCV virus load using real-time PCR before and after therapy. FibroScan was used to assess liver stiffness before and after treatment to evaluate liver fibrosis.
Out of 150 HCV-4 patients, 141 (94%) achieved SVR12 to (SOF/DAV+RIB) regimen. Only 9 patients were resistant to the treatment (6%). Our findings are consistent with those of Abdelrahman et al, who found that 264 patients (88 percent) obtained SVR after following DAAs therapy, while 37
13.5
0 59.6
0 24.1
44.4
2.8
55.6
0 10 20 30 40 50 60 70
SVR NR
Percent %
0 1 2 3
patients (12 percent) did not (Abdelrahman et al., 2019). Our results are likewise in accord with Nelson et al who indicated that a 12-week regimen of SOF /DAC + RBV was associated with an overall SVR rate of 89 percent(Nelson et al., 2015). Pham and his colleagues, on the other hand, experienced different outcomes. Only 40.6 percent (368/906) of the participants reached SVR12, while 59.4 percent (n = 538) did not (Pham et al., 2018).Fontaine et al reported 100% SVR in treatment of HCV-4 using the same treatment protocol (Fontaine et al., 2015).
Our study demonstrated a significant decrease in liver fibrosis within 12 weeks after end of DAA treatment, as reported by others (Dolmazashvili et al., 2017; Pan et al., 2018). In most patients who achieved SVR, non-invasive serum indicators of liver fibrosis (APRI, FIB-4, and AAR scores) improved considerably 12 weeks after the conclusion of treatment (SVR12). The scores on the APRI, FIB-4, and AAR have all reduced by 46.23 percent, 36.86 percent, and 33.88 percent, respectively.
These findings aligned with those of Makhlouf et al., who reported a 50.42 percent and 33.88 percent decrease in APRI score and FIB-4 index, respectively (Makhlouf et al., 2021). These findings are consistent with those of De Pace et al., who discovered a considerable reduction in APRI score and a slight increase in platelet count from baseline to EOT. (De Pace et al., 2019).
Tag-Adeen et al. found substantial improvement in the APRI score and Fib-4 index after reaching SVR in a research conducted at Qena University Hospital with 80 CHC patients who received different DAAs regimens. (Tag-Adeen et al., 2017). Others have found a significant reduction in liver stiffness scores between 6 and 12 months after initiating DAA treatment (Dolmazashvili et al., 2017;
Pan et al., 2018; Sriphoosanaphan et al., 2020) . These findings, which agree with ours, point to a reduction in liver fibrosis as a result of viral clearance following SVR with DAAs.
In the era of DAA, improvement in liver functions and hepatic fibrosis has been obviously demonstrated after successful eradication of HCV(Charlton et al., 2015; Curry et al., 2015).
Biochemical indicators of liver cell damage include liver transaminases (ALT and AST enzymes).
The persistence of elevated ALT and AST levels is linked to the advancement of chronic hepatitis C and an increased risk of liver cirrhosis, making it a useful diagnostic tool (Attar & Van Thiel, 2016).
The current study demonstrated a significant decrease in liver transaminases (ALT and AST enzymes) in CHC patients receiving DAAs treatment after achieving SVR12 by − 40.52% and
−42.55% respectively (p value = 0.001).
Makhlouf et al. observed a highly significant difference between ALT and AST levels before DAAs treatment against ALT and AST levels after therapy at week 4, week 8, EOT, and 12 weeks after EOT, which is consistent with our findings (Makhlouf et al., 2021). Sriphoosanaphan et al. observed similar findings in a trial of 80 CHC patients receiving DAA medication; mean ALT levels reduced considerably from 79.9 53.3 U/L at baseline to 25.7 17.2 U/L and 22.3 11.0 U/L at 24 and 48 weeks, respectively, after DAA treatment (Sriphoosanaphan et al., 2020). De Pace et al. also found a significant drop in AST and ALT levels during treatment: baseline mean AST = 52 (32–81) UI/mL versus EOT AST = 21 (18–28) UI/mL, and baseline mean ALT = 52.5 (34–83.2) UI/mL vs EOT ALT = 17 (13–24.2) UI/mL.(De Pace et al., 2019). These findings imply that after reaching SVR
with DAAs, the inflammatory process and liver cell damage improve rapidly.
Many other recent studies reported a remarkable decrease in liver transaminases and improvement of the biochemical profile after successful DAAs therapy (Elsharkawy et al., 2017).
The recent study also demonstrated a significant rise in platelet count after achieving SVR12;
baseline 119.4±33.06 109 /L versus 133.3 ± 36.92 109 /L at week 12 after EOT with change percent 11.67% (p-value= 0.05). These findings are consistent with those of Makhlouf et al., who found an increase in platelet count of 11.67 percent from baseline to 12 weeks after EOT. (Makhlouf et al., 2021). As well, these results agreed with a study conducted at Mansoura University that reported an elevation of Platelets count after DAAs therapy (Mohammed & Omar, 2019). Salmon et al. also reported a favorable improvement of hematological parameters (especially the platelets) after achieving SVR (Salmon D, Dabis F, 2015).These findings can be explained by improvement of liver function after achieving SVR.
The current study investigated the potential role of HCV viral load as predictor for DAAs treatment response; we found that a very high baseline The presence of viral load has been linked to a lower risk of SVR. HCV viral load, log EQ/ML, and response to therapy had a strong connection (p=0.001, r=0.278), with HCV titers ranging from 2.54 to 9.65, with a median of 6.45 (IQR: 4.7-7.5) among responders and from 6.35 to 9.57, with a median of 8.3 (IQR: 7.5-9.5) among non-responders. This is consistent with the findings of Kowdley et al, who found that a high baseline viral load (>6 million IU/ml) was linked to treatment failure. Nelson et al, in contrast to our findings, found no link between baseline HCV viral load and SVR (Nelson et al., 2015). Abdelrahman and colleagues disagreed with our findings, reporting that the mean HCV RNA level in DAAs responders was 1.108+1.821 (X 106) IU/mL, whereas it was 1.531+2.156 (X 106) IU/mL in non-responders, with no statistically significant difference between the two groups(Abdelrahman et al., 2019). The difference might be due to change in HCV genotype, treatment protocolor duration of therapy (12w vs. 8w) between our study and others.
The stages of liver fibrosis are thought to be linked to PEG-IFN/RBV therapeutic response rates.
Patients with severe liver fibrosis (METAVIR score F3-F4), especially those with genotype 1, were more likely to be non-responders (NR) than those with minimal or mild fibrosis (F0-F2) (Cavalcante
& Lyra, 2015; Jovanovic-Cupic et al., 2016) . This lower SVR rate among cirrhotic patients is less markedly in the DAA era, (Ioannou et al., 2016; Sterling et al., 2015). Our study detected the significant role of stage of liver fibrosis in DAAs therapy prediction; The stage of liver fibrosis and response to treatment had a significant correlation (p<0.001, r=0.476), with 13.5 percent of sustained virological responders (SVR) belonging to stage 0, 59.6% to stage 1, 24.1 percent to stage 2, and 2.8 percent to stage 3. In the case of non-responders, 100% of the patients were in stages 2 and 3, with 44.4 percent in stage 2 and 55.6 percent in stage 3.
The current study found that patient age is an independent factor in predicting DAAs therapy response; there was a non-significant correlation (p=.066, r=0.155) between patient age and response to treatment, with responders ranging from 32 to 65 years old, with a median of 47 years, and non-
responders ranging from 35 to 67 years old, with a median of 59 years. A number of studies have been conducted to see how age affects the efficacy and tolerability of interferon-free therapies.
Despite differences in HCV genotype, cirrhosis prevalence, and treatment regimen, age did not appear to have a significant impact on treatment response in these investigations (Atsukawa et al., 2017; Morio et al., 2017; Sherigar et al., 2017; Su et al., 2017). In contrast Ogawa et al reported the significant predictive role of age in treatment response(Ogawa et al., 2017).
Conclusion:
SVR has been linked to HCV viral load and the degree of liver fibrosis. The use of a fibroscan to assess liver stiffness has become standard practise in patients on DAAs to monitor liver fibrosis. The APRI, FIB-4, and AAR scores showed significant changes when assessed at EOT because the platelet count and liver aminotransferase values that make up these scores showed the most significant improvement after effective DAAs therapy. It has been discovered that when a virus is eradicated, improvements in liver function and fibrosis can occur. As a result, it is proposed that more studies be performed with longer follow-up periods (median of 3 years).
ACKNOWLEDGMENTS
We are grateful for health care staff in Miniainsurance hospital for their cooperation
CONFLICTS OF INTEREST
The authors declare no conflict of interest.
AUTHOR CONTRIBUTIONS
Mahmoud S Mahmoud, Wafaa KM Mahdi, Rasha MM Khairy and Noha A Hassunaconceived and designed the analysis;Rasha MM Khairy, Aya N Gamil, Ebtisam S Mohamed and Noha A Hassunaperformed the laboratory analysis, collected the data;Rasha MM Khairy, Aya N Gamil, Ebtisam S Mohamed wrote the paper; All authors approved the final manuscript.
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