Introduction

Hepatitis C virus (HCV) infection was one of the global epidemics of this century that infected nearly 100 million people and now is the leading cause of liver and liver transplant-related deaths [1]. Hepatitis C virus is a ribonucleic acid (RNA) virus that is classified as a Flavivirus, generally entering the blood through transfusion or direct exposure to the blood circulation [2]. The main target of HCV is hepatocytes and B lymphocytes through receptors similar to CD81 found on liver cells and B lymphocytes or low-density lipoprotein (LDL) receptors [3].

Hepatitis C is an inflammatory liver disease that is still a health problem in the world, including in Indonesia. Hepatitis C is commonly found in injecting drug users (IDUs) and patients undergoing hemodialysis [4]. Transmission of HCV is mainly through exposure to blood and body fluids contaminated with the hepatitis C virus, including in the era before the use of disposable needles [5].

Since it was first discovered in 1989, hepatitis C therapy has developed quite rapidly. Interferon (IFN)-α was introduced as the first therapy for chronic hepatitis C infection, then enhanced by the pegylation process and the addition of ribavirin, resulting in improving virological response [6].

However, interferon therapy has several limitations, including factors that cause unresponsiveness to therapy, such as viral factors and host factors. The viral factors, such as genotype and viral load, are some factors that influence the virological response. While the host factors, such as elderly, gender, and obesity, are influencing the sensitivity of therapy [7,8,9].

Significant molecular and structural developments in the virology, life cycle, and pathogenesis of HCV led to the discovery of a new therapy, direct-acting antiviral (DAA), which was officially approved for chronic hepatitis C therapy in 2011 [10]. The availability of non-interferon antiviral agents or direct-acting antivirals has led to a major paradigm shift in the treatment of HCV infection. This therapy has been shown to achieve higher cure rates and minimal side effect profiles in clinical trials. However, due to different clinical characteristics and the presence of side effects and comorbidities, antiviral treatment in elderly, male, and obese patients with HCV infection remains a challenge in the present era [1, 7, 11, 12].

A large proportion of patients with chronic HCV infection in the United States are in the 50–70 years age range and have lived with HCV infection for 25–45 years. The extensive duration of HCV infection increases the incidence of liver disease and its associated sequelae. Several theories about old age include susceptibility to environmental factors such as oxidative stress with increasing age, decreased hepatic flow rate, decreased mitochondrial capacity, impaired immunity, and increased carcinogenic potential due to reduced ability to repair DNA [13]. The use of pegylated interferon/ribavirin in the elderly has several limitations. Various comorbidities, side effects, and poor tolerability increase with age in patients. Therefore, in elderly patients, it is often debated whether to start treatment with pegylated interferon/ribavirin [11].

Various studies using DAA therapy in the elderly have shown a better virological response. Studies by Sherigar et al. [14] in the USA and Kamel et al [15] in Egypt reported that the use of DAA therapy was not affected by patient age, which did not significantly affect the rate of virological response.

Hepatitis C virus infection generally affects men more than women, because women are more likely to have spontaneous viral recovery after acute HCV infection [16]. Risk factors such as alcohol consumption in men led to a twofold increase in the progression of fibrosis from HCV infection compared to women [17]. Several theories such as Toll-like receptor 7 (TLR7) play a role in the immune response in HCV infection, where the gene of TLR7 is located on the X chromosome so this might explain the sex difference in HCV infection [18].

Various studies have shown that young women have a better response to interferon therapy than men [19,20,21]. This is thought because of estrogen's role in the inhibition of the liver fibrosis process through an antifibrotic effect that depends on liver tissue receptors and enhances the response to antiviral therapy [20, 21].

Meanwhile, with DAA therapy, a study by Kanwal et al. [22] in the USA and Yunihastuti et al. [23] in Jakarta, Indonesia, found that there was no significant difference in virological response by gender, either male or female who received DAA therapy.

Patients with chronic HCV infection with a high body mass index (BMI) are closely associated with the incidence of steatosis, increased progression of fibrosis, and reduced responsiveness to antiviral therapy. The exact mechanism by which obesity reduces the efficacy of this antiviral therapy remains unclear. One hypothesis is that a high BMI induces the occurrence of metabolic syndrome resulting in insulin resistance, hepatitis steatosis, and a high initial viral load. In addition, obesity also causes interference with cytokine signaling which is manifested in increased levels of leptin, adiponectin, and resistin [24].

With interferon therapy, Alsio et al. [24] in the USA found chronic hepatitis C patients with a BMI of 30 kg/m2 with a virological response of only 62%. Meanwhile, with DAA therapy, studies by Tran et al. [8] in the USA and Hsu et al. [25] in Taiwan found that body mass index did not negatively affect virological response.

Identification of viral and host factors that influence disease progression can help understand the underlying mechanisms of chronic HCV infection [18]. Differences in age, gender, and body mass index sometimes give different results from innovative medical technologies. Meanwhile, in chronic HCV infection, previous studies have shown differences with previous interferon-based therapy based on age, sex, and body mass inde x[7,8,9, 22].

Methods

Aim

The current study aimed to determine the correlation between host factors, such as age, gender, and body mass index with virological response to DAA treatment in hepatitis C patients.

Study design and population

From April 2021 to October 2021, an observational, retrospective, cohort, and single-center study was conducted in Makassar, Indonesia at Wahidin Sudirohusodo Hospital. Eligible subjects were all adult patients with HCV chronic infection patient who started HCV naive therapy with DAA. Patients with hepatitis B coinfection, diabetes mellitus, and/or HCV treatment-experienced before were excluded. The primary endpoint was to determine the correlation between age, gender, and body mass index with virological response to DAA treatment in hepatitis C patients. The secondary endpoint was to determine the virological response to DAA treatment in hepatitis C patients.

Ethical considerations

This study has been approved by the Ethics Committee for Clinical Research of the Faculty of Medicine Hasanuddin University and Dr. Wahidin Sudirohusodo Hospital Makassar (No: 218/UN4.6.4.5.31/PP36/2021). Throughout the investigation process, ethical and data protection protocols related to anonymity and data confidentiality were complied with.

Data collection

Data of age, gender, body mass index, HCV-RNA, and treatment regimen were systematically obtained by reviewing patients’ medical records. All patients were followed up with HCV-RNA at the beginning and 12 weeks after treatment.

Statistical analysis

Data analysis was performed using SPSS software package version 25 (SPSS, Chicago IL). The method of analysis consisted of descriptive methods and statistical tests. The descriptive method aims to obtain general information about the research sample. The statistical method used descriptive statistical calculation and frequency distribution. The statistical test used is the chi-square test. Statistical test results are considered significant if the p-value is <0.05. The results obtained will be displayed in the form of a narrative equipped with tables and pictures.

Results

Baseline characteristics

This study consist of 86 subjects with 57 men (66.3%) and 29 women (33.7%), divided to the age category mostly <60 years with 67 subjects (77.9%). While the youngest was 22 years old and the oldest was 83 years old with a mean age of 48.69±13.94 years. From the BMI category, mostly normal BMI with 44 subjects (51.2%), while overweight and obese 36 subjects (41.9%), the lowest BMI 18.2 kg/m2 and the highest BMI 36.89 kg/m2 with a mean BMI of 23.17±3.71 kg/m2 (Table 1).

Table 1 Characteristics of research subjects (n=86)
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Based on descriptive statistics, the initial Log10 HCV-RNA level was 1.0 IU/mL and max 7.61 IU/mL with a mean of 5.63±1.24 IU/mL (Table 2), and the final HCV-RNA level after 12 weeks of therapy, 78 subjects (90.7%) were not detected, and 8 subjects (9.3%) were still detected.

Table 2 Descriptive values of age, BMI, and baseline HCV-RNA
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Age with virological response

Analysis of the correlation between age and virological response was carried out using the chi-square test by comparing each category with the achievement of virological response after 12 weeks of DAA therapy or SVR12. No significant relationship was found between age and virological response (p > 0.05) (Table 3).

Table 3 Analysis of the correlation of age with virological response
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Gender with virological response

No significant correlation was found between gender and virological response, but the table shows that of the 8 subjects whose virus was detected, 5 subjects (62.5%) were female (p > 0.05) (Table 4).

Table 4 Analysis of the correlation of gender with virological response
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Body mass index with virological response

There was no significant relationship between BMI and virological response, but the table shows that from 8 subjects whose virus was detected, 6 subjects (75%) were obese and overweight (p > 0.05) (Table 5).

Table 5 Analysis of the correlation of BMI with virological response
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Discussion

In this study with 86 subjects with chronic hepatitis C infection with DAA therapy, 78 subjects (90.7%) had undetectable HCV-RNA 12 weeks after DAA therapy. These results show that the SVR12 of chronic hepatitis C in patients with DAA therapy can reach >90%. Various studies have shown a high SVR12 with pan-genotype regimen DAA therapy, which in this study uses Sofosbuvir and Daclatasvir. Pott et al. [26] (2019) in Brazil on phase 4 randomized experimental study with 65 subjects receiving Sofosbuvir and Daclatasvir therapy, the SVR12 reached 100%. In a retrospective cohort study by Charatcharoenwitthaya et al. [27] (2020) in Thailand, there was a 98% SVR12 with Sofosbuvir and Daclatasvir. The same thing was also found in a meta-analysis conducted by Zoratti et al. [28] of 238 publications, where the SVR12 achievement ranged from 89–97% of genotypes 1–4 in Chronic Hepatitis C patients treated with Sofosbuvir and Daclatasvir.

Meanwhile, with interferon and ribavirin therapy, SVR12 can only be achieved in the range of 41–63% [29,30,31]. Thus, the use of DAA therapy in patients with chronic hepatitis C infection can achieve a higher SVR12 compared to interferon therapy.

Age correlation analysis in our study was carried out with the distribution of categories <60 years and ≥60 years according to WHO criteria, were compared with virological response after 12 weeks of DAA therapy or SVR12, with the results that no significant correlation was found between these two age groups (p > 0.05) (Table 3). The results of this analysis indicate that DAA therapy is well-tolerated, has high efficacy, and can be given to all ages, both adults and the elderly.

Studies by Elbaz et al., Pariente et al., and Nelson et al. supported this finding. In a prospective cohort study by Elbaz et al. [32] (2019) in Egypt in 285 subjects aged 60 years who received sofosbuvir and daclatasvir therapy, it was found that age did not affect the virological response with an SVR12 of 91.9% (p=0.44), with 8.1% failed to achieve SVR12 due to discontinuation of the drug due to adverse events and virological failure due to liver cirrhosis.

In another prospective cohort study by Pariente et al. [33] (2019) in France with 1123 subjects, in the fourth quartile with age 64 years, SVR12 up to 93.2% was achieved in the sofosbuvir and daclatasvir groups, and age did not decrease the virological response (p=044), where age increases exposure and efficacy of sofosbuvir because of a physiological decrease in glomerular filtration rate with age. While in a retrospective observational cohort study by Xia et al. [34] (21) in the USA, with 1106 HCV subjects with various DAA treatment regimens, the overall SVR12 was 97.8% with no significant difference between age and virological response.

Interferon-based regimens in elderly patients are associated with lower virologic response rates, due to side effects and reduced stimulatory effects of interferon on the aging immune system. Meanwhile, with DAA therapy in our study, we could achieve SVR >90% and it was not affected by age.

Analysis of gender correlation in our study found no significant association between men and women (p > 0.05) (Table 4), which differs from gender-dependent interferon therapy [19,20,21], DAA therapy still has high efficacy in both men and women. The observed significance is consistent with the results of prior studies by Margusino et al, Ahmed et al, and Yang et al. In a prospective cohort study by Margusino et al. [35] (2019) in Spain with 111 subjects with chronic HCV who received sofosbuvir and daclatasvir could achieve an SVR12 of 94.6%, where there was no significant difference from SVR12 to gender, both male and female (p=0.19).

Similarly, in a prospective observational study by Ahmed et al. [36] (2018) in Egypt, 249 chronic HCV subjects with SVR12 after receiving sofosbuvir and daclatasvir therapy, reached 96%, with no gender difference between men and women (p>0.05 ). Another prospective observational study by Yang [37] et al. (2019) in China with 498 chronic HCV genotypes 1, 2, and 3 subjects who were treated with sofosbuvir and daclatasvir had an SVR12 of 96.6%, with no difference between gender (p=0.423).

In the interferon era, there were differences in virological responses between males and females, due to faster viral clearance in women than men and hormonal activity, especially estrogen levels. can minimize this difference [16, 20, 21, 38]. And then in the current DAA era, this difference is disappearing which is probably the result of excellent antivirus efficacy so that it can minimize this difference.

The absence of a significant correlation (p>0.05) between BMI and virological response indicates the efficacy of DAA therapy is better than interferon. However, 8 subjects who did not achieve SVR12 found 75% (6 subjects) with obese and overweight. This is thought to occur due to insulin resistance that occurs in obese and overweight patients.

This is consistent with studies conducted by Allam et al., Gupta et al., and Gayam et al. In a prospective cross-sectional study conducted by Allam et al. [39] (2019) in Egypt with 182 chronic HCV subjects treated with sofosbuvir and daclatasvir, the SVR12 achievement was up to 97% with no significant association between obesity and virological response (p>0.05). Likewise in a prospective cohort study by Gupta et al. [40] (2018) in India, with 149 chronic HCV subjects treated with sofosbuvir and daclatasvir, SVR12 was achieved by 97.3% without a significant association between BMI and SVR12 (p>0.05).

Another study using the Sofosbuvir regimen but in combination with other DAAs was conducted by Gayam et al. [41] (2018) in the USA in a retrospective cohort study with 112 chronic HCV subjects with a combination regimen of ledipasvir or velpatasvir, with an SVR12 up to 92%. In the analysis of multivariate logistic regression models, no significant association was found between higher BMI and virological response to SVR12 (p=0.085). In our study, 75% of subjects who did not achieve SVR12 with overweight and obesity BMI could not be analyzed further, because many independent variables were not known.

Conclusion

The virological response of SVR12 with DAA treatment, in this study sofosbuvir and daclatasvir, in chronic hepatitis C patients reached 90.7%, with age, gender, and body mass index do not influence the success of DAA treatment. With a success rate above 90%, DAA therapy can be given to patients with chronic hepatitis C infection with elderly, male or female gender, and obesity. Further research is needed to assess other variables, such as DAA regimen, liver function level, insulin resistance level, liver fibrosis degree, viral genotype, and cirrhotic state.