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].
