Dobrowolska K, Zarębska-Michaluk D, Pawłowska M, Tudrujek-Zdunek M, Lorenc B, Berak H, Janczewska E, Mazur W, Janocha-Litwin J, Klapaczyński J, Sitko M, Dybowska D, Parfieniuk-Kowerda A, Piekarska A, Jaroszewicz J, Flisiak R. Sex-related differences in patients with chronic hepatitis C infection treated with direct-acting antiviral drugs. World J Hepatol 2025; 17(6): 105899 [DOI: 10.4254/wjh.v17.i6.105899]
Corresponding Author of This Article
Dorota Zarębska-Michaluk, PhD, Professor, Department of Infectious Diseases and Allergology, Jan Kochanowski University, Żeromskiego 5, Kielce 25-369, Poland. dorota1010@tlen.pl
Research Domain of This Article
Infectious Diseases
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
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/
Krystyna Dobrowolska, Collegium Medicum, Jan Kochanowski University, Kielce 25-317, Poland
Dorota Zarębska-Michaluk, Department of Infectious Diseases and Allergology, Jan Kochanowski University, Kielce 25-369, Poland
Malgorzata Pawłowska, Dorota Dybowska, Department of Infectious Diseases and Hepatology, Faculty of Medicine, Nicolaus Copernicus University, Bydgoszcz 85-030, Poland
Magdalena Tudrujek-Zdunek, Department of Infectious Diseases, Medical University of Lublin, Lublin 20-081, Poland
Beata Lorenc, Pomeranian Center of Infectious Diseases, Medical University of Gdańsk, Gdańsk 80-214, Poland
Hanna Berak, Outpatient Clinic, Hospital for Infectious Diseases, Warsaw 02-201, Poland
Ewa Janczewska, ID Clinic Mysłowice, Mysłowice 41-400, Poland
Włodzimierz Mazur, Department of Clinical Infectious Diseases in Chorzów, Medical University of Silesia, Katowice 40-055, Poland
Justyna Janocha-Litwin, Department of Infectious Diseases and Hepatology, Wrocław Medical University, Wrocław 50-367, Poland
Jakub Klapaczyński, Department of Internal Medicine and Hepatology, The National Institute of Medicine of the Ministry of Interior and Administration, Warsaw 02-507, Poland
Marek Sitko, Department of Infectious and Tropical Diseases, Jagiellonian University, Kraków 30-688, Poland
Anna Parfieniuk-Kowerda, Robert Flisiak, Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-540, Poland
Anna Piekarska, Department of Infectious Diseases and Hepatology, Medical University of Łódź, Łódź 91-347, Poland
Jerzy Jaroszewicz, Department of Infectious Diseases and Hepatology, Medical University of Silesia, Bytom 41-902, Poland
Author contributions: Dobrowolska K, Zarębska-Michaluk D, and Flisiak R designed the study; Dobrowolska K, Zarębska-Michaluk D, Pawłowska M, Tudrujek-Zdunek M, Lorenc B, Berak H, Janczewska E, Mazur W, Janocha-Litwin J, Klapaczyński J, Sitko M, Dybowska D, Parfieniuk-Kowerda A, Piekarska A, Jaroszewicz J, and Flisiak R collected the data; Dobrowolska K conducted the statistical analysis; Dobrowolska K, Zarębska-Michaluk D, and Flisiak R were responsible for data interpretation; Dobrowolska K, Zarębska-Michaluk D, Pawłowska M, and Flisiak R prepared the manuscript; Dobrowolska K, Zarębska-Michaluk D, and Pawłowska M conducted the literature search; and all authors revised and approved the final version of the manuscript.
Institutional review board statement: The study was approved by the Ethics Committee of Jan Kochanowski University, resolution number 57/2024, date of approval July 25.
Informed consent statement: Due to the retrospective nature of the study, a waiver of consent was in effect.
Conflict-of-interest statement: Zarębska-Michaluk D has acted as a speaker and advisor for AbbVie and Gilead. Pawłowska M has acted as a speaker for AbbVie and Gilead. Berak H has acted as a speaker for Abbvie. Janczewska E has acted as a speaker and/or advisor for AbbVie, Gilead, MSD, and Ipsen, and has received funding for clinical trials from AbbVie, Allergan, BMS, Celgene, Cymabay, Dr Falk Pharma, Exelixis, GSK, and MSD. Mazur W has acted as a speaker and/or advisor for AbbVie, Gilead, and Merck, and has received funding for clinical trials from AbbVie, Gilead, and Janssen. Klapaczyński J has acted as a speaker for Gilead and AbbVie. Sitko M has acted as a speaker for AbbVie and Gilead. Piekarska A has acted as a speaker and/or advisor for AbbVie, Gilead, Merck, and Roche; Jaroszewicz J has acted as a speaker and/or advisor for AbbVie, Gilead, Merck, Roche, Alfasigma, MSD, Gilead, and PRO.MED. Flisiak R has acted as a speaker and/or advisor and has received funding for clinical research from AbbVie, Gilead, Merck, Roche, and Novo Nordisk. Dobrowolska K, Tudrujek-Zdunek M, Janocha-Litwin J, and Dybowska D have no conflict to declare.
Data sharing statement: Data supporting reported results can be provided upon request from the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dorota Zarębska-Michaluk, PhD, Professor, Department of Infectious Diseases and Allergology, Jan Kochanowski University, Żeromskiego 5, Kielce 25-369, Poland. dorota1010@tlen.pl
Received: February 10, 2025 Revised: April 18, 2025 Accepted: May 24, 2025 Published online: June 27, 2025 Processing time: 136 Days and 1.1 Hours
Abstract
BACKGROUND
Sex is one of the known factors influencing the risk of hepatitis C virus (HCV) infection and the natural course of the disease.
AIM
To evaluate sex-related differences in the characteristics and outcomes of direct-acting antiviral (DAA) treatment in HCV-infected patients.
METHODS
The study included consecutive 9457 women and 9529 men, treated with DAA for chronic HCV infection from July 2015 to the end of 2023 whose data were collected in the nationwide multicenter retrospective Epiter-2 project. Women were divided into pre-menopausal (15-44 years), menopausal (45-55 years) and post-menopausal (> 55 years) and compared with age-matched men.
RESULTS
Regardless of age, women had a significantly lower body mass index, prevalence of genotype 3 infection and proportion of cirrhosis compared to men. Psychiatric disorders (except depression), hepatitis B virus and human immunodeficiency virus co-infections, as well as alcohol and drug addiction, were significantly less common in women than in men in all age groups. The sustained virologic response was significantly higher in women compared to men in each age group and amounted to 98.4% and 96.6%, respectively (P < 0.001). Independent predictors of treatment failure in women were genotype 3 infection, cirrhosis and postmenopausal age. Mild adverse events were reported significantly more often by women, regardless of age with the highest percentage in the postmenopausal group.
CONCLUSION
DAA treatment is more effective in women than in men, regardless of age, but in postmenopausal women, the effectiveness is relatively the lowest.
Core Tip: Sex is the factor influencing the risk of hepatitis C virus infection and the natural course of the disease. An analysis of nearly 19000 patients treated with direct-acting antivirals for chronic hepatitis C according to sex and reproductive status documented that regardless of age, women have lower body mass index, less frequent infection with genotype 3, less frequent co-infections with hepatitis B and human immunodeficiency viruses, and less advanced liver disease. Antiviral treatment is more effective in women than in men, irrespective of age, but postmenopausal women have relatively the lowest effectiveness and the highest incidence of adverse events.
Citation: Dobrowolska K, Zarębska-Michaluk D, Pawłowska M, Tudrujek-Zdunek M, Lorenc B, Berak H, Janczewska E, Mazur W, Janocha-Litwin J, Klapaczyński J, Sitko M, Dybowska D, Parfieniuk-Kowerda A, Piekarska A, Jaroszewicz J, Flisiak R. Sex-related differences in patients with chronic hepatitis C infection treated with direct-acting antiviral drugs. World J Hepatol 2025; 17(6): 105899
Sex, in the sense of referring to various biological and physiological characteristics, such as reproductive organs, chromosomes, hormone, is a recognized independent factor that influences the risk of hepatitis C virus (HCV) infection and the natural history of the disease[1,2]. HCV infection is more common in men. According to 2020 data, in Europe, of all registered cases, two-thirds were men, and their predominance was documented in every age category[3]. This is mainly due to the fact that women are much more likely to experience spontaneous viral clearance. The female sex hormone 17β-estradiol creates an antiviral state in the hepatocytes through activation of type I interferon (IFN), increasing the likelihood of viral clearance by interfering with HCV entry into the cell and subsequent folding of HCV particles and their release. In addition, women have a higher number of CD4+ T cells compared to men, which may be crucial in the acute phase of infection, when vigorous antiviral CD4+ T cells facilitate viral clearance[4,5]. However, the prevalence of HCV infection is also related to risky behaviors that promote transmission of the virus, and in this area, there have been recent changes in the epidemiology of HCV infection with respect to sex[6]. These changes are especially evident among women of reproductive age, which is of particular concern because of the risk of vertical transmission of HCV[7]. The opioid epidemic, which is linked to an increase in drug use among women, is blamed for these changes[8]. In 2019, an estimated 15 million women of the age of 15-44 years were affected by HCV worldwide with a prevalence of 0.78%[9]. Over the 30 years, global incidences of acute hepatitis C in females aged 15-19 years and HCV-related cirrhosis in females aged 44-49 increased by 46% and 73%, respectively. In the United States, between 2006-2014, the number of reported cases of acute hepatitis C increased 3.4-fold[10]. Given the risk of vertical transmission and the associated adverse perinatal outcomes of HCV infection during pregnancy, early prevention, screening, and treatment are critical in young women, ideally before pregnancy[11].
Also arguing in favor of early diagnosis and antiviral therapy implemented at a young age is the fact that rates of liver fibrosis (LF) and progression to cirrhosis appear to be slower in younger women compared to men at the same age. However, this difference disappears in older women, probably due to hormonal changes during menopause[12,13]. The aim of this study was to assess the sex-related differences in the characteristics of HCV-infected patients and to assess the impact of female sex on treatment with direct-acting antivirals (DAAs) depending on age and menopausal status.
MATERIALS AND METHODS
The analysis used data collected in the nationwide multicenter retrospective Epiter-2 project, which has been ongoing since 2015, the beginning of the DAA era in Poland. In the 22 leading hepatology centers participating in the project, 18986 consecutive adult patients, including 9457 women and 9529 men, received DAA therapy for chronic HCV infection from July 2015 to the end of 2023. Women were divided into groups according to their menopausal status, which was determined according to World Health Organization (WHO) recommendations[14]. For the purpose of the analysis, three age groups of women were created: 15-44 years (pre-menopause), 45-55 years (menopause), and > 55 years (post-menopause), and compared with the age-matched groups of men. Antiviral therapy was fully reimbursed by the National Health Fund. The type of treatment was chosen by the treating physician, taking into account the provisions of the drug program of National Health Fund, the recommendations of the Polish Group of Experts for HCV in effect at the time, and the Summary of Product Characteristics[15].
Data collection
Retrospective data collected in the Epiter-2 database and entered via an online questionnaire included baseline parameters such as age, body mass index (BMI), genotype (GT), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) co-infections, comorbidities, and comedications. HIV co-infection was defined using the 4th generation HIV test detecting the presence of the p24 antigen and/or antibodies against HIV, further investigated by the presence of HIV RNA. The HBV co-infection was ruled in based on the presence of anti-hepatitis B core (HBc) antibodies with or without the presence of HBV surface antigen. The active HBV infection was established based on the presence of HBV surface antigen in the serum. The history of previous unsuccessful antiviral therapies, the characteristics of the current therapy, and its safety were gathered. A comparative analysis was performed between both sexes in the age groups defined above.
Assessment of liver disease severity
The advancement of liver disease was assessed using transient or shear-wave elastography. The values of liver stiffness in kilopascals were converted into corresponding fibrosis levels in accordance with recommendations of the European Association for the Study of the Liver and presented as a Metavir score (fibrosis stage 0-4)[16]. Information on past liver decompensation, diagnosis of hepatocellular carcinoma (HCC), the presence of esophageal varices, and history of liver transplantation were gathered in the database. Patients with liver cirrhosis were assessed at the beginning of antiviral therapy on the Child-Pugh scale, and those scored as stage B and C were considered decompensated.
Assessment of treatment effectiveness and safety
The effectiveness of antiviral therapy was assessed by measuring HCV RNA 12 weeks after the end of treatment and an undetectable value at this time point was defined as a sustained virological response (SVR). Patients whose viral load was detectable 12 weeks after treatment completion were recognized as virological failures, whereas those who did not have this evaluation were considered lost to follow-up (LTFU) and identified as non-virological failures. In case of a missed visit, to minimize the number of patients in LTFU group, the managing physician tried contacting the patient via telephone to set up a new appointment and finalize the follow-up process. Safety data were reported during treatment and for a 12-week follow-up period after completion of therapy. Treatment modification or discontinuation and adverse events (AEs), including serious AEs and deaths, were recorded. Patients diagnosed with cirrhosis were observed for the AEs of special interest related to the complications of advanced liver diseases, such as decompensation and gastrointestinal bleeding.
Ethics
The type of treatment used was dictated by the clinical status of the patients, including the presence of liver impairment and kidney failure, and followed requirements specified in the characteristic of the product and Polish Group of Experts HCV recommendations[15]. All patients with HBV infection in whom the HBV treatment with nucleos(t)ide analogs was initiated before the start of DAA therapy, continued the treatment. In case of patients with HIV- or HBV-co-infection the risk of any potential drug-drug interaction between antiretroviral drugs/nucleos(t)ide analogs was ruled out before the initiation of DAA regimen[17]. Data was collected retrospectively pursuant to personal data protection principles. Informed consent was obtained from patients or their legal guardians. The study was approved by the Ethics Committee of Jan Kochanowski University, Resolution number 57/2024, date of approval July 25, 2024.
Statistical analysis
Continuous data was assessed with the Shapiro-Wilk test and did not meet the Gaussian distribution. Therefore, it was presented as a median and interquartile range and minimum and maximum values for some variables. To check the significance of the difference the Mann-Whitney test was performed. Categorical data were described as numbers and percentages. The χ2 test was chosen to carry out analysis for nominal variables.
The intent-to-treat (ITT) analysis included all patients who started the treatment, while the per-protocol (PP) analysis concerned only those with complete HCV RNA evaluation performed 12 weeks post-treatment. The model for multiple logistic regression was built to predict the odds of virological failure. The variables used in the model proved to be statistically significant in the univariate analysis conducted between virological failures and those with virological clearance (GT3, fibrosis stage 4, history of HCC, pangenotypic therapy, history of previous therapy, addiction to alcohol, obesity, male sex). The results were expressed as odds ratio and corresponding 95% confidence interval. A P value less than 0.05 was considered significant. Statistical analyses were performed using Statistica 13.0 (StatSoft, Tulsa, OK, United States) and GraphPad Prism 5.1 (GraphPad Software, Inc., La Jolla, CA, United States).
RESULTS
Population characteristics
The study population of 18986 patients was divided into groups by age bracket and sex (Table 1). There were 3118 women and 4163 men in the 15-44 age group, and 1689 and 2185 in the 45-55 age group, respectively. In contrast, the oldest group of patients over the age of 55 was dominated by women, there were 4650 of them, and their median age (interquartile range) was significantly higher compared to men, who numbered 3181, 65 years (60-71, 56-93) vs 63 years (59-69, 56-97), P < 0.001 (data not shown in the Table 1).
Table 1 Baseline demographic and clinical characteristics of women and men depending on age, n (%).
BMI was significantly lower, and GT3 infection was less frequent among women than among men, regardless of age. Fibrosis stage 4 corresponding to cirrhosis was diagnosed significantly more often among men compared to women, and the difference was the most notable among those aged 45-55 years (32.63% vs 18.89%, P < 0.001), followed closely by the youngest group (15.59% vs 6.8%). Comorbidities were significantly more common in men in the 15-44 age bracket compared to women (41.99% vs 37.6%, P = 0.003). Interestingly, while in the post-menopausal age, the difference evened out, the trend was reversed in women considered to be in the menopausal age (59.92% vs 58.76%). Irrespective of age, arterial hypertension was the most frequent comorbidity, followed by diabetes which was seen significantly more frequently among men than women in every age group. The prevalence of autoimmune diseases was significantly higher in women regardless of age. Depression was registered more often in women although, significance was reached only among the menopausal (6.28% vs 3.48%, P = 0.0003), and post-menopausal (4.95% vs 3.18%, P = 0.0007) groups (Table 1). Interestingly, psychiatric disorders such as schizophrenia and bipolar disorder, were reported mostly in men, and the difference was significant in the 15-44 and 45-55 age bracket (Table 1).
Overall, HIV and HBV co-infections (defined as a presence of HBc antibodies) were more common in men. However, the difference between sexes was most visible in the 45-55 age group (12.91% vs 5.62%, P < 0.001 for HIV co-infection, and 18.9% vs 14.86%, P = 0.0027 for HBV co-infection). Moreover, HBV co-infection (anti-HBc+) was more prevalent in women of all ages compared to coinfection with HIV (Table 1). The active HBV infection marked by the presence of hepatitis B surface antigen was present in 190 patients, and over half of them was younger than 45 years. It occurred more frequently in men, but only in the middle age range did the difference reach statistical significance. Out of 190 patients, 75 fulfilled requirements for the HBV treatment initiation in accordance to polish guidelines on HBV. Therapy with tenofovir was the most prevalent with 37 (49.3%) patients treated, entecavir was used in 30 (40%), while lamivudine was administered in 8 patients (10.7%). HIV-infected patients were mostly treated with tenofovir-based anti-retroviral regimens (874 patients, 77%). Behavioral risk factors such as addiction to drugs and alcoholism were marked significantly more often in men than women of all ages (Table 1).
History of HCC was positive more often in males than females regardless of the age and the difference was significant. While non-HCC tumors were diagnosed more frequently among men in the youngest and oldest age groups, only the 45-55 age cohort reached statistical significance with women reporting tumors more often than men (2.55% vs 1.1%, P = 0.007) (Table 1). Single women, one from the menopausal group and two from the postmenopausal group were using hormone replacement therapy. Overall, 146 patients underwent orthotopic liver transplantation, history of liver transplantation was more common in men, and the difference was statistically significant in the oldest age group.
DAA treatment characteristics and effectiveness
The size of the group without a history of prior treatment increased with decreasing age of the cohorts although in each group women were less likely to be treatment-experienced. The most commonly used regimens in the previous therapy course were IFN-based options, and IFN-free regimens were more eagerly employed in men as compared to women regardless of age. However, the biggest discrepancy in that regard is seen among patients from the 45-55 years and 15-44 years old subgroups (18.18% vs 4.51%, and 17.3% vs 5.72%, respectively) (data not shown).
Current antiviral treatment with GT-specific and pangenotypic regimens, although evenly distributed between the sexes, shows little inclination to reserve the latter for men (Table 2). The analysis of treatment response carried out for the whole population, without age division, showed that women significantly more often achieved SVR compared to men, both in ITT and PP analysis (96.06% vs 92.75%, P < 0.001; 98.43% vs 96.65%, P < 0.001, respectively) (Figure 1A). Moreover, SVR of at least 98% achieved by women in the PP analysis was preserved even after applying age division and was significantly higher than in the corresponding male group (98.95% vs 97.37%, P < 0.001 for 15-44 years old; 98.66% vs 94.99%, P < 0.001 for 45-55 years old; 98% vs 96.86%, P < 0.001 for > 55 years old) (Figure 1B-D). The worst treatment response was observed among women in the post-menopausal age with SVR reaching 95.83% and 98% in the ITT and PP analysis respectively (Figure 1D). Interestingly, SVR was achieved least frequently by men aged 45-55 years old (91.17% in ITT and 94.99% in PP analysis), while the best treatment outcome was observed in the youngest group, regardless of sex (Figure 1B and C).
Figure 1 Comparison of sustained virologic response between women and men in intent-to-treat and per protocol analysis in the whole group.
A: Regardless of age; B: Age groups 15-44 years; C: 45-55 years; D: > 55 years. ITT: Intent-to-treat; PP: Protocol analysis.
Table 2 Comparison of treatment characteristics of women and men depending on age, n (%).
Parameter
Women 15-44 years, n = 3118
Men 15-44 years, n = 4163
P value
Women 45-55 years, n = 1689
Men 45-55 years, n = 2185
P value
Women > 55 years, n = 4650
Men > 55 years, n = 3181
P value
History of previous therapy
0.001
0.0006
0.06
Treatment-naïve
2748 (88.13)
3550 (85.28)
1399 (82.83)
1704 (77.99)
3572 (76.86)
2369 (74.5)
Treatment-experienced
370 (11.87)
613 (14.72)
290 (17.17)
481 (22.01)
1076 (23.14)
811 (25.5)
Current regimen
< 0.001
0.0004
0.02
Genotype-specific
1573 (50.45)
1817 (43.65)
823 (48.73)
930 (42.56)
2872 (61.76)
1869 (58.76)
Pangenotypic
1545 (49.55)
2346 (56.35)
866 (51.27)
1255 (57.44)
1778 (38.24)
1312 (41.24)
The LTFU rate in the entire analyzed population was 2.7%, and for both genders were comparable in all age groups, although the highest proportion of LTFU was documented in the group of menopausal women (45 women, 2.61%) and men aged 15-44 years (169 men, 4.06%). Further evaluation showed that men with cirrhosis in the age range 15-44 and 45-55 years were significantly more likely to be LTFU than women in the same age groups (17.16% vs 5.06%, P = 0.027, 40.91% vs 20%, P = 0.048, respectively). No other parameters, including GT3 infection, behavioral risk factors such as addiction to drugs, addiction to alcohol or methadone therapy, or the presence of psychiatric disorders, showed a significant impact on loss to follow-up (data not shown). According to the multiple logistic regression analysis performed in the entire analyzed population, alcohol, male sex, positive history of previous therapy, GT3 infection, and presence of cirrhosis were independently associated with treatment failure (Table 3). Model built for women showed that in females factors independently increasing the risk of virological failure were GT3 infection [2.308 (1.499-3.555), P < 0.001], presence of cirrhosis [1.969 (1.378-2.813), P < 0.001)] and age over 55 years [1.64 (1.142-2.356), P = 0.007] (Figure 2).
Figure 2 Forest plot of odds ratio with confidence interval (odds ratio, 95% confidence interval, P value) from multiple logistic regression showing factors independently increasing the risk of virological failure 12 weeks post-treatment in females.
Table 3 Factors independently associated with virologic failure in multiple logistic regression.
Parameter
Effect measure
Wald statistic
OR
95%CI
P value
Intercept
2198.843
0.009
0.007-0.011
< 0.001
Alcohol
Yes
5.181
1.725
1.079-2.759
0.023
Male sex
Yes
33.278
1.832
1.491-2.25
< 0.001
History of previous therapy
Yes
14.923
1.535
1.235-1.908
< 0.001
GT3 infection
Yes
115.101
3.154
2.557-3.891
< 0.001
F4
Yes
92.802
2.608
2.146-3.169
< 0.001
Treatment safety
In over 96% of patients, regardless of age, treatment was carried out according to schedule. The frequency of therapy modification in the form of ribavirin dose modification and the incidence of discontinuation of DAA therapy were comparable in all groups but occurred most frequently in men aged 15-44 and in menopausal and postmenopausal women (Table 4). AEs were reported significantly more often by women irrespective of age with the highest prevalence among those aged > 55 years (19.74%). AEs with the highest occurrence were weakness/fatigue and headache. While weakness/fatigue reached a significant difference only in the 15-44 age bracket (6% vs 4.28%, P = 0.005), headache was noted significantly more frequently across all ages.
Table 4 Safety and characteristics of current therapy in women and men depending on age, n (%).
Serious AEs were rare and more common in men, but the difference was not statistically significant. Among the patients experiencing severe AEs were 5 patients who underwent liver transplantation. Four of them (two women aged 67 years and 53 years and two men aged 32 years and 67 years) underwent liver transplantation during the 12-week post-treatment follow-up period, two due to HCC diagnosed before DAA therapy and two due to decompensated liver cirrhosis diagnosed before DAA therapy. These patients completed treatment as planned and achieved SVR. One patient (female, age 38) required liver transplantation during therapy (week 10th of the 12-week regimen) and therefore had treatment completely discontinued, but also achieved SVR. The reason for transplantation was decompensation of liver function. Both cirrhosis and incidents of decompensation had been reported in this patient in the past, before DAA therapy.
AEs of special interest were rare, and their occurrence increased with age. Among patients older than 55 years, ascites and hepatic encephalopathy were reported significantly more frequently among men than women (1.51% vs 0.75%, P = 0.009, and 1.07% vs 0.37%, P = 0.001, respectively) (Table 4), and it was the only AEs of special interest that reached significant difference. A total of 113 patients died, deaths were more frequent in men, and more than 75% of them were in the oldest age group. None of the registered deaths was assessed by the treating physician as related to the antiviral treatment. Twelve patients (10.62%) died due to the liver cirrhosis decompensation, two of them due to esophageal varices hemorrhage. However, in all of the aforementioned cases, the hepatic cirrhosis and liver decompensation incidences were present before treatment initiation. Two patients committed suicide (1.77%), one (0.88%) died due to a narcotic drugs overdose. In other patients cause of death was defined as related to other comorbidities such as cardiovascular disease and neoplasms other than HCC. In 84 (74.34%) the cause of death remains unknown (data not shown).
DISCUSSION
To the best of our knowledge, the presented analysis conducted in a very large real-world evidence (RWE) population of nearly 19000 patients to compare HCV-infected men and women in terms of baseline characteristics and the effects and safety of DAA antiviral therapy is unique on the global scale. Since, according to available reports, in addition to gender-based differences, the course of HCV infection in women can also be expected to evolve due to hormonal management, this study divided the analyzed groups into age ranges corresponding to menopausal status according to WHO guidelines. In the population analyzed women were fewer in number than men, which seems to be in line with reports of a higher prevalence of HCV infection in men due to a higher rate of spontaneous viral clearance among females[18]. In a meta-analysis evaluating the gender differences in HCV infection among Egyptian citizens, it was found that despite no significant difference in seroprevalence of HCV antibodies between males and females, the HCV RNA positivity was detected significantly more often in males than females[19]. The difference noted in this analysis is small when considering all age groups together. However, larger disparities emerge when comparing different age ranges. While women were significantly less represented than men in the younger age groups of 15-44 and 45-55, the trend is reversed in the over-55 group. The alarming trend of an increase in the frequency of infections in women of reproductive age described in some developed countries, including the United States, Canada, and Australia, associated with increased drug use among this population does not seem to have had an impact on the epidemiology of HCV infections in Poland so far[6,8,20]. While the situation in Europe appears to be stable at the moment, the European Drug Report 2024 nevertheless highlights that drug consumption is a growing problem in the region. Due to the polydrug phenomenon, when opioids are mixed with other substances such as benzodiazepines or cocaine, the matter becomes more complex[21]. However, as the war continues and prompts migration movements, there is a risk of an increase in HCV infections in Europe due to the influx of Ukrainian children and teenagers, who have the highest prevalence of HCV infection among children in Eastern Europe. Not to discount are also migration movements from other countries such as Uzbekistan[22,23]. Moreover, an increase in the illicit drug use was noted among Ukrainian teenagers from 12% to 18% in 2016 and 2020 respectively[24]. In the population this study analyzed, the percentage of women burdened by drug addiction in any age category did not exceed 1% and was significantly lower than that of men regardless of age. The same significant differences to the disadvantage of men were noted in the case of alcohol addiction, also a risk factor for HCV infection. The highest percentage of drug users was noted in the age group 15-44, while alcohol addiction was most often reported by those aged 45-55 (4.3% vs 1.01%, P < 0.001). According to the latest report on addiction trends in Poland, an estimated 1.9% of Polish adults had ever been addicted to alcohol in 2018, and 0.64% extrapolated that they had been actively addicted in the past 12 months. In both this analysis and the cited report, drug addiction is considered less common than alcohol abuse[25].
It is important to consider the difference in life expectancy between men and women in Poland, especially since we documented in this analysis a significantly higher median age for women in the oldest group compared to men from the respective age group. According to the Central Statistics Office 2023 report, mortality rates for men are higher than for women, with nearly 44% of men not living to age 75 compared to only 22.6% of women. Although 2023 is considered the year with the highest recorded life expectancy in Poland’s history, the gender gap is much higher compared to other European countries. Out of 34 European countries, Poland ranks 28th with a life expectancy of 73.4 years for men and 81.1 years for women[26].
Across all age ranges, we observed a significantly different distribution of GTs in both sexes, corresponding to these differences, a higher percentage of GT-specific therapies in women and pangenotypic options in men[27]. The impact of GT on spontaneous clearance, more prevalent among women, was analyzed in some studies, but the results are inconsistent and no conclusion has been reached. According to a Polaris Observatory study released in 2017, GT1b is the most common GT in Poland (83%) followed by GT3 (10%) and GT4 (4.9%)[28]. This exact distribution is reflected in this analysis among patients aged 45-55. However, among women and men from the 15-44 age bracket, GT1a became the third most prevalent GT (8.63% for women and 9.85% for men). Regardless of age, GT3 was more common in men than in women. In several western studies, a higher prevalence of GT3 infection was associated with intravenous drug use, and while in this study we didn’t distinguish between intravenous and non-intravenous drug users, out of 204 people addicted to drugs, 84 (40.98%) were men, infected with GT3. However, geographical localization carries an impact on the GT distribution among people who inject drugs; in Africa GT4 remains the most common, while in Asia GT2 and GT6 are more prevalent within the group[29]. Infection with GT1b was more common among women of all ages, and its prevalence increased with age which stays in line with the reports from other studies[30,31]. It is considered a cohort effect due to the presence of patients born between 1945 and 1965 and referred to as “baby boomers” who are five times more likely to have hepatitis C. We saw a considerably higher prevalence of the GT4 variant among patients in the 15-44 and 45-55 age brackets; GT4 remains the most common HCV variant in the Middle East and Africa, and its spread in Europe can be attributed to migration and transmission of HCV infection among HIV co-infected individuals[28,32]. HIV co-infection, as well as HBV co-infection, occurred significantly more often among men in the analyzed population, regardless of age, and these findings are consistent with published data for Poland[33].
Cirrhosis, which reflects the progression of LF, was significantly more common in men than in women regardless of age (6.8% vs 15.59% in the 15-44 range, 18.89% vs 32.63% in the 45-55 range), and the difference was least pronounced in the oldest group (32% vs 38.98%). According to available data, the lower progression of LF and the lower incidence of liver cirrhosis in younger women compared to men of the same age are also due to the protective role of sex hormones[34]. It has been documented that the risk of fibrosis in women changes over time and is directly related to reproductive status. The presence of estradiol and estrogen receptors in the liver protects hepatocytes from oxidative stress, inflammatory damage, and cell death, so menopause, the period when the influence of female hormones decreases, is associated with accelerated LF, and the differences between the two sexes even out, which support this findings[35,36]. Despite the data indicating the benefits of estrogen replacement therapy in terms of antifibrotic effects, there are great concerns about initiating this type of therapy by gynecologists due to concerns about side effects in patients with chronic HCV infection[37]. Therefore, in this analysis, only three women used such therapy and we were unable to assess its potential impact. The lower severity of liver disease in women was also reflected in a lower rate of HCC and a frequency of liver transplantation as compared to men in all age groups. These results are consistent with the results of other published studies[1,37]. The latest analysis of the global burden of disease study 2021 indicates that men have a higher burden of disease than women overall, and diseases affect them earlier than women[38]. These data are reflected in this analysis, as the prevalence of at least one comorbid disease overall was significantly higher in men in the youngest age group.
Worth noting is the statistically higher BMI and higher incidence of diabetes in men than women regardless of age. This observation stays in line with other studies where men are more likely to be overweight, have a history of heart disease, and are less likely to engage in health-seeking behavior than females[39]. It is worth mentioning that among African Americans with HCV infection, the female gender was an independent risk factor for steatosis, and steatosis was independently associated with fibrosis progression. The impact of a race should be further evaluated in the context of multi-etiological fibrosis[40]. According to the latest data on the Polish population, men are more likely than women to be overweight and obese, which supports our findings on BMI[41]. Women of all ages in the studied population, in turn, were significantly more likely to suffer from autoimmune diseases, which is a well-documented phenomenon[42]. The more frequent prevalence of depression in women, described in this analysis, is also reflected in world literature and is explained by the influence of sex hormones and fluctuations in their levels during puberty and menopause[38,43]. The significantly higher percentage of treatment-experienced men as compared to women in our analysis is probably due to the fact that in the era of IFN therapy, they responded worse to antiviral treatment[44-46].
Also, in the era of DAA regimens, the effectiveness achieved in male individuals is lower, as we showed in this study in a very large population of patients. Overall, the rate of SVR was significantly higher in women compared to men and amounted to 98.4% and 96.6%, respectively (P < 0.001), and statistically significant differences in favor of women were documented across all age groups. This stays in line with results from other countries, such as Egypt, where SVR was high in both groups but slightly higher in females[47]. Female sex as a positive predictor of response to DAA treatment was also identified in other RWE studies, but it should be emphasized that this analysis shows this relationship in a very large population of patients, which increases its significance[48]. Using the multiple logistic regression models, we identified male sex as one of the variables independently increasing the risk of virological failure which stays in line with other results[48]. Furthermore, by analyzing the response to therapy in relation to menopausal status, we showed that despite a better response than men regardless of age, postmenopausal women respond relatively worse. The decrease in effectiveness with age is not so evident, as in the case of IFN therapies, and SVR in this population still reaches 98%[49]. The slightly lower SVR noted in the oldest group of females may be linked to the higher multimorbidity in this group, which resulted in a higher loss to follow-up rate. Multivariate analysis model conducted in a female population identified age over 55 in women as one of the factors independently associated with treatment failure. Interestingly, in another study, it was found that in females, the age ≥ 55 years was the only independent predictor for exhibiting higher viral loads[50]. It underlines the necessity of an early diagnosis and treatment of the HCV infection. During the pre-menopausal period, women can benefit from the protective role of female sex hormones, which mitigate the risk of fibrosis[1,13]. Screening and early diagnosis of HCV in women of reproductive age, accompanied by counseling about reproductive planning before/during HCV treatment, is necessary to carry out optimized care in this population[51,52]. The study conducted in China demonstrated that screening the birth cohorts, as part of the population-wide screening, is a cost-effective method of lowering costs linked to chronic hepatitis C infection and its complications[53]. HCV treatment initiation in the reproductive period removes the possibility of vertical transmission from mother to child, and many complications linked to it, such as a higher rate of intensive care unit admission of neonates born to HCV-infected mothers[7,54]. Many children born to mothers with HCV infection are going undetected due to the lack of screening of the pediatric population, which impacts the linkage to care and treatment, that, in light of highly effective therapies, is an unacceptable outcome[55-58].
While the effectiveness of therapy was significantly higher among women, AEs were reported more frequently by them, regardless of age, with the highest frequency in the oldest age group. The most frequent were weakness/fatigue and headaches, similar to results found in other studies[47]. A scoping review revealed that women across different countries are not only more active in AE reporting, but they are also more open to receiving health-related advice from family members or friends and often seek health information on their own[59]. Moreover, with age, the rate of AEs reporting increases, and it can be due to the combination of factors such as frailty, polypharmacy, multimorbidity, and changes in drug metabolism[60]. The effect was also seen in a cohort of DAA-treated patients aged 60 years or older when compared with a younger cohort in a retrospective observational cohort study from Tianjin, China[61]. What is important, however, severe AEs were reported more often by men. Also, deaths were more common across all age brackets in men than women, but the difference reached significance only in the oldest cohort, which may reflect the difference in life expectancy between sexes in Poland.
This study has limitations that should be stressed. The retrospective nature of the study increases the risk of data entry errors, missing data, possible bias, and underestimation of the incidence of AEs. We did not include data on patients’ nationality. However, the Polish population is relatively homogeneous, and immigrants with the right to public health care are primarily Ukrainian war refugees. Evaluation of drug and alcohol addictions was based on patients’ declarations. The presence and stage of liver steatosis were not analyzed. Menopausal status was assessed based on the age ranges suggested by WHO and was not verified by hormonal tests. The strongest point of this study is the evaluation of a large, RWE population from many hepatology centers treating patients according to the same principles and recommendations, which means that the results obtained can be generalized. So far, such a large RWE population has not been analyzed in terms of differences in DAA therapy depending on sex. It is also worth noting the very low percentage of people LTFU (2.7%), typical of the population in clinical trials rather than in routine clinical practice, which, on the one hand, proves patient adherence, and on the other hand, the use of effective strategies to keep patients under observation.
CONCLUSION
Women chronically infected with HCV have a significantly lower BMI, less frequent GT3 infection, and less frequent HBV and HIV co-infection than men. Liver cirrhosis is documented significantly less frequently in women than in men, although this difference decreases with age, being the smallest in the postmenopausal period. Early diagnosis of HCV infection in women allows timely treatment and avoids the consequences associated with the risk of infecting the child and the progression of the disease, which can be expected during menopause due to the loss of protective sex hormones. Especially since DAA treatment is more effective in women than in men, regardless of age, but in postmenopausal women, the effectiveness is relatively the lowest and the frequency of side effects is the highest.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: Poland
Peer-review report’s classification
Scientific Quality: Grade A, Grade B, Grade C
Novelty: Grade B, Grade B, Grade D
Creativity or Innovation: Grade B, Grade B, Grade D
Scientific Significance: Grade A, Grade B, Grade C
P-Reviewer: Dabbous H; Henderson H S-Editor: Wu S L-Editor: A P-Editor: Yu HG
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