Effect of HCV eradication by DAAs on liver steatosis, carotid atherosclerosis, and associated metabolic comorbidities: A systematic review

The beneficial effect of Hepatitis C virus (HCV) eradication by direct antiviral agents (DAAs) on liver fibrosis is well defined. Despite this, the impact of viral eradication in both hepatic and extra‐hepatic metabolic features is underreached. This systematic review aimed to synthesize the evidence on the impact of HCV eradication by DAAs on liver steatosis, carotid atherosclerosis, glucidic impairment, dyslipidaemia, and weight gain.


| INTRODUC TI ON
Hepatitis C virus (HCV) infection is a common cause of chronic liver disease, and according to World Health Organization (WHO) data, it is estimated that HCV caused 290 000 deaths per year worldwide. 1ronic hepatitis C (CHC) is related to both hepatic and extrahepatic manifestations.Indeed, it is considered a systemic disease associated with metabolic disorders, such as type 2 diabetes mellitus (T2DM) and dyslipidaemia, cardiovascular diseases (CVDs), and impaired renal function. 2In the last years, the introduction of interferon (IFN)-free, oral direct antiviral agents (DAAs) has dramatically changed the history of CHC infection.6][7] Conversely, the effect of SVR by DAAs on cardiometabolic manifestations of CHC is still controversial and the current guidelines provide only limited recommendations for the management of noncirrhotic patients after SVR. 8 HCV is a well-known risk factor for the development of liver steatosis through the accumulation of intrahepatic low-density lipoprotein (LDL) and reduction of very low-density lipoprotein (VLDL) secretion. 9HCV particles also attach to the lipid droplets to promote the virus assembly. 10For this reason, CHC seems to be associated with a reduction in VLDL secretion and consequent hypolipidaemia. 11There is good agreement in studies regarding an increase in total cholesterol (TC) and LDL after viral eradication, 12 while the changes in triglycerides (TGs) and high-density lipoprotein (HDL) are less consistent. 13though genotype 3 displayed greater affinity to lipid droplets, all genotypes favoured the development of liver steatosis. 14[17] CHC is related to an increase in proinflammatory cytokines and reactive oxygen species (ROS) that play a direct proatherogenic role through the induction of arterial inflammation. 18Additionally, carotid plaques contain HCV genomic sequences. 19As a result, HCV infection seems to be related to an increased risk of carotid atherosclerosis, expressed both as an increase in carotid intima-media thickness (cIMT) and plaques, a well-known marker of cardiovascular damage. 20A reduction in cIMT and plaques is expected after SVR, but the evidence seems contradictory. 21,22e inflammatory milieu promoted by HCV fostered lipid peroxidation and interfered with glucose and lipid metabolism. 23These factors are related to liver steatosis and atherosclerosis but also insulin resistance (IR) and T2DM. 24,25IR is the link between CHC and T2DM, and glucose metabolism seems to be improved after SVR 26,27 at least in the short term. 28,29nally, a higher body mass index (BMI) seems to be associated with the worst metabolic profile both before and after SVR, 13,26 but the effect of viral eradication on BMI changes is not well defined.
HCV-associated dysmetabolic syndrome aggregates this cluster of dysmetabolic conditions (IR, steatosis, hypocholesterolemia, and visceral fat hypertrophy).While it differs from the traditional concept of metabolic syndrome on the grounds of reduced plasma lipids levels, it equals the cardiovascular risk.The increased T2DM Conclusion: Despite high heterogeneity and relatively short follow-up of included studies, we can conclude that the presence of metabolic risk factors should be strictly evaluated due to their impact on liver steatosis, glucidic and lipid homeostasis, and on weight gain to better identify patients at risk of liver disease progression despite the virus eradication.

K E Y W O R D S
body weight, carotid atherosclerosis, diabetes mellitus, dyslipidaemia, fatty liver, hepatitis C virus

Key points
• There is previous evidence that HCV impairs both glucidic and lipidic metabolism and fosters the development of liver steatosis and carotid atherosclerosis through both direct and indirect mechanisms.Despite this evidence, the impact of viral eradication on liver steatosis, CVDs, glucose and lipid metabolism, and weight is still controversial.
• Our results suggest that the presence of metabolic derangement affects all the mentioned outcomes, especially liver steatosis, dyslipidaemia, and weight gain, and could prevent the beneficial effect of viral eradication with the risk of progression of liver damage.
• Further studies specifically designed for the evaluation of metabolic changes before and after SVR are needed to better understand the follow-up of patients with CHC after viral eradication.
risk confers an additive risk of developing CHC and HCC, which may contribute to rise even more the cardiovascular risk. 30e to the controversial role of viral eradication on metabolic comorbidities and the impact of liver steatosis, carotid atherosclerosis, diabetes, dyslipidaemia, and obesity on general morbidity and mortality, this systematic review aimed to compile the evidence assessing the effect of HCV eradication by DAAs on liver steatosis and carotid atherosclerosis, both evaluated with noninvasive techniques.
Additionally, we aimed to investigate the effect of viral eradication on glucidic impairment, dyslipidaemia, and excessive weight gain, to help physicians to identify patients at risk of developing a metabolic liver disease after SVR needing a closer follow-up after viral eradication.To the best of our knowledge, this is the first review providing a comprehensive synthesis of the evidence on this important topic.

| MATERIAL S AND ME THODS
This systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA) 2020 guidelines. 31The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42021287827).

| Eligibility criteria
Experimental studies that analysed, as primary or secondary outcomes, the presence of liver steatosis, atherosclerosis, changes in glycemic and/or lipid metabolism, and changes in weight/BMI before and after treatment for CHC with DAAs were included.Table 1 summarized the PICO (population, intervention, control, and outcome) description.
Studies concerning IFN-based regimens, without an evaluation before and after viral eradication, based on patients with coexisting chronic infectious disease other than hepatitis C (e.g., human immunodeficiency virus-HIV, hepatitis B virus-HBV), conducted in the postliver transplant setting, and that used scores for the diagnosis of liver steatosis were excluded.Moreover, we excluded studies with no original data (reviews and editorial articles), dissertations/ thesis, commentaries, conference abstracts, qualitative reports, and studies not published in peer-reviewed journals and not available in English, Italian, or Portuguese.

| Information sources and search strategy
A systematic search of peer-reviewed articles (published up to December 2022 or ahead of print) was performed in four electronic databases (PubMed, Cochrane Database of Clinical Trials, Scopus, and Web of Science).In addition, reference lists of included studies and review articles were manually screened to identify additional pertinent studies.For all databases, the search strategy used combined Medical Subject Headings (MeSH) terms and Boolean operators AND/OR.In detail, the searches included the combination of terms concerning the population of interest (e.g., chronic hepatitis C), the use of DAAs therapy (e.g., viral eradication), the outcomes of interest (e.g., carotid atherosclerosis), and the use of imaging techniques for the evaluation of atherosclerosis and liver steatosis (e.g., ultrasonography).The complete search strategy is shown in Table S1.

TA B L E 1
Eligibility criteria are summarized according to the PICO format.
a study was considered potentially eligible based on title and abstract, the full text was obtained and screened.Discrepancies were resolved by consensus with a third author (HCP), when necessary.
Data were managed using Rayyan QCRI Software. 32

| Data collection process and items
Data extraction was conducted by the same two reviewers (AC and ICR) and included information about the article (e.g., authors, year), study design, participants (e.g., demographics), intervention (e.g., type of DAAs therapy), outcomes (e.g., evaluation of changes in liver steatosis), and techniques used before and after therapy based on the outcomes (e.g., abdominal US for liver steatosis).For studies with missing data, the corresponding author was contacted by email.The uncertainties after data extraction were solved by the same third author (HCP).

| Effect measures and synthesis methods
The general characteristics of the included studies are qualitatively synthesized and presented in tabular form organized by outcomes. We

| Certainty assessment
Two authors (AC and ICR) independently rated the quality and strength of the body of evidence for each outcome using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. 34The final rating was high, moderate, or low (certainty about the estimate of effect).Any discrepancies were resolved by consensus or through a third author (HCP).

| Study characteristics
Only five studies (5%) were randomized control trials (RCTs), whereas the others had a pre-and posttreatment design (48% were prospective and 47% were retrospective).Over 30% of the studies were conducted in both Europe (35%) and Asia (32%), while 9% were conducted in the United States, 6% in South America and 18% in North Africa.The noninvasive evaluation of liver steatosis before and after SVR was performed in 18 studies, while carotid atherosclerosis was examined in only four studies.Most studies, especially the retrospective ones, had more than one outcome and evaluated both glucose and lipid metabolism before and after SVR (sixty-two and fifty-nine articles, respectively), while 30 examined weight changes as a primary or secondary endpoint.The follow-up period ranged from 12 weeks to 10 years after SVR.

| Quality assessment
Regarding the methodological quality of the 97 studies included, 33 were rated as "strong," 57 were classified as "moderate," and 7 were rated as "weak."Although all included studies were intervention ones, the majority (95%) were nonrandomized trials and therefore rated as moderate for the study design and thus nonrated on blinding.Concerning only the RCTs, they were rated as moderate regarding the blinding of participants during the recruitment.Regarding reporting of withdrawals and dropouts, 3 prospective studies were rated as weak because of the high rate of withdrawals, whereas the other studies were rated as strong or moderate.With regard to adjusting analyses for confounders, 0 studies were classified as strong, 38 as moderate, and 59 as weak.
In terms of data collection tools, 88 studies were rated as strong, 0 as moderate, and 9 as weak for not providing information about validity or reliability of their measures.
For a detailed classification of each domain and study, see Table S2.

| Changes in liver steatosis
5][46][47] Table 2 summarizes the characteristics of the studies (n = 11) that evaluated changes in liver steatosis in the whole cohort of patients, while Table 3 summarizes the characteristics of studies (n = 7) that perform specific subanalysis.
The most common imaging technique used to diagnose liver steatosis is abdominal US, 48 whereas Fibroscan is a noninvasive and validated technique that simultaneously evaluates both fibrosis and steatosis using vibration-controlled transient elastography (VCTE). 49 provides a measurement of liver steatosis through the controlled attenuation parameter (CAP) and of liver fibrosis through the liver stiffness measurement (LSM). 50e majority of studies evaluated liver steatosis through CAP at Fibroscan and/or abdominal US.Only one study considered proton density fat fraction (PDFF) at magnetic resonance imaging (MRI). 43ereas 36% of studies did not show a significant difference in the presence or degree of liver steatosis before and after SVR by DAAs, the other 54% of studies experienced an increase in liver steatosis degree after viral eradication.

Increase in liver steatosis after SVR by DAAs
Six studies showed an increase in liver steatosis.Patients with lesser steatosis degree at baseline, and with metabolic comorbidities, experienced a greater increase in steatosis after SVR, 15,17,26,[39][40][41] with the development of de novo steatosis in patients without steatosis at baseline. 16Interestingly, a two-way relationship between liver fibrosis and steatosis was observed.The presence of liver steatosis after viral eradication was negatively correlated with the hepatic fibrosis regression commonly observed after SVR. 16,17,39Indeed, patients with steatosis worsening had higher values of LSM after SVR. 39Moreover, the presence of baseline cirrhosis was associated with an increase in liver steatosis in patients treated with ribavirin (RBV). 28Notably, when we considered the four studies without evidence of an absolute change in liver steatosis after SVR, [35][36][37][38] we found a trend toward increased liver steatosis, although these studies covered only a small percentage of patients.57.9 ± 13.3 51.5% 1 (16%), 1a (23%), 1b (43%), 1a/1b (5%), 2b (1%), 3 (4%), 3a (6%), 4 (2%) Excluded patients with chronic renal disease, neoplastic disease, HbA1c > 9.5%, higher alcohol intake (>40 g/day for man and >20 g/day for women), pregnant women Not specify The increase of steatosis evaluated by CAP seems to be unrelated to the type of DAAs regimen. 41A study emphasized that male patients with metabolic comorbidities at baseline developed de novo steatosis after SVR. 16

Reduction in liver steatosis after SVR by DAAs
One study showed a reduction in liver steatosis in the whole cohort of patients evaluated as PDFF changes at MRI. 43 A reduction in liver steatosis after SVR was observed especially in patients with baseline steatosis 15,44,46 but without metabolic comorbidities.Indeed, lower BMI and higher HDL levels at baseline were significantly associated with the amelioration of liver steatosis, 15,16,43 regardless of viral genotype. 43nversely, the presence of metabolic risk factors such as a higher baseline level of HbA1c precludes the amelioration of liver steatosis after SVR. 46e type of DAAs regimen may have a role in steatosis resolution.Patients treated with sofosbuvir (SOF) plus daclatasvir (DAC) showed a reduction in liver steatosis compared to patients treated with SOF plus simeprevir (SIM). 44,47However, unavailable genotype specification on papers precludes us from assuming an antiviral regimen's impact.Moreover, noncirrhotic patients treated with RBV showed a reduction in liver steatosis after SVR. 28

| Changes in carotid atherosclerosis
2 The studies observed a reduction in both cIMT and in the percentage of patients with increased cIMT, defined as cIMT > 0.9 mm, without significant changes in carotid plaques.The reduction of cIMT seems to be irrespective of the increase in TC showed after viral eradication, whereas both studies observed an amelioration in fasting glucose. 21,52Interestingly, another study conducted in patients without T2DM showed a significant reduction in the percentage of patients with carotid plaques after SVR despite cIMT did not significantly differ both as a linear value and as a percentage of increased cIMT. 53tably, one study showed the opposite result.The authors evaluated both the greatest cIMT value measured, defined as max-cIMT, and the mean-cIMT derived from three measurements.
After SVR, an increase in max-cIMT in male patients was observed, whereas mean-cIMT did not differ in both males and females.
Max-cIMT seems to be related to higher levels of small dense LDL (sdLDL).

| Changes in metabolic outcomes
Tables S3-S5 summarize the characteristics of studies evaluating changes in glucose metabolism, lipid parameters, and weight/BMI after SVR by DAAs.

Changes in glucose metabolism
5][56] The majority of studies (43 out of 62) showed an overall improvement in glucidic metabolism after viral eradication in both patients with T2DM and prediabetes at baseline and in patients without T2DM.
On the other hand, 19 studies did not show changes in glycaemia, HbA1c, and homeostasis model assessment (HOMA)-IR after SVR by DAAs.No studies have shown a worsening of glucidic control after SVR.
Amelioration in glucidic parameter.The decrease in HbA1c and HOMA-IR after SVR implied a significant reduction in patients with uncontrolled T2DM and evidence of IR of 17% and 41%, respectively. 57,58The HOMA-IR improvement appears unrelated to HbA1c improvement and, despite a brief increase at 1 month of antiviral therapy, it persists 1 year after viral eradication. 59,602][63] The greater improvement in IR was observed in female patients, 64 and it was irrespective of the type of antiviral regimens. 65The impact of previous treatment was contradictory.In fact, while one study showed that the amelioration in fasting glucose, insulin, and HOMA-IR was seen in both naïve and treatment-experienced patients, 66 another study observed that only previously treated patients had a reduction in glycaemia after SVR. 67As a consequence of the reduction in IR, several studies showed an increase in insulin sensitivity, expressed as an increase in HOMA-S. 61,63,68,69Patients with baseline IR showed an improvement in beta-cell function with greater amelioration in glycemic control after SVR, 70 while nondiabetic patients did not reveal a significant change in beta-pancreatic cell function. 71

Amelioration in glucidic parameter-the role of liver fibrosis and steatosis
Baseline insulin and HOMA-IR were greater in cirrhotic patients compared to noncirrhotic ones. 28,54After SVR, cirrhotic patients showed a significant reduction in IR, fasting glucose, 21,52,61,72 HbA1c, 62,73 and 2-h plasma glucose. 74The amelioration of glycemic parameters in cirrhotic patients seems to be irrespective of BMI and the presence of T2DM, 74 but after SVR, they showed higher HOMA-IR values compared to patients without baseline advanced fibrosis. 58Moreover, an inverse relationship between the degree of baseline liver fibrosis and the amelioration of IR after SVR was seen. 61Child A cirrhosis, female sex, and baseline glycaemia seem to be the factors related to a reduction in fasting glucose >5% after viral eradication. 67Patients without advanced fibrosis showed a higher reduction in the relative risk of developing T2DM after SVR by DAAs, independently of the type of antiviral drug. 63While the improvement in IR seems to be similar in both patients with a reduction and with an increase in liver steatosis after SVR, 43 patients with liver steatosis had higher glycaemia value after viral eradication compared to patients without steatosis. 36elioration in glucidic parameter-the impact of RBV.No significant differences were observed in HbA1c changes in patients treated with RBV compared to others. 27,75Regarding HOMA-IR, it increased during the treatment with RBV and after returned to the baseline levels. 60elioration in glucidic parameter-focus on diabetic patients.Studies that enrolled only diabetic patients showed a significant decrease in fasting glucose, HbA1c, and 2 h postprandial blood glucose after viral eradication in more than 65% of patients. 76-79A greater reduction in fasting glucose and HbA1c was seen at SVR; afterwards, they increased but did not reach the baseline levels. 75Interestingly, more than 20% of diabetic patients had a normalization of HOMA-IR after SVR, with the consequent reduction in oral antidiabetic drugs and insulin dosage. 57,61,80,81Studies with longer follow-up showed that the improvement in glycemic control persists also after 1.5 years apart SVR. 82Diabetes-free survival was higher for patients who achieved SVR, especially for those with a lower BMI. 83Conversely, patients with overweight/obesity and baseline HbA1c over 8% need a higher antidiabetic drug dosage after SVR. 27,84[85][86] Conversely, higher fibrosis stage before treatment, longer T2DM duration, a positive family history of diabetes, the Child class B, and the oesophageal varices were associated with lower improvement of glycemic control. 75,78,85,87Viral eradication seems to have the greater impact on the improvement of both HbA1c and HOMA-IR in diabetic patients, whereas in prediabetic patients it is related only with the reduction of HbA1c. 63,88e type of antidiabetic drugs had an impact on HbA1c reduction after SVR.The highest percentage of HbA1c reduction was seen in patients treated with insulin compared to patients treated with only oral antidiabetics. 62,89elioration in glucidic parameter-patients with baseline IR.Patients with baseline IR showed a significant decrease in HOMA-IR after SVR until 72 weeks after therapy and then increased. 26Conversely, patients without baseline IR had an increase in HOMA-IR values after viral eradication. 90,91Older age, higher baseline transaminases, higher TC and TGs, and higher fibrosis stage were the factors associated with baseline IR, 26,92 and the higher the BMI, the lower the reduction in IR. 92 The major predictor of the reduction in IR in patients with baseline IR was the level of HOMA-IR before treatment. 69o changes in glucidic parameter.Among the 19 studies that showed no changes in glycaemia, HbA1c, and HOMA-IR after SVR by DAAs, a significant reduction in HbA1c at the end of treatment was seen in one, but after SVR, HbA1c levels increased again to the baseline levels. 13No differences were seen among patients with and without advanced fibrosis, 80,93,94 even if cirrhotic patients treated with RBVfree regimens seem to experience an increase in mean insulin and HOMA-IR. 28

Changes in lipid parameters
The majority of included studies (n = 59) considered the changes in lipid metabolism after viral eradication by DAAs as primary or secondary outcomes.All studies observed a worsening in TC and LDL after viral eradication by DAAs.Concerning HDL, 17 studies did not show a significant change after SVR, 20 studies observed an increase in HDL after SVR, especially in female patients with metabolic syndrome, 22,45,64,72,95 but not during the treatment when HDL declined, 13,91,96 and only 2 studies revealed a reduction in HDL. 61,91107 Changes in TC and LDL.It may be perceived that viral eradication relates to worsening in TC and LDL, in addition to patients who not achieved SVR had unaltered lipid metabolism. 13,66,108ctors associated with the increase in TC and LDL were the presence of dyslipidaemia without a specific treatment, a noncirrhotic liver, and a higher waist circumference at baseline. 104Specifically, female sex seems to be associated with the increase in TC but not in LDL, 104 whereas higher baseline BMI, higher HOMA-IR, higher TGs, lower HCV-RNA, and lower AST at baseline appear associated with the increase in LDL. 13,15,46,69,101e changes in TC and LDL were independent of T2DM or hypertension. 61,91e increase in TC and LDL started during the therapy and reached a greater increase from the end of treatment 13 to 3 months after SVR. 68,96After this point, the increase of TC and LDL was less marked, reached a plateau at 1 year after treatment, 91,104 and after 2 years from viral eradication, TC and LDL remained higher compared to baseline. 95,104As a consequence of the increase in TC and LDL after SVR, approximately 20% of patients treated showed cholesterol levels over the optimal range 109 and the use of lipid-lowering drugs increased. 110anges in TC and LDL-the role of liver fibrosis.The levels of TC and LDL at baseline were inversely correlated with liver stiffness. 111ter SVR, both cirrhotic and noncirrhotic patients experienced an increase in TC and LDL, even if the highest increase was observed in noncirrhotic. 13,21,61,104,112In patients with cirrhosis, both TC and LDL reached a peak at 12 weeks posttreatment, after that their values decreased but remained higher than baseline. 28eatosis grade at baseline, older age, and smoke were the factors associated with the higher increase in TC and LDL in cirrhotic patients. 13,15,46,104spite the evidence, it is noteworthy that three studies did not observe an association between lipid changes after SVR and fibrosis stage. 40,61,68Furthermore, diabetic patients experienced an increase in TC and LDL after SVR, irrespective of fibrosis stage. 73anges in TC and LDL-the impact of drug regimen.Following SVR, changes in TC and LDL were independent of the RBV-free antiviral regimen used. 13Regarding RBV, a comparative study between patients treated with SOF/RBV, with DAC/asunaprevir (ASV), and with SOF/ledipasvir (LDV) showed that TC and LDL decreased at the beginning of the treatment with RBV.Subsequently, their values increased but a significant change from baseline to SVR was not observed.In patients treated with DAC/ASV and SOF/LDV, TC and LDL start to increase at the end of treatment and during the treatment, respectively. 28,98,101tients treated with lipid-lowering drugs did not show a change in their lipid profile, 104 except for patients treated with SOF/LDV irrespective of fibrosis stage. 100anges in TC and LDL-the effect of viral genotype and genetic polymorphism.According to studies that examined the impact of viral genotypes on TC and LDL after SVR, their increase was well defined in genotypes 1a, 1b, 3, and 6, 97,108 whereas for genotype 2 data were contradictory. 97,108rrently, only one study has examined the effect of the genetic polymorphism interleukin (IL)28B TG/GG involved in HCV resistance to IFN treatment 113 on lipid changes following SVR, showing that this polymorphism increases LDL at SVR and 2 years later. 95anges in HDL.Among the studies that showed an increase in HDL, it appears to be consistent after the viral eradication, whereas during treatment HDL declined. 13,91,96Higher baseline fibrosis, female sex, and the presence of metabolic syndrome seem to be the factors related to the increase in HDL after SVR. 22,45,46,64,72,95On the other hand, a low fibrosis stage was associated with a reduction in HDL. 61The study of Lee et al. 91 showed that patients with an increase in BMI and HOMA-IR after SVR experienced a reduction in HDL 3 years after therapy.Concerning the impact of steatosis on HDL changes, one study showed a negative correlation between CAP values and HDL levels after SVR. 15 Changes in HDL-the effect of viral genotype and drug regimen.According to viral genotype, HDL seems to increase in both HCV genotypes 1a, 1b, 2, and 3, but the highest increase in HDL after SVR was seen in patients infected with genotypes 1a, 1b, and 3. 97,108 A reduction in HDL levels was experienced during treatment with RBV.Later, HDL levels increased but not above baseline. 28A similar effect was seen in patients treated with ombitasvir (OBV)/ paritaprevir (PTV)/ritonavir (RIT). 60Conversely, patients treated with SOF/LDV experienced an increase in HDL during the therapy.
After treatment, HDL returned to baseline levels irrespective of the type of antiviral treatment. 60anges in TGs.While the majority of studies did not evidence a significant change in TGs levels after SVR, in longer follow-up studies TGs seem to be higher after 2 years from SVR compared to baseline, 37,58 especially in male patients. 64Moreover, TGs seem to increase later compared to TC and LDL. 104nversely, some studies showed a reduction in TGs after SVR, 106 especially in female patients with higher baseline TGs. 43,55anges in TGs-the role of liver fibrosis and steatosis.The role of liver fibrosis in TGs changes after SVR is not well defined.While some studies did not evidence a significant change in TGs in both cirrhotic and noncirrhotic patients, 96 other studies showed a reduction in TGs in cirrhotic patients until week 12, after that the values quickly increased. 28,91On the other hand, some studies experienced an increase in TGs especially in patients without advanced fibrosis at baseline, 61,68 whereas Doyle et al. demonstrated an increase in TGs in patients with cirrhosis treated with RBV. 28tients who developed or worsened steatosis after SVR also revealed an increase in TGs levels. 16,39anges in TGs-the effect of viral genotype and drug regimen.Patients infected with genotype 1b 56 or 3 107 had a reduction of TGs levels after SVR, whereas patients infected with genotype 1a did not show a significant change. 97Similar to HDL, the effect of antiviral regimens on TGs levels was seen only during therapy but not at the end of treatment.In patients treated with OBV/PTV/RIT, TGs increased during the treatment, whereas TGs did not change in patients treated with SOF/LDV.After the treatment, TG levels were superimposable to baseline. 60In patients treated with RBV, TGs increased until week 12 posttreatment, then they lowered. 28Moreover, the modification of TG levels was similar between treatment naïve and treatmentexperienced patients. 79anges in other lipid particles.VLDL tends to decrease during the treatment, but after that, they increase to baseline levels, and no significant changes in VLDL were observed after SVR. 99,105sdLDL increased after SVR in both patients who used lipid-lowering drugs and patients without baseline dyslipidaemia. 22Interestingly, a direct association between sdLDL levels >35 mg/dL and baseline LDL levels was observed. 103On the other hand, during therapy, an increase in LDL particle size has been observed, 102 but they returned to baseline sizes after the end of treatment. 56anges in weight and/or BMI Thirty-one articles evaluated, as a primary or secondary outcome, the change in BMI and/or patient's weight after viral eradication by DAAs.The majority of studies (21 out of 30) did not show a significant change in mean BMI or weight after SVR.Conversely, 7 studies revealed an increase in BMI after SVR, 27,40,90,[114][115][116][117] while 3 studies showed a reduction in mean BMI. 53,81,118crease in weight/BMI.The baseline presence of IR, the worsening of steatosis after SVR, higher fibrosis stage/cirrhosis, younger age, and moderate alcohol consumption seem to be the factors related to the increase in BMI after SVR. 47,91,116Regarding BMI at baseline, an inverse correlation between BMI and weight gain after SVR was seen. 117The BMI started to increase from 12 to 24 weeks posttreatment 91,114 and persisted until 3 years of follow-up, 116 especially in male patients with obesity at baseline. 117anges in body weight and BMI did not seem to be related to modifications in physical activity or lifestyle, 61 and it was irrespective of previous antiviral treatment. 61,90,114crease or no change in weight/BMI.Interestingly, the reduction or lack of change in BMI seems not to be influenced by the presence of T2DM, the use of RBV, and the viral genotype. 53,80,81,97,118Moreover, the change in liver steatosis after SVR did not impact the BMI. 16,119

| DISCUSS ION
In this systematic review, we summarized the current research on Obesity and IR promote liver inflammation and boost the progression of fibrosis through the activation of fibrogenic phenotype in the hepatic stellate cells, 122 and existent steatosis after SVR interferes with the amelioration of liver fibrosis. 123C is associated with hypolipidaemia due to the binding of HCV particles to lipoprotein. 124For this reason, HCV eradication leads to TC and LDL rise.Nevertheless, there are other factors related to the increase in lipid metabolites, such as the presence of dyslipidaemia, higher waist circumference and BMI at baseline, and the presence of IR.The presence of advanced fibrosis is related to lower TC levels, probably because partial liver failure reduces the capacity to export cholesterol to the bloodstream. 111For this reason, the increase in TC and LDL after viral eradication is less marked in cirrhotic patients.
The presence of liver steatosis is a key factor associated with the increase in TGs and the reduction in HDL after SVR, fostering the HCV induces IR through the downregulation of insulin sensitivity and the promotion of liver steatosis, 126,127 and the viral eradication doubtless relates to the amelioration of IR.Contrary to the IR improvement in both diabetic and nondiabetic patients, the coexistence of metabolic risk factors, advanced fibrosis, and HCV genotype 3 infection seems to prevent the reduction of IR.As expected, the presence of liver steatosis negatively affects the reduction of glycaemia after SVR.RBV is associated with a haemolytic effect, probably because affects the integrity and function of the red blood cell membranes. 128Despite this, the use of RBV-drug regimen does not affect the changes in HbA1c levels.
Finally, patients' weight remains unaltered after SVR in the majority of studies, probably due to a short follow-up.Nevertheless, the presence at baseline of metabolic syndrome, liver steatosis, and higher fibrosis degree is associated with a significant increase in mean weight and BMI after SVR, whereas the impact of T2DM on weight gain appears to be less prominent.
Even after viral eradication, metabolic syndrome promotes the development and progression of preexisting liver fibrosis. 129gardless of the underlying causes, the presence of liver fibrosis is closely related to CVDs.This connection originates from the interplay between fibrosis and components of metabolic syndrome, especially IR, coupled with an inflammatory environment marked by increased oxidative stress that fosters cardiovascular damage. 130 contrast to metabolic dysfunction-associated steatotic liver disease, HCV-associated dysmetabolic syndrome is characterized by hypolipidaemia. 30Nevertheless, the risk of fibrosis progression is high in CHC, probably due to the strong association between CHC and T2DM. 131,132Since liver fibrosis after SVR is the main predictive factor for further liver decompensation and HCC development, 133 the evaluation of residual fibrosis risk after SVR is detrimental to defining the HCC-screening program.To date, several scores have been developed to better identify patients with a high risk of HCC development after viral eradication, but the personalized approach to HCC surveillance is still far away.As a result of our systematic review, the evaluation of metabolic comorbidities, especially weight and IR before and after SVR, and the presence of liver steatosis after SVR could be useful to better identify patients at risk for the progression of liver fibrosis after viral eradication, thus requiring a stricter follow-up.
This pioneer systematic review evaluated several metabolic parameters after SVR that could impact the progression of liver disease.Moreover, the assessment of steatosis and atherosclerosis in a noninvasive manner makes the results of this systematic review widely practical and useful.
Despite its strengths, this review has several limitations that should be considered.First, the heterogeneity of the studies prevented us from drawing firm conclusions.Since they enrolled patients with different liver disease severity, genotypes, and drug regimens, they only occasionally considered on analysis outcomes.
Also, the number of studies targeting some of the outcomes is very limited.Additionally, the follow-up periods are less than 1 year for the majority of studies.Significantly, changes in parameters such as BMI, liver steatosis, and carotid atherosclerosis probably required longer follow-ups.Considering sex-related specificities on chronic liver disease, additional data on sex comparisons about the diverse metabolic parameters are also necessary. 134This parallel is almost inexistent across the selected studies, since there is a particular and restricting lack of data on premenopausal women.Furthermore, the presence of chronic kidney disease contributes to a proinflammatory status, thereby fostering the progression of atherosclerotic damage and myocardial remodelling.This, in turn, promotes the development of CVDs, including heart failure and ischemic disease. 135CHC is linked to renal function impairment, and notably, DAAs such as sofosbuvir have been associated with nephrotoxicity. 136Despite these observations, many studies do not thoroughly investigate baseline renal function and its alterations following viral eradication. 137nally, almost half of the studies were rated as "not strong quality," calling for improvements in conducting experimental designs.
Noteworthy, these results do not consider lifestyle changes (i.e., alcohol drinking habits) that may follow DAA treatment/SVR achievement and could impact metabolic parameters.Scarce evidence associates DAA treatment with declined frequency of alcohol misuse and mean improvement in AUDIT-C scores. 138,139mistructured interviews elucidate that after SVR some patients felt released from earlier limitations, but the majority maintain high concern about liver status and attentive to their health. 140So, it would be important future research on lifestyle characterization and its impact on cardiovascular damage and reduce risk of disease progression.
These findings call for more studies on the impact of metabolic comorbidities on the progression of liver disease severity after SVR by DAAs.Longer follow-ups are needed to better identify how many patients will develop liver steatosis, carotid atherosclerosis, IR/T2DM, dyslipidaemia, and overweight/obesity; explore other parameters such as uric acid; and to identify baseline features that could predict the risk of developing a metabolic disease after viral

Figure 1
Figure 1 illustrates the flow diagram of the literature search and study selection process.The literature search provided a total of 6724 articles.After the removal of duplicates, 3951 articles were assessed for eligibility.Of these, 3811 articles met the exclusion criteria based on title and abstract screening, leaving 140 articles for full-text screening.Ninetyseven articles met the inclusion criteria and were included in this systematic review.

F I G U R E 1
Flow diagram of studies, according to PRISMA 2020 statement.TA B L E 2Characteristics of studies evaluating changes in liver steatosis after SVR by DAAs without differences across the patients enrolled.
metabolic changes, expressed as liver steatosis, carotid atherosclerosis, glucose and lipid parameters, and weight/BMI, after a successful HCV eradication by DAAs.Our results indicate that TC and LDL increase after viral eradication by DAAs, whereas the levels of HDL and TGs seldom but may worsen in the presence of metabolic comorbidities at baseline.Despite the worsening in lipid metabolism, scarce evidence suggests that eradication results in a reduction in cIMT and carotid plaques.Evidence on the effect of viral eradication by DAAs on liver steatosis, glucidic homeostasis, and weight is less consistent.A disparity of results for each parameter is found in literature, 120 although across studies metabolic comorbidities at baseline negatively impact outcomes.Despite HCV, especially genotype 3, is a well-known risk factor for the development of liver steatosis, 121 the effect of viral eradication is still debated.The presence of metabolic risk factors promotes the development of de novo steatosis in patients without steatosis at baseline and prevents steatosis resolution if previously diagnosed.
development of dyslipidaemia.The inconsistent results concerning HDL and TGs could be explained by the shorter follow-up.In fact, TC and LDL increased significantly sooner compared to HDL and TGs and HDL showed the latest increase.On the other hand, viral eradication improves the antioxidant capacity of HDL with consequent reduction of systemic inflammation and promotes the carriage of cholesterol from peripheral tissue, such as the arterial wall, to the liver.102Also, sdLDL is increased after viral eradication, promoting atherogenic damage due to lower affinity to LDL receptors and penetration capacity on vascular wall.125 sdLDL levels seem to be responsible for the increase in cIMT.However, only four interventions exploring these changes after viral eradication by DAAs exist to date, demanding further exploration.The reduction in cIMT and carotid plaques concurs for a lower cardiovascular damage after viral eradication across studies, even with maximum cIMT increased.This discrepancy could be explained by the change in both quantitative and qualitative lipid profiles, as the increased antioxidant capacity of HDL could explain the improvement in cIMT and carotid plaques.

Table 4
summarizes the characteristics of studies evaluating changes in carotid atherosclerosis after SVR by DAAs.Only four articles evaluated changes in carotid atherosclerosis (plaques and/or cIMT) before and after viral eradication by DAAs, through the use of carotid Doppler US.Two studies observed a significant reduction in cIMT after SVR by DAAs in patients with advanced fibrosis/compensated cirrhosis at baseline.
Characteristics of studies evaluating changes in atherosclerosis after SVR by DAAs.