Therapeutic regimens containing direct-acting antivirals (DAAs) have been available for more than a decade and have revolutionized the treatment of patients with chronic hepatitis C virus (HCV) infection [1]. Globally, an estimated 50 million people are chronically infected with HCV, with approximately 1 million new infections occurring annually, highlighting the ongoing public health burden of this disease [2]. The introduction of DAAs has shifted HCV from a progressive, often debilitating chronic disease to a condition that can be cured in the vast majority of patients. The oral administration, short duration of therapy, and favorable safety profile of DAAs have markedly improved treatment convenience compared to interferon (IFN)-based regimens, allowing therapy to be extended to virtually all HCV-infected patients, irrespective of liver disease stage or the presence of comorbidities [3, 4].

However, the appropriateness of antiviral therapy should be considered in patients with a very poor prognosis due to a concomitant incurable condition, such as advanced metastatic malignancy [5]. DAA therapy is also not recommended during pregnancy due to insufficient safety data for the fetus, although this limitation is expected to be temporary. Children older than three years, patients with compensated or decompensated liver cirrhosis, and those with renal insufficiency, multiple comorbidities, human immunodeficiency virus (HIV) coinfection, or active malignancy are considered eligible for therapy [6-9]. The efficacy of DAAs is exceptional, with overall cure rates exceeding 95%, although certain factors, including advanced liver disease and infection with HCV genotype 3, may reduce the probability of achieving sustained virological response (SVR) [10].

Despite viral eradication, patients may remain at risk for complications such as hepatocellular carcinoma (HCC), fibrosis progression, or other liver-related conditions, particularly those with pre-existing advanced liver disease or ongoing risk factors [11, 12]. With the growing population of patients achieving SVR, there is an urgent need to define optimal post-treatment management strategies, including the frequency and type of follow-up, risk stratification, and preventive measures. In response to this need, the European Association for the Study of the Liver (EASL) published updated recommendations in August 2024 based on available evidence and expert opinion. According to these guidelines, the primary determinants of post-SVR care are baseline liver disease severity, comorbidities affecting liver function and overall health, and ongoing behavioral or environmental risks for HCV reinfection. Assessment of liver disease during pretreatment evaluation is primarily performed using non-invasive methods, with vibration-controlled transient elastography (VCTE) recommended as the preferred modality. In settings where elastography is unavailable, serum biomarkers such as fibrosis-4 index (FIB-4) and aspartate transaminase (AST) to platelet ratio index (APRI) may be used, and the combined use of multiple non-invasive tests can improve the accuracy of detecting advanced fibrosis and cirrhosis [13]. In cases of discordant results, additional diagnostic methods are recommended to ensure precise staging of liver disease [14, 15].

The aim of this review is to provide a comprehensive overview of current evidence and guideline recommendations for the post-SVR management of patients treated with DAAs, emphasizing individualized follow-up strategies, long-term risk mitigation, and optimization of liver health outcomes.

A patient whose liver stiffness measured by elastography prior to DAA therapy corresponds to fibrosis stages F0-F2 is defined as having non-advanced liver disease. Patients in this category who achieve SVR can generally be considered fully cured, as available data indicate that the risk of liver decompensation in this population is negligible, and the risk of HCC is very low [16, 17]. Therefore, in the absence of comorbidities affecting liver function, these patients typically do not require ongoing specialist follow-up and may be safely referred to primary care physicians for routine management. Before referring patients with non-advanced fibrosis to primary care, it is essential to assess risk factors for steatotic liver disease (SLD), which currently ranks among the leading causes of chronic liver disease and is more prevalent in patients with HCV than in the general population [18].

These risk factors include excessive alcohol consumption, diabetes mellitus, arterial hypertension, dyslipidemia, and obesity. Patients with such risk factors should receive targeted education emphasizing the need for continued specialist monitoring of comorbid conditions, adherence to regular physical activity, maintenance of a healthy diet, avoidance of alcohol abuse, and achievement of a healthy body weight. Even patients without evident risk factors at the time of referral should be counseled on lifestyle modifications, as these measures serve as primary prevention against SLD. This is particularly important considering that weight gain is commonly observed following successful DAA therapy [19, 20].

Patients with non-advanced fibrosis who also have SLD due to metabolic disorders or alcohol consumption may remain under specialist care after achieving SVR but can eventually be considered for transition to primary care follow-up. This decision should be based on the patient’s adherence to lifestyle and dietary recommendations, successful weight management, and effective control of comorbidities, with objective confirmation through repeated elastography measurements or serum fibrosis indices.

Figure 1 illustrates a simplified chronic hepatitis C care pathway from diagnosis to treatment and post-cure follow-up, while Figure 2 presents an algorithm for the management and monitoring of patients after eradication of HCV infection.

Patients with advanced liver disease, as defined by pre-treatment non-invasive assessments (elastography or serum fibrosis markers), should remain under specialist hepatology care following successful DAA therapy, regardless of the presence of other comorbid liver conditions, due to the ongoing risk of liver-related events and HCC [21, 22]. According to the European Association for the Study of the Liver (EASL), advanced liver disease associated with HCV corresponds to a liver stiffness ≥ 10 kPa on VCTE, fibrosis stages F3-F4 on the METAVIR or Batts-Ludwig scales from liver biopsy, the presence of esophageal or gastric varices in the absence of prehepatic causes of portal hypertension, or a hepatic venous pressure gradient (HVPG) ≥ 6 mmHg.

For patients diagnosed with advanced liver disease, baseline non-invasive assessments should be complemented by clinical evaluation, endoscopy to assess for esophageal varices, and laboratory tests of liver function, including serum bilirubin, albumin, prothrombin time, and platelet count (PLT) as a surrogate marker for portal hypertension. These parameters are used to calculate the Child-Pugh (CP) score, which provides an estimation of hepatic functional reserve and helps stratify patient risk.

Clinical and laboratory assessment of liver function should be conducted immediately after completion of therapy and then at intervals of 6-12 months during long-term follow-up. Elastography should be repeated immediately after DAA therapy and then annually. Available data indicate that liver stiffness typically decreases shortly after successful antiviral therapy, reflecting the reduction of inflammatory activity, while regression of fibrosis contributes to stiffness reduction predominantly in the long term [23, 24]. A similar pattern has been observed for serum fibrosis markers. Therefore, monitoring strategies for post-SVR patients should reference pre-treatment values. It has even been suggested that post-DAA threshold values for liver stiffness and serum markers defining advanced fibrosis or cirrhosis may need to be adjusted, though prospective studies integrating multiple assessment methods are required to validate this approach.

Effective antiviral therapy frequently leads to a significant reduction in the hepatic venous pressure gradient and regression of esophageal varices [25]. Long-term studies have shown that esophageal varices can partially or completely regress after HCV eradication, with one cohort reporting that 21.9% of patients experienced variceal regression over a median follow-up period of 5.2 years [26]. Nevertheless, the risk of liver-related events, such as variceal bleeding, ascites, and hepatic encephalopathy, is primarily associated with clinically significant portal hypertension (CSPH), rather than the mere presence or size of varices. The combination of liver stiffness and platelet count allows non-invasive CSPH assessment, often eliminating the need for routine endoscopy in many patients with compensated advanced liver disease following successful DAA therapy [14, 27, 28]. In patients with varices detected prior to DAA treatment, follow-up endoscopy and intervention should be guided by baseline variceal grade. In patients without varices at baseline, management depends on post-SVR liver stiffness. According to EASL and Baveno VII criteria, endoscopy may be safely omitted in patients with liver stiffness < 20 kPa and PLT ≥ 150 G/l, effectively ruling out clinically significant portal hypertension [29]. Patients with post-SVR liver stiffness ≥ 20 kPa and/or PLT < 150 G/l should undergo endoscopic assessment for varices, while those with liver stiffness > 25 kPa are additionally recommended to initiate non-selective β-blocker (NSBB) therapy, such as carvedilol, if not previously administered. It is worth mentioning that, according to the American Association for the Study of Liver Diseases, carvedilol is usually preferred due to its additional anti-alpha-adrenergic effect. The PREDESCI study demonstrated that NSBBs not only prevent primary variceal bleeding but also reduce the incidence of any decompensation events unrelated to bleeding, supporting their use independently of variceal grade. In this study, 201 patients without high-risk varices were randomized to receive either β-blockers (67 propranolol, 33 carvedilol) or placebo. Over a median follow-up of several years, the incidence of liver decompensation or death was 16% in the β-blocker group compared to 27% in the placebo group, corresponding to a hazard ratio of 0.51 (95% CI: 0.26-0.97, p = 0.041) [30]. Consequently, the main criterion for NSBB therapy is CSPH, and withdrawal may be considered if CSPH resolves after HCV eradication.

If monitoring of patients with compensated advanced liver disease indicates disease progression, appropriate interventions should be implemented based on the observed clinical manifestations, including diuretics, rifaximin, lactulose, NSBB therapy, endoscopic treatment of varices, paracentesis for ascites, or referral to a liver transplant center. It is also important to consider patient education, adherence to lifestyle modifications, and management of comorbidities, as these factors can influence the long-term course of compensated advanced liver disease after SVR.

Emerging evidence suggests that additional non-invasive tests, including blood-based fibrosis scores and spleen stiffness measurement, may further refine CSPH risk assessment in post-SVR patients. The value of non-VCTE elastography modalities for non-invasive CSPH evaluation should also be investigated, as these may offer alternative or complementary options in clinical practice. Moreover, current non-invasive recommendations for the post-SVR setting should be validated by prospective studies evaluating liver-related event rates across different risk strata, ensuring that monitoring strategies accurately predict long-term outcomes.

In patients with decompensated cirrhosis, initially classified as CP class B or C at the start of DAA therapy, improvement in liver function after achieving SVR is defined by the persistent resolution of hepatic insufficiency symptoms and complications. These include ascites, hepatic encephalopathy, and variceal bleeding, accompanied by a sustained improvement in CP score to class A or a reduction of at least 3 points in the Model for End-Stage Liver Disease (MELD) score [14]. This definition provides a clinically meaningful threshold to identify patients who have achieved significant functional recovery.

In some patients who were listed for liver transplantation prior to DAA therapy, such functional improvement can lead to delisting, especially in those without baseline ascites and with MELD scores below 15.
Observational data suggest that up to 30% of such patients may no longer require transplantation following viral eradication [31]. Nevertheless, these patients remain at residual risk of re-decompensation, estimated at less than 10%, and therefore require ongoing monitoring for signs of hepatic deterioration [32].

Long-term studies on the incidence and predictors of liver function improvement after successful DAA therapy in decompensated cirrhosis demonstrate considerable variability, depending on baseline CP class, type and severity of decompensation events, liver function parameters, body mass index (BMI), and duration of follow-up after SVR [33-35]. Despite some patients experiencing marked recovery, the majority do not achieve a clinically significant reversal of decompensation [34]. The most important factor limiting recovery is the persistence of CSPH, which continues to drive complications despite viral clearance.

A narrower concept than decompensation reversal is recompensation, which is defined as the sustained absence of hepatic decompensation symptoms and complications for at least one year without the need for ongoing pharmacologic therapy. This includes resolution of ascites without diuretics, absence of hepatic encephalopathy without lactulose or rifaximin, and no variceal bleeding even without transjugular intrahepatic portosystemic shunt (TIPS) placement. Recompensation represents an important clinical goal because it reflects true stabilization of hepatic function and long-term improvement in prognosis. Rates of recompensation remain limited even after etiologic treatment. In a large cohort of patients with hepatitis C-related decompensated cirrhosis treated with direct-acting antivirals, recompensation according to Baveno VII criteria was achieved in approximately 25% of patients over a median follow-up of 16.5 months. Factors associated with a higher likelihood of recompensation included lower baseline bilirubin and international normalized ratio, as well as the absence of large esophageal or gastric varices, highlighting the importance of preserved liver function and less advanced portal hypertension [36].

Improvement in liver function and reduction of the risk of further decompensation after DAA therapy is typically a slow process. It is generally recommended to observe patients for at least two years after SVR to fully evaluate functional recovery, as changes in laboratory parameters, imaging findings, and clinical status may occur gradually over this period. During follow-up visits, which should be conducted at least every six months, clinicians should assess the presence and severity of ascites, monitor for signs of hepatic encephalopathy, and evaluate the need for ongoing therapy with diuretics, lactulose, or rifaximin [37]. Adjustments in medication doses or discontinuation may be appropriate in response to clinical and biochemical improvement. Imaging studies and laboratory tests should be used to objectively track changes in liver morphology and function over time.

For patients with decompensated cirrhosis who fail to demonstrate meaningful improvement in liver function within two years after SVR, referral for liver transplantation should be reconsidered. Even in patients showing partial improvement, continued surveillance is critical, as late re-decompensation remains a possibility, particularly in the presence of residual portal hypertension, metabolic comorbidities, or ongoing risk factors such as alcohol use or obesity.

Additional considerations may include nutritional support, optimization of comorbid conditions, and patient education regarding lifestyle modification to support liver health. These interventions, alongside antiviral therapy, may contribute to more durable recompensation and a lower risk of complications over time.

Despite successful DAA therapy, patients with pre-existing liver cirrhosis remain at significant risk for the development of HCC [21]. Although long-term observational studies have documented a gradual decline in the annual risk of HCC following viral eradication, even studies with the longest post-treatment follow-up exceeding 8 years report incidence rates that surpass the cost-effectiveness threshold of 1.5% per year [38]. Interestingly, global annual HCC incidence in patients with advanced chronic liver disease (ACLD) achieving SVR ranges from 0.2% to 2.5%, which is comparable to HCC rates observed in patients with cirrhosis due to well-controlled HBV infection or non-viral causes such as alcohol- or MASLD-related cirrhosis [39, 40]. Consequently, lifelong oncological surveillance is recommended in this population, and there is an increasing need for more effective and risk-adapted HCC surveillance strategies [3, 41-43]. The primary goal of surveillance is the early detection of HCC, allowing for timely implementation of potentially curative therapies, which can substantially improve overall survival.
Given the current state of knowledge, surveillance should continue for life, although it cannot be ruled out that this recommendation will change as new evidence emerges from longer follow-up after SVR. Monitoring for this purpose includes performing liver ultrasound (USG) every 6 months, including measurement of α-fetoprotein (AFP) levels [3, 43-45]. In situations where US imaging is technically challenging or difficult to interpret – such as in patients with obesity, hepatic steatosis, or a nodular cirrhotic liver – or when AFP levels are elevated, additional imaging modalities should be used more liberally as a replacement or adjunct to US. These include contrast-enhanced four-phase computed tomography (CT) or magnetic resonance imaging (MRI) with liver-specific contrast agents [41]. Combining imaging with serum markers enhances sensitivity and allows earlier detection of small or atypically located lesions.

In addition to AFP, several novel biomarkers have been proposed to improve early HCC detection and risk stratification. AFP-L3, a fucosylated isoform of AFP, has been shown to be more specific for HCC, particularly in early-stage disease. Another promising marker is des-gamma-carboxy prothrombin (DCP/PIVKA-II), which reflects impaired vitamin K-dependent carboxylation in malignant hepatocytes. Furthermore, composite models such as GALAD (incorporating gender, age, AFP, AFP-L3, and DCP) and GAAD have demonstrated improved diagnostic performance compared to single biomarkers, although their routine use in post-SVR surveillance requires further validation [46].

For patients with advanced fibrosis (F3) prior to DAA therapy, post-SVR HCC risk is lower than in those with established cirrhosis (F4). Evidence supporting routine HCC surveillance in this subgroup is limited, and recommendations from professional scientific societies are inconsistent, reflecting concerns about cost-effectiveness vs. clinical benefit [47, 48]. According to EASL, patients with F3 fibrosis should not be categorically excluded from HCC monitoring after SVR, whereas AASLD and the Polish HCV Expert Group do not recommend routine surveillance in this population [3, 42, 43]. In individuals with F3 fibrosis and additional risk factors for HCC, such as non-alcoholic fatty liver disease, metabolic syndrome, or excessive alcohol intake, surveillance should be individualized, taking into account the cumulative risk of tumor development [47].

The aim of oncological surveillance is to detect hepatocellular carcinoma (HCC) at an early stage, enabling curative treatment and improving survival. Therefore, individualized surveillance strategies are recommended for patients in whom curative treatment would not be feasible even if the cancer were detected at an early stage. The intensity and modality of surveillance should also be tailored to the patient’s overall health status and eligibility for curative therapy. Patients in whom early-stage HCC would not alter management – such as elderly individuals, those with severe comorbidities, or patients with decompensated cirrhosis not eligible for liver transplantation – may benefit from a modified or less intensive surveillance strategy [41]. However, the optimal age at which surveillance could be safely discontinued has not been established. Decisions should consider comorbidities, functional status, and overall life expectancy.

Moreover, integrating lifestyle interventions, optimization of metabolic risk factors, and management of comorbid liver disease may contribute to reducing residual HCC risk, highlighting the importance of a comprehensive post-SVR care plan beyond antiviral therapy.

In addition to advanced fibrosis or cirrhosis, several other clinical and biochemical factors have been associated with an increased risk of HCC after SVR, although the strength and consistency of these associations remain variable across studies. Observational data suggest that markers of impaired liver function, such as lower albumin levels and higher ALBI scores, may identify patients at increased risk. Similarly, thrombocytopenia has been associated with higher HCC incidence. Non-invasive fibrosis markers, including elevated liver stiffness measurements assessed by transient elastography or magnetic resonance elastography, as well as composite indices such as FIB-4, have also been associated with increased risk. Metabolic and demographic factors, including male sex, older age, and the presence of diabetes mellitus, further contribute to higher risk.

Additionally, elevated or persistently abnormal AFP levels, even within moderately increased ranges, may indicate a higher likelihood of HCC development. Emerging data also suggest a potential role for genetic risk scores and composite models integrating multiple variables, although their clinical utility is not yet fully established.

Importantly, most of these associations are derived from retrospective cohort studies with heterogeneous populations and varying cut-off values, and quantitative risk estimates are not consistently reported. Therefore, while these factors may help identify higher-risk individuals, they require further prospective validation before being incorporated into standardized surveillance algorithms.

Finally, patient education plays a critical role in surveillance adherence. Educating patients about the ongoing risk of HCC despite viral clearance, the rationale for regular imaging, and the importance of attending follow-up visits can improve long-term outcomes and facilitate early intervention when HCC is detected. Coordinated care involving hepatologists, radiologists, and primary care providers ensures that surveillance is systematic, timely, and responsive to changes in patient condition or risk profile.

The annual incidence of HCV reinfection among individuals who continue high-risk behaviors is estimated to range from 1% to 10.5% [49-51]. Populations at particular risk include people who inject drugs (PWID), men who have sex with men (MSM), and incarcerated individuals. These groups are not only more exposed to potential reinfection, but often face challenges in accessing regular healthcare, adherence to follow-up, and harm-reduction interventions. Following the achievement of SVR, it is recommended that individuals in these high-risk populations undergo routine monitoring for HCV reinfection through quantitative HCV RNA testing every six months [14]. This interval is considered optimal for early detection of reinfection, allowing timely re-initiation of antiviral therapy before significant liver damage occurs. In cases where HCV RNA is detected, prompt retreatment with DAAs should be initiated in accordance with current guidelines. Close follow-up should continue after retreatment to ensure viral eradication and to monitor for subsequent reinfection, particularly in settings where risk behaviors persist. Additionally, integrating HCV monitoring with broader preventive services, such as screening for HIV and other blood-borne infections, may improve overall health outcomes in these vulnerable populations.

Hepatitis C virus infection is associated with a range of extrahepatic manifestations, particularly immune-mediated conditions such as mixed cryoglobulinemia, cryoglobulinemic vasculitis, and HCV-related glomerulonephritis, which may persist despite viral eradication [11, 12]. Although treatment with DAAs and achievement of SVR leads to clinical and immunological improvement in most patients, complete resolution is not always observed, and a subset of patients remains at risk of relapse or ongoing disease activity [14].

In patients with cryoglobulinemic vasculitis, SVR is typically followed by regression of clinical symptoms such as purpura, arthralgia, and weakness, accompanied by improvement in laboratory parameters including cryoglobulins, rheumatoid factor, and complement levels [3, 42, 43]. However, persistence of laboratory abnormalities or recurrence of symptoms may occur, particularly in individuals with cirrhosis or elevated rheumatoid factor after SVR, as well as in the context of triggering events such as infections or malignancies. Therefore, assessment of both clinical and immunological response approximately 12 months after SVR is essential. Patients who achieve complete remission, defined as resolution of symptoms and normalization of laboratory markers, may no longer require dedicated follow-up for vasculitis, although clinical vigilance should be maintained. In contrast, individuals with persistent laboratory abnormalities despite clinical improvement should undergo regular monitoring, including annual evaluation of cryoglobulins, rheumatoid factor, and complement levels, given the ongoing risk of relapse and potential B-cell clonal expansion. Patients with incomplete response or persistent symptoms require long-term multidisciplinary care [14].

Renal involvement, most commonly in the form of cryoglobulinemic glomerulonephritis, represents a clinically important manifestation associated with worse prognosis [3, 42, 43]. While SVR may result in improvement or even resolution of renal abnormalities, this effect is largely dependent on the stage of kidney disease, with early changes being more likely reversible than advanced chronic kidney disease. In patients with a reduced glomerular filtration rate after SVR, further evaluation should include urinalysis, albumin-to-creatinine ratio, and assessment of cryoglobulins, alongside evaluation of additional risk factors for chronic kidney disease such as hypertension or diabetes. In cases of persistent abnormalities, collaboration with a nephrologist is recommended. Overall, despite viral clearance, patients with prior immune-mediated extrahepatic manifestations require individualized and, in many cases, prolonged follow-up due to the risk of persistent disease activity or relapse [14].

While successful DAA therapy achieves viral eradication in the vast majority of patients with chronic HCV infection, it does not represent the endpoint of care for all individuals. Patients with pre-existing liver comorbidities or advanced liver disease, including those with compensated and decompensated cirrhosis, remain at risk of ongoing hepatic complications, including hepatocellular carcinoma, portal hypertension-related events, and decompensation episodes. Such patients should continue to receive specialist hepatology follow-up, with individualized monitoring plans based on liver fibrosis stage, clinical history, and residual risk factors. Additionally, high-risk populations, such as people who inject drugs, men who have sex with men, and incarcerated individuals, should undergo regular post-SVR HCV RNA testing to detect reinfection early, allowing timely retreatment and minimizing further liver injury.

This research received no external funding.

Institutional review board statement: Not applicable.

The authors declare no conflict of interest.