EARLY NONINVASIVE EVALUATION OF LIVER FIBROSIS AFTER HEPATITIS C TREATMENT: THE IMPACT OF INFLAMMATION

Avaliação precoce não invasiva da fibrose hepática após tratamento da hepatite c: o impacto da inflamação

ABSTRACT

Background:  Liver biopsy (LB) is still the gold standard method for assessing hepatic fibrosis (HF), associated diseases, and liver inflammation. Nowadays, noninvasive techniques such as Acoustic radiation force impulse (ARFI) elastography have been introduced instead of liver biopsy. However, there are controversies about the time it should be performed after treatment for hepatitis C virus (HCV).

Objective:  To evaluate hepatic fibrosis using ARFI technology before and after successive treatments for chronic HCV.

Methods:  We prospectively included 50 adult patients with chronic HCV (genotype 1). Patients were first submitted to triple therapy with first-generation protease inhibitors (boceprevir and telaprevir) at the hepatitis division of the Gastroenterology Department of the Federal University of São Paulo. The non-responders underwent re-treatment with interferon-free direct-acting antiviral agents (DDAs - sofosbuvir associated with daclatasvir or simeprevir). Assessment of hepatic stiffness by ARFI was performed before and after the first treatment and before and after the re-treatment with DDAs.

Results:  ARFI values decreased significantly after treatments. In patients on first-generation protease inhibitor therapy and achieving sustained virological response (SVR), ARFI decreased from 2.41±0.58 pre-treatment to 2.02+/-0.58 (P<0.042) post-treatment. In patients who did not reach SVR, that is, non-responders, a significant reduction was similarly observed (2.39±0.63 to 2.03±0.54; P<0.001 before and after treatment, respectively). Before starting the re-treatment, non-responders had elevated ARFI values again, dropping after SVR following re-treatment (from 2.46±0.57 to 1.45±0.68, P<0.004). Laboratory parameters such as AST and ALT were directly correlated to ARFI elastography.

Conclusion:  The evaluation of hepatic elastography by the ARFI method before and after (6 - 9 months) successive treatment of hepatitis C in responders and non-responders led to the conclusion that the reduction of elastography parameters seems to be related to a decrease in hepatic inflammation rather than a reduction in fibrosis per se.

Keywords:
Hepatitis C; HCV; liver fibrosis; treatment

HIGHLIGHTS

•The study evaluated hepatic fibrosis using acoustic radiation force impulse (ARFI) before and after successive treatments for chronic HCV.

•Adult patients with chronic HCV were submitted to triple therapy with first-generation protease inhibitors.

•The non-responders underwent re-treatment with interferon-free direct-acting antiviral agents (DDAs). ARFI was used to assess hepatic stiffness before and after the first treatment and for re-treatment with DDAs.

•ARFI values decreased significantly after treatments and for patients who did not reach sustained virological response (SVR). Before re-treatment, non-responders again had elevated ARFI values, dropping after SVR was achieved in 100% of patients. Laboratory parameters such as AST and ALT were directly correlated to ARFI.

•The reduction of elastography parameters seems to be related to a decrease in hepatic inflammation rather than a reduction in fibrosis per se.

RESUMO

Contexto:  A biópsia hepática (BH) é o padrão-ouro para avaliar a fibrose hepática (FH), investigar doenças associadas e a inflamação hepática. Métodos não invasivos, como a radiação acústica por impulso de força (RAIF), foram introduzidos, embora haja controvérsias sobre o momento em que deve ser realizada após o tratamento do vírus da hepatite C (HCV).

Objetivo:  Avaliar a fibrose hepática utilizando a tecnologia RAIF antes e após tratamentos sucessivos para HCV.

Métodos:  Incluímos prospectivamente 50 pacientes adultos com hepatite C crônica (genótipo 1). Os pacientes foram submetidos inicialmente à terapia tripla com inibidores de protease de primeira geração (boceprevir e telaprevir) no setor de Hepatite do Departamento de Gastroenterologia da Universidade Federal de São Paulo. Os pacientes que não responderam foram submetidos a retratamento com agentes antivirais de ação direta livres de interferon (DDAs - sofosbuvir associado a daclatasvir ou simeprevir). A avaliação da rigidez hepática pela RAIF foi realizada antes e depois do primeiro tratamento e antes e após o retratamento com DDAs.

Resultados:  Os valores de RAIF diminuíram significativamente após os tratamentos. Para pacientes em terapia tripla com inibidores de protease de primeira geração e que atingiram RVS, a RAIF diminuiu de 2,41±0,58 pré-tratamento para 2,39±0,63 (P<0,042) pós-tratamento. Nos pacientes que não atingiram RVS, ou seja, não respondedores, foi observada redução significativa de forma semelhante (2,39±0,63 para 2,03±0,54; P<0,001 antes e após o tratamento, respectivamente). Antes de iniciar o retratamento, os não respondedores apresentaram novamente valores elevados de RAIF, caindo após RVS ao retratamento (de 2,46±0,57 para 1,45±0,68, P<0,004). Parâmetros laboratoriais como AST e ALT estavam diretamente correlacionados com a elastografia RAIF.

Conclusão:  A avaliação da fibrose hepática pelo método RAIF antes e depois (6 e 9 meses) do tratamento sucessivo da hepatite C em respondedores e não respondedores sugere que a redução dos parâmetros elastográficos parecem estar relacionados com uma diminuição da inflamação hepática e não a uma redução na fibrose.

Palavras-chave:
Hepatite C; HCV; fibrose hepática; tratamento

INTRODUCTION

It is estimated that approximately 54-57 million people worldwide are infected with the hepatitis C virus (HCV), and around 400 thousand deaths occur every year due to complications related to the disease, mainly cirrhosis and hepatocellular carcinoma^1-4. Liver biopsy still represents the “gold standard” in diagnosing and staging chronic HCV^1,4,5. However, with such an invasive method, lethality rates of 0.03% and morbidities of 1% to 2% of cases are reported, particularly bleeding^6,7.

Liver biopsy is no longer the first option for evaluating liver fibrosis in hepatitis C patients. It has been replaced by noninvasive methods, especially for patients with limitations to the biopsy procedure⁸. Acoustic radiation force impulse (ARFI), also known as point-shear wave elastography, is a noninvasive ultrasonographic method assessing the degree of liver fibrosis through parenchyma elasticity^7,9,10. The technique has a high positive predictive value (93.2%) for significant fibrosis and an excellent negative predictive value (97.8%) for excluding cirrhosis¹⁰.

Related to treatment, studies have demonstrated the regression of liver fibrosis and even cirrhosis after the eradication of HCV^11-14. Patients with sustained virological response (SVR) after therapy with direct-acting antivirals (DAAs) demonstrate significant regression of elastography parameters, associated with reduction of fibrosis-4 (FIB-4) scores and aspartate aminotransferase/platelet ratio index (APRI)¹⁵. However, conflicting evidence exists as to whether the improvement in liver stiffness is due to a reduced necroinflammation and not necessarily to fibrosis regression per se¹⁶. Moreover, it is still questioned whether fibrosis can be reversible in patients cured after the treatment of hepatitis C^16,17.

Therefore, this study aims to evaluate the early modification of liver stiffness before and after HCV treatment using triple therapy (pegylated interferon, ribavirin, and protease inhibitor) and re-treatment with interferon-free direct-acting antivirals (DAAs) for non-responders using ARFI elastography along with biochemical parameters.

METHODS

Study design

This is a descriptive, prospective, and longitudinal study conducted at the Hepatitis Clinic of the Gastroenterology Department of the Federal University of Sao Paulo. Adult patients with hepatitis C were prospectively included and followed from 2015 to 2018.

Patients who met the treatment criteria, according to the current Clinical Protocol and Therapeutic Guidelines², during the study period were followed. The patients were consecutively submitted to triple therapy: pegylated interferon (PEG-IFN), associated with ribavirin (RBV), and a protease inhibitor (telaprevir or boceprevir). Non-responder patients to triple treatment were submitted to re-treatment with interferon-free direct-acting antivirals (DAAs), according to the PCDT in force at that time².

All patients approved and signed the informed consent form. The study was approved by the Research Ethics Committee of the Federal University of São Paulo (Number 1116/2015).

Inclusion criteria included patients with hepatitis C virus genotypes 1 and 4, both genders, aged 18 to 70, who agreed to participate in the study. Exclusion criteria included patients with a history of excessive alcohol intake, other liver diseases (hemochromatosis, Wilson’s disease, autoimmune hepatitis, primary biliary cirrhosis, among others), active opportunistic diseases, current or planned pregnancy, psychiatric disorders, and patients who did not sign the Informed Consent Form.

Clinical and laboratory evaluation

All patients underwent clinical evaluation and biochemical tests, including serum aminotransferases (AST and ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (AP), and bilirubin. HCV infection was diagnosed by detecting anti-HCV antibodies using the third-generation enzyme immunoassay (EIA-3) (Ortho Clinical Diagnostics, Raritan, NJ, USA). Patients with reactive anti-HCV were submitted to HCV-RNA quantification by real-time polymerase chain reaction (RT-PCR) using a commercial kit (Abbott, USA) with a 12 IU/mL detection limit. HCV genotyping was performed by real-time PCR using the commercial Abbott Real Time HCV Genotype II (Abbott, USA)⁵.

Evaluation of liver fibrosis

Acoustic ARFI elastography was performed between 9 and 12 months after the end of treatment (6 and 9 months after the evaluation of SVR), using the Siemens Acuson S2000 device (Siemens Medical Systems, Mountain View, CA, USA) with a 4C1 convex transducer. The patient remained in dorsal decubitus with the right arm in maximal abduction to expose the intercostal spaces. The region of interest (ROI) was placed approximately 3 cm below the liver capsule through an intercostal space free of large vascular structures and without visible focal liver lesions. The procedure was performed by a trained examiner with at least 2 years of experience in liver elastography using a particular software package (virtual touch quantification). Ten valid liver stiffness measurements were obtained in each patient, expressed in m/s. The median values were obtained.

Liver Fibrosis Staging (The METAVIR score) was used as follows: F0 - no fibrosis; F1 - portal fibrosis without septa; F2 - portal fibrosis with few septa; F3 - numerous septa without cirrhosis; and F4 - cirrhosis. The cutoff points adopted for the degree of fibrosis by ARFI elastography were F0-F1 <1.5 m/s; F2 1.5-1.59 m/s; F3 1.59-1.72; F4 >1.72 m/s.

Statistical analysis

Quantitative variables are presented as mean, standard deviation, median, and interquartile range. Qualitative variables are described as absolute and relative frequencies. The paired Student’s t-test or the Wilcoxon test was used to compare the results before and after treatment, according to the normality of the data distribution assessed by the Shapiro-Wilk test. The significance level adopted was 5%.

RESULTS

Among the 131 patients referred for triple therapy (Peg-IFN+RBV+IP) between August 2013 and July 2014, 50 met the inclusion criteria.

The general characteristics of the patients can be observed in Table 1. Most patients were female (58%), white ethnicity (74%), with a median age of 57 years (minimum 31 years and maximum 69 years). Regarding comorbidities, systemic arterial hypertension and diabetes were present in 58% and 34% of patients, respectively. All patients had fibrosis grades 3 or 4 and HCV genotype 1. Laboratory data from patients is shown in Table 2.

TABLE 1
General characteristics of 50 hepatitis C virus (HCV) patients included in the study.

Characteristics	N=50
Age, years (minimum - maximum)	57 (31-69)
Gender, n (%)
Males	21 (42)
Females	29 (58)
Ethnicity, n (%)
White	37 (74)
Brown	8 (16)
Black	3 (6)
Oriental	2 (4)
Diabetes, n (%)	17 (34)
Hypertension, n (%)	29 (58)
Genotype do HCV, n (%)
1 undetermined	15 (30)
1a	15 (30)
1b	20 (40)
Fibrosis METAVIR, n (%)
1	1/48 (2.1)
2	4/48 (8.3)
3	22/48 (45.8)
4	21/48 (43.8)

TABLE 2
Laboratory data of 50 HCV-patients included in the study.

Laboratorial parameter	N=50
AST baseline, x ULN	2.56 (1-8)
ALT baseline, x ULN	2.81 (0.8-7.1)
Albumina baseline, g/dL	3.9±0.54
Hemoglobina baseline, g/dL	14.6±1.5
Neutrófilos baseline, cels/mm3	2,646.5 (1,204-5,910)
Plaquetas baseline, cels/mm3	133,258.0±58,181.8
Creatinina baseline, mg/dL	0.76 (0.55-1.61)

• AST: aspartato aminotrasnferase; ALT: alanina aminotrasnferase; ULN: upper limit of normality.

Comparing the ALT, AST, and ARFI values, we found that these parameters were significantly reduced in both responder (SVR) and non-responder (NR) groups (Table 3). The ARFI values decreased from 2.41 to 2.02 (pre x post-treatment for the SVR group; P=0.042) and 2.39 to 2.03 (pre x post-treatment for the NR group; P<0.001).

TABLE 3
Comparative analysis of ALT, AST and ARFI values according to the response to antiviral therapy

	Grup SVR		Grup NR
	N=11	P	N=39	P
ARFI, m/s
ARFI pre	2.41±0.58	0.042	2.39±0.63	<0.001
ARFI post	2.02±0.58		2.03±0.54
AST, xULN
AST pre	2.03 (0.7-6.0)	0.028	2.66 (0.8-7.9)	0.036
AST post	0.92 (0.5-5.0)		1.72 (0.5-9.0)
ALT, xULN
ALT pre	2.68 (0.9-5.5)	0.012	2.90 (0.8-7.1)	0.001
ALT post	0.84 (0.3-3.7)		1.68 (0.3-4.5)

• Continuous variables are described as mean ± SD or median (variation). ALT: alanine aminotransferase; AST: aspartate aminotransferase; SVR: sustained virological response; NR: non responders; ULN: upper limit of normality.

For AST, the SVR group changed from 2.03 to 0.92 upper limit of normal (pre- x post-treatment, P=0.028) and 2.66 to 1.72 upper limit of normal (pre- x post-treatment, P=0.036) for the NR group. Finally, for ALT, the reduction was from 2.68 to 0.84 (pre- x post-treatment, P=0.012) and from 2.90 to 1.68 upper limit of normal (pre-x post-treatment, P=0.001) for the SVR group and NR group, respectively (Table 3).

The 22 non-responder patients were re-treated with IFN-free DAAs, and ARFI was repeated 6 to 9 months after re-treatment. It is noteworthy that all non-responder patients (100%) achieved SVR after re-treatment with second-generation DAAs. The liver enzymes and ARFI values in the pre- and post-re-treatment with DAAs were significantly reduced for all parameters (Table 4). Values changed for ALT from 3.02 to 0.61 (P<0.001, pre x post-re-treatment), AST from 2.93 to 0.74 (P<0.001, pre x post-re-treatment), and for ARFI from 2.46 to 1.45 (P=0.004, pre x post-re-treatment).

TABLE 4
Comparative analysis of liver enzymes before and after the retreatment with DAAs of the 22 patients non-responders to the initial triple treatment

		P
ALT, x ULN
Pre-retreatment	3.02 (0.57-9.07)	< 0.001
Post-retreatment	0.61 (0.45-1.33)
AST, x ULN
Pre-retreatment	2.93 (0.77-6.20)	< 0.001
Post-retreatment	0.74 (0.40-2.35)
ARFI, m/s
Pre-retreatment	2.46±0.57	0.004
Post- retreatment	1.45±0.68

• Continuous variables are described as madian (variation). ALT: alanine aminotransferase; ULN: upper limito f normality; AST: aspartate aminotransferase.

DISCUSSION

Early noninvasive evaluation of liver fibrosis using ARFI was significantly reduced after initial treatment with triple therapy (Peg-IFN+RBV+PI), as well as for non-responders. ARFI decreased again after re-treatment with DAAs for the non-responders to triple therapy. Similarly, ALT and AST enzymes experienced a significant decrease before and after treatment with triple therapy and re-treatment with DAAs.

Many studies reported a reduction in liver stiffness after successful treatment of hepatitis C, regardless of the method used for evaluation^{7,9,10,15,16,18,19}. However, an interesting finding here was the reduction of ARFI and aminotransferases even for non-responders to initial triple therapy. The decrease in liver stiffness in non-responders had previously been observed, involving a significant reduction in patients who achieved SVR and, to a lesser extent, but still present, in those who did not respond, using the transient elastography method¹⁷. This finding seems related to the anti-inflammatory and/or antifibrotic effects of PEG-IFN. Indeed, this finding is expected since IFN has an inhibitory effect on hepatic neo-fibrogenesis and improved organ necroinflammation²⁰.

Of the 50 treated patients, 39 did not complete treatment with first-generation DAAs associated with Peg-IFN. Therefore, the number of SVRs post-triple therapy and a protease inhibitor was not significant (22%), contrasting with the results reported for the Advance and Illuminate studies for SVR rates above 60% using telaprevir²¹. In the Sprint-2 study, SVR was also significant and above 65% using boceprevir²². Since these were industry-sponsored studies, patients with a higher likelihood of response were selected and followed, contrasting with our real-world data.

The anti-inflammatory effect of the first course of therapy reported here was transitory, and ALT and liver stiffness were high again before re-treatment. However, after re-treatment with DAAs, and 100% SVR, the aminotransferases decreased and normalized in most patients, and for ARFI, there was a significant reduction in liver stiffness values. Some patients shifted from advanced fibrosis to less pronounced stages of liver fibrosis. Approximately six patients transitioned from F4 to F3, 06 patients from F4 to F2, and 07 patients from F4 to F1. Other studies demonstrated a significant reduction in liver stiffness after HCV treatment with DAAs using ARFI and transient elastography methods^7,9,16.

Since the post-treatment evaluation in this study was performed early (minimum of 6 and maximum of 9 months after the SVR), the reduced ARFI parameters may be related to the decrease in liver inflammatory activity. The same was observed in non-responders treated with triple therapy. In fact, the improvement of ARFI values in patients treated with DAAs could be directly related to two phases, as proposed by some authors¹⁶. In the first phase, the decline in liver stiffness could be due to reduced liver necroinflammation, seen by a decrease in aminotransferase values in this period. In the second, later phase, beyond 24 weeks, fibrosis regression could occur¹⁶. Necroinflammatory activity, represented by elevated aminotransferases, is a factor that interferes in the evaluation of liver stiffness by elastography. The changes could wrongly increase the score and overestimate fibrosis, especially in patients with less advanced fibrosis²³.

The limitations of our study involve the absence of a comparative analysis with a post-treatment liver biopsy to confirm the fibrosis regression. Additionally, fibrosis assessment was performed for up to 9 months, so longer evaluations were not conducted. Future studies may definitively address these questions.

In conclusion, we could not determine whether improved ARFI parameters were due to liver fibrosis regression or a decreased liver inflammatory pattern; however, the results suggest the last hypothesis. In addition, it is necessary to cautiously evaluate elastography data post-treatment, as ARFI liver stiffness values decreased over time, along with reduced levels of AST and ALT. Moreover, it is known that ARFI overestimates the degree of fibrosis in patients with elevated aminotransferase levels. Thus, the assessment of liver fibrosis by ARFI elastography should include other biochemical markers to establish new cutoff levels for previously treated patients²⁴. The timing of fibrosis assessment should be observed in future studies, as reduced liver stiffness on early evaluations (between 6 to 9 months after treatment) may be related to changes in necroinflammatory activity per se.

ACKNOWLEDGMENTS

We acknowledge all members of the Hepatitis division of the Gastroenterology Department of the Federal University of São Paulo who contributed to this work.

REFERENCES

• ¹ Martinello M, Solomon SS, Terrault NA, Dore GJ. Hepatitis C. Lancet. 2023;402:1085-96. doi: 10.1016/S0140-6736(23)01320-X.
  » https://doi.org/10.1016/S0140-6736(23)01320-X
• ² BRASIL. Ministerio da Saúde. PCDT 2019. Protocolo Clínico e Diretrizes Terapêuticas para Hepatite C e Coinfecções 2019; 68 p.
• ³ Westbrook RH, Dusheiko G. Natural history of hepatitis C. J Hepatol. 2014;61(1 Suppl):S58-68. doi: 10.1016/j.jhep.2014.07.012.
  » https://doi.org/10.1016/j.jhep.2014.07.012
• ⁴ Terrault NA, Francoz C, Berenguer M, Charlton M, Heimbach J. Liver Transplantation 2023: Status Report, Current and Future Challenges. Epub ahead of print 2023. DOI: 10.1016/j.cgh.2023.04.005.
  » https://doi.org/10.1016/j.cgh.2023.04.005
• ⁵ Alqahtani SA, Sulkowski MS. Chronic Hepatitis C: Advances in Therapy and the Remaining Challenges. Med Clin North Am. 2023;107:423-33.
• ⁶ Sebastiani G, Alberti A. Non invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy. World J Gastroenterol. 2006;12:3682-94. Doi: 10.3748/wjg.v12.i23.3682.
  » https://doi.org/10.3748/wjg.v12.i23.3682
• ⁷ Ragazzo TG, Paranagua-Vezozzo D, Lima FR, de Campos Mazo DF, Pessoa MG, Oliveira CP, et al. Accuracy of transient elastography-fibrosc®, acoustic radiation force impulse (ARFI) imaging, the enhanced liver fibrosis (ELF) test, APRI, and the FIB-4 index compared with liver biopsy in patients with chronic hepatitis C. Clinics. 2017;72:516-25. Doi: 10.6061/clinics/2017(09)01.
  » https://doi.org/10.6061/clinics/2017(09)01
• ⁸ BRASIL. Ministerio da Saúde Secretaria de Vigilância em Saúde. Protocolo Clínico e Diretrizes Terapêuticas (PCDT). Brasilia, 2015.
• ⁹ Alem SA, Abdellatif Z, Mabrouk M, Zayed N, Elsharkawy A, Khairy M, et al. Diagnostic accuracy of acoustic radiation force impulse elastography (ARFI) in comparison to other noninvasive modalities in staging of liver fibrosis in chronic HCV patients: single-center experience. Abdom Radiol. 2019;44:2751-58. Doi: 10.1007/s00261-019-02031-1.
  » https://doi.org/10.1007/s00261-019-02031-1
• ¹⁰ Bota S, Sporea I, Şirli R, Popescu A, Gradinaru-Tascau O. How useful are ARFI elastography cut-off values proposed by metaanalysis for predicting the significant fibrosis and compensated liver cirrhosis? Med Ultrason. 2015;17: 200-5.
• ¹¹ Mallet V, Gilgenkrantz H, Serpaggi J, Verkarre V, Vallet-Pichard A, Fontaine H, et al. Brief communication: The relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med. 2008;149:399-403. Doi: 10.7326/0003-4819-149-6-200809160-00006.
  » https://doi.org/10.7326/0003-4819-149-6-200809160-00006
• ¹² Singal AG, Volk ML, Jensen D, Di Bisceglie AM, Schoenfeld PS. A Sustained Viral Response Is Associated With Reduced Liver-Related Morbidity and Mortality in Patients With Hepatitis C Virus. Clin Gastroenterol Hepatol. 2010;8:280-8, 288.e1. Doi: 10.1016/j.cgh.2009.11.018.
  » https://doi.org/10.1016/j.cgh.2009.11.018
• ¹³ El Braks R, Ganne-Carrié N, Fontaine H, Paries J, Grando-Lemaire V, Beaugrand M, et al. Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alpha and ribavirin. World J Gastroenterol. 2007;13:5648-53. Doi: 10.3748/wjg.v13.i42.5648.
  » https://doi.org/10.3748/wjg.v13.i42.5648
• ¹⁴ Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: An update. Hepatology. 2009;49:1335-74. Doi: 10.1002/hep.22759.
  » https://doi.org/10.1002/hep.22759
• ¹⁵ Bachofner J, Valli PV, Bergamin I, Kröger A, Künzler P, Baserga A, et al. Excellent outcome of direct antiviral treatment for chronic hepatitis C in Switzerland. Swiss Med Wkly. 2018;148:w14560. Doi: 10.4414/smw.2018.14560.
  » https://doi.org/10.4414/smw.2018.14560
• ¹⁶ Knop V, Hoppe D, Welzel T, Vermehren J, Herrmann E, Vermehren A, et al. Regression of fibrosis and portal hypertension in HCV-associated cirrhosis and sustained virologic response after interferon-free antiviral therapy. J Viral Hepat. 2016;23:994-1002. Doi: 10.1111/jvh.12578.
  » https://doi.org/10.1111/jvh.12578
• ¹⁷ Sáez-Royuela F, Linares P, Cervera LA, Almohalla C, Jorquera F, Lorenzo S, et al. Evaluation of advanced fibrosis measured by transient elastography after hepatitis C virus protease inhibitor-based triple therapy. Eur J Gastroenterol Hepatol. 2016;28:305-12. Doi: 10.1097/MEG.0000000000000533.
  » https://doi.org/10.1097/MEG.0000000000000533
• ¹⁸ Herlihy T, Moran M, Heeney A, Okhai H, De Franceso D, Cronin C, et al. A comparison of transient elastography with acoustic radiation force impulse elastography for the assessment of liver health in patients with chronic hepatitis C: Baseline results from the TRACER study. Ultrasound. 2023;31:244-53. Doi: 10.1177/1742271X221139181.
  » https://doi.org/10.1177/1742271X221139181
• ¹⁹ Castera L, Winnock M, Pambrun E, Paradis V, Perez P, Loko MA, et al. Comparison of transient elastography (FibroScan), FibroTest, APRI and two algorithms combining these noninvasive tests for liver fibrosis staging in HIV/HCV coinfected patients: ANRS CO13 HEPAVIH and FIBROSTIC collaboration. HIV Med. 2014;15:30-9. Doi: 10.1111/hiv.12082.
  » https://doi.org/10.1111/hiv.12082
• ²⁰ Fabris P, Carlotto A, Bianco T Del, Malfatti F, Tramarin A, Miotti MA, et al. Therapy of chronic hepatitis C with PEG-IFN α-2b plus ribavirin in patients with genotype 2 or 3: 16 versus 24 weeks, clinical outcome and direct cost analyses. Eur J Gastroenterol Hepatol. 2013;25:1396-401.
• ²¹ Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection. N Engl J Med. 2011;365:1014-24. Doi: 10.1056/NEJMoa1014463.
  » https://doi.org/10.1056/NEJMoa1014463
• ²² Poordad F, Bronowicki J, Gordon SC, Zeuzem S, Jacobson IM, Sulkowski MS, et al. Factors that predict response of patients with hepatitis C virus infection to Boceprevir. Gastroenterology. 2012;143:608-18.e5. Doi: 10.1053/j.gastro.2012.05.011.
  » https://doi.org/10.1053/j.gastro.2012.05.011
• ²³ Tapper EB, Cohen EB, Patel K, Bacon B, Gordon S, Lawitz E, et al. Levels of Alanine Aminotransferase Confound Use of Transient Elastography to Diagnose Fibrosis in Patients With Chronic Hepatitis C Virus Infection. Clin Gastroenterol Hepatol. 2012;10:932-7.e1. Doi: 10.1016/j.cgh.2012.01.015.
  » https://doi.org/10.1016/j.cgh.2012.01.015
• ²⁴ Choi M, Kwon H, Cho J, Oh J, Nam K, Kang M, et al. Serial change of liver stiffness measured by acoustic radiation force impulse imaging in chronic liver disease: Correlation with biochemical markers. J Med Ultrason. 2014;41:311-7. Doi: 10.1007/s10396-013-0508-6.
  » https://doi.org/10.1007/s10396-013-0508-6

• Disclosure of funding:
  none
• Declaration of use of artificial intelligence:
  none

Edited by

• Associate Editor:
  Edna Strauss

Publication Dates

• Publication in this collection
  20 Dec 2024
• Date of issue
  2024

History

• Received
  17 Apr 2024
• Accepted
  29 Oct 2024