Post–sustained Virologic Response Liver Stiffness May Underestimate Fibrosis After Direct Acting Antiviral-containing Therapy

To the Editor—Patients with chronic hepatitis C virus (HCV) and advanced fibrosis or cirrhosis remain at elevated risk of developing hepatocellular carcinoma (HCC), despite sustained virologic response (SVR) with direct-acting antivirals (DAAs), and therefore require ongoing HCC surveillance [1–4]. Vibration-controlled transient elastography (VCTE) is well validated as a non-invasive fibrosis surrogate in patients with active viremia [5]. However, data is lacking to support the American Gastroenterological Association’s recommendation to use the VCTE-measured liver stiffness (LS) cutoff of > 9.5 kPa to rule in/out ≥F3 fibrosis in patients post-SVR after DAA therapy [5].

We present a case series of patients with chronic HCV who achieved SVR with a DAA-containing regimen and underwent post-SVR VCTE and liver biopsy (LB) within 12 months of each other at the University of California, San Francisco. We excluded patients with cirrhosis at pre-treatment LB, who were treated with a non–DAA-containing regimen, who had undergone a liver transplant, or who had a LB size of <10 mm or less than 6 portal tracts. LS measurements were performed in a fasting state by a trained operator using FibroScan 502 Touch (Echosens, Paris, France; probe size varied by body habitus). Liver biopsies were performed by a percutaneous or transjugular approach. Fibrosis was scored by the METAVIR scoring system. Study approval was obtained from the University of California, San Francisco, Institutional Review Board.

We identified 18 patients who underwent post-SVR LB for various reasons, most commonly because of discordant pre-SVR fibrosis staging (Table 1). The median age was 65 years, 78% were male, and 50% were non-Hispanic white. At the time of post-SVR LB, the median body mass index was 25.5 kg/m², no patients had hepatitis B virus, and 1 (5%) patient had human immunodeficiency virus. There were 2 (11%) patients who had diabetes, 5 (28%) who had hyperlipidemia, and 1 (6%) who was actively drinking. There were 9 (50%) patients who underwent pre-treatment VCTE, and 9 (50%) who had pre-treatment LB (Table 1).

Table 1.

Demographic, Clinical, and Histologic Characteristics for All 18 Patients, by Post-sustained Virologic Response Liver Biopsy Fibrosis Stage (<F3 or ≥F3 Fibrosis)

ID	Gender	Race	HCV Genotype	Treatment Regimen	Pre-SVR Fibrosis Estimate			Post-SVR Clinical Characteristics and Fibrosis Estimate						Time From SVR12 to Biopsy, in Weeks	Reason for Liver Biopsy
					Serum Markers	LSM	Histology	Age	AST	ALT	BMI	LSM	Histology
Post-SVR LB F0-F2 Fibrosis
1	Male	White, non-Hispanic	1a	LDV/SOF	<F3 (FIB-4, APRI) ≥F3 (FibroSure)	5.3	Stage 1	66	16	22	23.7	4.3	Stage 0–1	77	Discordant fibrosis staging pre-SVR
2	Male	Other, non-Hispanic	1a	TPV + P/R	<F3 (FIB-4) ≥F3 (APRI)	NA	Stage 1	65	16	20	29.1	4.2	Stage 1	195	Discordant fibrosis staging pre-SVR
3	Male	White, Hispanic or Latino	1a	LDV/SOF	≥F3 (FIB-4, APRI, FibroSure)	9.0	NA	65	22	29	19.7	6.7	Stage 1	68.5	Discordant fibrosis staging pre-SVR
4	Female	Other, non-Hispanic or Latino	2	SOF + RBV	<F3 (FIB-4) ≥F3 (APRI)	11.2	Stage 0–1	65	21	25	31.4	6.8	Stage 1	35	Discordant fibrosis staging pre-SVR
5	Male	White, non-Hispanic	1a	TPV + P/R	<F3 (FIB-4) ≥F3 (APRI)	NA	NA	64	20	30	21.6	6.0	Stage 1	117.5	Discordant fibrosis staging pre-SVR
6	Male	White, non-Hispanic	1a	LDV/SOF	<F3 (FIB-4) ≥F3 (APRI; FibroSure)	8.0	NA	66	53	76	22.4	6.2	Stage 2	69	Biopsy performed during HCC resection
7	Male	White, non-Hispanic	1a	LDV/SOF	<F3 (FIB-4, APRI, FibroSure)	12.0	Stage 1	68	17	18	28.3	4.3	Stage 2	30.5	Discordant fibrosis staging pre-SVR
8	Male	African American	1b	LDV/SOF	<F3 (APRI) ≥F3 (FIB-4, Fibrosure)	7.8	Stage 1	69	45	43	22.3	5.5	Stage 2	155.5	Discordant fibrosis staging pre-SVR
9	Male	African American	1a	LDV/SOF	<F3 (FIB-4, APRI) ≥F3 (FibroSure)	4.8	NA	60	64	58	26.9	4.5	Stage 2	101	Elevated aminotransaminases
Post-SVR LB ≥F3 Fibrosis
10	Male	Other, Hispanic or Latino	1b	LDV/SOF	<F3 (FIB-4; APRI) ≥F3 (FibroSure)	NA	Stage 0	64	34	19	25.1	14.0	Stage 3–4	2.5	Discordant fibrosis staging pre-SVR
11	Male	White, non-Hispanic	1a	TPV + P/R	≥F3 (FIB-4, APRI)	NA	Stage 3	65	40	34	34.5	12.3	Stage 3–4	69.5	Pre-kidney transplant evaluation to assess fibrosis
12	Male	African American	1a	LDV/SOF	≥F3 (FIB-4, APRI, FibroSure)	NA	Stage 2	48	57	55	23.0	21.8	Stage 4	41	Elevated aminotransaminases
13	Female	White, non-Hispanic	1a	LDV/SOF + RBV	<F3 (FIB-4, APRI)	NA	Stage 3–4	68	18	19	25.3	6.1	Stage 3	49	Fibrosis re-staging after SVR
14	Male	White, non-Hispanic	3	SOF/VEL	<F3 (FIB-4) ≥F3 (APRI; FibroSure)	NA	NA	63	20	21	29.5	7.1	Stage 3	21	Biopsy performed during HCC resection
15	Male	African American	1a	GZR/EBR	≥F3 (FIB-4, APRI) <F3 on FibroSure	NA	NA	71	24	30	31.9	4.8	Stage 3	49	Discordant fibrosis staging pre-SVR
16	Female	Other, Hispanic or Latino	3	SOF + RBV	<F3 (FIB-4, APRI) ≥F3 (FibroSure)	27.0	NA	54	18	22	21.6	7.9	Stage 4	154	Fibrosis staging prior to stem cell transplant for multiple myeloma
17	Female	White, non-Hispanic	1a	LDV/SOF	<F3 (FIB-4) ≥F3 (APRI)	17.6	NA	47	22	20	25.6	7.1	Stage 4	43	Discordant fibrosis staging post-SVR
18	Male	White, non-Hispanic	1	GLE/PIB	<F3 (FIB-4, APRI)	NA	NA	71	16	17	30.1	8.9	Stage 4	1	Biopsy performed during HCC resection

Abbreviations: ALT, alanine aminotransferase; APRI, aspartate aminotransaminase to platelet ratio index; AST, aspartate aminotransferase; BMI, body mass index; EBR, elbasvir; FIB-4, fibrosis-4 index; GLE, glecaprevir; GZR, grazoprevir; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LB, liver biopsy; LDV, ledipasvir; LSM, liver stiffness measurement; NA, not available; P/R, peginterferon/ribavirin; PIB, pibrentasvir; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response; SVR12, sustained virologic response 12 weeks after completion of antiviral therapy; TPV, telaprevir; VEL, velpatasvir.

Post-SVR, 9 patients had F0-2 fibrosis on LB and concordant LS ruling out advanced fibrosis (LS ≤ 9.5 kPa; Table 1). There were 9 patients who had ≥F3 fibrosis on LB. Of these, 6 (67%) had LS ≤ 9.5 kPa and therefore would have been incorrectly classified as not having advanced fibrosis based on post-SVR VCTE alone. Importantly, 2 patients with ≥F3 fibrosis despite low post-SVR LS were diagnosed with HCC, which was detected with HCC surveillance. All patients with post-SVR LS > 9.5 kPA had ≥F3 fibrosis on biopsy.

In this series of patients who underwent both LB and VCTE post-SVR, we found that reliance on post-SVR LS alone would have misclassified 6 of 18 patients, and that VCTE underestimated the fibrosis stage in these patients. Of these 6 patients, 2 developed HCC. Our findings suggest that a >9.5 kPa LS cutoff to identify ≥F3 fibrosis may be less sensitive post-SVR, compared to pre-SVR. Optimal post-SVR LS cutoffs have been reported to be lower than pre-SVR in the interferon era [6]; however, to our knowledge, our data is among the first to report similar findings with DAA use. Possible explanations are that liver remodeling post-SVR may interfere with LS measurement or that reductions in LS may primarily reflect reductions in inflammation, rather than fibrosis regression [7–9].

Our study was limited by a small sample size, precluding our ability to determine optimal LS cut-offs in the post-SVR setting. However, we were able to highlight discrepancies between LS and histology. Additionally, LB post-SVR was performed in patients who had indeterminate or discordant pre-treatment fibrosis staging. This may have biased our population towards those with more advanced fibrosis. Even so, our findings demonstrate that low LS post-SVR did not reliably rule out advanced fibrosis in patients with indeterminate pre-treatment fibrosis staging. Finally, although all biopsies were read by a senior pathologist, they were not all read by the same pathologist.

In summary, LS cutoffs derived in patients with chronic HCV may be less reliable after viral eradication, underscoring the importance of accurate pre-treatment fibrosis staging to guide post-treatment management. We urge caution when making HCC surveillance decisions based on post-SVR fibrosis staging, until larger validation studies are performed.

Notes

Author contributions. A. K. and J. C. P. developed the study concept and design and analyzed and interpreted the data. A. K. drafted the manuscript. J. M., M. P., and J. C. P. critically revised the manuscript for important intellectual content. J. M., N. H., and R. Y. acquired the data.

Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financial support. Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R25HL125451. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Potential conflicts of interest. J. M. is on advisory boards for AbbVie, Gilead Sciences, and Merck. M. P.’s spouse is employed by Hoffmann La Roche. J. C. P. has received research support from Gilead Sciences and Merck and has an ownership interest in Bristol-Myers Squibb, Johnson and Johnson, Merck, and Abbvie. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.