Entecavir resistance in a patient with treatment‑naïve HBV: A case report

Marino,Andrea; Cosentino,Federica; Ceccarelli,Manuela; Moscatt,Vittoria; Pampaloni,Alessio; Scuderi,Daniele; D'Andrea,Flavia; Rullo,Emmanuele Venanzi; Nunnari,Giuseppe; Benanti,Francesco; Celesia,Benedetto Maurizio; Cacopardo,Bruno

doi:10.3892/mco.2021.2275

Entecavir resistance in a patient with treatment‑naïve HBV: A case report

Authors:
- Andrea Marino
- Federica Cosentino
- Manuela Ceccarelli
- Vittoria Moscatt
- Alessio Pampaloni
- Daniele Scuderi
- Flavia D'Andrea
- Emmanuele Venanzi Rullo
- Giuseppe Nunnari
- Francesco Benanti
- Benedetto Maurizio Celesia
- Bruno Cacopardo
View Affiliations

Affiliations: Department of Clinical and Experimental Medicine, Division of Infectious Diseases, ARNAS Garibaldi Hospital, University of Catania, I-95122 Catania, Italy, Department of Clinical and Experimental Medicine, Unit of Infectious Diseases, University of Messina, I-98124 Messina, Italy
Published online on: April 6, 2021 https://doi.org/10.3892/mco.2021.2275
Article Number: 113
Copyright: © Marino et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Among nucleos(t)ide analogue therapies for hepatitis B virus (HBV) treatment, entecavir (ETV) and tenofovir disoproxil fumarate (TDF)/tenofovir alafenamide are associated with the lowest rate of drug resistance. ETV is a drug requiring at least three substitutions in the reverse transcriptase (RT) domain to develop resistance, which is a rare occasion in treatment‑naïve patients. However, pre‑existing or acquired single mutations in the RT domain could lead to a virological breakthrough, after viral suppression. The present case report describes a 58‑year‑old female patient with hepatitis B virus (HBV) and high viral load who started HBV treatment with ETV. After 85 weeks of treatment, HBV‑DNA declined to 0 IU/ml and remained undetectable for 3 years. However, after that period of time, the HBV‑DNA rebounded, followed by the rise of liver enzymes (aspartate aminotransferase and alanine transaminase). Only the substitution M204I was detected in the HBV polymerase region. The patient was then switched to TDF treatment, achieving normalization of the liver enzymes and a decline in HBV‑DNA levels. The present case report suggests that nucleoside‑naïve patients should be cautiously monitored for resistance, even more than biochemically (transaminases, bilirubin) and virologically (HBV‑DNA), even if complete HBV suppression is achieved.

View Figures

View References

1	Schweitzer A, Horn J, Mikolajczyk RT, Krause G and Ott JJ: Estimations of worldwide prevalence of chronic hepatitis B virus infection: A systematic review of data published between 1965 and 2013. Lancet. 386:1546–1555. 2015.PubMed/NCBI View Article : Google Scholar
2	Ott JJ, Stevens GA, Groeger J and Wiersma ST: Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 30:2212–2219. 2012.PubMed/NCBI View Article : Google Scholar
3	European Association for the Study of the Liver. Electronic address: simpleeasloffice@easloffice.eu; European Association for the Study of the Live. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 67:370–398. 2017.PubMed/NCBI View Article : Google Scholar
4	Baldick CJ, Eggers BJ, Fang J, Levine SM, Pokornowski KA, Rose RE, Yu CF, Tenney DJ and Colonno RJ: Hepatitis B virus quasispecies susceptibility to entecavir confirms the relationship between genotypic resistance and patient virologic response. J Hepatol. 48:895–902. 2008.PubMed/NCBI View Article : Google Scholar
5	Doğan ÜB, Öztürk AB, Akın MS, Yalaki S and Sayan M: A case of entecavir resistance which is developed after complete viral suppression during entecavir treatment for nucleoside-naïve chronic hepatitis B. Turk J Gastroenterol. 25 (Suppl 1):S206–S209. 2014.PubMed/NCBI View Article : Google Scholar
6	Lok ASF and McMahon BJ: Chronic hepatitis B: Update 2009. Hepatology. 50:661–662. 2009.PubMed/NCBI View Article : Google Scholar
7	Bartholomeusz A and Locarnini SA: Antiviral drug resistance: Clinical consequences and molecular aspects. Semin Liver Dis. 26:162–170. 2006.PubMed/NCBI View Article : Google Scholar
8	Zoulim F: Hepatitis B virus resistance to entecavir in nucleotide naïve patients: Does it exist? Hepatology. 44:1404–1407. 2006.PubMed/NCBI View Article : Google Scholar
9	Colonno RJ, Rose R, Baldick CJ, Levine S, Pokornowski K, Yu CF, Walsh A, Fang J, Hsu M, Mazzucco C, et al: Entecavir resistance is rare in nucleoside naïve patients with hepatitis B. Hepatology. 44:1656–1665. 2006.PubMed/NCBI View Article : Google Scholar
10	Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, Wichroski MJ, Xu D, Yang J, Wilber RB and Colonno RJ: Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years-of therapy. Hepatology. 49:1503–1514. 2009.PubMed/NCBI View Article : Google Scholar
11	Suzuki F, Akuta N, Suzuki Y, Yatsuji H, Sezaki H, Arase Y, Kawamura Y, Hosaka T, Kobayashi M, Ikeda K, et al: Selection of a virus strain resistant to entecavir in a nucleoside-naïve patient with hepatitis B of genotype H. J Clin Virol. 39:149–152. 2007.PubMed/NCBI View Article : Google Scholar
12	Lee HW, Kim HJ, Hong SP, Cha BK, Chang HY, Choi CH, Do JH, Kim JG and Chang SK: Simultaneous emergence of entecavir resistance mutations in a nucleoside-naïve chronic hepatitis B patient. Intervirology. 55:380–384. 2012.PubMed/NCBI View Article : Google Scholar
13	Kobashi H, Fujioka S, Kawaguchi M, Kumada H, Yokosuka O, Hayashi N, Suzuki K, Okanoue T, Sata M, Tsubouchi H, et al: Two cases of development of entecavir resistance during entecavir treatment for nucleoside-naïve chronic hepatitis B. Hepatol Int. 3:403–410. 2009.PubMed/NCBI View Article : Google Scholar
14	Gherlan GS: Liver ultrasound elastography: More than staging the disease. World J Hepatol. 7:1595–1600. 2015.PubMed/NCBI View Article : Google Scholar
15	Cho WH, Lee HJ, Bang KB, Kim SB and Song IH: Development of tenofovir disoproxil fumarate resistance after complete viral suppression in a patient with treatment-naïve chronic hepatitis B: A case report and review of the literature. World J Gastroenterol. 24:1919–1924. 2018.PubMed/NCBI View Article : Google Scholar
16	Hulgan T and Haas DW: Toward a pharmacogenetic understanding of nucleotide and nucleoside analogue toxicity. J Infect Dis. 194:1471–1474. 2006.PubMed/NCBI View Article : Google Scholar
17	Liu Y, Corsa AC, Buti M, Cathcart AL, Flaherty JF, Miller MD, Kitrinos KM, Marcellin P and Gane EJ: No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg-patients with chronic hepatitis B after 8 years of treatment. J Viral Hepat. 24:68–74. 2017.PubMed/NCBI View Article : Google Scholar
18	Lai CL, Chien RN, Leung NWY, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J, et al: A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 339:61–68. 1998.PubMed/NCBI View Article : Google Scholar
19	Kobayashi S, Ide T and Sata M: Detection of YMDD motif mutations in some lamivudine-untreated asymptomatic hepatitis B virus carriers. J Hepatol. 34:584–586. 2001.PubMed/NCBI View Article : Google Scholar
20	Lee CZ, Lee HS, Huang GT, Yang PM and Sheu JC: Detection of YMDD mutation using mutant-specific primers in chronic hepatitis B patients before and after lamivudine treatment. World J Gastroenterol. 12:5301–5355. 2006.PubMed/NCBI View Article : Google Scholar
21	Tunçbilek S, Köse Ş, Elaldi A and Akman S: Lamivudine resistance in untreated chronic hepatitis B patients in Turkey. Turkish J Gastroenterol. 19:99–103. 2008.PubMed/NCBI
22	Huang CJ, Wu CF, Lan CY, Sung FY, Lin CL, Liu CJ, Liu HF and Yu MW: Impact of Genetic Heterogeneity in Polymerase of Hepatitis B virus on dynamics of viral load and hepatitis B progression. PLoS One. 8(e70169)2013.PubMed/NCBI View Article : Google Scholar
23	Choi YM, Lee SY and Kim BJ: Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression. World J Gastroenterol. 24:1708–1724. 2018.PubMed/NCBI View Article : Google Scholar
24	Zhang Q, Liao Y, Cai B, Li Y, Li L, Zhang J, An Y and Wang L: Incidence of natural resistance mutations in naïve chronic hepatitis B patients: A systematic review and meta-analysis. J Gastroenterol Hepatol. 30:252–261. 2015.PubMed/NCBI View Article : Google Scholar
25	Kim JE, Lee SY, Kim H, Kim KJ, Choe WH and Kim BJ: Naturally occurring mutations in the reverse transcriptase region of hepatitis B virus polymerase from treatment-naïve Korean patients infected with genotype C2. World J Gastroenterol. 23:4222–4232. 2017.PubMed/NCBI View Article : Google Scholar