Naturally occurring amino–acid substitutions to nucleos(t)ide analogues in treatment naive Turkish patients with chronic hepatitis B

Abstract

Naturally occurring amino-acid substitutions in the hepatitis B virus (HBV) polymerase gene may be responsible for resistance to nucleoside/nucleotide (NUCs) analogues. To date, only pre-existing lamivudine resistance has been extensively studied. The aim of the present study was to determine the naturally occurring or pre-existing amino-acid substitutions related to NUCs in treatment naive Turkish patients with chronic hepatitis B (CHB). The investigation involved a total of 88 patients (65 males and 23 females; mean age, 34 years; range, 15-61 years) who were diagnosed with CHB between April 2008 and January 2009. According to HBeAg status, 66 patients were HBeAg-negative and 22 patients were HBeAg positive. Naturally occurring substitutions in the HBV polymerase region were detected by DNA sequencing in 17 (19%) and 30 (34%) patients, based on manual and geno2pheno tool database interpretation, respectively. Each amino-acid substitution appeared alone and included rtA194T, rtV214A, rtQ215S, rtI233V and rtN236T. The median values for viral load, ALT and AST were 3.3 log(10) (2.0-6.0) IU/mL, 36 (12-515) U/L and 27 (13-284) U/L, respectively, but these did not correlate with the observed amino-acid substitutions in the polymerase region. By direct sequencing, genotype D of HBV was found to still be dominant among Turkish patients. In conclusion, every patient who is diagnosed with CHB should be monitored before the start of treatment for more effective management of patient treatment options.

Naturally Occurring Polymerase and Surface Gene Variants of Hepatitis B Virus in Turkish Hemodialysis Patients with Chronic Hepatitis B

“…In the present study, we determined naturally occurring mutations mostly related to L-nucleosides (which are currently approved NUCs employed for the treatment of CHB patients). Our previous study showed that naturally occurring mutations, which confer resistant to acyclic nucleoside phosphonates, were predominant in treatment-naive CHB patients with normal renal function (23).…”

“…Although most patients were identified to be hepatitis B e-antibody-positive asymptomatic carriers, they were found to be older in age with low hepatitis B e-antigen positivity, low alanine aminotransferase level, and low HBV DNA levels (Table 1). Our previous reports established that the frequencies of naturally occurring primary and compensatory mutations are very high in treatmentnaive HD patients when compared to treatment-naive CHB patients with normal renal function (15,23). However, clinical manifestation and the number of viral genomic substitutions in HBV carriers may be influenced by aging under long-term pressure from the host immune system.…”

Management of Chronic Hepatitis B Virus Infection: A Consensus Report of the Study Group for Viral Hepatitis of the Turkish Society of Clinical Microbiology and Infectious Diseases

“…LAM ve LdT kullanımının yaygın ya da zorunlu olduğu popülasyonlarda (ülke-mizde bir süre öncesine kadar geçerli olan SUT'a göre KHB'li hastalarda HBV DNA düzeyi <10 7 İÜ/ml ise NA tedavisi yalnız LAM ya da LdT ile başlatılabilmekteydi) primer ve kompansatuar ilaç direnci mutasyonları sıklıkla saptanmaktadır (153)(154)(155)(156). KHB'li hastaların NA tedavilerinde ortaya çıkabilen primer ve kompansatuar ilaç direnci mutasyonları ve S geninde yol açtıkları aminoasid değişiklikleri Tablo 5'te görülmektedir.…”

“…HBV pol geninde NA hedef bölgesinde meydana gelen kompansatuar mutasyonlar, KHB'li hastaların tedavilerinde gereksiz ya da hatalı ilaç değişiklikleri yapılmasına yol açmaktadır. Hem NA naif hem de LAM ve/veya ADV tedavisi alan KHB hastalarında rtQ215H/Q/P/S kompansatuar mutasyonları sık saptanmaktadır (153)(154)(155)(156)(157). Bu nedenle NA tedavilerinde yapılacak ilaç değişikliklerinde ve rasyonel bir NA yönetiminde HBV ilaç direnci analizleri yapılması önemlidir.…”

Molecular Characterization of Drug Resistance in Hepatitis B Viruses Isolated from Patients with Chronical Infection in Turkey

“…Specific primer pairs were constructed (forward: 5' -TCGTGGTGGACTTCTCTCAATT -3' and reverse: 5, -CGTTGACAGACTTTCCAATCAAT -3') for the amplification of the HBV pol gene region (11). The PCR conditions were as follows: denaturation at 95°C for 10 minutes followed by 35 cycles consisting of an annealing step at 95°C for 45 seconds, extension at 60°C for 45 seconds, and a final step at 72°C for 45 seconds.…”