Hepatitis B Virus Deoxyribonucleic Acid Levels Research Articles

YMDD motif mutations in chronic hepatitis B antiviral treatment naïve patients: a multi-center study

ObjectiveThis study aimed to determine the natural prevalence of variants of tyrosinemethionine- aspartic acid-aspartic acid (YMDD) motif in patients with chronic hepatitis B (CHB), and to explore its relation with demographic and clinical features, hepatitis B virus (HBV) genotypes, and HBV DNA levels. MethodsA total of 1,042 antiviral treatment naïve CHB patients (including with lamivudine [LAM]) in the past year were recruited from outpatient and inpatient departments of six centers from December 2008 to June 2010. YMDD variants were analyzed using the HBV drug resistance line probe assay (Inno-Lipa HBV-DR). HBV genotypes were detected with polymerase chain reaction (PCR) microcosmic nucleic acid cross-ELISA, and HBV deoxyribonucleic acid (DNA) was quantitated with real-time PCR. All serum samples underwent tests for HBV, HCV, and HDV with ELISA. ResultsYMDD variants were detected in 23.3% (243/1042) of CHB patients. YMDD mutation was accompanied by L180M mutation in 154 (76.9%) patients. Both wild-type HBV and YMDD variant HBV were present in 231 of 243 patients. Interestingly, 12 patients had only YIDD and/or YVDD variants without wild YMDD motif. In addition, 27.2% (98/359) of HbeAg-positive patients had YMDD mutations, which was higher than that in HbeAg-negative patients (21.2%, 145/683). The incidence of YMDD varied among patients with different HBV genotypes, but the difference was not significant. Moreover, the incidence of YMDD in patients with high HBV DNA level was significantly higher than that in those with low HBV DNA level. ConclusionMutation of YMDD motif was detectable at a high rate in CHB patients in this study. The incidence of YMDD may be correlated with HBeAg and HBV DNA level.

The efficacy and safety of antiviral therapy with lamivudine to stop the vertical transmission of hepatitis B virus

The purpose of this study was to investigate the efficacy and safety of lamivudine (LAM) in stopping the vertical transmission of hepatitis B virus (HBV). Pregnant women with normal alanine transaminase (ALT) (n = 100) and with abnormal ALT (n = 100) who were positive for hepatitis B e antigen (HBeAg), and with HBV DNA (deoxyribonucleic acid) levels ≥1.0 × 107 copies/ml were enrolled in this study. One hundred volunteers (50 with normal ALT, 50 with abnormal ALT) received 100 mg of LAM daily from the 24th to 32nd week of gestation and the untreated 100 volunteers served as controls. All infants received passive-active immunoprophylaxis. Compared to the control group, the study group got a marked reduction in serum levels (P < 0.001) and high negativity (P < 0.001) of HBV DNA before delivery. They also got normalization in ALT levels as much as controls received general medication (P > 0.05). The prenatal transmission rate in the study group was significantly lower than that of the control group (P < 0.05). There were no differences in incidences of congenital malformation between the two groups (P > 0.05). LAM treatment can effectively and safely stop vertical transmission of HBV and normalize the ALT levels of pregnant women.

Antiviral therapy for pre- and post-liver transplantation patients with hepatitis B

The goals of antiviral therapy for hepatitis B patients on the liver transplantation (LT) waiting list are 2-fold: 1) to achieve clinical stabilization, thereby delaying/preventing the need for LT; and 2) to attain low hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels prior to transplant, thereby reducing the risk of recurrent HBV postLT. Lamivudine was the first nucleoside analog to be approved for use in HBV treatment, and has been shown to be safe for long-term use. The combination of hepatitis B immune globulin and lamivudine has been the most common prophylactic therapy to prevent recurrent HBV infection post-LT since the late 1990s, and lamivudine monotherapy was the mainstay of treatment of recurrent HBV in the late 1990s and early 2000. The initial enthusiasm of lamivudine was tempered by the realization that lamivudine does not eradicate HBV, thus most preand post-LT patients require lifelong treatment to maintain viral suppression. Unfortunately, long-term use of lamivudine is associated with increasing rates of drug resistance, from 15 to 30% of patients after 1 yr of treatment to 70% of patients after 4 to 5 yr. Virologic breakthrough due to antiviral resistance has been reported to cause hepatitis flares and in rare instances hepatic decompensation. In the transplant setting, where patients already have decompensated cirrhosis or are receiving immunosuppressive therapy, the risk of severe hepatitis flare and worsening liver failure is higher, and for patients whomanage to receive a timely transplant, the risk of HBV recurrence post-LT is increased. With the approval of 2 nucleoside/tide analogs: adefovir and entecavir, and others in development, the management of preand post-LT hepatitis B patients is continuously evolving. There is an urgent need for safe and effective rescue therapy for patients with lamivudine-resistant HBV, and alternative first-line antiviral therapy with a lower rate of resistance for treatmentnaive patients. These therapies must have rapid and potent antiviral activity, long-term safety, and very low rates of resistance. In this issue of the Journal, Schiff et al. report the final results of a large open-label, multicenter study with 226 waitlisted and 241 post-LT patients with lamivudine-resistant HBV treated with adefovir dipivoxil 10 mg once daily for a median duration of 39 and 99 weeks, respectively. Almost all patients continued lamivudine at some time, but the exact duration of overlapping treatment is not certain. Adefovir resulted in a mean decrease in serum HBV DNA level of 3.5 to 4.0 log10 copies/mL after 48 weeks of treatment, and an increasing proportion of patients had undetectable serum HBV DNA over time. The high proportion of patients with substantial viral suppression may be related to the concomitant use of lamivudine in all patients. In 1 small study of patients with compensated liver disease and lamivudine-resistant HBV, serum HBV DNA decreased at a similar rate in patients randomized to adefovir monotherapy or a combination of lamivudine and adefovir. However, several recent studies have showed that combination of lamivudine and adefovir results in more marked viral suppression and lower risk of adefovir resistance than adefovir monotherapy. Despite the use of combination therapy, 35% of waitlisted patients and 22% of post-LT patients in the current study still had detectable serum

Antepartum immunoprophylaxis of three doses of hepatitis B immunoglobulin is not effective: a single‐centre randomized study

To investigate the efficacy of antepartum administration of three doses of hepatitis B immunoglobulin (HBIg), currently being used in China, 250 pregnant women who were seropositive for hepatitis B e antigen (HBeAg) were randomly divided into study (117 cases) and control groups (133 cases). Subjects in the study group received HBIg 400 IU intramuscularly once a month at the third, second and first month before delivery; subjects in the control group received no antepartum treatment. All neonates received passive-active immunization after birth. The maternal hepatitis B virus (HBV) markers, hepatitis B surface antigen (HBsAg) titres and HBV deoxyribonucleic acid (DNA) levels were measured at week 28 of gestation (before the antepartum treatment) and at labour; the neonatal serum HBV markers were detected at birth and at 12 months after birth. No side-effects were found in any of the women or their neonates. No statistical differences were seen between the maternal HBsAg and HBV DNA levels of the study and control groups at labour nor the protective efficacy rates of postnatal immunoprophylaxis at 12 months after birth (P > 0.05, respectively). To conclude, antepartum administration of three doses of HBIg for the HBeAg-positive women is inefficacious.

Lack of correlation between HBsAg and HBV DNA levels in blood donors who test positive for HBsAg and anti‐HBc: implications for future HBV screening policy

Studies showing a significant correlation between hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels have focused on the HBV seroconversion window period. HBsAg levels relative to HBV DNA results in 200 HBsAg-positive, anti-hepatitis B core antigen (HBc)-reactive blood donations were analyzed using quantitative polymerase chain reaction (PCR) (detection limit 400 copies/mL), two research PCR assays with increasing sensitivities (65 copies/mL and 1.3 copies/mL, respectively), and a quantitative HBsAg assay; HBsAg and HBV DNA levels were correlated with HBV serologic profiles; and the potential for replacing HBsAg screening with nucleic acid testing (NAT) was analyzed. Serologic profiles for over 90 percent of the donor samples were consistent with chronic HBV infection. Correlation between HBsAg and HBV DNA concentrations was weak (correlation coefficient = 0.33). Thirty-six percent (72/200) of donor samples had DNA levels under 400 copies per mL. Retesting of the 72 samples by more sensitive PCR assays showed that 60 out of 200 (30%) were positive by PCR with sensitivity of 65 copies per mL, whereas 6 out of 200 (3%) required PCR sensitivity of 1.3 copies per mL for positivity. Three percent (6/200) were negative by all three NAT assays. HBV DNA levels in HBsAg-positive, anti-HBc-reactive blood donations can be extremely low. About 6 percent of donations would be negative by current minipool HBV NAT methods. About 3 percent of donations would remain undetected by sensitive single-donor NAT. These results indicate caution in any consideration of dropping HBsAg screening.

Histopathology and clinical correlates of end-stage hepatitis B cirrhosis: A possible mechanism to explain the response to antiviral therapy

In chronic liver disease associated with histological necroinflammation, clinical severity is frequently greater in those with higher grades of activity. Conventional wisdom assumes that necroinflammation is mild or absent in patients with end-stage hepatitis B virus (HBV) cirrhosis due to the frequent presence of mildly elevated aminotransferase levels, the absence of hepatitis B e antigen (HBeAg), and low or undetectable HBV deoxyribonucleic acid (DNA) levels. However, a histopathologic analysis of such patients has not been undertaken. The aims of this study were 1) to assess severity and histological features of inflammation, 2) to correlate the severity of inflammation with biochemical and virologic parameters, and 3) to define the relationship between inflammation and clinical severity in explanted livers from patients undergoing liver transplantation for HBV cirrhosis. Characteristics of 34 consecutive patients undergoing liver transplantation for HBV cirrhosis were correlated with inflammation and immunohistological findings in the explanted livers. High-grade inflammation (grades 3 and 4) was found in many cases (47.1% interface hepatitis; 14.8% lobular inflammation; and 20.6% portal inflammation). The presence of positive cytoplasmic staining for hepatitis B core antigen (HBcAg) was associated with grade 3 or 4 interface hepatitis (P = .046) and lobular hepatitis (P = .005). There was no correlation between inflammatory activity and age, Asian ethnicity, aminotransferase levels, total bilirubin levels, HBeAg seropositivity, and detectable HBV DNA level. Patients with high-grade inflammation had greater degrees of hepatic decompensation. In conclusion, high-grade inflammation is common in end-stage HBV cirrhosis, but it is not readily detected by biochemical and virologic parameters. High-grade inflammation is associated with a greater degree of hepatic decompensation.

Markers of viral replication in patients with chronic hepatitis B virus infection.

Serum samples from 56 patients with biopsy-proven chronic B viral hepatitis without superimposed delta hepatitis were analyzed for the various markers of viral replication, including serum hepatitis B e Ag (HBeAg), hepatitis B virus deoxyribonucleic acid (HBV-DNA), and hepatitis B core antigen (HBcAg) in the liver tissues. Twenty-seven patients had persistent viral hepatitis (PH) and 29 patients had chronic active hepatitis (CAH) with or without cirrhosis. HBV-DNA was identified in the sera of 81% of patients with PH and 60% of patients with CAH. Significantly higher levels of HBV-DNA were found in patients with PH than in those with CAH. Both HBeAg in serum and HBcAg in liver correlated positively with serum HBV-DNA. Nine patients had serum HBV-DNA in the absence of HBeAg (four had anti-HBe), and seven of these nine patients had stainable HBcAg in the liver (two did not have staining). None of these patients had hepatic HBcAg in the absence of serum HBV-DNA. When these patients were stratified according to their epidemiologic background, serum HBV-DNA was present in a significantly higher number of male homosexuals than in any other groups. This was unrelated to their status of human immunodeficiency viral serology.