Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B

Peginterferon (PEG-IFN) treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN ± lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months posttreatment and through long-term follow-up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non-WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non-WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio [OR] 2.90, 95% confidence interval [CI]: 1.15-7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26-24.63, P = 0.013) and patients with non-A genotypes with detectable mutants had a low probability of response. CONCLUSION: The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG-IFN for HBeAg-positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy.     

Hepatitis B viremia in HIV-coinfected individuals under antiretroviral therapy

BackgroundAntiretroviral therapy (ART) has decreased AIDS incidence and mortality, rendering comorbidities, such as hepatitis B more relevant for people living with human immunodeficiency virus (HIV). Since antiretroviral drugs may also inhibit hepatitis B virus (HBV) replication, analyzing the impact of ART on management of hepatitis B in this population is important.ObjectiveTo assess HBV viremia among HIV/HBV coinfected individuals on ART and its associated factors.MethodFor this cross-sectional study, HIV/HBV-coinfected individuals, aged over 18 years, who were on ART for over six months and receiving care at an outpatient clinic in São Paulo were recruited. Sociodemographic characteristics, information about viral exposure, clinical and laboratory data, including evaluation of liver fibrosis were obtained. Plasma HBV DNA was measured by polymerase chain reaction. Viral genome sequencing was conducted for genotyping and identification of drug resistance-conferring mutations if viral load exceeded 900 IU/mL.ResultsOut of 2,946 patients who attended the clinic in 2015, 83 were eligible and 56 evaluated. Plasma HBV DNA was detected in 16 (28.6%) (95% CI: 18.0–41.3%), all on lamivudine and tenofovir treatment. HBV DNA detection was associated with lower education (p = 0.015), higher international normalized ratios (p = 0.045), history of an AIDS-defining illness [OR: 3.43 (95% CI: 1.10–11.50)], and HBeAg detection [OR: 6.60 (95% CI: 1.84–23.6)]. In contrast, a last CD4+ count above 500 cells/mm³ in the year prior to inclusion [OR: 0.18 (95% CI: 0.04–0.71)] and detection of anti-HBe [OR: 0.21 (95% CI: 0.04–0.99)] were negatively associated. Patients with HBV DNA above 900 IU/mL were infected with subgenotypes A1 (n = 3) and D2 (n = 1), and exhibited viral mutations associated with total resistance to lamivudine and partial resistance to entecavir.ConclusionsDespite being on ART, a significant proportion of HIV/HBV-coinfected individuals present HBV viremia. Characterization of factors that are associated with this finding may help professionals provide better management to these patients.     

Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B

BACKGROUND AND AIMS: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). METHODS: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level > or =1.2 times the upper limit of normal, and serum HBV DNA level > or =6 log(10) copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. RESULTS: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG(16) was -0.07 in the lamivudine group compared with -2.45 and -2.46 log(10) copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001). Median change from baseline in serum HBV DNA level at week 48 was 0.0, -3.59, and -4.04 log(10) copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative. CONCLUSIONS: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.     

Incidence and risk factors for incomplete HBV DNA suppression in HIV/HBV‐co‐infected patients initiating tenofovir‐based therapy

Suppression of hepatitis B virus (HBV)‐DNA to undetectable levels is an important goal for HIV/HBV‐co‐infected patients receiving anti‐HBV‐active antiretroviral therapy (ART), and current guidelines recommend that this outcome should be reached by 1 year of treatment. However, the proportion of patients that fail to achieve an undetectable HBV DNA at this time point and its determinants remain unknown in clinical practice. The objective of this study was to determine the incidence and risk factors for incomplete HBV suppression following 1 year of tenofovir‐based ART. We performed a cohort study among tenofovir‐treated HIV/HBV‐co‐infected patients. Patients had HBV viraemia, initiated tenofovir‐based ART and had HBV DNA measured at 1 year of therapy. The primary outcome was incomplete HBV suppression (HBV DNA ≥2.6 log IU/mL) at 1 year. Logistic regression determined odds ratio (ORs) of incomplete HBV suppression for risk factors of interest. Among 133 patients, 54% (95% CI, 46–63%) had incomplete HBV suppression at 1 year. Incomplete suppression was associated with higher baseline HBV DNA (OR, 1.46 per log IU/mL increase; 95% CI, 1.1–1.94) and detectable HIV viraemia at 1 year (OR, 2.52; 95% CI, 1.19–5.32). Among 66 patients with suppressed HIV RNA at 1 year, 28 (42%) failed to achieve an undetectable HBV DNA. Failure to suppress HBV DNA by 1 year occurred in a sizeable proportion of tenofovir‐treated HIV/HBV‐co‐infected patients. Higher HBV DNA and detectable HIV viraemia were risk factors for incomplete HBV suppression.     

Long-term outcome of tenofovir disoproxil fumarate use against hepatitis B in an HIV-coinfected cohort

Objectives

Tenofovir disoproxil fumarate (TDF) is active against hepatitis B virus (HBV) and HIV. However, the long‐term efficacy of tenofovir disoproxil fumarate (TDF) is not well known and the appearance of resistance is a major concern. We have studied the efficacy of TDF against HBV in patients treated at an Infectious Diseases Unit.

Methods

We carried out a retrospective observational study of the efficacy of TDF against HBV replication in a cohort of 52 HIV‐coinfected patients who received TDF for at least 6 months.

Results

The median duration of follow‐up of TDF treatment was 34 months. Forty‐one patients (79%) were positive for HBV envelope antigen (HBeAg) and 35 had received previous lamivudine monotherapy for a median duration of 32 months. Virological breakthrough was observed in nine cases (17%). At the end of the follow‐up period, HBV DNA levels were <1000 copies/mL in 42 patients (81%) and <200 copies/mL in 31 patients (60%). There were no significant differences between the lamivudine‐naïve and lamivudine‐experienced groups. In the lamivudine‐experienced group, the duration of previous lamivudine monotherapy was associated with failure to achieve HBV DNA levels <200 copies/mL (P=0.036). Adding lamivudine or emtricitabine to TDF did not improve virological suppression. In 39 patients who achieved <200 HBV DNA copies/mL during TDF treatment, virological breakthrough was seen only in two patients (5%) after a median follow‐up duration of 39.7 months.

Conclusions

TDF was able to control HBV replication in most HIV‐coinfected patients after a median follow‐up duration of 34 months, regardless of previous lamivudine treatment. However, a sizeable proportion of patients developed virological breakthrough.     

Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients

Tenofovir disoproxil fumarate (TDF) has shown in vitro activity against both HIV and hepatitis B virus (HBV). We retrospectively evaluated the efficacy of TDF (300 mg/d), administered as a part of anti-retroviral therapy, in a large cohort of HIV/HBV-coinfected patients. Sixty-five HIV/HBV-coinfected patients who received TDF for at least 6 months with serum HBV DNA levels above 2.3 log10 copies/mL at TDF initiation and who had stored serum samples before and during TDF therapy were included. Serum HBV DNA was measured on stored samples. The median follow-up period was 12 (Q1-Q3: 8-17) months. Serum hepatitis B e antigen (HBeAg) was positive in 54 patients (83.1%). Fifty-two patients (80.0%) were receiving lamivudine (LAM) (150 mg twice a day), and 68.8% had documented LAM resistance at baseline. Among HBeAg-positive patients, the median reduction from baseline (8.17; Q1-Q3 = 7.30-8.30 log10 copies/mL) of serum HBV DNA was 4.56 log10 copies/mL (Q1-Q3 = 3.33-5.55) (P < .0001). In HBeAg-negative patients, serum HBV DNA decline from baseline (4.83; Q1-Q3 = 2.69-6.40 log10 copies/mL) was 2.53 log10 copies/mL (Q1-Q3 = 0.39-4.10). At the end of the study, HBV DNA became undetectable in 29.6% and 81.6% of the HBeAg-positive and HBeAg-negative patients, respectively. Serum HBeAg became negative in 4 patients, 2 of whom acquired serum hepatitis B e antibody. In conclusion, this retrospective analysis demonstrates the efficacy of TDF against wild-type, presumed precore mutants and LAM-resistant HBV when used as a part of anti-retroviral therapy in HIV-coinfected patients.     

Combination of tenofovir and lamivudine versus tenofovir after lamivudine failure for therapy of hepatitis B in HIV-coinfection

OBJECTIVE: At present sequential monotherapy for chronic hepatitis B with hepatitis B virus (HBV)-polymerase inhibitors is clinical practice. It is unknown to date whether combination therapy with lamivudine plus tenofovir could be superior to sequential therapy with tenofovir after the occurrence of lamivudine resistance. METHODS: We conducted a multicenter, 1: 2 matched pair analysis comparing patients with HBV/HIV-coinfection starting an antiretroviral regimen including tenofovir plus lamivudine with patients who had highly replicative, lamivudine resistant HBe-antigen positive chronic hepatitis B and started with tenofovir as the only active HBV polymerase inhibitor subsequent to lamivudine. RESULTS: At baseline patients on tenofovir plus lamivudine (n = 25) had a median HBV DNA of 5.9 x 10(7) copies/ml compared to 1.37 x 10(8) copies/ml in the tenofovir arm (n = 50; P = 0.32). A sustained undetectable HBV DNA < 1000 copies/ml was achieved in 19/25 (76%) patients on tenofovir plus lamivudine and in 42/50 (84%) on tenofovir (P = 0.53). A loss of HBe-antigen was observed in 9/25 (36%) patients on tenofovir plus lamivudine and in 12/50 (24%) patients on tenofovir (P = 0.29). HBs-antigen loss was found in 1/25 (4%) and 3/50 (6%) patients. CONCLUSIONS: In this cohort of HBV/HIV-coinfected individuals, full HBV DNA suppression was achieved in the majority of patients independent of treatment allocation. Loss of HBe- and HBs-antigen was not different between the two study arms. Over a median treatment period of 116 weeks tenofovir was as effective as tenofovir plus lamivudine. Longer treatment periods may be needed to evaluate potential benefits of first-line combination therapy for chronic hepatitis B.     

Association of on‐treatment serum hepatitis B surface antigen level with sustained virological response to nucleos(t)ide analog in patients with hepatitis B e‐antigen positive chronic hepatitis B

Aim: This study evaluated the on‐treatment serum hepatitis B surface antigen (HBsAg) level during nucleos(t)ide analog (NUC) therapy and the correlation with off‐treatment sustained virological response (SVR). Methods: Fifty‐one consecutive patients with hepatitis B e‐antigen (HBeAg) positive chronic hepatitis B who achieved HBeAg loss/seroconversion after NUC therapy and completed 12 months or more of additional therapy were included. Serum HBsAg and hepatitis B virus (HBV) DNA levels were determined at baseline, 3, 6, 9 and 12 months, and at the end of treatment. SVR was defined as HBV DNA levels of less than 10 000 copies/mL until 6 or 12 months off‐treatment without reappearance of HBeAg. Results: Twenty‐two (43.1%) and 13 (25.5%) patients maintained SVR at 6 and 12 months off‐treatment, respectively. In univariate analyses, a decline of HBsAg of 0.5 log₁₀ IU/mL or less at 6 months (P = 0.006) and 12 months (P = 0.013), the mean change in HBsAg level at 6 months (P = 0.024), and lamivudine or entecavir treatment (P = 0.019) were significant predictive factors for SVR at 6 months off‐treatment. A decline of HBsAg of 0.5 log₁₀ IU/mL or less at 6 months and lamivudine or entecavir treatment were independent factors on multivariate analyses (odds ratio [OR], 16.67; 95% confidence interval [CI], 1.86–142.86 [P = 0.012]; and OR, 14.83; 95% CI, 1.18–185.73 [P = 0.036]; respectively). Conclusion: On‐treatment serum HBsAg level predicted early off‐treatment SVR to NUC therapy in patients infected with genotype C.     

Prevalence and risk factors for viral blipping in chronic hepatitis B patients treated with nucleos (t) ide analogues

The clinical relevance of viral blipping during nucleos (t) ide analogue (NA) treatment is unclear in chronic hepatitis B (CHB). We investigated the prevalence, risk factors and clinical outcomes for those with viral blipping during NA treatment. A retrospective cohort study investigated consecutively treated CHB patients from May 2008 to February 2015 on the NAs such as entecavir (ETV), tenofovir (TDF) and lamivudine (LAM). Included patients were previously treatment naive. Viral blipping was defined as serum HBV DNA >20 IU/mL on one occasion, and not >200 IU/mL, with subsequent measurement returning to undetectable levels, that is <20 IU/mL. A total of 242 treatment‐compliant CHB patients were included with 44 (18.2%) experiencing viral blipping. In multivariable Cox regression, Asian race (HR=7.40, 95% CI 1.01–54.29, P<.049), LAM therapy (vs ETV/TDF, HR=2.53, 95% CI 1.29–4.95, P<.007), higher creatinine (per SD, HR=1.47, 95% CI 1.21–1.79, P<.001), HBeAg positivity (HR=2.68, 95% CI 1.39–5.03, P<.003) and longer time to achieve undetectable HBV DNA (per month, HR=1.05, 95% CI 1.02–1.08, P=.001) were associated with an increased risk of viral blipping. Viral blipping did not show any significant association with viral breakthrough, HBsAg loss, ALT flares or disease progression. Viral blipping is a frequent event during NA therapy; however, it did not lead to any clinically significant outcomes. Thus, it may not require more frequent blood work and patient visits in clinical practice.     

Quantitative polymerase chain reaction assay for serum hepatitis B virus DNA as a predictive factor for post-treatment relapse after lamivudine induced hepatitis B e antigen loss or seroconversion

BACKGROUND AND AIMS: Lamivudine induces favourable virological and biochemical responses but post-treatment relapses are frequent, even in patients with hepatitis B e antigen (HBeAg) loss or seroconversion. The aim of this study was to determine whether extended lamivudine therapy for up to 12 months after HBeAg loss/seroconversion could decrease the risk of post-treatment virological relapse. In addition, we monitored serum hepatitis B virus (HBV) DNA levels using a quantitative polymerase chain reaction (PCR) assay during extended lamivudine therapy and analysed predictive factors for post-treatment relapse. PATIENTS AND METHODS: A total of 49 patients who exhibited HBeAg loss/seroconversion during lamivudine therapy received extended lamivudine therapy for six months (group 1, n=23) or 12 months (group 2, n=26) after HBeAg loss/seroconversion. Serum HBV DNA levels were quantified by a PCR based assay at the time of HBeAg loss/seroconversion, and at cessation of therapy. RESULTS: Post-treatment virological relapse rates at two years were 59% in group 1 and 50% in group 2. Age, time interval to HBeAg loss/seroconversion, and serum HBV DNA levels at the time of cessation of therapy were independent predictive factors for post-treatment relapse. The post-treatment relapse rate was 37% at two years in patients with serum HBV DNA levels of <200 copies/ml but 73% in those with > or =10(3) copies/ml. CONCLUSIONS: Extended lamivudine therapy for up to 12 months did not decrease the rate of post-treatment virological relapse, and monitoring of serum HBV DNA by a quantitative PCR method was helpful in predicting post-treatment relapse.     

Response to long-term lamivudine treatment (up to 5 years) in patients with severe chronic hepatitis B, role of genotype and drug resistance

Lamivudine is effective in suppressing viral replication, normalizing alanine aminotransferase (ALT), and improving histological appearance in HBe positive and negative hepatitis. It is unclear whether hepatitis B virus (HBV) genotype influences the response to lamivudine. We report the long-term response of patients with chronic hepatitis B with and without cirrhosis at baseline treated with lamivudine according to HBV genotype. Retrospective review of charts of all patients treated with lamivudine monotherapy between 1993 and 2002. Response to therapy defined as ALT in the normal range, undetectable HBV DNA, and in the HBeAg positive group loss of HBeAg and/or the development of anti-HBe. HBV DNA measured by the Digene Hybrid capture assay (sensitivity 1.4 x 10(6) copies/mL). YMDD mutation at rtL180M and rtM204V/I measured by restriction digest of amplified products. Genotyping performed by sequencing and phylogenetic tree analysis of the preS region of the virus genome. Seventy-one patients treated with lamivudine for 6 months or more, 53 (75%) were male, average age 47 years, 38 (54%) were HBeAg+ and 33 (46%) HBeAg-. Mean baseline HBV DNA viral titre was 1280.2 copies/mL and 518 copies/mL respectively. Cirrhosis was present in 30 (42%). Sera were examined for YMDD mutations at last patient visit in 61 (86%), and were detected in 45 (74%), there being no association with a particular genotype. Data from up to 5 years on lamivudine indicated no difference in biochemical or virological response between genotypes. Cirrhosis was more prevalent with specific genotypes. We found no influence of HBV genotype on the development of resistance to lamivudine, however liver disease severity was influenced by genotype.     

Effect of virological response on post-treatment durability of lamivudine-induced HBeAg seroconversion

Lamivudine-induced HBeAg seroconversion may not be durable in Korean patients with hepatitis B virus (HBV) infection. It is unknown whether virological response during lamivudine treatment affects the post-treatment outcome. We retrospectively analysed 124 consecutive HBeAg-positive chronic hepatitis B (CHB) patients treated with lamivudine. Lamivudine was given at a dose of 100 mg per day. HBV DNA levels in sera obtained before and during therapy were measured by the Digene Hybrid Capture II assay and Digene Ultrasensitive Hybrid Capture II assay, respectively. HBeAg seroconversion was achieved in 42 of the 124 patients (33.8%) treated with lamivudine. Mean duration of treatment in HBeAg seroconverters was 12.86 +/- 4.44 months. During the follow-up period, the cumulative relapse rates at 3 months and 6 months post-treatment in 42 patients with HBeAg seroconversion were 40.5% and 57.4%, respectively. Among 31 seroconverted patients whose sera were available at the second month of treatment, HBV DNA remained at > 4.7 x 103 genomes/mL in 15 patients and decreased to < 4.7 x 103 genomes/mL in the remaining 16 patients. HBV DNA levels at the second month of treatment was not related with relapse after discontinuation of treatment (66.7% vs. 43.8%, P= 0.2). At the time of HBeAg seroconversion, HBV DNA remained at > 4.7 x 103 genomes/mL in five patients and decreased to < 4.7 x 103 genomes/mL in the remaining 37 patients. Relapse rates were increased in patients who remained at > 4.7 x 103 genomes/mL compared with patients with HBV DNA levels < 4.7 x 103 genomes/mL (100% vs. 51.4%, P < 0.001). Thus, monitoring of serum HBV DNA at the time of HBeAg seroconversion may be helpful for predicting relapse in patients with lamivudine-induced HBeAg seroconversion.     

Prevalence and virological profiles of hepatitis B infection in human immunodeficiency virus patients

AIM: To determine the prevalence of hepatitis B virus (HBV) in adult human immunodeficiency virus (HIV) patients with CD4+ T-cell count less than 500/mm 3 and without antiretroviral therapy; to describe different HBV-HIV coinfection virological profiles; and to search for factors associated with HBs antigen (HBsAg) presence in these HIV positive patients.METHODS: During four months (June through September 2006), 491 patients were received in four HIV positive monitoring clinical centers in Abidjan. Inclusion criteria: HIV-1 or HIV-1 and 2 positive patients, age ≥ 18 years, CD4+ T-cell count < 500/mL and formal and signed consent of the patient. Realized blood tests included HIV serology, CD4+ T-cell count, quantitative HIV RNA load and HBV serological markers, such as HBsAg and HBc antibody (anti-HBcAb). We performed HBeAg, anti-HBe antibody (anti-HBeAb), anti-HBc IgM and quantitative HBV DNA load in HBsAg positive patients. Anti-HBsAb had been tested in HIV patients with HBsAg negative and anti-HBcAb-positive. HBV DNA was also tested in 188 anti-HBcAb positive patients with HBsAg negative status and without anti-HBsAb. Univariate analysis (Pearsonχ 2 test or Fischer exact test) and multivariate analysis (backward step-wise selection logistic regression) were performed as statistical analysis. RESULTS: Mean age of 491 patients was 36 ± 8.68 years and 73.3% were female. Type-1 HIV was found in 97% and dual-type HIV (type 1 plus type 2) in 3%. World Health Organization (WHO) clinical stage was 1, 2, 3 and 4 respectively in 61 (12.4%), 233 (47.5%), 172 (35%) and 25 patients (5.1%). Median CD4+ T-cell count was 341/mm 3 (interquartile range: 221-470). One hundred and twelve patients had less than 200 CD4+ T-cell/mm 3 . Plasma HIV-1 RNA load was elevated (≥ 5 log 10 copies/mL) in 221 patients (45%). HBsAg and anti-HBcAb prevalence was respectively 13.4% and 72.9%. Of the 66 HBsAg positive patients, 22 were inactive HBV carriers (33.3%), 21 had HBeAg positive hepatitis (31.8%) and 20 had HBeAg negative hepatitis (30.3%). HBeAg and anti-HBeAb were indeterminate in 3 of them. Occult B infection prevalence (HBsAg negative, anti-HBcAb positive, anti-HBsAb negative and detectable HBV DNA) was 21.3%. Three parameters were significantly associated with the presence of HBsAg: male [odds ratio (OR): 2.2;P = 0.005; 95% confidence interval (CI): 1.3-3.8]; WHO stage 4 (OR: 3.2;P = 0.01;95% CI: 1.3-7.9); and aspartate aminotransferase (AST) level higher than the standard (OR: 1.9;P = 0.04; 95% CI: 1.02-3.8). CONCLUSION: HBV infection prevalence is high in HIV-positive patients. HBeAg positive chronic hepatitis and occult HBV infection are more frequent in HIVpositive patients than in HIV negative ones. Parameters associated with HBsAg positivity were male gender, AIDS status and increased AST level.     

Determinants for sustained HBeAg response to lamivudine therapy

There are inconsistent data on the durability of hepatitis B e antigen (HBeAg) seroconversion after lamivudine is discontinued. The aim of this study was to examine the determinants for sustained HBeAg response to lamivudine therapy. Both host and viral factors as well as the drug factor were compared between 43 patients with sustained HBeAg response and 39 patients whose response was not sustained. All of them received a mean period of 16 months (range, 3-55 months) lamivudine therapy and had achieved complete response (HBeAg seroconversion plus HBV DNA seroclearance by hybrid capture assay and normal alanine aminotransferase [ALT]) and were followed-up for a mean period of 44 months (range, 12-88 months). Stepwise logistic regression model was used to estimate the sustained response on the presence of the following variables: age; gender; pretherapy ALT; total bilirubin and HBV DNA levels; time to HBeAg seroconversion; additional lamivudine treatment after HBeAg seroconversion; total duration of treatment; hepatitis activity index scores; periportal, intralobular, and portal inflammation and fibrosis scores; scores excluding fibrosis; status of precore mutation; basal core promoter mutation; and genotype. The results showed that genotype (OR, 5.922; 95% CI, 1.611-21.768; P =.007), age (OR, 0.943; 95% CI, 0.891-0.997; P =.040), and additional treatment (OR, 1.097; 95% CI, 1.028-1.171; P =.005) were independent factors to sustained HBeAg response. Further categorical analysis disclosed that patients with genotype B, age < or =36 years, and additional lamivudine treatment over 8 months have higher sustained response. In conclusion, HBV genotype, age, and additional treatment are the major determinants for the sustained HBeAg response to lamivudine therapy.     

Prolonged antiviral therapy for hepatitis B virus-infected health care workers: a feasible option to prevent work restriction without jeopardizing patient safety

To prevent transmission of hepatitis B virus (HBV) from health care workers (HCWs) to patients, highly viraemic HCWs are often advised to restrict performing exposure prone procedures (EPPs). To prevent loss of highly qualified medical personnel and simultaneously minimize transmission risk to patients, we offered highly viraemic HCWs antiviral therapy and evaluated the effects of this strategy. Eighteen chronic HBV-infected HCWs have been monitored every 3-6 months for a median period of 5.6 years (range 1.1-12.5 years). Antiviral therapy was offered if HBV DNA was above 10(5) copies/mL and EPPs were performed or active liver disease was present. Median HBV DNA levels, the percentage of days with HBV DNA above 10(3), 10(4) and 10(5) copies/mL, and reduction of HBV DNA during antiviral treatment have been analysed for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative HCWs separately. Prolonged viral suppression was achieved in both HBeAg-positive, as well as HBeAg-negative HCWs. In HBeAg-negative HCWs treatment with interferon or lamivudine maintained HBV DNA levels below 10(5) copies/mL. For HBeAg-positive HCWs continuous treatment with tenofovir or entecavir was essential for reaching low viraemia persistently. In 2004, median HBV DNA levels in both HBeAg-negative and HBeAg-positive HCWs were below 10(3) copies/mL and all HCWs executed their professional work full-range. For both HBeAg-positive and HBeAg-negative HCWs, antiviral treatment is effective in persistent suppression of virus levels below 10(5) copies/mL. This observation supports antiviral therapy as a viable management option instead of work restriction, with the provision of regular expert monitoring including quantification of HBV DNA.     

Intrahepatic hepatitis B virus covalently closed circular DNA can be a predictor of sustained response to therapy

BACKGROUND & AIMS: This study aimed to determine whether intrahepatic hepatitis B virus (HBV) covalently closed circular (ccc) DNA and total HBV DNA levels at the end of therapy would predict sustained response to therapy. METHODS: Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients receiving either lamivudine monotherapy or combination of peginterferon and lamivudine had liver biopsy at the end of 1 year therapy and were followed for 52 more weeks after cessation of therapy. Serum HBV DNA, intrahepatic HBV ccc DNA, and total HBV DNA levels were determined. RESULTS: Forty-seven patients, including 34 males and 13 females, were studied. Twenty-seven patients received combination therapy, and 20 patients received lamivudine monotherapy. Twenty-nine patients had end-of-treatment virologic response, and 15 patients had sustained response 52 weeks after therapy. At the end of treatment, log serum HBV DNA levels correlated well with log intrahepatic HBV cccDNA and log intrahepatic total HBV DNA levels. Log intrahepatic cccDNA and log intrahepatic total DNA levels were significantly lower among patients with sustained virologic response. The adjusted odds ratio for log cccDNA was 5.3 (95% CI: 1.5-18.2, P = .009) and, for log intrahepatic HBV DNA, was 4.4 (95% CI: 1.3-14.7, P = .015) to predict sustained virologic response. Using log cccDNA at -0.80 copies/genome equivalent as cutoff, the sensitivity, specificity, and positive and negative predictive values and accuracy of predicting sustained virologic response were 73%, 78%, 56%, 86%, and 77% respectively. CONCLUSIONS: Intrahepatic HBV cccDNA and intrahepatic total HBV DNA levels at the end of therapy are superior to serum HBV DNA as surrogates of sustained virologic response.     

Alanine aminotransferase levels are not significantly elevated in patients with HIV/HBV co-infection and lamivudine resistance

In hepatitis B virus (HBV) monoinfection, alanine aminotransferase (ALT) levels are linearly correlated with HBV DNA levels and lamivudine resistance. In human immunodeficiency virus (HIV)/HBV co-infection, little is known about the association between ALT, HBV DNA, and lamivudine resistance. We assessed HBV DNA, lamivudine resistance and ALT levels in 45 time points in 11 patients with HIV/HBV co-infection during lamivudine-containing antiretroviral therapy. High HBV DNA levels (>10(6) copies/mL) and lamivudine resistance developed in 45% and 91% of patients, respectively. However, ALT levels were not elevated in the setting of high HBV DNA levels (mean ALT, 48 IU/mL) or lamivudine resistance (mean ALT, 44 IU/mL). HBV viraemia and lamivudine resistance during extended lamivudine-containing antiretroviral therapy are common in HIV/HBV co-infection, occurring in the absence of significant ALT elevations. In HIV/HBV co-infection, measurement of HBV DNA and HBV resistance mutations may identify HBV virological failure before biochemical changes and should be routinely used in the management of HIV/HBV co-infection.     

Predictors of residual viremia in HIV-infected patients successfully treated with efavirenz and lamivudine plus either tenofovir or stavudine

In human immunodeficiency virus (HIV)-infected patients successfully treated with highly active antiretroviral therapy (HAART), a low level of HIV RNA persists in plasma at steady state for years and varies among patients. To understand predictors of residual viremia, we measured HIV RNA levels <50 copies/mL in patients after 1 year of treatment with efavirenz and lamivudine plus either tenofovir disoproxil fumarate (n=55) or stavudine (n=45), by use of an HIV RNA assay with a limit of detection of 2.5 copies/mL. The mean posttreatment HIV RNA levels were 0.58 log(10) copies/mL (3.8 copies/mL) in the tenofovir arm and 0.61 log(10)copies/mL (4.1 copies/mL) in the stavudine arm (P=.24). Forty-seven percent of patients receiving tenofovir, compared with 29% of patients receiving stavudine, had undetectable residual viremia (P=.07). In multivariate analyses, we found that lower baseline HIV RNA levels in plasma, lower HIV DNA levels in peripheral blood mononuclear cells, and inclusion in the tenofovir arm each independently predicted undetectable residual viremia (P<.05). However, a level of residual viremia <50 copies/mL was not associated with CD4 cell count changes or risk of virologic rebound through 72 weeks of follow-up.     

Profile of patients triply infected with HIV and the hepatitis B and C viruses in the HAART era

HIV-HCV-HBV-coinfected patients were assessed to characterize the viral interactions in the setting of HIV coinfection and in the HAART era. All positive anti-HCV antibody and HBs antigen-positive HIV-infected patients were identified at five HIV clinics. Antihepatitis delta (HDV) antibody, serum HIV RNA, HCV RNA, and HBV DNA quantification and genotype determinations were performed. Out of 67 patients identified 47 (70%) were receiving anti-HBV therapy. HCV RNA and HBV DNA were detectable in 52.5% and 37% of patients, respectively. All possible patterns were found, regardless of anti-HBV therapy. HDV coinfection was associated with undetectable HCV RNA [RR 9.52 (95% CI 1.85-49.01); p = 0.007]. Independent factors predicting undetectable HBV DNA lacked HBeAg [RR 13.94 (95% CI 3.05-63.72); p = 0.001] and use of anti-HBV therapy [RR 11.42 (95% CI 2.43-53.54); p = 0.002]. Replication and genotypes of HCV or HBV had no impact on the replication of the other virus. In conclusion, in this cohort of triple infection (HBV/HCV/HIV) various viral patterns were identified. Spontaneous HCV clearance was frequent, and it was independently associated with HDV coinfection. In the absence of HBV therapy, HBV most often actively replicates. HBV/HCV replication or genotypes were not related to the replication of the other virus.     

Early response to lamivudine therapy in clinically non-cirrhotic chronic hepatitis B patients with decompensation.

This study aimed to elucidate the rate and predictors of early (6 months) therapeutic responses to lamivudine, the rate of early mortality and the use of the model for end-stage liver disease (MELD) and Index in predicting the survival in patients with a clinical diagnosis of non-cirrhotic chronic hepatitis B with decompensation. Ninety-eight patients with lamivudine therapy were enrolled and MELD and Index scores were calculated. Surviving patients were treated with lamivudine for more than 6 months. Four (4.1%) of the 98 patients died after initiation of lamivudine therapy. After a 6-month lamivudine therapy, 80 (85.1%) patients and 71 (75.5%) patients had normal alanine aminotransferase (ALT) values and negative hepatitis B virus (HBV) DNA (<200 copies/mL), respectively, and hepatitis B e antigen (HBeAg)-negative patients had a significantly higher rate of negative HBV DNA than HBeAg-positive patients (P=0.002). The rates of HBeAg seroconversion and negative HBV DNA were 28.8 and 63.5%, respectively, and patients with HBeAg seroconversion had a significantly higher rate of negative HBV DNA (P=0.004). By multivariate analyses, older age, HBV nongenotype B infection, negative HBeAg and higher ALT levels were factors associated with negative HBV DNA, and a higher ALT level was associated with HBeAg seroconversion at month 6 after lamivudine therapy. MELD score and Index score were significantly associated with death and areas under the receiver operating characteristic curve for predicting survival were 0.936 and 0.907 respectively. We concluded that after 6-month lamivudine therapy, the patients who survived achieved favourable biochemical, virological responses and rate of HBeAg seroconversion. Both MELD and Index scoring systems are good models to predict the 6-month survival.