Partial Virological Response Research Articles

Effective antiviral therapy with entecavir in chronic hepatitis B virus carriers

To evaluate the short-term effect and safety of entecavir for the treatment of chronic hepatitis B (CHB) virus carriers. Ninety-three cases of CHB virus infection (hepatitis B surface antigen (HBsAg)-positive, hepatitis B e antigen (HBeAg)-positive, hepatitis B core antibody (HBcAb)-positive, HBV DNA≥1x10(5) copies/mL) were divided into two groups: CHB virus carrier (47 cases) and CHB (46 cases). All of the 93 cases were given 0.5 mg entecavir orally once a day for 48 weeks. Virology, serology and biochemistry tests were perrmed at treatment weeks 0, 4, 12, 24 and 48. Side effects of entecavir and the incidence of liver cirrhosis and hepatocellular carcinoma were recorded. The CHB virus carrier and CHB group had complete virological response rates of 14.9% and 17.4% at week 4, 51.1% and 63.0% at week 12, 76.6% and 89.1% at week 24, and 97.9% and 100% at week 48, respectively; there was no significant difference between the two groups (P>0.05). The CHB virus carrier and CHB group had partial virological response rates of 42.6% and 47.8% at week 4, 57.44% and 65.2% at week 12, 85.0% and 89.1% at week 24, and 100% and 100% at week 48, respectively; there was no significant difference between the two groups (P>0.05). No cases in either group experienced virologic breakthrough during the treatment course. The CHB virus carrier and CHB group had serological response (HBeAg-negative) rates of 0 and 4.3% at week 4, 2.1% and 8.7% at week 12, 4.3% and 13.0% at week 24, and 8.5% and 21.7% at week 48, respectively; there was no significant difference between the two groups (P>0.05). The CHB virus carrier and CHB group had HBeAg seroconversion rates of 0 and 0 at week 4, 0 and 4.4% at week 12, 2.1% and 10.9% at week 24, and 6.4% and 17.4% at week 48, respectively; there was no significant difference between the two groups (P>0.05). No case in either group showed HBsAg-negativity and seroconversion during the treatment course. The CHB group had a biochemical response (alanine aminotransferase normalization) rate of 26.1% at week 4, 65.2% at week 12, 91.3% at week 24, and 97.8% at week 48.No case in either group showed biochemical breakthrough during the treatment course. There were no cases of liver cirrhosis or hepatocellular carcinoma in either group. There were no side effects of the entecavir treatment experienced in either group. Antiviral therapy with entecavir is effective, safe and well tolerated in CHB virus carriers.

Tenofovir‐based alternate therapies for chronic hepatitis B patients with partial virological response to entecavir

Entecavir (ETV) is a first-line antiviral therapy for treating chronic hepatitis B (CHB); however, some patients have suboptimal response to ETV. Currently, there are limited data on how to approach these patients. Therefore, our aim was to compare the effectiveness of two alternate therapies--tenofovir (TDF) monotherapy and combination therapy of ETV+TDF--in CHB patients with ETV partial virological response. We conducted a retrospective study of 68 patients who had partial virological response to ETV, defined as having detectable HBV DNA following at least 12 months of ETV, and were switched to TDF monotherapy (n = 25) or ETV+TDF (n = 43). Patients were seen in seven US liver/community-based clinics and started on ETV between 2005 and 2009. The majority of patients were male; the vast majority were Asian and had positive hepatitis B e antigen (HBeAg). Patients in both groups had similar pretreatment characteristics. Complete viral suppression (CVS) rates with TDF monotherapy and ETV+TDF were similar after 6 months (71% vs 83%, P = 0.23) and 12 months (86% vs 84%, P = 0.85), and there was no statistically significant difference in CVS rates even when only patients with higher HBV DNA levels at switch (>1000 IU/mL) were evaluated. Multivariate analysis indicated that ETV+TDF was not an independent predictor of CVS compared to TDF monotherapy (OR = 1.19, P = 0.63). In conclusion, TDF monotherapy and ETV+TDF are comparable in achieving CVS in CHB patients with partial virological response to ETV. Long-term alternate therapy with one pill (TDF monotherapy) vs two pills (ETV+TDF) could lead to lower nonadherence rates and better treatment outcomes.

Prediction of prognosis to lamivudine in patients with spontaneous reactivation of hepatitis B virus-related acute-on-chronic liver failure: Using virologic response at week 4

Background/aimsCurrent results had demonstrated lamivudine (LAM) contributed to improve liver function and short-term prognosis in patients with hepatitis B virus-related acute-on-chronic liver failure (ACLF), but data concerning the outcome of long-term prognosis are limited. Our objective was to explore the prediction value of early viral response for prognosis and LAM resistance in ACLF patients with lamivudine treatment within 96weeks. MethodsOne hundred and forty consecutive subjects were recruited, 76 patients were treated with LAM and supportive treatment (LAM group) and 64 patients only received supportive treatment (non-NAs group). All the patients were followed up until death or 96weeks. The primary end point was overall survival rate at 96weeks, as well as the relationship between the virologic response at weeks 4 or 12 and prognosis and resistance at 96weeks. ResultsAt 96weeks, the cumulative survival was higher in the LAM group than that in the non-NA group (43/76 (56.58%) vs 9/64 (14.06%), respectively, p=0.000). The survival rate of patients achieved complete viral response (CVR) at week 4 was higher than that of those with partial virologic response (PVR) during the 96-week follow-up (27/29 [93.10%] vs 16/45 [35.56%], p=0.000). In CVR patients, there was a significant improvement in model for end-stage liver failure (MELD) scores compared to PVR. Logistic recurrence indicated that both 4-week CVR and MELD scores were an independent predictor of the 96-week survival. Twelve patients developed LAM resistance (22.22%); all of them came from the PVR at 4weeks. ConclusionLAM can significantly improve the long-term survival rate, and 4weeks CVR can predict the long-term clinical outcome and LAM-resistant in patients with HBV-related ACLF.

Associations between human TRIM22 gene expression and the response to combination therapy with Peg-IFNα-2a and ribavirin in Iranian patients with chronic hepatitis C.

Interferons are able to exert an antiviral effect against hepatitis C virus (HCV) infection via induction of interferon-stimulated genes (ISGs). This study tested whether differential expression of an important ISG with antiviral properties, tripartite motif 22 (TRIM22), correlates with a response to Peg-IFNα-2a/RBV combination therapy in treatment-naive patients with chronic hepatitis C. A total of 32 patients with chronic hepatitis C were enrolled in this study and received standard Peg-IFNα-2a/RBV combination therapy. HCV viral load was measured during treatment, at the end of treatment, and 6 months later to determine the treatment outcome. Quantitative real-time PCR was used to assess the expression levels of TRIM22 in peripheral blood mononuclear cells (PBMCs) of the patients before antiviral therapy. Of the 32 patients, 26 (81.3%) were males. In this study, there were 16 (50%) individuals with a sustained virologic response (SVR), and a virologic relapse was observed in the remaining half of the subjects. Testing for the presence of genomic HCV RNA in blood during therapy revealed a rapid virologic response (RVR) in 10 (31.2%) and a partial and complete early virologic response (EVR) in 8 (25%) and 24 (75%) of the cases, respectively. TRIM22 mRNA levels were significantly higher in patients with a sustained virologic response than in relapsers (P = 0.002) and in patients with a rapid virologic response than in the others (P = 0.040). No statistically significant difference was seen in the expression of TRIM22 between patients with a partial early virologic response and a complete early virologic response. This study showed that pretreatment upregulation of TRIM22 may be associated with responsiveness to Peg-IFNα-2a/RBV combination therapy.

Lamivudine therapy in HBeAg negative chronic hepatitis B patients

Background: Lamivudine therapy in chronic hepatitis B (CHB) treatment is not encouraged because of its lower resistance barrier. In this study, we aimed to investigate the long-term efficacy of lamivudine treatment in HBeAg negative CHB patients. Methods & Materials: This retrospective study is conducted in three different tertiary care hospitals. Virological response (VR) is defined as undetectable HBV DNA by a sensitive PCR assay during therapy. Partial virological response (PVR) is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 6 months of therapy in compliant patients. Virological breakthrough also called as relapse is defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/ml compared to the lowest value of HBV DNA level on therapy. Results: A total of 145 patients (57,9% male) were evaluated. Theirmean agewas 44,6 years and 23 (15,9%) of themwere treated with interferons previously. The median value of the ISHAK histological activity index (HAI) and fibrosis were 6 (range: 2-16) and 1 (range: 1-5). Themeanvalue of ALT, AST, andHBVDNAwere57U/L, 42 U/L and 1.189.806 IU/mL, respectively. Treatment of fifty-three (36,6%) patientswas switched tomore potent drugs due to PVR (29; 20%) or relapse (24; 16,6%). Relapse was observed between 13 and 36 months in majority of relapsers (12 cases in 13 to 24 months and 8 cases in 25 to 36months). VRwas observed in 92 (63,4%) and their median time on lamivudine therapy was 34,5 months (range: 6-78 months). Baseline characteristics of virologic responders and switched group were shown in Table 1. Conclusion: Our results showed that more than 60% patients maintain viral suppression more than thirty months. Lamivudine can still be a reliable drug especially in low-income countries because of its low cost. However, lamivudine should be used with more caution in patients who have low thrombocyte and high HAI, fibrosis, ALT, and AST levels.

P1043 REAL-LIFE PERSISTENCE AND ADHERENCE IN ETV TREATED CHRONIC HEPATITIS B PATIENTS: RESULTS OF A GERMAN PROSPECTIVE MULTICENTER OBSERVATIONAL STUDY

P1043 REAL-LIFE PERSISTENCE AND ADHERENCE IN ETV TREATED CHRONIC HEPATITIS B PATIENTS: RESULTS OF A GERMAN PROSPECTIVE MULTICENTER OBSERVATIONAL STUDY J. Petersen, T. Wilke, S. Mauss, R. Heyne, C. Herold, M. Wiese, K. Boeker, T. Pichl, D. Hueppe. ifi – Institut fur Interdisziplinare Medizin, Hamburg, IPAM Wismar, Wismar, Medizinisches Versorgungszentrum, Duesseldorf, Leberzentrum Checkpoint, Berlin, Internisten am Ring, Nuernberg, Gesellschaft fur Klinische Studien, Leipzig, Leberpraxis Hannover, Hannover, BristolMyers Squibb GmbH & Co. KGaA, Munich, Gastroenterologische Gemeinschaftspraxis Herne, Herne, Germany E-mail: petersen@ifi-medizin.de Background and Aims: Entecavir (ETV) is a very effective and safe treatment option in chronic hepatitis B (CHB) patients. However, some patients show only a partial virologic response. The most reasonable explanation is non-persistence/non-adherence. Persistence and adherence measurement is underrepresented in clinical trials. Therefore, the extent of non-persistence (NP), nonadherence (NA) and clinical outcomes of any NP/NA were measured in ETV-treated patients in a real-life study. Methods: In a prospective observational multicenter study, persistence and adherence were measured based on documented ETV prescriptions within a 12 month period. A patient was defined as NP if he missed all treatment doses in >30 subsequent days. Adherence was measured based on medication possession ratio (MPR) between first and last documented prescription (NA if MPR 30 subsequent days (NP group), 30% of patients in the NP group (n =9) and none of the persistent patients were classified as non-adherent. Mean MPR for all patients was 95.3%. 84.4% of persistent/adherent patients and 63.0% of patients in the NP group reached undetectable HBV-DNA levels (p = 0.022). So far no significantly correlating factors for NP/NA could be detected.

Dynamic comparison between Daan real-time PCR and Cobas TaqMan for quantification of HBV DNA levels in patients with CHB

BackgroundHepatitis B virus (HBV) DNA levels are crucial for managing chronic hepatitis B (CHB). It was unclear whether Daan real-time polymerase chain reaction test (Daan test) or COBAS TaqMan HBV DNA Test (Cobas TaqMan) was superior in measuring different HBV DNA levels in clinical specimens.MethodsWe enrolled 67 treatment-naïve, HBV surface antigen-positive CHB patients (high baseline viral levels) who received either lamivudine/adefovir or entecavir. Serum samples were tested at baseline and treatment week 24 using the Daan test and Cobas TaqMan.ResultsIn the 67-baseline samples, the HBV DNA levels with the Cobas TaqMan (7.90 ± 0.73 log10 IU/mL) were significantly greater than those of the Daan test (7.11 ± 0.44 log10 IU/mL; P < 0.001). Of the 67 24-week samples (low viral levels), the Cobas TaqMan detected 59 (88.1%; 8 undetected); the Daan test detected 33 (49.3%; 34 undetected; P < 0.001). The Cobas TaqMan detected HBV DNA in 26 of 34 samples undetectable by the Daan test (range, 1.4–3.7 log10 IU/mL) or 38% of samples (26/67). The reductions in viral load after 24 weeks of oral antiviral treatment in the 33 samples that were positive for both the Daan test and the Cobas TaqMan test were significantly different (3.59 ± 1.11 log10 IU/mL versus 4.87 ± 1.58 log10 IU/mL, respectively; P = 0.001). Spearman correlation analysis showed positive correlation between results from two tests (rp = 0.602,P<0.001). The HBV genotypes and the anti-viral treatment did not affect the measurements of the HBV DNA by the Daan assay and the Cobas Taqman assay.ConclusionThe Cobas Taqman was more sensitive at low viral loads than the Daan test and the change from complete to partial virological response could affect clinical decisions. The Cobas Taqman may be more appropriate for detection of HBV DNA levels.

Impact of comorbid hepatic steatosis on treatment of chronic hepatitis C in Japanese patients and the relationship with genetic polymorphism of IL28B, PNPLA3 and LDL receptor.

The impact of hepatic steatosis on interferon therapy for patients with chronic hepatitis C (CHC) has been associated with single-nucleotide polymorphisms (SNP) of IL28B, patatin-like phospholipase domain-containing protein 3 (PNPLA3), and low-density lipoprotein (LDL) receptor. Whether this holds true for Japanese patients, however, remains unresolved. The present study prospectively enrolled 226 Japanese patients with CHC, and investigated the impact of hepatic steatosis and its related SNPs, including rs8099917 of IL28B, rs738409 of PNPLA3, and rs14158 of LDL receptor, on outcomes of peg-interferon and ribavirin therapy. In multivariate logistic regression analysis, significant factors affecting the severity of hepatic steatosis were high body mass index and the minor alleles of IL28B SNP (p＝0.020 and 0.039, respectively). The risk alleles of PNPLA3 SNP also showed weak association (p＝0.059). Severe steatosis and the minor alleles of IL28B SNP were significantly associated with null or partial virological response in patients with HCV genotype 1, as were female gender, and low LDL cholesterol (p＝0.049, and ＜0.001, respectively). The SNP genotype of PNPLA3 and LDL receptor did not have a significant impact on therapeutic outcomes. With respect to the SNP sites examined, the SNP of PNPLA3 has a weak association with severe hepatic steatosis, but not with the outcome of interferon therapy.

Continuous Long-Term Entecavir Therapy in Naïve Chronic Hepatitis B Patients Showing Partial Virologic Response

Background/AimsWe investigated the efficacy of continuous long-term entecavir 0.5 mg treatment in naïve chronic hepatitis B patients showing a partial virologic response (PVR).MethodsA total of 227 patients were included. PVR was defined as a more than 1 log10 IU/mL decline in detectable serum hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR; ≥20 IU/mL) at week 48. A complete virologic response (CVR) was defined as undetectable serum HBV DNA by PCR (<20 IU/mL) at week 48.ResultsAt week 48, the rate of the PVR was 64/227 (28.2%). Among patients with PVR, the cumulative rates of virologic response (serum HBV DNA <20 IU/mL) at weeks 96 and 144 were 45.2% and 73.8%, respectively. The cumulative rates of genotypic resistance were not significantly different between patients with a PVR and patients with a CVR (p=0.057). However, the cumulative rates of virologic breakthrough were higher in patients with PVR than in patients with CVR (4% vs 0% and 11.2% vs 0% at weeks 96 and 144, respectively; p<0.001).ConclusionsLong-term continuous entecavir 0.5 mg treatment in patients with a PVR resulted in an additional virologic response without a significant increase in genotypic resistance. However, the rate of virologic breakthrough was higher in the partial responders.

Partial Virological Response to Adefovir Add-On Lamivudine Rescue Therapy in Patients with Lamivudine-Resistant Chronic Hepatitis B

Background/Aims: In patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB) receiving adefovir (ADV) add-on LAM therapy, insufficient viral suppression or the appearance of additional ADV resistance has remained unresolved. This study determined the partial virological response (PVR) criteria to predict a virological response (VR) at week 96 in these patients. Methods: 96 patients with LAM-resistant CHB (ADV add-on LAM therapy >2 years) were analyzed. For predicting VR at week 96, the area under the receiver operating characteristic curve values at different time points were compared to establish the optimal time point, and the maximal Youden index was calculated to determine the optimal cut-off hepatitis B virus (HBV) DNA level. Results: 50 (52.1%) patients achieved VR at 2 years after ADV add-on LAM therapy. The optimal PVR criteria were determined to be HBV DNA 500 IU/ml at week 48. 44 (45.8%) patients who met optimal PVR criteria showed a significantly higher risk for detectable HBV DNA levels at week 96 than those with a favorable VR (HBV DNA <500 IU/ml) at week 48. Conclusions: This study suggested optimal PVR criteria in patients with LAM-resistant CHB receiving ADV add-on LAM therapy. Modification of the antiviral agent regimen should be considered if the serum HBV DNA level exceeds 500 IU/ml at week 48.

T-15 Interim analysis of the Italian Master-Entas cohort study: entecavir can improve liver function in patients with chronic hepatitis B and liver cirrhosis

ance and side effects. Median age was 55 years (24–83) and median time to the first visit was 3.5 months. Forty-four per cent had liver cirrhosis. Seventeen patients were NUC experienced (8 LAM, 5 ADV+LAM, 1 LdT+LAM, 2 ADV, 1 TNF), 1/17 NUC experienced patients started a combination treatment with TDF-ETV. Cumulative rates of undetectable hepatitis B virus DNA were 62.8%, 83.1%, 89% and 89% and normalization of ALT was 59.2%, 78.7%, 87.1% and 81.2% at 6, 12, 18 and 24 months of follow-up. Thirty-nine patients were HBeAg positive and 17 achieved negative HBeAg with anti-HBe seroconversion in 15 cases (38.4%). HBsAg loss was observed in 5 patients. Two patients switched to TDF, in one case because of virologic failure and in the second one because of partial virologic response. Drug resistance mutations were evaluated in 10 patients at the first visit showing in a LAM-ADV experienced, patient mutation A181T and in the second LAM experienced patient, mutation A181V. During follow-up, drug resistance mutations were assessed in 15 patients, identifying A181V-T184S in a subject (LAM-ADV experienced) and L180M-M250V-M204V in the patient presenting virological failure (LAM experienced). Treatment compliance was in 96.3% of the patients, in 9/11 not compliant subjects undetectable HBV-DNA was achieved. The study of Entecavir treatment in field practice confirms its efficacy in suppressing HBV replication with rare drug resistance mutations and its safety in patients with chronic hepatitis and liver cirrhosis.

Clinical course of patients with insufficient viral suppression during entecavir therapy in genotype C chronic hepatitis B

The clinical course of patients with insufficient virologic suppression diagnosed with chronic hepatitis B undergoing entecavir therapy is unclear. We retrospectively investigated the long-term clinical outcomes of entecavir treatment for more than 12 months in 355 nucleos(t)ide-naïve chronic hepatitis B patients, particularly those with primary non-response or partial virologic response. The median duration of entecavir therapy was 40 months (range, 12-64 months). Virologic response was achieved in 315 patients (88.7%). One hundred forty-four (96.6%) of 149 HBeAg-negative patients achieved virologic response. Among 206 HBeAg-positive patients, 52 (25.2%) achieved HBeAg seroconversion. Virologic breakthrough was observed in 7 patients (2.0%). Of these 7 patients, 5 (1.4%) had genotypic resistance to entecavir. Primary non-response and partial virologic response were evident in 6 (1.7%) and 63 (17.7%) patients, respectively. During continuous prolonged entecavir therapy, virologic response of patients with primary non-response and partial virologic response was achieved in 6 (100%) and 28 (44.4%) patients, respectively. The vast majority of chronic hepatitis B patients in this study achieved virologic response through prolonged entecavir therapy, with only 1.4% chance of viral resistance. Furthermore, all patients with primary non-response were able to achieve virologic response without adjustment of antiviral therapy.

Efficacy of Entecavir Treatment for up to 5 Years in Nucleos(t)ide-Naïve Chronic Hepatitis B Patients in Real Life

Objective: To analyze the efficacy and safety of entecavir (ETV) treatment for up to 5 years in nucleos(t)ide-naïve chronic hepatitis B patients in real life.Methods: We retrospectively analyzed 230 nucleos(t)ide naïve chronic hepatitis B patients who received ETV 0.5 mg/day monotherapy for at least 3 months, of whom 113 were HBeAg positive and 117 were HBeAg negative. The primary endpoints was cumulative probability of achieving a virological response (undetectable serum HBV DNA, <100IU/mL). Secondary endpoints were rates of ALT normalization (ALT < upper limit of normal), HBeAg seroconversion, resistance, and safety.Results: The median follow-up duration was 27.5 months (3-73 months) and mean age was 42 years. With 230, 214, 180, 142, 88, 42 and 11 patients followed-up for at least 3 months,6 months, 1, 2, 3, 4 and 5 years, respectively. In all, Incremental increases were observed in the rates of undetectable HBV DNA. 67.0%, 85.0%, 89.4%, 94.4%, 95.5%, 97.6%, 100% had undetectable HBV DNA at month 3, month 6, 1 year, 2 years, 3 years, 4 years and 5 years. Proportions of patients achieving normal ALT were 73.9%, 85.5%, 82.8%, 89.4%, 80.7%, 85.7%, 100%, respectively. The rate of HBeAg seroconversion reached 21.4% and 15.4% at year2, 3, respectively. One patient achieved HBsAg seroclearance after 1 year, and achieved anti-HBs seroconversion at year 3. Of 180 patients, HBV DNA was detectable (partial virological response, PVR) in 19 patients at year 1 of follow-up, twelve of 14 (85.7%) patients with PVR need more than 1 year of continuous ETV therapy to achieved VR. At baseline, no ETV-resistance was detected in 25 ETV-naïve patients. One patient developed ETV-resistance mutations due to noncompliance. No serious adverse event was reported.Conclusion: Long-term ETV treatment of nucleos(t)ide-naïve was effective and safe in real life. Adjustment of ETV monotherapy in nucleos(t)ide-naïve patients with a partial virological response at 1 year may be unnecessary.

A 96-Week Randomized Trial of Switching to Entecavir in Chronic Hepatitis B Patients with a Partial Virological Response to Lamivudine

Growing numbers of chronic hepatitis B (CHB) patients in the Asia-Pacific region have failed first-line therapy with low genetic barrier drugs. This prospective, 96-week study investigated the antiviral efficacy, safety and tolerability of switching to entecavir versus maintaining lamivudine in CHB patients with a partial virological response to lamivudine. A total of 72 hepatitis B e antigen (HBeAg)-positive patients, with serum HBV DNA≥60 IU/ml after ≥6 months lamivudine monotherapy were randomized 1:1 to receive either entecavir 1.0 mg/day, or continued lamivudine 100 mg/day. Mean duration of prior lamivudine treatment was 15.1 months in the lamivudine-maintained patients and 16.1 months in the entecavir-switch patients, with mean baseline HBV DNA levels of 4.66 and 4.55 log(10) IU/ml, respectively. A greater proportion of entecavir-switch than lamivudine-maintained patients achieved undetectable HBV DNA at all time points (67.6% versus 11.4% at week 96; P<0.001). Entecavir-switch patients achieved a greater mean decrease in HBV DNA level by week 4, maintained through week 96. Entecavir-switch patients with baseline HBV DNA<5 log(10) IU/ml were more likely to achieve a virological response at week 96. A total of 6 (17.6%) entecavir-switch and 2 (5.7%) lamivudine-maintained patients achieved HBeAg loss, and 3 (8.8%) entecavir and 1 (2.9%) lamivudine patients achieved HBeAg seroconversion. Genotypic resistance to the assigned intervention emerged in 82.9% (29/35) of lamivudine-maintained patients, and in 3% (1/34) of entecavir-switch patients after 96 weeks. Switching to entecavir in patients with a partial virological response to lamivudine resulted in increased virological efficacy and lower rates of antiviral resistance than maintaining lamivudine.

Multidrug‐resistant hepatitis B virus resulting from sequential monotherapy with lamivudine, adefovir, and entecavir: Clonal evolution during lamivudine plus adefovir therapy

Whether multidrug-resistant (MDR) hepatitis B virus (HBV) harbors mutations co-located in the same HBV clones that confer reduced sensitivity to antiviral therapy remains uncertain. This study investigated the evolution of MDR HBV strains developed from sequential monotherapy with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) during LAM plus ADV salvage therapy. Sera were obtained from six patients who had developed sequential resistance to LAM, ADV, and ETV before and during LAM plus ADV therapy. The HBV genomes from each patient were amplified, cloned, and sequenced. Among 6 sets of 20 clones obtained before salvage therapy, all clones harbored the rtM204V mutation, and ETV-resistant mutations were detected with the rtM204V in 108 clones. The rtA181 mutation was not detected at baseline, but emerged in five patients during therapy. Among 9 sets of 20 clones obtained during salvage therapy, 39 clones harbored rtA181T/V ± rtN236T mutations, which were detected in the absence of rtM204 and ETV-resistant mutations in 37 clones (94.9%). Only two clones (5.1%) harbored both rtA181T/V and ETV-resistant mutations. The rtA181T/V mutation emerged after reversion from ETV-resistant mutants to wild-type HBV. Five patients achieved a partial virologic response to LAM plus ADV therapy. In conclusion, the majority of MDR mutations existed in different genomes. Suboptimal response to LAM plus ADV therapy may not result from the co-localization of MDR HBV mutations in the same genome, but instead the low antiviral potency of these drugs. Thus, more potent antiviral drug combinations may be an effective salvage therapy for patients infected with MDR HBV.

Long-term impact of entecavir monotherapy in chronic hepatitis B patients with a partial virologic response to entecavir therapy

Objective. Partial virologic response (PVR) in chronic hepatitis B (CHB) patients during antiviral therapy is associated with an increased risk of occurrence of viral resistance and treatment failure. The aim of this study was to evaluate the clinical and virological responses of partial responders to long-term entecavir (ETV) monotherapy. Material and method. In this open-labeled prospective study, 128 treatment-naïve CHB patients treated with 0.5 mg ETV once daily for more than 12 months were monitored at baseline and at 3-month intervals during treatment. Results. At baseline, the mean age of subjects was 47.0 ± 13.0 years, and the median duration of treatment was 27 months; 85 subjects (66.4%) were HBeAg-positive, and 47 patients (36.7%) had liver cirrhosis. Eighteen of 128 patients (14.0%) showed PVR to 48 weeks of ETV treatment, and 13 patients were followed up for over 24 months. Among them, 9 of 13 patients (69.2 %) achieved a complete virologic response (VR, HBV-DNA < 60 IU/mL) during prolonged ETV treatment. Four showed persistent PVR, but only one patient with poor compliance developed genetic resistance to ETV at month 27. The occurrence of PVR was independently associated with a high viral load, more than 7 log10 IU/mL (p = 0.014). Conclusions. CHB patients with a high viral load, more than 7 log log10 IU/mL, are related to the occurrence of PVR during ETV monotherapy. Long-term ETV monotherapy may be effective for suppressing serum HBV DNA levels in treatment- naïve CHB patients with a PVR to ETV.

Viral response at 6 months is associated with treatment outcome of adefovir add‐on therapy for lamivudine‐resistance

Adefovir add-on therapy is recommended for patients infected with lamivudine-resistant hepatitis B virus (HBV). We aimed to describe the long-term treatment outcome and predictors for good response of adefovir add-on therapy. A total of 559 chronic hepatitis B (CHB) patients who had been treated for at least 12 months with adefovir add-on therapy due to resistance to lamivudine were retrospectively included. Complete virologic response (CVR) was defined as serum HBV DNA <9IU/mL. Viral responses at 6months were classified as PCR negativity, partial virologic response (PVR, HBV DNA <2000 IU/mL), or inadequate virologic response (IVR, HBV DNA≥2000IU/mL). The median duration of follow-up was 31.5 months (range, 12-56). The cumulative probabilities of CVR during adefovir add-on therapy were 58%, 70%, 78%, and 80% at 12, 24, 36, and 43 months, respectively. The cumulative rates of resistance to adefovir were 0.4%, 0.8%, and 3.1% at 12, 24, and 36 months, respectively. The only baseline factor associated with CVR (hazard ratio 0.83, 95% confidence interval 0.62-0.91, P≤0.001) and resistance to adefovir (hazard ratio 1.925, 95% confidence interval 1.13-3.30, P=0.017) was serum HBV DNA level. Comparison of the cumulative rates of CVR and resistance to adefovir according to viral response at 6months showed significant differences among the three groups (P<0.0001 and P= 0.0005, respectively). Pre-treatment HBV DNA level and viral response at 6months is associated with treatment outcome for adefovir-add on therapy in lamivudine resistance.

Efficacy of lamivudine on acute-on-chronic liver failure in patients with chronic hepatitis B

To observe the therapeutic effects of lamivudine treatment in patients with early- to mid-stage hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). Clinical data of 73 hospitalized patients with HBV-ACLF were retrospectively analyzed. Prothrombin time (PT, active coagulation), HBV DNA, and model for end-stage liver disease (MELD) score data from treatment weeks 4, 8, 24, and 48 were collected and analyzed using the statistical t-test. During the treatment duration, the complete virologic response rates were 57.5% (42/73) at 4 weeks, 71.0% (44/62) at 8 weeks, 83.1% (49/59) at 24 weeks, and 86.5% (45/52) at 48 weeks. The partial virologic response rates were 30.1% (22/73) at 4 weeks, 25.8% (16/62) at 8 weeks, 17.0% (10/59) at 24 weeks, and 13.5% (7/52) at 48 weeks. At week 48, the survival rate was 71.2% (52/73) and the probability of survival was higher in the complete virological response rate (VRR) group than in the partial VRR group [45/73 (61.6%) vs. 7/73 (30.1%), respectively; P = 0.000]. In addition, there were significant improvements in the serum normalization rate of HBV DNA, alanine aminotransferase, aspartate aminotransferase, albumin, total bilirubin, PT and MELD score in surviving patients compared to baseline (P less than 0.05) and in the complete VRR group compared to the partial VRR group (P less than 0.05). Antiviral therapy using lamivudine may be an effective therapeutic option for patients with HBV-ACLF.

Partial Response to Entecavir and Tenofovir in Naïve Patients with Chronic Hepatitis B: Clinical Relevance and Management

Entecavir and tenofovir are the currently recommended first line analogues for treatment of naive patients with chronic hepatitis B. Despite their overall efficacy and high genetic barrier granting for a low risk of resistance, both regimens will fail to completely suppress HBV DNA at week 48 in 10% of HBeAg-negative and 30% of HBeAg-positive patients. A pre-treatment level >8 log10 IU/mL HBV DNA and poor medication adherence were the most significant predictors of a partial virological response (PVR). While the clinical relevance of PVR is still poorly understood, nucleos(t)ide (NUC)-naive PVR patients who maintained detectable levels of viremia in follow up, were at risk of developing resistance to ETV. Patients with a suboptimal decline of viremia during the first 48 weeks of therapy with ETV and/or a residual viremia >1,000 IU/mL, can be protected by a rescue switch to TDF. Resistance to TDF has not been described so far, yet the long-term risk of PVR in TDF-treated patients remains unclear.

High‐dose silibinin rescue treatment for HCV‐infected patients showing suboptimal virologic response to standard combination therapy

Incomplete suppression of hepatitis C virus (HCV) replication with persistence of minimal viremia (partial virologic response) leading to treatment failure can be observed in a significant proportion of HCV type 1-infected patients during antiviral therapy. Recently, high-dose intravenous silibinin has demonstrated strong antiviral activity against HCV. We were therefore interested in whether patients with partial virologic response can be rescued by the on-treatment addition of a short-term course of high-dose intravenous silibinin infusions. Twenty patients who failed to achieve a complete virologic response to different interferon-based regimens qualified for the rescue strategy and received 1400 mg/day silibinin infusions on two consecutive days. Complete viral suppression (below the limit of detection <6 IU/mL, TMA assay) could be induced in 13 of 20 patients within the first week after the short-term silibinin infusion, and all but one of them also remained HCV RNA negative during the subsequent follow-up period on continued peginterferon plus ribavirin treatment. In the remaining seven patients, no complete suppression could be achieved although four showed a significant HCV RNA reduction in response to silibinin. Silibinin infusions were generally well tolerated, and activation of abdominal peristalsis with nausea, diarrhoea and vomiting were the most prominent side effects. Of the twelve patients who exhibited a durable response to peginterferon and ribavirin treatment, three achieved an SVR, two achieved a week 12 SVR and four suffered a viral relapse. Three patients could not complete the assigned antiviral treatment with peginterferon alpha and ribavirin for nonvirological reasons. Short-term administration of high-dose intravenous silibinin might be an interesting approach to rescue patients with ongoing minimal residual viremia while on interferon-based therapy. These preliminary findings may stimulate further studies to evaluate more refined therapeutic strategies.