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

Entecavir and tenofovir are the currently recommended first line analogues for treatment of na?ve 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.     

Virologic Response and Safety of Tenofovir Versus Entecavir in Treatment-Na?ve Chronic Hepatitis B patients

Background/Aims:

This study aimed to evaluate the antiviral response and safety of tenofovir (TDF) versus entecavir (ETV) in treatment-naïve CHB patients.

Patients and Methods:

We performed a retrospective cohort study of treatment-naive CHB patients who were treated with TDF or ETV. We analyzed virologic, biochemical, and serologic responses at 3, 6, and 12 months.

Results:

A total of 107 patients (TDF group = 49, ETV group = 58) were included. Baseline characteristics were similar between the two groups. The estimated proportion of complete virologic response (CVR) in the TDF or ETV group was 44.9% versus 39.7% at 6 months and 89.6% versus 83.2% at 12 months, respectively (P = 0.991). Viral breakthrough was not observed in both groups. One patient in the TDF group and two patients in the ETV group experienced HBeAg loss, respectively (P = 0.657). High HBV DNA level at baseline was a significant negative predictor of virologic response by Cox regression analysis (P = 0.007). The safety profile was similar between the two groups. There was no case with serious adverse event.

Conclusions:

Both TDF and ETV were effective in achieving CVR and had a favorable safety profile in treatment-naïve CHB patients. High viral load at baseline was a negative predictive factor of CVR.     

Long-Term Treatment Efficacy and Safety of Clevudine Therapy in Na?ve Patients with Chronic Hepatitis B

Background/Aims

Clevudine (CLV) has potent antiviral activity against chronic hepatitis B (CHB) virus infection. The long-term efficacy and safety of CLV therapy in naïve patients with CHB were investigated.

Methods

In this retrospective study, 152 naïve Korean patients with CHB who received 30 mg of CLV once daily for at least 12 months were investigated.

Results

The cumulative rates at months 12, 24, and 36, respectively, were 65.8%, 74.7%, and 74.7% for undetectable serum hepatitis B virus (HBV) DNA (<12 IU/mL); 77.6%, 86.2%, and 86.2% for normalization of serum alanine aminotransferase (<40 IU/L); 17.6%, 23.5%, and 23.5% for hepatitis B e antigen (HBeAg) loss or seroconversion; and 6.6%, 22.5%, and 30.0% for viral breakthrough. HBeAg positivity (p=0.010), baseline serum HBV DNA level ≥6 log₁₀ IU/mL (p=0.032) and detectable serum HBV DNA (≥12 IU/mL) at week 24 (p=0.023) were independently associated with the development of viral breakthrough. During follow-up, CLV-induced myopathy developed in 5.9% of patients.

Conclusions

The results of long-term CLV therapy for the treatment of naïve patients with CHB showed a high frequency of antiviral resistance and substantial associated myopathy. Therefore, we advise that CLV should not be used as a first-line treatment for naïve patients given the availability of other more potent, safer antiviral agents.     

Clinical Course of Partial Virologic Response with Prolonged Tenofovir Therapy in Nuclos(t)ides-Naïve Patients with Chronic Hepatitis B

Digestive Diseases and Sciences - The clinical course of chronic hepatitis B (CHB) patients with partial virologic response (PVR) during tenofovir disoproxil fumarate (TDF) therapy remains unclear....     

Similar Response to Entecavir 0.5 and 1.0 Mg in Treatment-Naïve Chronic Hepatitis B Patients: A Case-Control Study

Background and Aims

The dose recommendation for entecavir (ETV) is 0.5 mg daily for treatment-naïve chronic hepatitis B (CHB) patients and 1.0 mg daily for lamivudine-refractory patients; however, few data are available for the efficacy of a 1.0-mg daily dose in treatment-naïve CHB patients. Our goal is to examine the treatment outcome of treatment-naïve patients placed on ETV 0.5 mg or ETV 1.0 mg daily through week 48.

Methods

Cases were 40 consecutive hepatitis B e antigen (HBeAg)-positive CHB patients treated with ETV 1.0 mg daily between January 2005 and September 2010, and controls were 40 consecutive CHB patients treated with ETV 0.5 mg daily between January 2005 and September 2010 at three US gastroenterology/liver clinics. Controls were matched for age (±5 years), sex, HBeAg, and baseline hepatitis B virus (HBV) DNA (±0.5 log₁₀ IU/ml). Complete viral suppression was defined as undetectable HBV DNA by polymerase chain reaction (<100 IU/ml).

Results

Both groups had similar distributions of age (38 ± 11 years), male patients (55 %), and mean HBV DNA (7.7 ± 1.1 log₁₀ IU/ml). The complete viral suppression rate was similar in both cases and controls through week 24 (15 vs. 15 %, p = 1.00) and week 48 (22 vs. 36 %, p = 0.17). Non-adherence was reported in three patients in the ETV 1.0 mg daily cohort at week 48.

Conclusions

There were no significant differences in the proportion of patients with complete viral suppression in patients treated with ETV 0.5 mg daily or the higher daily dose of 1.0 mg.     

Tenofovir in the Treatment of Na?ve and Refractory Chronic Hepatitis B: A Single Center Experience in Saudi Arabia

Background/Aims:

Tenofovir disoproxil fumarate (TDF) is a nucleotide analog used in the treatment of chronic hepatitis B (CHB) infection. This study evaluated the efficacy of TDF in achieving undetectable HBV DNA after 48 weeks of treatment in a Saudi cohort of CHB patients.

Patients and Methods:

This retrospective study included patients treated at a tertiary care center in Saudi Arabia from January 2009 to December 2012. Of the 68 eligible patients, 51 were treatment naïve and 17 were treatment-refractory. Twenty-three patients tested positive for HBeAg. The remaining 45 patients were HBeAg-negative.

Results:

The mean HBV DNA viral load decreased from 95 million IU/mL at baseline to 263 IU/mL after 48 weeks of treatment (P < 0.001). Overall, 62% of patients achieved a complete virological response (CVR) and 37% a partial virological response (PVR). Respective CVR and PVR rates according to subgroup were: HBeAg-positive (21.7% and 78.3%) and HBeAg-negative (84.4% and 15.6%). At 48 weeks, HBV DNA was undetectable in 66.7% of treatment-naïve and 53% of treatment-refractory patients (P = 0.3). Seroconversion occurred in 13 (57%) of HBeAg-positive patients. Two (3%) of the HBeAg-negative patients lost HBsAg at follow up. Mean alanine aminotransferase decreased significantly from 134 U/L before treatment to 37 U/L at 48 weeks (P < 0.001). Significant adverse events were not encountered during the study period.

Conclusion:

Forty-eight weeks of treatment with TDF reduced HBV DNA to undetectable levels in more than half of our patients regardless of whether they were treatment-naïve or refractory. HBeAg-negative (vs positive) patients experienced a better response rate.     

Characteristics of Treatment Na?ve Chronic Hepatitis B in Bangladesh: Younger Populations are More Affected; HBeAg-negatives are More Advanced

Background/Aim:

Bangladesh is a densely populated country with intermediate endemicity for chronic hepatitis B (CHB). The aim of the present study was to evaluate the biochemical, virological and histological character of CHB patients and to examine the relationship between these indices.

Materials and Methods:

One thousand and twenty-two patients of CHB fulfilled our inclusion criteria. Inclusion criteria were (1) HBsAg positive for at least 6 months, (2) HBeAg-positive or negative and (3) hepatitis B virus (HBV) DNA positive. Patients with detectable antibodies to human immunodeficiency virus (HIV), hepatitis Delta virus (HDV) or hepatitis C virus (HCV), with previous antiviral treatment, overt cirrhosis and hepatocellular carcinoma, were excluded. Of these, 191 patients were randomly selected for liver biopsy and were evaluated for analysis.

Results:

In the 191 patients, male to female ratio was 4.6:1; age distribution was 26.5 ± 8.5 (mean ± standard deviation) years. One hundred and seventy-eight (93.2%) patients were under 40 years. Sixty-eight (35.6%) patients were HBeAg-negative, had less DNA load, and were significantly older, more fibrotic and cirrhotic (P < 0.001). Correlation was not found between DNA level and histological activity. Histological activity was not correlated with ALT level in HBeAg-positive patients (P < 0.001).

Conclusion:

CHB affects the younger population in Bangladesh. HBeAg-positive CHB was associated with more fibrosis and cirrhosis. Serum HBV DNA levels do not correlate with the severity of histological lesions in all patients. Evaluation by liver biopsy remains gold standard for taking decision of treatment.     

HCV Therapy in 2011: Development of New Treatment Paradigms for Na?ve and Non-Responder Patients

The approval of the first direct-acting antiviral (DAA) drugs for treatment of HCV in 2011 has lead to improved sustained viral response (SVR) rates up to 79% in treatment-na?ve or relapse genotype 1 (G1) patients, and up to 59% for non-responder G1 patients. This review discusses the clinical skills required for the use of direct-acting anti-viral drugs (DAA), the use of genetic tests and HCV RNA assays, resistance-associated variants (RAV), treatment of special populations, and future directions. The results of the pivotal phase 3 trials with both telaprevir and boceprevir are summarized, including the efficacy, safety and tolerability, drug-drug interactions and management of the most common side-effects. Treatment strategies implemented in order to minimize the development of resistance with these first-generation protease inhibitors are explored. The use of these drugs ushers in a new era for the treatment of HCV but should be done with both care and caution.     

Pegylated Interferon-α Plus Ribavirin Therapy Improves Left Ventricular Diastolic Dysfunction in Patients With Chronic Hepatitis C Attaining Sustained Virological Response

Background

Pegylated interferon (pegIFN) in combination with ribavirin (RBV) has successfully improved the rate of sustained virological response (SVR) in chronic hepatitis C virus (HCV) infected individuals, which reduces the progression of the chronic liver disease. However, the influence of combination therapy (pegIFN/RBV) on cardiac function has yielded ambiguous results. The present study aimed to evaluate the effects of combination therapy with pegIFN/RBV on cardiac function of HCV-infected individuals with SVR.

A Randomized, Controlled Study of Thymosin-α1 Therapy in Patients with Anti-HBe, HBV-DNA-Positive Chronic Hepatitis B

No consistently effective therapy is yet available for the treatment of chronic HBsAg, anti-HBe, HBV-DNA-positive hepatitis. A multicenter trial has shown that the response rates are not significantly different when patients with anti-HBe-positive hepatitis are treated with six-month course of thymosin-₁ or of interferon-. However, since among these patients, interferon's real efficacy is still debated, with sustained biochemical response achieved in only a few of the treated patients, we conducted this controlled study to investigate the safety and efficacy of thymosin-₁ as compared with no treatment. Forty-four chronic hepatitis B virus (HBV) carriers, who were anti-HBe- and HBV-DNA-positive, were randomized, with stratification for the presence of cirrhosis at baseline liver biopsy, to receive either thymosin-₁ at a dose of 900 g/m² twice a week for six months or no treatment. At entry, both groups of patients were comparable for sex, age, liver histology, ALT, IgM anti-HBc, and HBV-DNA levels. Forty-two patients were followed-up for 20 months (median; range 12–32 months) after completion of therapy: one dropped out, and one developed hepatocellular carcinoma at six months. Thymosin-₁ treatment had no side effects. Six months after the end of the therapy, HBV-DNA was negative and ALT had normalized in 14% of treated cases and in 4.5% of control group, while IgM anti-HBc was negative (<0.200) in 14% of the treated patients and in 4.5% of the controls. Among the treated patients, the median ALT levels stayed significantly lower compared to the pretreatment values during the treatment period and six months of follow-up. During the first year, there were six flares of hepatitis in the control group and five among the treated patients (P = NS), yielding a per year average of 0.3 and 0.23 flares per patient, respectively. Among the treated patients, median IgM anti-HBc levels were low with respect to baseline values 4–10 months after treatment started. None became HBsAg negative. In conclusion, these results indicate that, in anti-HBe, HBV-DNA-positive chronic hepatitis B, thymosin-₁ therapy alone does not increase the response rate, but may contribute to reduce the immune-mediated liver cell necrosis as indirectly assessed by ALT and IgM anti-HBc levels.     

Can the Response to Iron Therapy Be Predicted in Anemic Nondialysis Patients with Chronic Kidney Disease?

Background and objectives: Anemia is iron responsive in 30 to 50% of nondialysis patients with chronic kidney disease (CKD), but the utility of bone marrow iron stores and peripheral iron indices to predict the erythropoietic response is not settled. We investigated the accuracy of peripheral and central iron indices to predict the response to intravenous iron in nondialysis patients with CKD and anemia.Design, setting, participants, & measurements: A diagnostic study was conducted on 100 nondialysis patients who had CKD and anemia and were erythropoiesis-stimulating agent and iron naive. Bone marrow iron stores were evaluated by aspiration. Hemoglobin, transferrin saturation index (TSAT), and ferritin were measured at baseline and 1 month after 1000 mg of intravenous iron sucrose. Posttest predictive values for the erythropoietic response (≥1-g/dl increase in hemoglobin) of peripheral and central iron indices were calculated.Results: The erythropoietic response was noted in a higher proportion in bone marrow iron-deplete than in iron-replete patients (63 versus 30%). Peripheral iron indices had a moderate accuracy in predicting response. The positive (PPV) and negative predictive values (NPV) were 76 and 72% for a TSAT of 15% and 74 and 70% for a ferritin of 75 ng/ml, respectively. In the final logistic regression model, including TSAT and ferritin, the chances of a positive response increased by 7% for each 1% decrease in TSAT.Conclusions: Because an erythropoietic response is seen in half of patients and even one third of those with iron-replete stores responded whereas peripheral indices had only a moderate utility in predicting response, the therapeutic trial to intravenous iron seems to be a useful tool in the management of anemia in nondialysis patients with CKD.Iron deficiency is common, and intravenous iron supplementation is a recognized therapy of anemia in long-term hemodialysis patients (HD), especially in those who are treated with epoetin (1–6). Several studies suggested that iron deficiency—evaluated by bone marrow iron examination—is common also in predialysis patients with chronic kidney diseases (CKD). In the reported series, the prevalence of bone marrow iron depletion varied widely from 23 to 90% (7,8). The role of iron supplementation in nondialysis patients with CKD is much less clear than in HD patients, although studies have reported a positive response to intravenous iron even without concomitant epoetin administration in 38 to 68% of patients (9–12).The prediction of erythropoietic response is clinically important, because the conventional markers of iron status—serum ferritin level and transferrin saturation index (TSAT)—although simple and relatively inexpensive, are not highly accurate in predicting response to iron in this population (5,7,8,11), and the safety of intravenous iron is a matter of concern in patients with CKD (13,14). Moreover, there are no published data relating iron stores, peripheral iron indices, and the response to intravenous iron. We conducted a study to investigate the accuracy of peripheral and central iron status indices to predict the response to intravenous iron in nondialysis patients who had CKD and anemia and were erythropoiesis-stimulating agent and iron naive.     

Pentraxin-3: A Novel Marker for Indicating Liver Fibrosis in Chronic Hepatitis B Patients?

Background: Pentraxin-3 (PTX-3) is an important marker that plays a role in suppressing inflammation and tissue repair. The aim of this study is to investigate the diagnostic and prognostic characteristics of PTX-3 in chronic hepatitis B (CHB) patients and the relationship between PTX-3 levels and fibrosis.Methods: A total of 52 CHB patients and 40 healthy subjects were included in the study. All of the CHB patients underwent liver biopsy and were then scored using an Ishak histologic scoring system. Blood samples were collected to evaluate the PTX-3 levels.Results: Of the subjects who participated in the study, 53% were female. The PTX-3 levels were determined as 5.63 ng/mL in the control group, and as 0.88 ng/mL in the CHB patient group. PTX-3 levels were found to be 1.19 ng/mL in stage 1, 0.89 ng/mL in stage 2, 0.68 ng/mL in stage 3, and 0.55 ng/mL in stage 4. Of the CHB patients, 44.2% had significant fibrosis, while 55.7% were identified as not having significant fibrosis. The PTX-3 values were 0.64 and 1.0 ng/mL in patients with and without significant fibrosis, respectively. The cut-off value for PTX-3 in predicting the absence of significant fibrosis was estimated as 0.9 ng/mL.Conclusion: The CHB patients were found to have lower serum PTX-3 levels compared to the control group, and these levels decreased even further as the stage of fibrosis progressed. In addition, the significant decrease in PTX-3 levels in patients with stage 1 fibrosis compared to the control group shows that PTX-3 can be used as a non-invasive marker for the early detection of fibrosis (P < .001).     

Very Low Viral Load (VLVL) Relapse Following Treatment of Naïve Patients with Chronic Hepatitis C

Background

Sustained virologic response (SVR) to treatment of naïve patients with chronic hepatitis C (HCV) with pegylated interferon and ribavirin is 50–60%. Patients who relapse have a poor response to re-treatment. We report a group of relapse patients with SVR to low-dose re-treatment after 6 months.

Aim

Characterization of HCV relapse patients with very low viral load (VLVL) (HCV RNA <5,000 IU/ml) 6 months after stopping full-dose initial treatment.

Methods

We identified 120 consecutive naïve patients over 4 years treated with pegylated interferon alpha-2a and ribavirin with full-dose therapy for 24 weeks (non-genotype 1) or 48 weeks (genotype 1) with baseline liver biopsy and at least 6 months of follow-up after treatment. HCV RNA by PCR and hepatic blood tests were obtained monthly during treatment and at least 1, 3, and 6 months post treatment.

Results

Of the initially treated patients, 54.2% had SVR, 25% non-response and 20.8% relapsed. Four of 25 who relapsed (16%) and one similar patient referred to our program had HCV RNA <5,000 IU/ml 6 months after stopping treatment (VLVL relapse). Significant differences (P < 0.05) compared with the 21 other relapse patients included all five patients who were genotype 1; 4/5 had cirrhosis, baseline HCV RNA was lower, and all had SVR to less intensive re-treatment for 6 months.

Conclusion

VLVL relapse patients should be sought, because SVR to re-treatment is common despite genotype 1 cirrhosis.