Roeland Zoutendijk

Entecavir treatment for chronic hepatitis B: Adaptation is not needed for the majority of naïve patients with a partial virological response†‡

Entecavir (ETV) is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)‐naïve chronic hepatitis B (CHB) patients. The aim of this study was to investigate the long term efficacy and safety of ETV in NA‐naïve CHB patients, particularly in those with detectable hepatitis B virus (HBV) DNA after 48 weeks, in whom treatment adaptation is suggested by current guidelines. In a multicenter cohort study, we investigated 333 CHB patients treated with entecavir monotherapy. The NA‐naïve population consisted of 243 patients, whereas 90 were NA‐experienced. Virological response (VR) (HBV DNA <80 IU/mL) was achieved in 48%, 76%, and 90% of hepatitis B e antigen (HBeAg)‐positive and in 89%, 98%, and 99% of HBeAg‐negative NA‐naïve patients at weeks 48, 96, and 144, respectively. Thirty‐six of 175 (21%) NA‐naïve patients with at least 48 weeks of follow‐up had a detectable load at week 48 (partial virological response [PVR]). Twenty‐nine (81%) patients with PVR reached VR during prolonged ETV monotherapy, and none of them developed ETV‐resistance. Among 22 patients with HBV DNA <1,000 IU/mL at week 48, VR was achieved in 21 (95%) patients, compared with eight of 14 (57%) patients with HBV DNA ≥1,000 IU/mL. Continuous HBV DNA decline was observed in most patients without VR during follow‐up, and in three patients adherence was suboptimal according to the treating physician. ETV was safe and did not affect renal function or cause lactic acidosis. Conclusion: ETV monotherapy can be continued in NA‐naïve patients with detectable HBV DNA at week 48, particularly in those with a low viral load because long‐term ETV leads to a virological response in the vast majority of patients. (HEPATOLOGY 2011;)

Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis

Objective Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression. Design In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80 IU/ml. Results Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20 months (IQR 11–32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10). Conclusion VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000 IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis.

Serum HBsAg Decline During Long-term Potent Nucleos(t)ide Analogue Therapy for Chronic Hepatitis B and Prediction of HBsAg Loss

Nucleos(t)ide analogues strongly inhibit viral replication in chronic hepatitis B (CHB) infection, but knowledge of their long-term effect on serum hepatitis B surface antigen (HBsAg) levels and HBsAg loss is lacking. Seventy-five CHB patients with virological response (VR) to ETV or TDF were included. HBsAg decline 2 years after VR was most pronounced in HBeAg-positive patients. Age, alanine aminotransferase, and HBeAg loss were associated with HBsAg decline in HBeAg-positive patients. Predicted median time to HBsAg loss was 36 years for HBeAg-positive and 39 years for HBeAg-negative patients. Thus, most patients treated with ETV and TDF will probably need decades of therapy to achieve HBsAg loss.

Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians

Background Hepatocellular carcinoma (HCC) risk-scores may predict HCC in Asian entecavir (ETV)-treated patients. We aimed to study risk factors and performance of risk scores during ETV treatment in an ethnically diverse Western population. Methods We studied all HBV monoinfected patients treated with ETV from 11 European referral centres within the VIRGIL Network. Results A total of 744 patients were included; 42% Caucasian, 29% Asian, 19% other, 10% unknown. At baseline, 164 patients (22%) had cirrhosis. During a median follow-up of 167 (IQR 82–212) weeks, 14 patients developed HCC of whom nine (64%) had cirrhosis at baseline. The 5-year cumulative incidence rate of HCC was 2.1% for non-cirrhotic and 10.9% for cirrhotic patients (p<0.001). HCC incidence was higher in older patients (p<0.001) and patients with lower baseline platelet counts (p=0.02). Twelve patients who developed HCC achieved virologic response (HBV DNA <80 IU/mL) before HCC. At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with development of HCC. Discriminatory performance of HCC risk scores was low, with sensitivity ranging from 18% to 73%, and c-statistics from 0.71 to 0.85. Performance was further reduced in Caucasians with c-statistics from 0.54 to 0.74. Predicted risk of HCC based on risk-scores declined during ETV therapy (all p<0.001), but predictive performances after 1 year were comparable to those at baseline. Conclusions Cumulative incidence of HCC is low in patients treated with ETV, but ETV does not eliminate the risk of HCC. Discriminatory performance of HCC risk scores was limited, particularly in Caucasians, at baseline and during therapy.

Fluid, electrolyte and acid–base disorders associated with antibiotic therapy

Antibiotics are among the most frequently prescribed drugs in medicine. Their use, however, is often limited by associated renal toxic effects. The most common manifestation of these toxic effects is decreased glomerular filtration rate. However, they can also occur while renal function remains near to normal. This Review focuses on antibiotic-associated fluid, electrolyte and acid–base disorders that do not greatly reduce glomerular filtration. Renal tubules can be affected by antibiotics at various locations. In the proximal tubule, toxic effects of tetracyclines and aminoglycosides can result in complete proximal tubular dysfunction, also known as Fanconi syndrome. Aminoglycosides (and capreomycin) can also affect the loop of Henle and lead to a Bartter-like syndrome. In the collecting ducts, antibiotics can cause a diverse range of disorders, including hyponatremia, hypokalemia, hyperkalemia, renal tubular acidosis, and nephrogenic diabetes insipidus. Causative antibiotics include trimethoprim, amphotericin B, penicillins, ciprofloxacin, demeclocycline and various antitubercular agents. Here, we describe the mechanisms that disrupt renal tubular function. Integrated with the physiology of each successive nephron segment, we discuss the receptors, transporters, channels or pores that are affected by antibiotics. This insight should pave the way for pathophysiology-directed treatment of these disorders.

Hepatitis B Surface Antigen Declines and Clearance During Long-Term Tenofovir Therapy in Patients Coinfected With HBV and HIV

BACKGROUND The kinetics of hepatitis B surface antigen (HBsAg) are predictive in HBV-infected patients treated with pegylated interferon. Knowledge about the value of HBsAg levels in patients coinfected with HBV and human immunodeficiency virus (HIV) is lacking. METHODS We quantified serum HBsAg in a Dutch multicenter cohort of 104 patients coinfected with HIV and HBV who were treated with tenofovir disoproxil fumarate (TDF) as part of highly active antiretroviral therapy. The median duration of therapy was 57 months (interquartile range, 34-72 months). RESULTS Hepatitis B e antigen (HBeAg)-positive patients achieved a decline of 2.2 log IU/mL in HBsAg, whereas HBeAg-negative patients only achieved a decline of 0.6 log IU/mL during 6 years of TDF therapy. Declines in HBsAg at months 6 and 12 correlated with CD4 cell count for HBeAg-positive patients. Five HBeAg-positive patients (8%) and 3 HBeAg-negative patients (8%) cleared HBsAg. HBeAg-negative patients who cleared HBsAg had lower baseline HBsAg as compared to patients who remained HBsAg positive. The majority of patients who cleared HBsAg achieved this end point within the first year. In HBeAg-positive patients, decline in HBsAg at month 6 was predictive of achieving HBsAg seroclearance. CONCLUSIONS Receipt of TDF therapy by HIV/HBV-coinfected patients for up to 6 years led to a significant decrease in HBsAg in the HBeAg-positive population. HBsAg kinetics early during treatment were predictive of HBsAg seroclearance and correlated with an increased CD4 cell count, underlining the importance of immune restoration in HBV clearance.

Hepatitis B surface antigen monitoring and management of chronic hepatitis B.

Summary.  Serum hepatitis B surface antigen (HBsAg) levels reflect intrahepatic hepatitis B virus (HBV) covalently closed circular DNA and may be a valuable addition to HBV DNA in the management of patients with chronic hepatitis B (CHB). Among HBeAg‐negative CHB patients with low HBV DNA levels, HBsAg quantification may help distinguish those with active CHB from true inactive carriers with a very favourable prognosis, thus limiting the need for long‐term intensive monitoring of ALT and HBV DNA levels. In patients treated with peginterferon (PEG‐IFN), achievement of a decline in HBsAg during therapy appears to be an important marker for treatment outcome, and several groups have proposed stopping rules based on HBsAg thresholds. A recently described stopping rule incorporating a combination of HBsAg and HBV DNA levels can accurately identify HBeAg‐negative patients, especially those with HBV genotype D, not responding to PEG‐IFN. Current applications of HBsAg levels in the monitoring of patients treated with nucleo(s)tide analogues are still being evaluated. First data from these studies show that HBsAg decline, and thus subsequent clearance, is confined to those with an active immune response to HBV, such as HBeAg‐positive patients with elevated ALT, or those who achieve HBeAg clearance.

Efficacy and tolerance of a combination of tenofovir disoproxil fumarate plus emtricitabine in patients with chronic hepatitis B: A European multicenter study

BACKGROUND AND AIMS The combination of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) is used extensively to treat HIV infection and also has potent activity against hepatitis B virus (HBV) infection. The aim of this study was to assess the efficacy and tolerance of TDF + FTC in patients with chronic hepatitis B (CHB). METHODS Seventy eight consecutive CHB patients from five European centers were included. All started a TDF + FTC combination between October 2005 and March 2010. Virological, biochemical, and clinical data were recorded during follow-up. Tolerance was also monitored. Patients were classified into either treatment simplification (TS), where efficacy of the previous treatment was obtained at TDF + FTC initiation, and treatment intensification (TI), where the previous line of therapy had failed. RESULTS TDF + FTC was given as a TI to 54 patients (69%) and as a TS to 24 (31%). Among patients with TI, 83% were males. The median baseline HBV-DNA was 4.4 log10 IU/mL, and median alanine-transaminase (ALT) was 1.10 × ULN. Sixty percent were HBeAg positive, 47% had significant fibrosis (≥ F3 Metavir equivalent), and 29% had confirmed cirrhosis. Median treatment duration was 76 weeks (interquartile range 60-116). Kaplan-Meier analysis showed that, 48 weeks after TI, the probability of being HBV-DNA becoming undetectable was 76%, and reached 94% at week 96. No viral breakthrough occurred. Patients with TS (87% males, median baseline HBV-DNA 1.1 log10 IU/mL, median ALT 0.79 × ULN, 33% HBeAg positive, 61% with significant fibrosis) were treated for a median duration of 76 weeks. In this subgroup, all patients but one remained HBV-DNA undetectable and no ALT flare-up occurred during follow-up. Creatinine levels did not show kidney-function deterioration in either group of patients. CONCLUSIONS After a median follow-up of > 76 weeks, the TDF + FTC combination showed encouraging antiviral efficacy and a good safety profile in all patients with CHB. TDF + FTC may represent an interesting clinical option to simplify therapy and increase the barrier to resistance, which should be assessed in the long term.

Close Monitoring of Hepatitis B Surface Antigen Levels Helps Classify Flares During Peginterferon Therapy and Predicts Treatment Response

Host-induced flares are associated with presence of only wild-type hepatitis B virus (HBV) and result in decline and clearance of HBV DNA, hepatitis B e antigen, and hepatitis B surface antigen (HBsAg). Monitoring of HBsAg levels during and after flares may help predict a favorable treatment outcome.

Hepatitis B e antigen levels and response to peginterferon: Influence of precore and basal core promoter mutants

Hepatitis B e antigen (HBeAg) levels may predict response to peginterferon (PEG-IFN) but are also influenced by presence of precore (PC) and core promoter (BCP) mutants. HBeAg was measured in 214 patients treated with PEG-IFN±lamivudine for 52weeks. Patients were classified at baseline as wildtype (WT) or non-WT (detectable PC/BCP mutants). Combined response (HBeAg loss with HBV DNA<2000IU/mL), HBeAg response (HBeAg loss with HBV DNA>2000IU/mL) or non-response was assessed at week78. Mean baseline HBeAg levels were 2.65logIU/mL in combined responders, 2.48 in non-responders and 2.24 in HBeAg responders (p=0.034). Baseline HBeAg levels were not associated with combined response after stratification by WT/non-WT. Within the PEG-IFN monotherapy group (n=104), patients with HBeAg<1logIU/mL at week24 had a higher probability of combined response (29% versus 12%, p=0.041). After stratification by WT/non-WT, WT patients with HBeAg<1logIU/mL at week24 had a probability of combined response of 78% (versus 19% in patients with >1logIU/mL, p<0.001), whereas no difference in response rates was observed in non-WT patients (p=0.848). The relationship between HBeAg levels and response to PEG-IFN depends upon the presence of PC/BCP mutants. HBeAg levels should therefore not be routinely used to select patients for PEG-IFN, nor for monitoring of therapy.