Journal of Viral Hepatitis, 2014, 21, 439–446
doi:10.1111/jvh.12149
Relevance of hepatitis B surface antigen levels in patients with chronic hepatitis B during 5 year of tenofovir treatment A. K. Singh, M. K. Sharma, S. S. Hissar, E. Gupta and S. K. Sarin
Institute of Liver & Biliary Sciences, New
Delhi, India Received January 2013; accepted for publication June 2013
SUMMARY. The role of quantitative hepatitis B surface anti-
gen (HBsAg) levels in patients receiving highly potent oral antiviral therapy is controversial, and here, we determined the HBsAg response in 121 chronic hepatitis B patients treated with tenofovir 300 mg daily. During tenofovir treatment, HBsAg decline of ≥1.0 log from baseline was seen in 16.1%, 16.3%, 18.4%, 34.6%, 36.4% and 11.8%, 15.2%, 14.8%, 28.6%, 20% at years 1, 2, 3, 4, 5 for HBeAg-positive and HBeAg-negative patients, respectively. Early decline in HBsAg levels at week 4 was predictive of subsequent significant HBsAg level decline. HBeAg seroconversion occurred in 29.9% of HBeAg-positive patients. On multinomial logistic regression, HBsAg level decline from baseline at week 4 and week 12 or any time subsequently did not correlate with HBeAg seroconversion and
INTRODUCTION Chronic infection with hepatitis B virus (HBV) is a worldwide health problem, with more than 400 million people thought to be infected. Moreover, these patients are at increased risk for disease progression to cirrhosis and hepatocellular carcinoma. Over recent years, there has been an increasing focus on quantitative HBsAg (q HBsAg) measurement and its use in the management of CHB. It was demonstrated that the measurement of serum HBsAg concentration during therapy may allow for the identification of sustained responders to PEG-IFN more reliably than serum HBV DNA [1]. There is scant data on quantitative HBsAg measurements during treatment with highly potent antiviral such as tenofovir, there are a few studies on an equally potent drug, entecavir, but there is no study on the long-term use of Abbreviations: CHB, chronic hepatitis B; HBV, hepatitis B virus; CHBV, chronic hepatitis B virus; HBsAg, hepatitis B surface antigen; NA, nucleot(s)ide analogue. Correspondence: Shiv K. Sarin, MD, DM, FNA, Director and Head Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, India. E-mail: [email protected]
© 2013 John Wiley & Sons Ltd
HBV DNA level decline from baseline at week 4 and week 12 (OR = 3.704; 95% CI = 1.511–9.076; P = 0.006 and OR = 1.732; 95% CI = 1.032–2.867; P = 0.037, respectively) was significantly predictive of seroconversion. A small proportion of chronic HBV-infected patients treated with tenofovir exhibit a significant (≥1.0 log) decline in HBsAg levels. Early decline in HBsAg levels at week 4 was predictive of subsequent and significant HBsAg level decline. The HBsAg decline did not correlate with HBeAg seroconversion in HBeAg-positive patients. Reduction in HBV DNA levels at week 4 and 12 correlated with seroconversion. Keywords: chronic hepatitis, HBeAg, HBsAg, HBV, seroconversion, tenofovir.
tenofovir in HBV mono-infected patients. Studies on entecavir have shown varied results. One study showed that a substantial HBsAg decline during entecavir therapy was restricted to HBeAg-positive patients and also to patients with baseline ALT levels greater than or equal to two times the upper limit of normal (P = 0.007), and it was most profound in those who lost HBeAg [2]. Another study found that during entecavir treatment, despite HBV DNA suppression, the majority of patients did not show significant decline in HBsAg levels and early decline of HBsAg levels at 12/ 24 weeks were not associated with HBV DNA suppression or HBeAg seroconversion [3]. A small study from Korea showed that a decrease >1 log10 IU/mL in serum HBsAg levels during therapy (5 of 28 patients) was associated with a much higher cumulative incidence of HBeAg loss (80% vs 30%, P = 0.034) after 1 year of ETV therapy [4]. In studies on tenofovir treatment, among both HBeAg-positive and HBeAg-negative patients, HBsAg decline was quicker in patients who lost HBsAg than in those who failed to clear HBsAg during 3 to 4-year treatment [5–7]. The immunological mechanisms do play a major role in viral clearance and outcome of tenofovir therapy [8,9]. In the present study, we aimed to determine the serum quantitative HBsAg levels in patients treated with tenofovir and predictors of significant HBsAg decline.
440
A. K. Singh et al.
PATIENTS AND METHODS Patients and study design A total of 121 consecutive adult (18–70 years) patients with chronic hepatitis B (CHB) treated with tenofovir, seen at the Institute of Liver and Biliary Sciences (ILBS), New Delhi, India, were included. Tenofovir was given at a dose of 300 mg daily with treatment duration of at least 1 year. This was an open label study and compliance to drug was self-reported by patients. Patients with CHB were included in the study, if they fulfilled the following inclusion criteria: (i) Adult males and females, 18–70 years old. (ii) Hepatitis B surface antigen (HBsAg) positive at the time of screening and for at least the previous six months, HBeAg positive or negative. (iii) Quantifiable serum HBV DNA levels of >2 000 IU/mL. Exclusion criteria included co-infection with hepatitis C, D or HIV infection; decompensated liver disease (defined by a serum bilirubin level more than 2.5 times the upper limit of normal, a prothrombin time prolonged by more than 3 s, a serum albumin level lower than 3 g/dL or a history of ascites, variceal haemorrhage or hepatic encephalopathy or Grade III & IV oesophageal varices unless banded); chronic hepatitis B with Child-Pugh B and C; evidence of liver disease due to other aetiology; serum creatinine more than 1.5 times upper limit of normal; haemoglobin
doi:10.1111/jvh.12149
Relevance of hepatitis B surface antigen levels in patients with chronic hepatitis B during 5 year of tenofovir treatment A. K. Singh, M. K. Sharma, S. S. Hissar, E. Gupta and S. K. Sarin
Institute of Liver & Biliary Sciences, New
Delhi, India Received January 2013; accepted for publication June 2013
SUMMARY. The role of quantitative hepatitis B surface anti-
gen (HBsAg) levels in patients receiving highly potent oral antiviral therapy is controversial, and here, we determined the HBsAg response in 121 chronic hepatitis B patients treated with tenofovir 300 mg daily. During tenofovir treatment, HBsAg decline of ≥1.0 log from baseline was seen in 16.1%, 16.3%, 18.4%, 34.6%, 36.4% and 11.8%, 15.2%, 14.8%, 28.6%, 20% at years 1, 2, 3, 4, 5 for HBeAg-positive and HBeAg-negative patients, respectively. Early decline in HBsAg levels at week 4 was predictive of subsequent significant HBsAg level decline. HBeAg seroconversion occurred in 29.9% of HBeAg-positive patients. On multinomial logistic regression, HBsAg level decline from baseline at week 4 and week 12 or any time subsequently did not correlate with HBeAg seroconversion and
INTRODUCTION Chronic infection with hepatitis B virus (HBV) is a worldwide health problem, with more than 400 million people thought to be infected. Moreover, these patients are at increased risk for disease progression to cirrhosis and hepatocellular carcinoma. Over recent years, there has been an increasing focus on quantitative HBsAg (q HBsAg) measurement and its use in the management of CHB. It was demonstrated that the measurement of serum HBsAg concentration during therapy may allow for the identification of sustained responders to PEG-IFN more reliably than serum HBV DNA [1]. There is scant data on quantitative HBsAg measurements during treatment with highly potent antiviral such as tenofovir, there are a few studies on an equally potent drug, entecavir, but there is no study on the long-term use of Abbreviations: CHB, chronic hepatitis B; HBV, hepatitis B virus; CHBV, chronic hepatitis B virus; HBsAg, hepatitis B surface antigen; NA, nucleot(s)ide analogue. Correspondence: Shiv K. Sarin, MD, DM, FNA, Director and Head Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, India. E-mail: [email protected]
© 2013 John Wiley & Sons Ltd
HBV DNA level decline from baseline at week 4 and week 12 (OR = 3.704; 95% CI = 1.511–9.076; P = 0.006 and OR = 1.732; 95% CI = 1.032–2.867; P = 0.037, respectively) was significantly predictive of seroconversion. A small proportion of chronic HBV-infected patients treated with tenofovir exhibit a significant (≥1.0 log) decline in HBsAg levels. Early decline in HBsAg levels at week 4 was predictive of subsequent and significant HBsAg level decline. The HBsAg decline did not correlate with HBeAg seroconversion in HBeAg-positive patients. Reduction in HBV DNA levels at week 4 and 12 correlated with seroconversion. Keywords: chronic hepatitis, HBeAg, HBsAg, HBV, seroconversion, tenofovir.
tenofovir in HBV mono-infected patients. Studies on entecavir have shown varied results. One study showed that a substantial HBsAg decline during entecavir therapy was restricted to HBeAg-positive patients and also to patients with baseline ALT levels greater than or equal to two times the upper limit of normal (P = 0.007), and it was most profound in those who lost HBeAg [2]. Another study found that during entecavir treatment, despite HBV DNA suppression, the majority of patients did not show significant decline in HBsAg levels and early decline of HBsAg levels at 12/ 24 weeks were not associated with HBV DNA suppression or HBeAg seroconversion [3]. A small study from Korea showed that a decrease >1 log10 IU/mL in serum HBsAg levels during therapy (5 of 28 patients) was associated with a much higher cumulative incidence of HBeAg loss (80% vs 30%, P = 0.034) after 1 year of ETV therapy [4]. In studies on tenofovir treatment, among both HBeAg-positive and HBeAg-negative patients, HBsAg decline was quicker in patients who lost HBsAg than in those who failed to clear HBsAg during 3 to 4-year treatment [5–7]. The immunological mechanisms do play a major role in viral clearance and outcome of tenofovir therapy [8,9]. In the present study, we aimed to determine the serum quantitative HBsAg levels in patients treated with tenofovir and predictors of significant HBsAg decline.
440
A. K. Singh et al.
PATIENTS AND METHODS Patients and study design A total of 121 consecutive adult (18–70 years) patients with chronic hepatitis B (CHB) treated with tenofovir, seen at the Institute of Liver and Biliary Sciences (ILBS), New Delhi, India, were included. Tenofovir was given at a dose of 300 mg daily with treatment duration of at least 1 year. This was an open label study and compliance to drug was self-reported by patients. Patients with CHB were included in the study, if they fulfilled the following inclusion criteria: (i) Adult males and females, 18–70 years old. (ii) Hepatitis B surface antigen (HBsAg) positive at the time of screening and for at least the previous six months, HBeAg positive or negative. (iii) Quantifiable serum HBV DNA levels of >2 000 IU/mL. Exclusion criteria included co-infection with hepatitis C, D or HIV infection; decompensated liver disease (defined by a serum bilirubin level more than 2.5 times the upper limit of normal, a prothrombin time prolonged by more than 3 s, a serum albumin level lower than 3 g/dL or a history of ascites, variceal haemorrhage or hepatic encephalopathy or Grade III & IV oesophageal varices unless banded); chronic hepatitis B with Child-Pugh B and C; evidence of liver disease due to other aetiology; serum creatinine more than 1.5 times upper limit of normal; haemoglobin
