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Sammanfattning Hepatit B virus (HBV) tillhör familjen hepadnavirus och kronisk HBV finns hos ungefär 257 miljoner människor. Kronisk HBV kan orsaka levercirros och hepatocellulärt karcinom (HCC) och andra svåra leversjukdomar vilket leder till 887,000 dödsfall per år. Symptomen för HBV är illamående, gulsot och mörkfärgat urin. HBV smittas genom sexuell kontakt och infekterat blod. Det smittas alltså vid barnafödsel, sprutor vid droganvändning och dålig hygien inom sjukvården. Det finns vaccin att ta för att förhindra spridningen av viruset. De behandlingar som finns för de som drabbas är antivirala läkemedel som är nukleos(t)id analoger och peginterferoner. Syftet med arbetet var att se om det är mer effektivt att använda kombinationsterapi med de antivirala läkemedlen adefovir (ADV) och lamivudin (LAM) jämfört med monoterapi med adefovir. Fem randomiserade kontrollerade studier söktes fram från pubmed. Resultaten från de studierna jämfördes sedan. Studierna visade att kombinerad läkemedelsterapi med ADV och LAM var mer effektivt än monoterapi med ADV. ADV och LAM i kombination visades mer effektivt eftersom det var fler patienterna i den gruppen som fick en inte detekterbar mängd HBV-DNA, fler patienter som fick en normal nivå av alaninaminotransferas (ALAT) och färre patienter som visade på utveckling av resistens mot ADV. Slutsatsen är att kombinationsterapi med ADV och LAM var mer effektivare än monoterapi med ADV. Det är för att när läkemedlen används tillsammans är de mer effektivare på att hämma viruset och minskar risken för att viruset ska kunna utveckla resistens., Hepatitis B virus (HBV) belongs to the hepadnavirus family and chronic HBV is present in approximately 257 million people. There is acute and chronic HBV types of infection. About two-thirds of those with acute HBV have mild symptoms. The rest get more pronounced symptoms such as nausea, fatigue and even jaundice. It then counts as chronic HBV if the person has high levels of the surface antigen for hepatitis B (HBsAg) for more than six months. Chronic HBV can cause liver cirrhosis and hepatocellular carcinoma (HCC) and other severe liver diseases leading to 887,000 deaths per year. HBV is transmitted through sexual contact, infected blood in contact with a wound and during childbirth. There are vaccines to take to prevent the spread of the virus. The treatments available for those affected by the virus are antiviral drugs that are nucleos(t)ide analogues and peg interferons. The aim of the study was to see if it is more effective to use combination therapy with the antiviral drugs adefovir (ADV) and lamivudine (LAM) compared to monotherapy with adefovir. The method used was to select five studies that were randomized controlled trials. The studies were taken from pubmed. After the studies were selected, they were compared with each other. The parts of the study that were focused on were how many patients received an undetectable level of HBV DNA, how many patients received a normal level of alanine aminotransferase (ALAT) and how many patients developed resistance to ADV. The studies showed predominantly that combined drug therapy with ADV and LAM was more effective than monotherapy with ADV. ADV and LAM in combination proved to be more effective as more patients in the group receiving ADV and LAM received an undetectable amount of HBV DNA, more patients received a normal level of ALAT and fewer patients showed the development of resistance to ADV. The results show that ADV and LAM are better at reducing the viral load. This combination also lowers the lev

Sammanfattning Hepatit B virus (HBV) tillhör familjen hepadnavirus och kronisk HBV finns hos ungefär 257 miljoner människor. Kronisk HBV kan orsaka levercirros och hepatocellulärt karcinom (HCC) och andra svåra leversjukdomar vilket leder till 887,000 dödsfall per år. Symptomen för HBV är illamående, gulsot och mörkfärgat urin. HBV smittas genom sexuell kontakt och infekterat blod. Det smittas alltså vid barnafödsel, sprutor vid droganvändning och dålig hygien inom sjukvården. Det finns vaccin att ta för att förhindra spridningen av viruset. De behandlingar som finns för de som drabbas är antivirala läkemedel som är nukleos(t)id analoger och peginterferoner. Syftet med arbetet var att se om det är mer effektivt att använda kombinationsterapi med de antivirala läkemedlen adefovir (ADV) och lamivudin (LAM) jämfört med monoterapi med adefovir. Fem randomiserade kontrollerade studier söktes fram från pubmed. Resultaten från de studierna jämfördes sedan. Studierna visade att kombinerad läkemedelsterapi med ADV och LAM var mer effektivt än monoterapi med ADV. ADV och LAM i kombination visades mer effektivt eftersom det var fler patienterna i den gruppen som fick en inte detekterbar mängd HBV-DNA, fler patienter som fick en normal nivå av alaninaminotransferas (ALAT) och färre patienter som visade på utveckling av resistens mot ADV. Slutsatsen är att kombinationsterapi med ADV och LAM var mer effektivare än monoterapi med ADV. Det är för att när läkemedlen används tillsammans är de mer effektivare på att hämma viruset och minskar risken för att viruset ska kunna utveckla resistens., Hepatitis B virus (HBV) belongs to the hepadnavirus family and chronic HBV is present in approximately 257 million people. There is acute and chronic HBV types of infection. About two-thirds of those with acute HBV have mild symptoms. The rest get more pronounced symptoms such as nausea, fatigue and even jaundice. It then counts as chronic HBV if the person has high levels of the surface antigen for hepatitis B (HBsAg) for more than six months. Chronic HBV can cause liver cirrhosis and hepatocellular carcinoma (HCC) and other severe liver diseases leading to 887,000 deaths per year. HBV is transmitted through sexual contact, infected blood in contact with a wound and during childbirth. There are vaccines to take to prevent the spread of the virus. The treatments available for those affected by the virus are antiviral drugs that are nucleos(t)ide analogues and peg interferons. The aim of the study was to see if it is more effective to use combination therapy with the antiviral drugs adefovir (ADV) and lamivudine (LAM) compared to monotherapy with adefovir. The method used was to select five studies that were randomized controlled trials. The studies were taken from pubmed. After the studies were selected, they were compared with each other. The parts of the study that were focused on were how many patients received an undetectable level of HBV DNA, how many patients received a normal level of alanine aminotransferase (ALAT) and how many patients developed resistance to ADV. The studies showed predominantly that combined drug therapy with ADV and LAM was more effective than monotherapy with ADV. ADV and LAM in combination proved to be more effective as more patients in the group receiving ADV and LAM received an undetectable amount of HBV DNA, more patients received a normal level of ALAT and fewer patients showed the development of resistance to ADV. The results show that ADV and LAM are better at reducing the viral load. This combination also lowers the lev

Medullary thyroid carcinoma (MTC) is the most aggressive form of thyroid carcinoma with a high rate of metastasis. The gain-of-function mutation in the RET proto-oncogene has been identified as the primary cause of the development of MTC, which is a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. The dominant-activating mutation in the RET proto-oncogene promotes the phosphorylation of RET receptor in a ligand independent manner. This leads to constitutive activation of downstream signaling pathways that are involved in cell growth, survival, and proliferation. Owing to their potential role in the tumor development, RET has been regarded as an exceptional molecular target for MTC treatment. Therefore, targeting RET activation with drug-like small molecules offers a potential treatment strategy for patients with MTC. Our approach included screening for potential hits utilizing a cell-based bioluminescence reporter system in which the luciferase gene expression is driven by the RET promoter. In this study, we provide three chemical drugs which effectively suppressed RET activity and can be repurposed to treat or control MTC. Each of the drugs included in this research represents a unique pathway and inhibitory mechanism, and each was successfully reduced MTC tumor growth, metastasis, invasion and survival. We believe these drugs are promising candidates for preclinical and clinical studies as mono-therapy and/or for use in combination with other agents to manage MTC.

Background: Five years of tenofovir DF (TDF) treatment of HBeAgand HBeAg + chronic HBV patients (Studies 102 and 103) resulted in sustained viral suppression and no TDF resistance; in addition, either halting or regression of fibrosis was seen in 96% of patients. Here we present 6 year results from these 2 ongoing 8 year studies. Method(s): After completing 48 weeks of double-blind comparison of TDF to adefovir, all patients were eligible to continue open-label TDF. Patients were assessed every 3 months for safety and efficacy with annual resistance surveillance and annual assessments of bone mineral density (BMD) by DXA (starting Year 4). Result(s): Of 641 patients randomized and treated, 585 (91%) entered the TDF extension phase; 466 (73%) remain on study at year 6. In an on-treatment analysis (missing = excluded), 99.6% and 99% of patients HBeAg- and HBeAg + patients, respectively, had HBV DNA<400 copies/mL and ALT normalization was achieved by 86% and 78% of HBeAg- and HBeAg + patients; 50% of HBeAg + patients achieved HBeAg loss and 37% experienced anti-HBe seroconversion. HBsAg loss and seroconversion (Kaplan-Meier %) was observed in 11% and 8% of HBeAg + patients, respectively; 1 HBeAg- patient had sustained HBsAg loss/seroconversion at Year 5 (Week 240). TDF was well tolerated over the 6 year evaluation period. Less than 2% discontinued TDF due to an adverse event, and <= 1.5% experienced a confirmed renal event (>= 0.5 mg/dL increase in serum creatinine, phosphorus<2 mg/dL, or CrCL<50 mL/min). BMD (T scores) was stable over 2 years of evaluation. No resistance to TDF was detected through Year 6. Conclusion(s): In these two trials, TDF remains safe and effective over a 6 year treatment period, with no detectable TDF resistance; a relatively low rate of renal events and no evidence of clinically relevant bone loss were also observed.

Background: Five years of tenofovir DF (TDF) treatment of HBeAgand HBeAg + chronic HBV patients (Studies 102 and 103) resulted in sustained viral suppression and no TDF resistance; in addition, either halting or regression of fibrosis was seen in 96% of patients. Here we present 6 year results from these 2 ongoing 8 year studies. Method(s): After completing 48 weeks of double-blind comparison of TDF to adefovir, all patients were eligible to continue open-label TDF. Patients were assessed every 3 months for safety and efficacy with annual resistance surveillance and annual assessments of bone mineral density (BMD) by DXA (starting Year 4). Result(s): Of 641 patients randomized and treated, 585 (91%) entered the TDF extension phase; 466 (73%) remain on study at year 6. In an on-treatment analysis (missing = excluded), 99.6% and 99% of patients HBeAg- and HBeAg + patients, respectively, had HBV DNA<400 copies/mL and ALT normalization was achieved by 86% and 78% of HBeAg- and HBeAg + patients; 50% of HBeAg + patients achieved HBeAg loss and 37% experienced anti-HBe seroconversion. HBsAg loss and seroconversion (Kaplan-Meier %) was observed in 11% and 8% of HBeAg + patients, respectively; 1 HBeAg- patient had sustained HBsAg loss/seroconversion at Year 5 (Week 240). TDF was well tolerated over the 6 year evaluation period. Less than 2% discontinued TDF due to an adverse event, and <= 1.5% experienced a confirmed renal event (>= 0.5 mg/dL increase in serum creatinine, phosphorus<2 mg/dL, or CrCL<50 mL/min). BMD (T scores) was stable over 2 years of evaluation. No resistance to TDF was detected through Year 6. Conclusion(s): In these two trials, TDF remains safe and effective over a 6 year treatment period, with no detectable TDF resistance; a relatively low rate of renal events and no evidence of clinically relevant bone loss were also observed.

Chronic hepatitis B continues to be a global problem, with an estimated 240 million cases according to the World Health Organization. Chronic infection with the hepatitis B virus (HBV) is associated with cirrhosis, hepatic decompensation, and hepatocellular carcinoma. There are currently several US Food and Drug Administration-approved medications for treating chronic hepatitis B, with Lamivudine (LAM) being the first oral agent made available. The major problem with LAM is significantly decreased effectiveness over time due to the development of anti-HBV resistance that can lead to virologic and biochemical breakthrough as well as hepatitis B flare, progression of liver disease, and decompensation of pre-existing cirrhosis. Despite its high anti-HBV resistant rate, LAM remains widely used in underdeveloped countries due to its wide availability and low cost compared to other antiviral medications, including those that are more effective. Therefore, it is still clinically important to learn how to prevent and treat LAM resistant strains of HBV. Several regimens with the other available antiviral agents have been studied, including switching to monotherapy with either Adefovir, Entecavir, or Tenofovir, adding Adefovir to LAM, and switching to a combination of Adefovir and Entecavir. This review article will examine molecular mechanisms and diagnosis of LAM anti-HBV resistance, risks for and approaches to reduce LAM anti-HBV resistance, and currently available rescue therapy regimens for LAM resistance.

Chronic hepatitis B continues to be a global problem, with an estimated 240 million cases according to the World Health Organization. Chronic infection with the hepatitis B virus (HBV) is associated with cirrhosis, hepatic decompensation, and hepatocellular carcinoma. There are currently several US Food and Drug Administration-approved medications for treating chronic hepatitis B, with Lamivudine (LAM) being the first oral agent made available. The major problem with LAM is significantly decreased effectiveness over time due to the development of anti-HBV resistance that can lead to virologic and biochemical breakthrough as well as hepatitis B flare, progression of liver disease, and decompensation of pre-existing cirrhosis. Despite its high anti-HBV resistant rate, LAM remains widely used in underdeveloped countries due to its wide availability and low cost compared to other antiviral medications, including those that are more effective. Therefore, it is still clinically important to learn how to prevent and treat LAM resistant strains of HBV. Several regimens with the other available antiviral agents have been studied, including switching to monotherapy with either Adefovir, Entecavir, or Tenofovir, adding Adefovir to LAM, and switching to a combination of Adefovir and Entecavir. This review article will examine molecular mechanisms and diagnosis of LAM anti-HBV resistance, risks for and approaches to reduce LAM anti-HBV resistance, and currently available rescue therapy regimens for LAM resistance.

Background CHB suppression with TDF improves transaminases, results in a regression of liver fibrosis and increases HBeAg seroconversion. Long term data in cirrhotic patients is needed. Aims Describe long-term clinical outcomes for the subset of cirrhotic patients enrolled in two ongoing pivotal trials of TDF (Studies 102 and 103) in comparison with non-cirrhotic patients. Methods A retrospective analysis of 2 pivotal studies of TDF was conducted to assess whether cirrhotic patients had different clinical outcomes than non-cirrhotic patients. In these studies, the safety and efficacy of TDF compared to adefovir was assessed for 48 weeks in HBeAg negative (Study 0102) and HBeAg positive (Study 0103) patients, followed by open-label TDF treatment. Results A total of 634 subjects were included. Cirrhotics had outcomes comparable to non-cirrhotics (see tables). There were no cases of hepatic encephalopathy or variceal bleeding in either group, and ascites occurred in one non-cirrhotic patient with HCC. The incidence of HCC was 1.5% in non-cirrhotics and 3.3% in cirrhotics (p = NS). Conclusion Cirrhotic patients differed from non-cirrhotic subjects at baseline, but demonstrated significant treatment benefits with 74% experiencing regression of cirrhosis. Cirrhotic patients treated with TDF had similar rates of viral suppression and serological responses as noncirrhotics and derived comparable clinical benefit after 5 years of viral suppression (Table Presented).

Background: Multi-drug resistant (MDR) HBV presents a serious clinical management challenge, particularly for patients with advanced liver disease. We present the long-term follow-up data from the TDF109 study that investigated the use of tenofovir (TDF)+/-lamivudine (LAM) for the treatment of well-characterized CHB patients who had previously failed LAM & adefovir (ADV) therapy. Method(s): TDF109 was an investigatorinitiated, prospective, multi-centre, open-label study of 60 patients treated with TDF. All patients had failed serial LAM & subsequent ADV add-on/switch therapy. The year 1 & 2 data have been previously reported (Patterson, S et al GUT 2011;60:247-254). At study entry, 38/60 patients (63%) were switched from ADV monotherapy to TDF, & 22/60 (37%) were switched from ADV/LAM to TDF/LAM. Those patients treated with TDF monotherapy with persistent viral replication at or after 24 weeks were switched to TDF/LAM. The primary endpoint for the current analysis was the number of patients with undetectable HBV DNA, defined as below the lower limit of quantification (LLOQ, DNA<20IU/ml, Cobas assay) after 4 years of follow-up. We also analysed the rate of viral decline based on the type of HBV resistance associated substitutions at baseline. Result(s): At year 2, 64% (38/59) had undetectable HBV DNA levels. At 4 years, 63% (38/60) had achieved viral suppression by intent-to-treat analysis. 4 patients had discontinued TDF & 4 patients were lost to follow-up. 38/51 (75%) had achieved viral suppression per protocol. In patients with quantifiable serum HBV DNA at 4 years, the median viral load (VL) was 1.72log10IU/ml (HBV DNA level was <2.55logIU/mL in all patients except in 1 non-compliant patient who had no markers of resistance. Independent predictors of time to undetectability using survival analysis included baseline HBV DNA level (p<0.001) & HBV genotype (AD (p=0.01). Substitutions associated with ADV resistance (rtA181T/V+/- rtN236T) were present in 18

Background Fanconi syndrome is a rare complication of long-term adefovir therapy for chronic hepatitis B virus (CHB). Aims We describe the first case series of two CHB patients diagnosed with avascular necrosis (AVN) in the setting of adefovir-induced Fanconi Syndrome. Methods The case records are as documented below: Results Case 1: A 52 year-old Asian male presented with decompensated cirrhosis from CHB eAntigen (eAg) positive disease. He was commenced on lamivudine (LMV) 100 mg daily in 2003. Adefovir was introduced following the development of LMV resistance. The dose was progressively increased to 20 mg daily to maintain viral suppression. The patient underwent bilateral total hip replacements in September 2011 to treat bilateral femoral head AVN and proximal femoral fractures. Biochemistry showed severe hypophosphataemia (PO4: 0.44 nmol/L RR: 0.80-1.50), vitamin D deficiency (19 nmol/L RR: 75-250) and de novo renal dysfunction with serum creatinine 160 mumol/L (RR: 55-105) and elevated ALP (546 U/L RR: 30-120). Further investigations revealed the full spectrum of Fanconi syndrome including: hypokalaemia, hypophosphataemia, non-anion gap metabolic acidosis and normoglycaemic glycosuria. Symptoms resolved two weeks after aggressive correction of vitamin D, calcium and phosphate. Adefovir and lamivudine combination therapy were ceased and the patient was switched to entecavir 1.0 mg daily. Case 2: A 64 year-old Asian female with eAg-negative CHB was treated with lamivudine 100 mg daily from 2001. Adefovir 20 mg daily was added in 2008 for a similar indication to Patient 1. In July 2010, the patient developed bilateral disabling knee pain associated with hypophosphataemia (0.51 nmol/L), increased ALP, elevated serum creatinine (101 mumol/L), hypouricaemia (111 U/L RR: 160-35), non-anion gap metabolic acidosis and hypokalaemia (2.6 mmol/L RR: 3.5-5.0). An MRI of the knees in July 2011 showed bilateral proximal insufficiency tibial fractures complicated by AVN. A DE

Background CHB suppression with TDF improves transaminases, results in a regression of liver fibrosis and increases HBeAg seroconversion. Long term data in cirrhotic patients is needed. Aims Describe long-term clinical outcomes for the subset of cirrhotic patients enrolled in two ongoing pivotal trials of TDF (Studies 102 and 103) in comparison with non-cirrhotic patients. Methods A retrospective analysis of 2 pivotal studies of TDF was conducted to assess whether cirrhotic patients had different clinical outcomes than non-cirrhotic patients. In these studies, the safety and efficacy of TDF compared to adefovir was assessed for 48 weeks in HBeAg negative (Study 0102) and HBeAg positive (Study 0103) patients, followed by open-label TDF treatment. Results A total of 634 subjects were included. Cirrhotics had outcomes comparable to non-cirrhotics (see tables). There were no cases of hepatic encephalopathy or variceal bleeding in either group, and ascites occurred in one non-cirrhotic patient with HCC. The incidence of HCC was 1.5% in non-cirrhotics and 3.3% in cirrhotics (p = NS). Conclusion Cirrhotic patients differed from non-cirrhotic subjects at baseline, but demonstrated significant treatment benefits with 74% experiencing regression of cirrhosis. Cirrhotic patients treated with TDF had similar rates of viral suppression and serological responses as noncirrhotics and derived comparable clinical benefit after 5 years of viral suppression (Table Presented).

Background: Multi-drug resistant (MDR) HBV presents a serious clinical management challenge, particularly for patients with advanced liver disease. We present the long-term follow-up data from the TDF109 study that investigated the use of tenofovir (TDF)+/-lamivudine (LAM) for the treatment of well-characterized CHB patients who had previously failed LAM & adefovir (ADV) therapy. Method(s): TDF109 was an investigatorinitiated, prospective, multi-centre, open-label study of 60 patients treated with TDF. All patients had failed serial LAM & subsequent ADV add-on/switch therapy. The year 1 & 2 data have been previously reported (Patterson, S et al GUT 2011;60:247-254). At study entry, 38/60 patients (63%) were switched from ADV monotherapy to TDF, & 22/60 (37%) were switched from ADV/LAM to TDF/LAM. Those patients treated with TDF monotherapy with persistent viral replication at or after 24 weeks were switched to TDF/LAM. The primary endpoint for the current analysis was the number of patients with undetectable HBV DNA, defined as below the lower limit of quantification (LLOQ, DNA<20IU/ml, Cobas assay) after 4 years of follow-up. We also analysed the rate of viral decline based on the type of HBV resistance associated substitutions at baseline. Result(s): At year 2, 64% (38/59) had undetectable HBV DNA levels. At 4 years, 63% (38/60) had achieved viral suppression by intent-to-treat analysis. 4 patients had discontinued TDF & 4 patients were lost to follow-up. 38/51 (75%) had achieved viral suppression per protocol. In patients with quantifiable serum HBV DNA at 4 years, the median viral load (VL) was 1.72log10IU/ml (HBV DNA level was <2.55logIU/mL in all patients except in 1 non-compliant patient who had no markers of resistance. Independent predictors of time to undetectability using survival analysis included baseline HBV DNA level (p<0.001) & HBV genotype (AD (p=0.01). Substitutions associated with ADV resistance (rtA181T/V+/- rtN236T) were present in 18

Background Fanconi syndrome is a rare complication of long-term adefovir therapy for chronic hepatitis B virus (CHB). Aims We describe the first case series of two CHB patients diagnosed with avascular necrosis (AVN) in the setting of adefovir-induced Fanconi Syndrome. Methods The case records are as documented below: Results Case 1: A 52 year-old Asian male presented with decompensated cirrhosis from CHB eAntigen (eAg) positive disease. He was commenced on lamivudine (LMV) 100 mg daily in 2003. Adefovir was introduced following the development of LMV resistance. The dose was progressively increased to 20 mg daily to maintain viral suppression. The patient underwent bilateral total hip replacements in September 2011 to treat bilateral femoral head AVN and proximal femoral fractures. Biochemistry showed severe hypophosphataemia (PO4: 0.44 nmol/L RR: 0.80-1.50), vitamin D deficiency (19 nmol/L RR: 75-250) and de novo renal dysfunction with serum creatinine 160 mumol/L (RR: 55-105) and elevated ALP (546 U/L RR: 30-120). Further investigations revealed the full spectrum of Fanconi syndrome including: hypokalaemia, hypophosphataemia, non-anion gap metabolic acidosis and normoglycaemic glycosuria. Symptoms resolved two weeks after aggressive correction of vitamin D, calcium and phosphate. Adefovir and lamivudine combination therapy were ceased and the patient was switched to entecavir 1.0 mg daily. Case 2: A 64 year-old Asian female with eAg-negative CHB was treated with lamivudine 100 mg daily from 2001. Adefovir 20 mg daily was added in 2008 for a similar indication to Patient 1. In July 2010, the patient developed bilateral disabling knee pain associated with hypophosphataemia (0.51 nmol/L), increased ALP, elevated serum creatinine (101 mumol/L), hypouricaemia (111 U/L RR: 160-35), non-anion gap metabolic acidosis and hypokalaemia (2.6 mmol/L RR: 3.5-5.0). An MRI of the knees in July 2011 showed bilateral proximal insufficiency tibial fractures complicated by AVN. A DE

Background: In CHB patients, quantitative hepatitis B surface antigen (QHBsAg) have recently been associated with predicting response to peg-interferon-alfa, including HBsAg seroconversion (SC) & loss or decline. Long-term nucleos(t)ide analogues (NA) suppresses HBV replication in the majority of patients, however very few actually undergo HBsAg SC. The utility of QHBsAg analysis in these patients is poorly understood & the impact of multi-drug resistant (MDR) variants has not been explored. Aim(s): To evaluate the QHBsAg decline in a wellcharacterized cohort of patients with MDR (rtA181T/V) HBV who were treated with >7years with multiple NA, including at least 3 years of tenofovir (TDF). Method(s): TDF109 was an investigator-initiated, prospective, multi-centre, open-label study of the efficacy of TDF rescue therapy in 60 patients who had previously failed lamivudine (LAM) & subsequent adefovir (ADV) add-on or switch therapy. We have previously presented virological outcome at 2 years (Patterson, Gut 2011). All patients have been maintained on TDF in long-term follow-up, now out to 4 years. QHBsAg titers were retrospectively quantified at baseline & every 6 months, expressed as IU/ml (Roche Elecsys). Sub-analysis according to baseline viral load & the type of HBV resistance-associated substitutions present at baseline was then performed. Result(s): At baseline, median QHBsAg titer was 5226IU/ml. Baseline QHBsAg positively correlated with HBV DNA levels at baseline, (R = 0.33, p=0.0168). There was a trend for higher baseline QHBsAg levels in HBeAg positive patients (p=0.13). The median HBsAg titers were 2772IU/ml, 2284IU/ml &1819IU/ml at year 1, 2&3 respectively (P<0.0001 for comparison of baseline to year 3). Patients with detectable rtA181T/V variants have a lower QHBsAg at baseline, but more gradual decline in QHBsAg (p=0.002). There was a trend for patients with no detectable resistance changes or LAM resistance HBV Pol at baseline, to have higher baseline QHBsA

Tenofovir disoproxil fumarate (TDF) has demonstrated potent activity in HBeAg positive and negative, treatment-naive and lamivudineexperienced, chronic hepatitis B patients. In vitro, different patterns of adefovir-associated resistance mutations have varying degrees of sensitivity to TDF. This analysis evaluates the efficacy of TDF in patients with suboptimal response (HBV DNA > 400 copies (c)/mL) on adefovir dipivoxil (ADV). Methods 160 HBeAg+ and HBeAg- patients with persistent viral replication after 24-96 weeks of ADV therapy were treated with TDF for up to 96 weeks in studies 0102, 0103, and 0106; 23% had prior lamivudine (LAM) experience. HBV DNA, HBsAg, HBeAg and ALT were routinely monitored; population sequencing of HBV polymerase was conducted at baseline and for patients with HBV DNA > 400 c/mL at week 96/last on treatment. An ITT analysis was conducted using non-completers = failures. Patients with confirmed HBV DNA >=400 c/mL could add emtricitabine (FTC) and were considered failures after FTC addition. Result(s): After 24 weeks of TDF monotherapy, 77% of patients had HBV DNA < 400 c/mL and 59% had normal ALT. This was maintained through 96 weeks. Similar results were observed in patients with LAM-resistance (n = 7) and ADV-resistance (n = 10) mutations at baseline. Among the 101 HBeAg+ patients, HBeAg loss and seroconversion was experienced by 15% and 10% respectively. Kaplan-Meier estimates for HBsAg loss and seroconversion over 96 weeks were 4.5% and 3.2%; 6 genotypes A/D and 1 genotype C. No patient discontinued due to an adverse event; 2 patients experienced SAEs considered related to TDF (ALT increased). Two patients experienced a 0.5 mg/dL increase in serum creatinine and remained on TDF treatment following dose reduction. No patient experienced a decrease in creatinine clearance to <50 mL/min. No amino acid substitutions associated with TDF resistance developed through 96 weeks. Conclusion(s): The majority of patients had complete viral suppress

Tenofovir disoproxil fumarate (TDF) has demonstrated potent activity in HBeAg positive and negative, treatment-naive and lamivudineexperienced, chronic hepatitis B patients. In vitro, different patterns of adefovir-associated resistance mutations have varying degrees of sensitivity to TDF. This analysis evaluates the efficacy of TDF in patients with suboptimal response (HBV DNA > 400 copies (c)/mL) on adefovir dipivoxil (ADV). Methods 160 HBeAg+ and HBeAg- patients with persistent viral replication after 24-96 weeks of ADV therapy were treated with TDF for up to 96 weeks in studies 0102, 0103, and 0106; 23% had prior lamivudine (LAM) experience. HBV DNA, HBsAg, HBeAg and ALT were routinely monitored; population sequencing of HBV polymerase was conducted at baseline and for patients with HBV DNA > 400 c/mL at week 96/last on treatment. An ITT analysis was conducted using non-completers = failures. Patients with confirmed HBV DNA >=400 c/mL could add emtricitabine (FTC) and were considered failures after FTC addition. Result(s): After 24 weeks of TDF monotherapy, 77% of patients had HBV DNA < 400 c/mL and 59% had normal ALT. This was maintained through 96 weeks. Similar results were observed in patients with LAM-resistance (n = 7) and ADV-resistance (n = 10) mutations at baseline. Among the 101 HBeAg+ patients, HBeAg loss and seroconversion was experienced by 15% and 10% respectively. Kaplan-Meier estimates for HBsAg loss and seroconversion over 96 weeks were 4.5% and 3.2%; 6 genotypes A/D and 1 genotype C. No patient discontinued due to an adverse event; 2 patients experienced SAEs considered related to TDF (ALT increased). Two patients experienced a 0.5 mg/dL increase in serum creatinine and remained on TDF treatment following dose reduction. No patient experienced a decrease in creatinine clearance to <50 mL/min. No amino acid substitutions associated with TDF resistance developed through 96 weeks. Conclusion(s): The majority of patients had complete viral suppress

Hepatitis B virus (HBV) antiviral drug resistance mutations prevent successful outcome of treatment and lead to worsening of liver disease. Detection of its emergence permits opportune treatment with alternative drugs. Unfortunately, the use of newly approved antivirals, including adefovir dipivoxil, emtricitabine, and telbivudine, is also associated with the development of drug resistance, albeit to a lesser extent than the use of lamivudine. The objectives of this work were to assess the performance characteristics (sensitivity and accuracy) of an updated drug resistance test, the INNO-LiPA HBV DR v2, which includes detection of mutations associated with lamivudine, adefovir, emtricitabine, and telbivudine resistance, and to compare the results with consensus sequencing of serum samples from patients treated with HBV antivirals. Diagnostic sensitivity, defined as detection of a positive amplification line on the line probe assay (LiPA) strip, was 94.8% (95% confidence interval [CI], 89.7 to 97.9) after initial testing, increasing to 96.3% (95% CI, 91.6 to 98.8) after repeat test 1 and to 100% (95% CI, 97.3 to 100.0) after repeat test 2. In diagnostic accuracy determinations, full concordance was observed between sequencing and LiPA for 77.0% of the codons tested (620/805 codons [95% CI, 74.0 to 79.9]), whereas LiPA and sequencing were partially concordant 22% of the time (177/805 codons). In 167 out of 177 cases, LiPA detected a wild-type/mutant mixture whereas sequencing detected only one of the two results. Performance testing of the new LiPA test, the INNO-LiPA HBV DR v2, showed convincing diagnostic sensitivity and accuracy. The ability of the test to detect mixed infections and minority viral populations associated with resistance to the current generation of antivirals, including adefovir, emtricitabine, and telbivudine, makes it a useful tool for HBV therapy monitoring.

Tenofovir disoproxil fumarate (TDF) displays potent activity against hepatitis B virus (HBV), including lamivudine (LAM) resistant HBV. Here we report the results after at least 1 year of treatment with TDF in a heavily pre-treated cohort of 61 patients with previous failure of both LAM and ADV and a high rate of genotypic resistance. Method(s): This was an open-label prospective multicentre study. Adults with HBV mono-infection who had previously failed LAM and had significant viral replication (HBV DNA >105 c/mL if HBeAg+, >104 c/mL if HBeAg-) after at least 24 weeks of ADV were switched to TDF 300 mg daily. Patients receiving combination ADV/LAM prior to baseline received TDF/LAM. Result(s): 61 patients were enrolled. Median age was 46.2 years (21-80), 46 (75%) were male, 38 (62%) were Asian, and 40 (66%) were HBeAg+. 39 (64%) were switched from ADV to TDF, the remainder from ADV/LAM to TDF/LAM. Median duration of prior antiviral exposure was 37.5 months (8-103) LAM and 22 months (6-85) ADV. Baseline mutations included: rtM204I/V (21 patients, 17 with L180M) as well as rtA181T/V, rtN236T, or both (10, 3, and 4 patients, respectively). Median baseline viral load was 6.12 log10 c/mL (4.0-8.8). One patient discontinued TDF at 10 days due to rash. No other adverse events thought to be related to TDF have been reported. Median follow-up for the remaining 60 patients is 84 weeks (48-132). The fall in median HBV DNA from baseline to weeks 12, 24, and 48 was 2.11, 2.76, and 4.24 log10 c/mL, respectively. At 48 weeks, 12/60 (20%) patients had HBV DNA >3.3 log10 c/mL, and this was associated with the presence of rtN236T at baseline (p = 0.024) or a higher baseline viral load (p = 0.042). 4 episodes of virological breakthrough (increase >1 log10 c/mL from nadir) have been observed to 48 weeks, 2 in the context of poor compliance. All 4 responded to ongoing TDF. Conclusion(s): TDF shows significant and ongoing antiviral activity against HBV in patients who have failed LAM an

Tenofovir disoproxil fumarate (TDF) displays potent activity against hepatitis B virus (HBV), including lamivudine (LAM) resistant HBV. Despite in vitro cross-resistance to adefovir (ADV), TDF shows clinical utility in the setting of prior ADV failure. Here we report the results after at least one year of treatment with TDF in a heavily pre-treated cohort of 61 patients with previous failure of both LAM and ADV and a high rate of genotypic resistance. Method(s): This was an open-label prospective multicentre study. Adults with HBV mono-infection who had previously failed LAM and had clinically significant viral replication (HBV DNA >105 c/mL if HBeAg+, >104 c/mL if HBeAg-) after at least 24 weeks of ADV were switched to TDF 300mg daily. Patients receiving combination ADV/LAM prior to baseline received TDF/LAM. The primary outcome was change in HBV DNA from baseline. All patients have had >48 weeks TDF. Result(s): 61 patients were enrolled. Median age was 46.2 years (21-80), 46 (75%) were male, 38 (62%) were Asian, and 40 (66%) were HBeAg+. 39 (64%) were switched from ADV to TDF, the remainder from ADV/LAM to TDF/LAM. Median duration of prior antiviral exposure was 37.5 months (8-103) LAM and 22 months (6-85) ADV. HBV genotype distribution was A=5; B=8; C=32; and D=16 patients. Baseline mutations included: rtM204I/V (21 patients, 17 with L180M) as well as rtA181T/V, rtN236T, or both (10, 3, and 4 patients, respectively). Median baseline viral load was 6.12 log10 c/mL (4.08.8). One patient discontinued TDF at 10 days due to rash. No other adverse events thought to be related to TDF have been reported. Median follow-up for the remaining 60 patients is 84 weeks (48-132). The change in median HBV DNA from baseline to weeks 12, 24, and 48 was-2.11,-2.76, and-4.24 log10 c/mL, respectively. At 48 weeks, 12/60 (20%) patients had HBV DNA >3.3 log10 c/mL and 2 of these displayed new mutations (one rtA181T and one rtN236T). HBV DNA >3.3 log10 c/mL at 48 weeks was associated wit

AVT resistance in CHB can cause viral rebound and disease progression however routine surveillance is not performed. The aim of the CHARM study was to establish the prevalence and characteristics for hepatitis B virus mutations in AVT treated patients in clinical practice. Method(s): In this large Australian, multi-centre, cross-sectional, epidemiological study, CHB patients receiving AVT for >=6 mo had serum HBV DNA measured (Versant v3.0; LOD >351 IU/mL) and direct sequence analysis of the polymerase catalytic region (amino acids 1-257) performed if HBV DNA was detectable. Demographics, clinical and serological information, patient assessed compliance and prior AVT history and mutations were collected. Result(s): To date 483 patients have been enrolled, these were predominantly male (74%), Asian (76%), overseas born (94%), HBeAg negative (64%), mean ALT 34 U/L (range 5-395) and median age 49 yrs (range 21-83). Median total duration of AVT was 50 mo (range 6-156) and 62% had received a prior AVT; 13% of patients had missed >=1 dose in the last 28 days. Current AVT was predominantly lamivudine (LAM) (25%), adefovir (ADV)+LAM (24%) or entecavir (ETV) 0.5mg (22%), median duration 43, 12 and 13 mo respectively. HBV DNA was detectable in 25% (123/483) of patients with 72% (89/123) having >=1 resistance mutation; a genotypic resistance prevalence of 18% (89/483). M204V/I 14% was most frequent; L180M 9%, A181V/T 3%, N236T 2%, V173L 2%, T184A/L/S 1%, S202G <1% were also reported. The majority of patients with mutations had received a prior AVT (83%) and were currently on ADV+LAM (39%), LAM (16%), ADV+ETV (12%) or ETV 1mg (11%). They were predominantly HBeAg positive (60%) with a mean ALT 45 U/L and 31% had ALT >ULN (40 U/L); 27% had a history of mutations. Conclusion(s): The majority of CHB patients with detectable HBV DNA on AVT, including combination AVT, had genotypic resistance. A significant proportion had accompanying biochemically active liver disease. These data hi

Hepatitis B virus (HBV) antiviral drug resistance mutations prevent successful outcome of treatment and lead to worsening of liver disease. Detection of its emergence permits opportune treatment with alternative drugs. Unfortunately, the use of newly approved antivirals, including adefovir dipivoxil, emtricitabine, and telbivudine, is also associated with the development of drug resistance, albeit to a lesser extent than the use of lamivudine. The objectives of this work were to assess the performance characteristics (sensitivity and accuracy) of an updated drug resistance test, the INNO-LiPA HBV DR v2, which includes detection of mutations associated with lamivudine, adefovir, emtricitabine, and telbivudine resistance, and to compare the results with consensus sequencing of serum samples from patients treated with HBV antivirals. Diagnostic sensitivity, defined as detection of a positive amplification line on the line probe assay (LiPA) strip, was 94.8% (95% confidence interval [CI], 89.7 to 97.9) after initial testing, increasing to 96.3% (95% CI, 91.6 to 98.8) after repeat test 1 and to 100% (95% CI, 97.3 to 100.0) after repeat test 2. In diagnostic accuracy determinations, full concordance was observed between sequencing and LiPA for 77.0% of the codons tested (620/805 codons [95% CI, 74.0 to 79.9]), whereas LiPA and sequencing were partially concordant 22% of the time (177/805 codons). In 167 out of 177 cases, LiPA detected a wild-type/mutant mixture whereas sequencing detected only one of the two results. Performance testing of the new LiPA test, the INNO-LiPA HBV DR v2, showed convincing diagnostic sensitivity and accuracy. The ability of the test to detect mixed infections and minority viral populations associated with resistance to the current generation of antivirals, including adefovir, emtricitabine, and telbivudine, makes it a useful tool for HBV therapy monitoring.

Despite the introduction of new nucleos(t)ide analogues in recent years, peginterferon is still recommended as a potential first-line treatment option by current practice guidelines for the management of chronic hepatitis B. Peginterferon offers the advantage of higher sustained off-treatment response rates compared to nucleos(t)ide analogues because of its immunomodulatory effects. Sustained transition to the inactive hepatitis B surface antigen (HBsAg) carrier state can be achieved in about 30% of hepatitis B e antigen (HBeAg)-positive patients and 20% of HBeAg-negative patients. Recent studies have focused on identification of pretreatment and on-treatment factors that allow the selection of patients who are likely to achieve a sustained response to peginterferon therapy in order to avoid the side-effects and costs associated with unnecessary treatment. Future studies need to address whether specific virologic benchmarks can guide individualized decisions concerning therapy continuation and whether peginterferon combined with new potent nucleos(t)ide analogues improves treatment outcomes.

Tenofovir disoproxil fumarate (TDF) displays potent activity against hepatitis B virus (HBV), including lamivudine (LAM) resistant HBV. Here we report the results after at least 1 year of treatment with TDF in a heavily pre-treated cohort of 61 patients with previous failure of both LAM and ADV and a high rate of genotypic resistance. Method(s): This was an open-label prospective multicentre study. Adults with HBV mono-infection who had previously failed LAM and had significant viral replication (HBV DNA >105 c/mL if HBeAg+, >104 c/mL if HBeAg-) after at least 24 weeks of ADV were switched to TDF 300 mg daily. Patients receiving combination ADV/LAM prior to baseline received TDF/LAM. Result(s): 61 patients were enrolled. Median age was 46.2 years (21-80), 46 (75%) were male, 38 (62%) were Asian, and 40 (66%) were HBeAg+. 39 (64%) were switched from ADV to TDF, the remainder from ADV/LAM to TDF/LAM. Median duration of prior antiviral exposure was 37.5 months (8-103) LAM and 22 months (6-85) ADV. Baseline mutations included: rtM204I/V (21 patients, 17 with L180M) as well as rtA181T/V, rtN236T, or both (10, 3, and 4 patients, respectively). Median baseline viral load was 6.12 log10 c/mL (4.0-8.8). One patient discontinued TDF at 10 days due to rash. No other adverse events thought to be related to TDF have been reported. Median follow-up for the remaining 60 patients is 84 weeks (48-132). The fall in median HBV DNA from baseline to weeks 12, 24, and 48 was 2.11, 2.76, and 4.24 log10 c/mL, respectively. At 48 weeks, 12/60 (20%) patients had HBV DNA >3.3 log10 c/mL, and this was associated with the presence of rtN236T at baseline (p = 0.024) or a higher baseline viral load (p = 0.042). 4 episodes of virological breakthrough (increase >1 log10 c/mL from nadir) have been observed to 48 weeks, 2 in the context of poor compliance. All 4 responded to ongoing TDF. Conclusion(s): TDF shows significant and ongoing antiviral activity against HBV in patients who have failed LAM an

Tenofovir disoproxil fumarate (TDF) displays potent activity against hepatitis B virus (HBV), including lamivudine (LAM) resistant HBV. Despite in vitro cross-resistance to adefovir (ADV), TDF shows clinical utility in the setting of prior ADV failure. Here we report the results after at least one year of treatment with TDF in a heavily pre-treated cohort of 61 patients with previous failure of both LAM and ADV and a high rate of genotypic resistance. Method(s): This was an open-label prospective multicentre study. Adults with HBV mono-infection who had previously failed LAM and had clinically significant viral replication (HBV DNA >105 c/mL if HBeAg+, >104 c/mL if HBeAg-) after at least 24 weeks of ADV were switched to TDF 300mg daily. Patients receiving combination ADV/LAM prior to baseline received TDF/LAM. The primary outcome was change in HBV DNA from baseline. All patients have had >48 weeks TDF. Result(s): 61 patients were enrolled. Median age was 46.2 years (21-80), 46 (75%) were male, 38 (62%) were Asian, and 40 (66%) were HBeAg+. 39 (64%) were switched from ADV to TDF, the remainder from ADV/LAM to TDF/LAM. Median duration of prior antiviral exposure was 37.5 months (8-103) LAM and 22 months (6-85) ADV. HBV genotype distribution was A=5; B=8; C=32; and D=16 patients. Baseline mutations included: rtM204I/V (21 patients, 17 with L180M) as well as rtA181T/V, rtN236T, or both (10, 3, and 4 patients, respectively). Median baseline viral load was 6.12 log10 c/mL (4.08.8). One patient discontinued TDF at 10 days due to rash. No other adverse events thought to be related to TDF have been reported. Median follow-up for the remaining 60 patients is 84 weeks (48-132). The change in median HBV DNA from baseline to weeks 12, 24, and 48 was-2.11,-2.76, and-4.24 log10 c/mL, respectively. At 48 weeks, 12/60 (20%) patients had HBV DNA >3.3 log10 c/mL and 2 of these displayed new mutations (one rtA181T and one rtN236T). HBV DNA >3.3 log10 c/mL at 48 weeks was associated wit

AVT resistance in CHB can cause viral rebound and disease progression however routine surveillance is not performed. The aim of the CHARM study was to establish the prevalence and characteristics for hepatitis B virus mutations in AVT treated patients in clinical practice. Method(s): In this large Australian, multi-centre, cross-sectional, epidemiological study, CHB patients receiving AVT for >=6 mo had serum HBV DNA measured (Versant v3.0; LOD >351 IU/mL) and direct sequence analysis of the polymerase catalytic region (amino acids 1-257) performed if HBV DNA was detectable. Demographics, clinical and serological information, patient assessed compliance and prior AVT history and mutations were collected. Result(s): To date 483 patients have been enrolled, these were predominantly male (74%), Asian (76%), overseas born (94%), HBeAg negative (64%), mean ALT 34 U/L (range 5-395) and median age 49 yrs (range 21-83). Median total duration of AVT was 50 mo (range 6-156) and 62% had received a prior AVT; 13% of patients had missed >=1 dose in the last 28 days. Current AVT was predominantly lamivudine (LAM) (25%), adefovir (ADV)+LAM (24%) or entecavir (ETV) 0.5mg (22%), median duration 43, 12 and 13 mo respectively. HBV DNA was detectable in 25% (123/483) of patients with 72% (89/123) having >=1 resistance mutation; a genotypic resistance prevalence of 18% (89/483). M204V/I 14% was most frequent; L180M 9%, A181V/T 3%, N236T 2%, V173L 2%, T184A/L/S 1%, S202G <1% were also reported. The majority of patients with mutations had received a prior AVT (83%) and were currently on ADV+LAM (39%), LAM (16%), ADV+ETV (12%) or ETV 1mg (11%). They were predominantly HBeAg positive (60%) with a mean ALT 45 U/L and 31% had ALT >ULN (40 U/L); 27% had a history of mutations. Conclusion(s): The majority of CHB patients with detectable HBV DNA on AVT, including combination AVT, had genotypic resistance. A significant proportion had accompanying biochemically active liver disease. These data hi

Hepatitis B is a major global health problem with an estimated 2 billion people having been infected with the hepatitis B virus (HBV) and an estimated 350-400 million people suffering chronic infection. Hepatitis B is the 10th leading cause of death worldwide and hepatocellular cancer, a complication of chronic hepatitis B infection, is the 5th most common cancer worldwide. In this thesis I review the virology, epidemiology, natural history and therapy of hepatitis B infection. The mainstay of medical management of chronic hepatitis B are oral nucleos(t)ide analogues which have the capacity to profoundly suppress viral replication and prevent disease progression. The major shortcoming of nucleos(t)ide therapy is the development of resistance. Therapy for these patients is increasingly difficult in the setting of multi-drug resistance. In this thesis I investigate the use a newer nucleotide, tenofovir disoproxil fumarate, in patients with previous multi-drug (lamivudine and adefovir dipivoxil) resistant hepatitis B. I show tenofovir is safe and effective in such patients, although probably less so than in nucleos(t)ide naïve patients. Post-liver transplant recurrence of hepatitis B may be severe and life threatening. Standard prophylaxis regimes utilise hepatitis B immune globulin (HBIG) and lamivudine indefinitely post-transplant. In this thesis I investigate the use of combination lamivudine and adefovir dipivoxil prophylaxis, either post-transplant (after a period of HBIG and lamivudine) or pre-transplant (avoiding the use of prolonged HBIG entirely). I show combination adefovir and lamivudine (both pre- and post-transplant) achieves and/or maintains suppression of hepatitis B viral replication and prevents the development of recurrence. This has the benefit of significant cost-savings and is less inconvenient for liver transplant recipients.

Significant advances in the management of chronic hepatitis B (CHB) have been made over the past decade. During this period we have witnessed improvements in survival as well as reduction of disease progression in CHB patients due to the introduction of effective antiviral therapy. The need for effective antiviral therapy is underscored by the results of the REVEAL-HBV study in which 3653 hepatitis B virus (HBV) carriers were followed over 12 year period. This study demonstrated that a persistently elevated serum HBV DNA level was the most important risk factor for the development of hepatocellular carcinoma (HCC). The ultimate goal of antiviral therapy for CHB patients should include halting the progression to cirrhosis and its life threatening complications and in preventing/reducing the development of HCC. An earlier study of 651 CHB patients with cirrhosis or advanced fibrosis from countries in Asia also demonstrated that treatment with lamivudine (LVD) not only delayed disease progression but also reduced the development of HCC. These landmark studies reaffirm the need for active antiviral therapy for CHB. Current treatment options for patients with CHB include interferon and nucleos(t)ide analogues. As we gain experience with these agents, it has become increasingly clear that long-term therapy benefits patients with CHB.