P Kooner

Assessment of Bone Mineral Density in Tenofovir-Treated Patients With Chronic Hepatitis B: Can the Fracture Risk Assessment Tool Identify Those at Greatest Risk?

BACKGROUND Tenofovir disoproxil fumarate (TDF) is an established nucleotide analogue in the treatment of chronic hepatitis B. Bone mineral density loss has been described in TDF-treated patients with human immunodeficiency virus infection, but limited data exist for patients with chronic hepatitis B. Dual X-ray absorptiometry (DEXA) was used to determine bone mineral density changes in TDF-exposed patients. We evaluated the accuracy of the Fracture Risk Assessment Tool (FRAX) as an alternative to DEXA in clinical practice. METHODS A total of 170 patients were studied: 122 were exposed to TDF, and 48 were controls. All patients underwent DEXA, and demographic details were recorded. FRAX scores (before and after DEXA) were calculated. RESULTS TDF was associated with a lower hip T score (P = .02). On univariate and multivariate analysis, advancing age, smoking, lower body mass index, and TDF exposure were independent predictors of low bone mineral density. In addition, the pre-DEXA FRAX score was an accurate predictor of the post-DEXA FRAX treatment recommendation (100% sensitivity and 83% specificity), area under the curve 0.93 (95% CI, .87-.97, P < .001). CONCLUSIONS TDF-treated patients with chronic hepatitis B have reduced bone mineral density, but the reduction is limited to 1 anatomical site. Age and advanced liver disease are additional contributing factors, underlining the importance of multifactorial fracture risk assessment. FRAX can accurately identify those at greatest risk of osteoporotic fracture.

PWE-144 Frax Score in the Assessment of Bone Mineral Density Changes in Tenofovir Treated Chronic Hepatitis B Patients

Introduction Tenofovir Disoproxil Fumarate (TDF) is an established oral antiviral (OAV) in the treatment of Chronic Hepatitis B (CHB). Bone Mineral Density (BMD) loss has been described in TDF treated HIV patients, but limited data exist in CHB. We have used DEXA scanning to determine BMD changes in TDF treated patients and have reported the possibility of BMD loss. DEXA scanning, however, is costly and requires longitudinal follow-up. We assessed the value of the FRAX® score and of bone biochemistry to evaluate their utility in TDF treated patients. Methods The FRAX score is a WHO web-based tool, used to calculate 10-year fracture risk and the need for lifestyle modification, DEXA scanning or preventative treatment. CHB patients treated with TDF for a minimum of 12-months and a control group not exposed to TDF were studied. 122 TDF exposed patients (male = 89), median age 45 (range = 26–64) and 48 patients (male = 31), median age 36 (range = 20–62) not exposed to TDF were DEXA scanned and included in the study. We calculated FRAX scores and recorded bone biochemical markers, comprising serum Alkaline Phosphatase (sALP), Calcium (sCa) and Phosphate (sPO). Results TDF treated patients had lower hip T-scores compared to controls (p = 0.02). On univariate analysis factors associated with a hip T-score < 1 included older age, lower BMI, smoking and TDF exposure (p = < 0.05). On multivariate analysis the same factors were associated with a hip T-score < 1, but TDF lost significance. For the development of a major osteoporotic fracture the pre-DEXA FRAX score was 4.77% compared to 4.33% (post-DEXA FRAX) (p = 0.9) and for a hip fracture this was 0.54% (pre-DEXA FRAX) and 0.77% (post-DEXA FRAX) (p = 0.5). The pre-DEXA FRAX score was a significant predictor of the post-DEXA FRAX treatment recommendation (p = < 0.001). TDF therapy was associated with increased sALP after 12-months, but this was not significant. No change was observed in pre-treatment sCa and sPO levels compared to those after 12-months exposure (p = 0.5 & 0.09 respectively). Conclusion Our results demonstrate the FRAX score alone can accurately predict the risk of developing an osteoporotic fracture in TDF treated CHB patients. This potentially obviates the need for DEXA scanning and the associated costs. The relationship between sALP and TDF is noteworthy, but bone parameters are of limited use in predicting BMD changes. Although BMD loss in TDF treated CHB patients remains unproven, we demonstrate the use of the FRAX score may determine those at risk of osteoporotic fractures in CHB. Disclosure of Interest None Declared.

PMO-166 Early experience with telaprevir for patients with advanced fibrosis or cirrhosis

Introduction The direct-acting HCV protease inhibitor telaprevir has recently been licensed for treatment of chronic genotype 1 HCV infection, and promises significant improvements in sustained virological response for these patients. However the patients who may benefit most from novel HCV therapies, namely those with advanced fibrosis or cirrhosis who have previously failed to respond to pegylated interferon (pegIFN) and ribavirin treatment, are relatively poorly represented in the telaprevir clinical trials. Efficacy, safety and tolerability were assessed in patients with genotype 1 HCV and advanced fibrosis/cirrhosis who have received telaprevir-containing treatment at the Royal London Hospital. Methods Laboratory results and case notes were reviewed for all patients treated with pegIFN, ribavirin and telaprevir at the Royal London Hospital between September 2011 and January 2012. Results Eight patients with genotype 1 HCV had commenced telaprevir-containing treatment. All had advanced fibrosis/cirrhosis (median Ishak score 5, range 4–6). One was treatment-naïve, three had previously failed to respond to pegIFN/ribavirin and four had relapsed after therapy. All patients had completed at least 4 weeks of telaprevir-containing therapy. With one exception, all patients achieved undetectable HCV RNA at week 4 of treatment; the patient who did not had a viral load of 168 IU/ml at week 4 and undetectable HCV RNA at week 8. One patient had completed 12 weeks of therapy, with undetectable HCV RNA. The most common side effects were fatigue (8/8), pruritis (4/8), rash (3/8), anal pain (3/8), depression (3/8), nausea (3/8), gastrointestinal disturbance (2/8) and oral candidiasis (2/8). Most side effects were successfully managed, although telaprevir was stopped in two patients at week 8 due to worsening rash and one patient withdrew from all therapy at week 4 due to tolerability. The most common laboratory abnormality was an early, transient rise in bilirubin (3/8). Significant anaemia (Hb). Conclusion Telaprevir in combination with pegIFN and ribavirin appears efficacious in patients with advanced fibrosis or cirrhosis, who have previously failed treatment with pegIFN and ribavirin alone. However, the incidence of significant side effects in this subgroup of patients is high and necessitates frequent follow-up with medical support. Side effects, particularly rash, may limit duration of telaprevir treatment. Whether this impacts on sustained virological response remains to be seen. Competing interests M Cunningham: None declared, J Schulz: None declared, L Payaniandy: None declared, Y Kallis: None declared, P Kennedy: None declared, P Kooner: None declared, R Marley: None declared, G Foster grant/research Support from: Roche, Janssen, Tibotec, Novartis, Consultant for: Abbott, BI, BMS, Chughai, Janssen, Merck, Novartis, Roche, Tibotec.

PMO-176 Induction maintenance treatment in chronic hepatitis B; step-down from tenofovir and lamivudine to lamivudine monotherapy is effective

Introduction Tenofovir Disoproxil Fumarate (TDF) is a potent and effective oral antiviral used to treat Chronic Hepatitis B (CHB), but concerns remain about possible long-term toxicity and the costs of indefinite use. An induction-maintenance treatment strategy may allow the use of combination Lamivudine (LAM) and TDF, to avert the development of resistance, followed by maintenance of viral suppression with LAM. To date, there are no data on such a step-down strategy in HBeAg negative CHB. Here we report on patients in whom we safely discontinued TDF, while maintaining viral suppression and normal liver biochemistry. Methods We selected patients who were had received combination therapy for a minimum of 18 months. Selection criteria included HBeAg negative disease, fibrosis score of <4/6 on biopsy, undetectable HBV DNA and normal serum ALT for a minimum of 12 consecutive months. Patients meeting these criteria were invited to stop TDF and step-down to maintenance LAM monotherapy. Patients were followed at monthly intervals to determine whether viral suppression and ALT normalisation was maintained in the absence of TDF. Results 21 patients (13 male), median age 47, (range 39–62) discontinued TDF. Median follow-up was 3 months (range 1–10 months). During monthly follow-up biochemical and serological data have been measured. All patients had undetectable HBV DNA prior to step-down therapy to LAM and this remained undetectable during follow-up. Pre-discontinuation of TDF the median ALT was 27 (range 15–38) and during follow-up, on LAM monotherapy, was 22 (range 15–45), (p=NS). Median HBsAg level pre-discontinuation of TDF was log 3.48 (range 1.55–4.49) and 3.49 (range 1.55–4.55), (p=NS) on LAM monotherapy. Conclusion We demonstrate no viral breakthroughs or biochemical flares on discontinuing TDF. These data suggest that an induction-maintenance strategy may be pursued in selected CHB patients to avoid long-term exposure to TDF and reduce the burden on healthcare budgets in the context of lifelong oral antiviral therapy. Competing interests None declared.

PMO-175 Can a 3-month “stopping rule” for pegylated-interferon-α be applied to a UK population of chronic hepatitis B infected patients of mixed genotype?

Introduction Stopping rules have been proposed for the early discontinuation of Pegylated-Interferon-α (PEG-IFN-α) therapy in those patients who are considered unlikely to respond. Recent studies have shown that no reduction in quantitative HBsAg and the absence of >2 log decline in HBV DNA at 12 weeks therapy can predict non-response. However, these data are almost exclusively from genotype A and D cohorts. Here we test how robust this strategy would be in clinical practice and whether this rule could be applied to a UK population of diverse HBV genotypes. Methods 49 patients (male=35) were treated with PEG-IFNα for CHB over the course of the study. Ten patients remain on therapy and eight patients discontinued due to poor compliance or intolerance. 31 patients (male=20), HBeAg positive (n=24), median age 31 (range 18–55) completed 48 weeks PEG-IFNα and were included in the analysis. HBV genotype was recorded for all patients (A=6, B=5, C=10, D=9, E=1). ALT, HBV DNA and HBsAg was quantified at baseline and longitudinally at 12-week intervals. Results Of the 31 patients, 10 were considered responders; seven were HBeAg positive and seroconverted on therapy and three were HBeAg negative pre-therapy and considered responders with sustained immune control off treatment. The decline in HBV DNA and qHBsAg by 12 weeks was 3.99 log, 0.17 log (HBeAg positive group) and 2.9 log, 0.5 log (HBeAg negative group) respectively. 16/31 patients were non-genotype A or D. Of the responders from this group there was a decline in HBV DNA and qHBsAg of 4.10 log and 0.58 log respectively by 12 weeks. On sub-group analysis by genotype, there was no statistically significant difference in HBV DNA and qHBsAg decline at 12 weeks across all genotypes, when comparing HBV DNA and qHBsAg between genotype A and D and non A and D patients (p=0.40 and 1.0 respectively). More over adopting the rule of >2 log decline in HBV DNA and no decline in qHBsAg by 12 weeks, reveals we would not exclude those likely to respond; as all responders achieve the outlined viral response by 12 weeks therapy. Conclusion These data highlight the utility of this stopping rule for PEG-IFNα across all genotypes. The absence of >2 log decline in HBV DNA and reduction in qHBsAg at 12 weeks therapy makes a favourable response unlikely. This rule should be adopted in clinical practice to avoid poorly tolerated side effects and the cost of completing 48 weeks therapy. Furthermore, this 12-week milestone would allow the early switch to an oral antiviral in PEG-IFNα non-responders. Competing interests None declared.

PMO-148 Evaluation of liver fibrosis in young adult patients with chronic hepatitis B virus

Introduction Current guidelines do not recommend treatment of Chronic Hepatitis B (CHB) in young adults as they are believed to be immune tolerant with minimal liver damage. Recently we demonstrated that young CHB patients have evidence of immune activity comparable to older patients. Therefore, a proportion of young patients will develop fibrosis as a consequence of immune mediated liver injury. Despite this, the most appropriate modality to assess liver fibrosis remains controversial. We compare the utility of liver biopsy and digital image analysis with FibroScan for assessment of CHB in young adults. Methods Young adult CHB patients were followed in a dedicated clinic and seen 3-monthly. Liver biopsy was performed where indicated and compared with FibroScan scores. Digital image analysis was performed on a selected number of Sirius red stained sections to evaluate percentage fibrosis. 167 patients were assessed; 101/167 (male=63); median age 26 (range 16–30) underwent liver biopsy and were included for analysis. Results 47/101 patients were eAg+. Overall median ALT was 41IU/L (range 14–426) & HBV DNA was 5.22 logIU/ml (range 1.4–9.3). Median Ishak fibrosis score was 1 (range 0–6); median FibroScan score was 5.95 kPa (range 2.6–35.2). There was no difference in the FibroScan score in patients with advanced (F5/6) and minimal fibrosis (F0/1); median FibroScan scores were 6 and 5.95 respectively, (p=ns). The correlation co-efficient between fibrosis and FibroScan was not statistically significant (p=0.46). FibroScan scores were confounded by ALT; using Prati criteria to define normal ALT (female <19 IU/l, male <30 IU/l), we noted an ALT twice ULN revealed a higher FibroScan score, regardless of fibrosis (p=0.05 and 0.04; males and females respectively). On the contrary, digital image analysis more accurately reflected fibrosis stage irrespective of ALT. Conclusion A proportion of young adult patients with CHB have significant liver disease on biopsy. This study highlights the limitations of FibroScan in assessing liver fibrosis in this cohort. Our data demonstrates the utility of digital image analysis in benchmarking fibrosis in young patients, potentially providing a more accurate methodology to assess progression of fibrosis over time. Competing interests None declared.

Single centre experience of use of transarterial chemoembolization (TACE) with doxorubicin eluting beads (DEB) for the treatment of hepatocellular carcinoma (HCC)

Introduction There is evidence that TACE can prolong survival in patients with inoperable HCC, and DEB may provide even further benefit, with a favourable side effect profile. This is the first UK report of experience with this treatment modality. Methods The authors performed a retrospective analysis of all patients receiving TACE with DEB for HCC at The Royal London Hospital between January 2009 and April 2010. Data collected included patient demographics, aetiology of liver disease and tumour characteristics. The Child-Pugh Score, Barcelona Clinic Liver Cancer (BCLC) stage, Cancer of the Liver Italian Programme (CLIP) score and Okuda stage were calculated. Complications following TACE were analysed and tumour response was assessed by 6-week post-treatment triphasic CT scanning (by mRECIST criteria). The authors also analysed overall survival to the end of follow-up. Results During the study period 14 patients received 21 cycles of TACE with DEB. There were 11 males (79%), and mean age was 64 years (SD 8.3). The main causes of liver disease were hepatitis C (29%), hepatitis B (21%), alcohol (21%). The median number of liver lesions was 2 (range 1–7), and the mean size of the largest lesion was 5 cm (range 1.2–11.2 cm). All patients had Child Pugh Score A5 to B7, and 71% were BCLC stage B or C. The median CLIP score was 1 (range 0–2), and 79% were Okuda stage 1. The mean Doxorubicin dose was 119 mg (range 37.5–150 mg). The only complications were postembolisation syndrome of pain and fever in one patient and a haematoma in one patient, requiring conservative treatment only. These resolved with no long-term sequelae. There were no episodes of neutropenia at day 10. All patients had a radiological response observed on the 6-week triphasic CT scan. Tumour response (mRECIST partial and complete) was observed in 76% of cases and after a mean follow-up of 8 months (range 1–16) 13 patients (93%) were alive. Conclusion TACE with DEB is a well tolerated and safe modality for treatment of inoperable HCC. This results demonstrate high rates of tumour response and a low complication rate. Further larger studies are warranted to evaluate this promising treatment.

P61 Bone mineral density loss in tenofovir treated Chronic Hepatitis B Virus (HBV) patients is a consequence of Vitamin D deficiency and not Tenofovir therapy

Introduction Tenofovir Disoproxil Fumarate (TDF) is now established as a very potent oral antiviral (OAV) agent in the treatment of chronic hepatitis B (CHB). However, as treatment with this OAV is often indefinite and potentially lifelong, concerns remain about its long-term safety. Bone Mineral Density (BMD) loss has been described in TDF treated HIV patients, but limited data exist for HBV treated patients. Furthermore, BMD loss has also been described in chronic liver disease in addition to being reported with certain patient characteristics. Aim The aim of this study was to determine the impact of TDF on BMD in an ethnically diverse HBV infected population undergoing long-term treatment with this agent. Method CHB patients treated with TDF for a minimum of 12 months were recruited to this single centre study. Patients were prospectively offered a dual x-ray absorptiometry (DEXA) scan. Serum bone profile and Vitamin D levels were requested simultaneously. BMD loss was defined by WHO criteria; T-score < −2.5 (osteoporosis) and between −1 and −2.5 (osteopenia). 107 consecutive TDF treated patients were included (78 males), median age 45 (range 26–64). A control group, 27 CHB patients (19 males), median age 32 (range 20–61), with no TDF exposure were also studied. Data on gender, ethnicity, BMI, fibrosis stage, co-morbidities and drug history were recorded in all subjects. Analysis was performed with SPSS V.19. Results BMD loss was present in 44% of the treatment group (osteopenia 81%, osteoporosis 19%) and in 44% of the control group (osteopenia 83%, osteoporosis 17%) (p=0.21). In the ethnically diverse population studied, there was more marked BMD loss in the non-white population (47%, treated group; 45%, controls) compared with the white population (30%, treated group; 40%, controls). By univariate analysis age, gender, ethnicity, fibrosis stage, BMI, co-morbidities and low Vitamin D level were all significant for reduced BMD (p≤0.05, all variables). On multivariate analysis gender, ethnicity, BMI, fibrosis, co-morbidities and Vitamin D all met statistical significance for a reduction in BMD, but Vitamin D deficiency only was significant for the presence of osteoporosis (p=0.0001). Conclusion Our results demonstrate the prevalence of reduced BMD in CHB patients of diverse ethnicity and identify Vitamin D deficiency and not TDF as the likely cause. This cross-sectional study does not exclude the potential for BMD loss with TDF and further longitudinal studies are required to determine its effect on BMD over time. Vitamin D deficiency should be appropriately treated to avoid any potential for BMD loss associated with TDF when considering treatment with this OAV agent.

Efficacy of Combination Tenofovir Plus Lamivudine Versus Tenofovir Monotherapy in Patients With Chronic Hepatitis B Virus

Introduction Highly effective oral antivirals (OAV) have been licensed for use in Chronic Hepatitis B (CHB). Efficacy of Tenofovir (TDF) and Entecavir (ETV) monotherapy has been demonstrated in randomised controlled trials. However, there may be a role for de novo combination therapy to reduce the development of resistance. For this reason, the authors offer patients combination therapy with TDF and Lamivudine (LAM) irrespective of whether they are OAV-naive or experienced. In this study the authors test the hypothesis that combination therapy is superior to TDF monotherapy as assessed by viral suppression and ALT normalisation. Methods A retrospective prospective study of 185 patients (male=135), from a single centre, was performed. Viral suppression, was defined as Results Median age of patients was 45 (range 18–81). 74% were eAg negative prior to starting TDF and LAM. Median ALT at baseline was 46 (range 12–1141). 86 patients were treatment naive prior to commencing combination therapy. Of 99 patients previously exposed to OAV9s, 65 were partial responders and 34 virally suppressed when switching to TDF and LAM. 125/185 patients had completed 12 months and 84, 24 months of combination therapy. Overall viral suppression was recorded in 84% and 94% at 12 and 24 months respectively and ALT normalisation was seen in 67% and 74% at 12 and 24 months respectively. In the OAV-naive group viral suppression was 81% compared with 84% in the OAV-experienced and ALT normalisation was 56% and 72% respectively in these groups at 12 months. In the published meta-analysis, viral suppression was 91% and ALT normalisation 67% at 12 months in a treatment naive group. Comparing real life with published data showed no statistical significance for viral suppression and normalisation of ALT for combination versus monotherapy (p=0.12 and p=0.2 respectively). Conclusion These data highlight the efficacy of TDF in generating and sustaining viral suppression and ALT normalisation at 12 months and beyond. Combination OAV therapy versus TDF monotherapy does not show superiority. Furthermore, there is no reported resistance with TDF to date, but data are limited to 4-year follow-up. Given that OAV resistance may occur over many years, combination OAV may still have a role in the treatment of CHB, however larger randomised controlled trials are needed to determine this.

Utility of HBsAg quantification in developing an individualised approach to the management of chronic hepatitis B virus in clinical practice

Introduction HBsAg is a surrogate marker of cccDNA, its loss is associated with sustained immune control and reduction in the development of HCC. HBsAg quantification (qHBsAg) has facilitated the on-treatment monitoring of response to pegylated interferon α (IFNα) with the potential to individualise therapy according to response. HBsAg decline with oral antivirals (OAV) is reported to be a slower process; however any reduction in HBsAg could potentially be used as a tool to determine duration of therapy, in lieu of recommended lifelong treatment. This study examined the utility of HBsAg quantification in developing individualised treatment strategies for both IFNα and OAV treated patients. Methods 86 CHB patients (male=72) were included for analysis. All patients underwent qHBsAg (ABBOTT Architect) in addition to longitudinal measurement of ALT and HBV DNA. 60 patients (male=54), median age 45 (range 21–70), were treated with combination Tenofovir and Lamivudine; qHBsAg was recorded at baseline, 12 and 24 months. 26 patients (male=18), median age 31 (range 18–55), were treated with IFNα. HBsAg was quantified at baseline, 12 and 24 weeks. HBsAg decline was compared in the OAV and IFNα groups at 12 and 24 months versus 12 and 24 weeks respectively. Results In the OAV group, baseline median ALT 42.5 (range 15–181) and median HBV DNA 3.43 log (range 1.5–7.9). At 12 months, ALT normalisation was achieved in 60% and undetectable DNA in 90%. Mean HBsAg decline in this group was 0.06 log at 12 months. ALT normalisation and viral suppression was sustained at 24 months. HBsAg decline, however, was not sustained and there was an overall mean increase of 0.1 log from baseline. In the IFNα group, baseline median ALT 113.6 (range 29–448) and median HBV DNA 7.21 log (range 3.58–9.25). HBsAg decline was measured 12 weekly. 8/26 (31%) patients had a >0.5 log decline at 12 weeks and this increased to 45% at 24 weeks. HBsAg decline was significantly greater in the IFNα group when compared with the OAV group at 12 weeks versus 12 months and more marked at 24 weeks versus 24 months (p=0.03 and p=0.006 respectively). Conclusion These data highlight the utility of qHBsAg in IFNα therapy and raises the possibility of an individualised, response guided approach allowing early changes in treatment regimen if indicated. Consistent with published data, the 24-week HBsAg is a better predictor of sustained immune control. Conversely, there was a limited HBsAg decline in OAV treated patients over prolonged follow-up and this reduction was not sustained. This suggests that HBsAg quantification alone cannot be used to individualise therapy and determine treatment duration with OAV9s.