New Agents Effective for Patients with Chronic Hepatitis D

Of all the viral hepatitis, chronic hepatitis D (CHD) remains a vexing problem. The lack of treatment options renders clinicians helpless against this infection. To tackle this infection, prenylation inhibitor lonafarnib (LNF), the first investigational agent for CHD was evaluated.

Patients with CHD were enrolled and given LNF for 12-24 weeks. The regimens used included: LNF 200 mg bid, 12 wks; LNF 300 mg bid, 12 wks; LNF 100 mg bid + ritonavir (RTV) 50 mg bid, 12 wks; LNF 75 mg bid + RTV 100 mg bid, 12 wks, followed by addition of pegylated interferon alfa, 12 wks; LNF 50 mg bid + RTV 100 mg bid, 24 wks.

After the completion of treatment 18.5% patients had post-treatment ALT flares (median ALT 190 U/mL, range 110–1355 U/mL. In these patients HDV RNA became negative and ALT normalized within 12-24 weeks after treatment. In these same patients HBV DNA levels rose as no patient was receiving simultaneous nucleotide analog treatment. However post the flare in these patients HBV DNA levels dropped and became undetectable in 2 patients.

Patients also experience improvement in fibrosis. It was noted that the fibrosis score reduced from 4 at baseline to 3, 2 to 0 and 6 to 4, respectively, in the 3 patients rebiopsied 6–18 months following initial ALT normalization and HDV-RNA negativity.

For the first time an agent has been able to induced therapeutic post-treatment immunological flares. This favourably alters the natural history of untreated CHD. Further studies will be needed to understand the impact of this new development

Abstract no. THU-161, C. Yurdaydin et al. Presented at the International Liver Congress 2017, 19^th-23^rd April, Amsterdam, Netherlands.

Decline of HBeAg Levels During Treatment with Tenofovir Can Predict HBeAg Seroconversion

Chronic hepatitis B usually requires long term treatment. However, patients who achieve endpoints like HBeAg seroconversion (SC), may be eligible to discontinue treatment. To better predict those who will undergo HBeAg SC, this study was undertaken in patients receiving tenofovir (TDF) treatment. 

Overall, 266 patients of genotypes (Gt) A-F were enrolled. HBeAg SC was observed in 45% of patients by week 192, with a median time to HBeAg SC of 64 weeks

Available serum samples from all patients for quantitative HBeAg levels at baseline (n = 235) and week 24 (n = 214) of treatment were analysed.  It was noted that those who achieved HBeAg SC were older (37.5 years vs. 31.1 years, p < 0.001), had Genotype A infection (Gt A: 76.7% vs. Gt non-A 36.3%, p < 0.001), and higher Knodell necroinflammatory grade (2 [2–3] vs. 3 [3–3], p = 0.04).

The probability of achieving HBeAg SC was not influenced by factors like baseline HBeAg, HBV DNA levels, and ALT levels. HBeAg SC was likely when there was atleast 1.63 log10 PE IU/mL reduction by the 24^th week of treatment in HBeAg levels. Hepatitis B patients were 52% like to experience HBeAg SC if there was a decline in HBeAg levels by week 24. Analysis showed that a reduction of 2.2 log10 PR IU/mL by week 24 was optimal for predicting SC [74% (37/50) vs. 35% (53/150), p < 0.001].

This study has shown that the levels of HBeAg while on treatment can predict HBeAg SC in patients treated with TDF. This simple biomarker may allow clinicians to identify and stop treatment for eligible patients.

Abstract no. THU-162, D. Wong et al. Presented at the International Liver Congress 2017, 19^th-23^rd April, Amsterdam, Netherlands.

HBsAg Loss is Rare but Durable in Patients Treated with Tenofovir

Patients with chronic hepatitis B (CHB) may end treatment when they experience HBsAg loss with or without anti-HBs seroconversion. This study was carried out to understand the durability of HBsAg loss and seroconversion in response to antiviral treatment.

This retrospective trial included patients from the pivotal trials of tenofovir in hepatitis B patients (Study “102”, “103”, “149”). Subjects were evaluated for up to 10 years in Studies 102 and 103 and for up to 120Weeks in Study 0149.

These studies evaluated patients, including those who stopped treatment, for loss of HBsAg and presence of anti-HBs for upto 24 weeks after treatment.

Out of the 1381 CHB patients analysed in this study 5.4% patients lost HBsAg. And out of these patients 69% had anti-HBs seroconversion. And out of those with anti-HBs seroconversion 21% experienced HBsAg seroreversion after a median duration of 26 weeks. The rest maintained their HBsAg loss. HBsAg loss was experienced 23 patients without seroconversion, out of which 6 (26%) experienced HBsAg seroreversion after a median duration of 10 weeks. Seroreversion was not influenced by anti-HBs status or treatment with nucleotide only or in combination with interferon. More than half of those who seroreverted did so within first 6 months of HBsAg loss. While most who maintained their HBsAg loss for more than 6 months did not have seroreversion.

Although seroconversion occurs in few patients, when it does occur it is long lasting. Those who experience seroreversion, generally do so within the first six months of HBsAg loss.

Abstract no. THU-174. H.L. Chan et al. Presented at the International Liver Congress 2017, 19^th-23^rd April, Amsterdam, The Netherlands.

ALT Flares in Pregnant Women Treated with Tenofovir

Pregnancy frequency alters the immune system and in those infected with hepatitis B, this changes the systems response to the infection. Tenofovir is given to pregnant women to reduce the hepatitis B viral load and prevent hepatitis B transmission to the infant. However, postdelivery there maybe flares in these patients. To better characterize these flares and its effect on the infection this study was carried out.

Pregnant chronic hepatitis B woman were followed during pregnancy and post-delivery. In all 325 were included out of which 87 received treatment with tenofovir during pregnancy. After delivery 44 patients stopped antiviral treatment. 238 patients did not meet the threshold for tenofovir treatment during pregnancy since HBV DNA <200,000 IU/ml and liver disease was absent.

Flares were noted both in patients who received treatment and those who did not. However, it was more common in those who discontinued treatment (70%) as compared to those who continued (42%) or were not treated (20%). 41% of HBeAg + and only 2% of HBeAg – patients were treated (p< 0.05). The viral characteristics were different in the treated group. The levels of HBeAg, HBV DNA and HBsAg levels were higher in the treated as compared to the untreated group (HBeAg: 1270 vs. 1.34; HBV DNA: 6.37 vs. 2.56; HBsAg: 4.08 vs. 2.61 all p < 0.01).

Flares were more common in those who had high HBV DNA levels at baseline in both the treated (6.12 vs. 3.37) and untreated (2.87 vs. 2.27) cohorts. Treated patients experienced HBeAg seroconversion 24% of the time and 43% had decline of HBsAg >0.5 log 10. In untreated patients: 3/5(60%) HBeAg + patients achieved HBeAg seroconversion and 5% patients had HBsAg decline >0.5 log10, both exclusive to patients without flares. Post-delivery HBsAg loss occurred in 6(2.5%) untreated patients (all HBsAg < 100 IU/ml). Flare did not resolve in 3/337 pts after 1 year post-delivery.

This study has shown that post-delivery ALT flares occurred largely in those who had high HBV DNA levels. Thus, flares were seen more in those receiving treatment with TDF to prevent transmission to the infant due to high viral levels. Immune reconstitution was noted post-partum in those who stopped treatment shortly after delivery.

Abstract no. THU-131. I. Carey et al. Presented at the International Liver Congress 2017, 19th-23rd April, Amsterdam, Netherlands.

Covert Hepatic Encephalopathy Leads to Increased Complications and Mortality in Stable Cirrhotic Patients

Covert hepatic encephalopathy (CHE) is a preclinical stage for overt hepatic encephalopathy. However, there are no studies which explore the natural progression of CHE in cirrhotic patients.

Wang et al. conducted a study to understand the natural history of CHE and identify factors which could lead to exacerbation and resolution of CHE.

Cirrhotic patients from a tertiary care hospital were enrolled and diagnosed for CHE using neuropychometric tests. Follow up time for the patients was 12 months. Patients were evaluated for the time to first hospitalization related to cirrhosis complications, resolution of CHE and transplant or death. These parameters were compared between CHE and no-CHE group.

 A total of 366 patients (age: 47.2 ± 8.6 years, male: 73.0%) were a part of this study. CHE was found to be present in 35.8% of patients. It was seen that patients with CHE had higher mortality rates and increased hospitalizations due to complications than no-CHE patients. Also, 17.6% CHE patients developed OHE. 42% patients suffered with persistent CHE whereas CHE was spontaneously resolved in 19.8% patients. Serum albumin <28 g/L (HR 5.22) was the only predictor for developing OHE. White blood creatinine >133 ?mol/L (HR 4.75) predicted mortality for CHE patients. Patients with Child-Pugh B/C (HR 0.084) and OHE history (HR 0.15) were predictors for spontaneous resolution of CHE.

Thus, this study showed the association of CHE with increased risk of complications and mortality in stable cirrhotic patients. This model based on predictors of CHE progression could help in the management of exacerbations and resolution of CHE

Abstract no. THU-026. A. Wang et al. Presented at the International Liver Congress 2017, 19^th-23^rd April, Amsterdam, Netherlands.

Increase in Gut Microbiota Post Liver Transplant Could Play a Role in Impaired Brain Recovery

It is assumed that patients completely recover cognitive function after liver transplant. However, this recovery might be incomplete in certain patient subgroups. Gut microbiota in pre-transplant patients especially Proteobacteria (e.g. Escherichia, Klebsiella etc.) are associated with poor outcomes. However, there is limited data available on this association.

J.S. Bajaj et al. conducted a study to assess whether gut microbiota alterations are associated with cognitive recovery in post-liver transplant (LT) patients.

Patients with cirrhosis who were listed for liver transplant were enrolled and followed till 6-month post-LT. Post-LT patients who had no incidence of infections and were stable on immunosuppressant’s were studied. Patient’s stool microbiota was analysed using multi-tagged pyrosequencing and cognitive testing using the Psychometric Hepatic Encephalopathy Score (PHES; range −15 to +4, higher being better). Stable/worsening of PHES was used as a definition to indicate cognitive impairment. Also, any increase in PHES was an improvement.

A total of 45 patients (age 56 ± 7 years, 32 men, 58% HCV, MELD 26 ± 8) were on rifaximin and 25 on lactulose. Patients undergoing liver transplant 6 ± 3 months after enrolment were re-evaluated 7 ± 2 months post-LT. Off all the patients included, post-LT, two patients developed rejection, four developed infections and four required biliary manipulation. But all these were resolved >3 months before the post-LT visit. All patients were alert and oriented and none of the patients developed recurrent cirrhosis or hepatic encephalopathy during the post-LT visit. Patients were on Bactrim and stable tacrolimus doses. Significant improvement was seen in PHES at baseline and post-LT (pre −5.9 ± 5.7 vs post −1.7 ± 3.1, p = 0.001). 29% (n=13) patients did not improve PHES post-LT. In such patients, Proteobacteria relative abundance was significantly higher (23% vs 0.1%, p = 0.01), while it was significantly lower in the group that showed improvement. Delta PHES was negatively correlated with delta Proteobacteria (r = −0.5, p = 0.05) i.e. a higher Proteobacteria was correlated with lower/worse PHES.

From these observations, it can be concluded that post-LT increase in Proteobacteria could play a role in incomplete brain recovery.

Abstract no. PS-112. J.S. Bajaj et al. Presented at the International Liver Congress 2017, 19^th-23^rd April, Amsterdam, Netherlands.

Liver Fibrosis is Present in HBeAg- Patients with Elevated Transaminases and High BMI

Chronic hepatitis B patients (CHB) with HBeAg – infection and persistently normal transaminases (NT) usually do not have substantial liver damage. However, few of these patients are seen with liver disease. Although not common there are important implications to figuring out indicators of liver damage in these patients with NT.

HBeAg – CHB patients with NT were studied in this trial. It included patients with NT for atleast 3 consecutive determinations during the first year and had minimum 1 year of follow up.

The final cohort of selected patients included 215 patients out of which 59% were males. The mean age was 47 years. A large proportion of subjects had BMI over 25 (62%). Alcohol consumption was moderate in 14%. During the follow-up of included individuals only 4% reported elevated transaminases (<1.5 times normal value) and 18% had a viral DNA > 2000 IU/ml.            Transient elastography was used to assess fibrosis and significant fibrosis was detected in 17.5%. The mean LS was 6.3 ± 5.8 kPa. 37 patients (23%) had LF in the gray area and 12 (7.5%) had severe fibrosis/cirrhosis, with 5% (8 patients) having a LS > 13 kPa. Liver stiffness was not influenced by age, race, alcohol consumption, or DNA levels.

Two factors were linked to the presence of liver fibrosis, elevated transaminases and high BMI. Liver fibrosis was seen in 21% of those with elevated transaminases during follow-up (only 3% with normal transaminases had fibrosis, p= 0.002) and in 86% of those with BMI >25 (56% with BMI <25 had liver fibrosis, p=0.002).

Since those with slight elevation of liver transaminases and BMI >25 are at risk of liver fibrosis, they are candidates for closer surveillance. Non-invasive tests can be used to monitor these patients and detect fibrosis in them.

Abstract no. FRI-143, C.S. Juan et al. Presented at the International Liver Congress 2017, Amsterdam, The Netherlands.

Adults Traditionally at Risk of Developing Chronic Hepatitis B Now Found to Have Delayed Clearance

It is well known that 95% of adults exposed to hepatitis B virus (HBV) will not develop a chronic infection. However, an exception to this observation are men who have sex with men (MSM) and people who use drugs (PWUD). Not much is known about how hepatitis B infection evolves in this population.

This research included 148 individuals (61 MSM, 81 PWUD); detected with HBV. The median follow-up in this cohort was 8.8 years. Seventy-one percent cleared HBV within 6 months of being detected with HBV (n = 106), 10.4% belonged to the delayed clearance group (n = 15) and 18.2% to the chronic HBV group (n = 27). Delayed clearance was those who had negative HBsAg and HBV DNA after 6 months of being detected with HBV.

Of these 27 individuals, 7 (25.9%) were HBsAg negative while HBV-DNA positive at their last visit. Among all HBV seroconverters, median time to clearance was 0.61 years. Among those who did not clear HBV initially, it was noted that within 5 years, 42.6% went on to clear HBV. The reasons for both delayed clearance and chronic infection included younger age and HIV/HCV coinfection.

A population that has traditionally been believed to be at an increased risk for chronic hepatitis B may clear the virus later. This finding adds new dimension to the follow-up and management of this population.

Abstract no. FRI-144, D.K. van Santen et al. Presented at the International Liver Congress 2017, 19^th to 23^rd April, Amsterdam, The Netherlands.

HBeAg positive patients find TAF is as Effective as TDF With Better Renal and Bone Safety at Week 96

The novel prodrug of tenofovir (TFV), tenofovir alafenamide (TAF), was evaluated in a double-blind study in HBeAg-positive patients. The safety of this new drug after two years of continued treatment has been examined.

Eligible patients in this study were randomized to TAF 25 mg once daily (n=581) or TDF 300 mg once daily (n=292) for 144 weeks. After 144 weeks, all patients were to shift to an open label study and receive TAF for 8 years. The efficacy has been summarised in the following table.

n/N (%)	TAF (N=581)	TDF (=292)	P value
Efficacy parameters
HBV DNA <29 IU/mL	423/581 (73)	218/292 (75)	0.47
ALT normalization (central laboratory)a	405/537 (75)	181/268 (68)	0.017
ALT normalization (AASLD criteria)b	299/572 (52)	121/290 (42)	0.003
HBeAg loss	123/565 (22)	51/285 (18)	0.20
HBeAg seroconversion	99/565 (18)	35/285 (12)	0.050
HBsAg loss	7/576 (1)	4/288 (1)	0.88
HBsAg seroconversion	6/576 (1)	0/288 (0)	0.078
Bone and Renal Parameters
Hip BMD, mean (SD) % Change	−0.33 (2.63)	−2.30 (2.95)	<0.001
>5% decline in hip BMD	21/491 (4)	38/249 (15)	<0.001
Spine BMD, mean (SD) % change	−0.69 (3.72)	−2.34 (3.91)	<0.001
>5% decline in spine BMD	53/495 (11)	59/251 (24)	<0.001
sCr, mean (SD) change (mg/dL)c	0.002 (0.088)	0.023 (0.090)	<0.001
eGFRCG median (Q1, Q3) change (mL/min)d	−1.8 (−9.0, 7.2)	−5.0 (−13.2, 3.0)	<0.001
≥25% decline in eGFRCG from baseline	60/577 (10)	52/288 (18)	0.002
Confirmed eGFRCG <50 mL/mine	0/581 (0)	5/292 (2)	0.004
PO4, median (Q1, Q3) change (mg/dL)f	−0.1 (−0.4, 0.2)	−0.1 (−0.4, 0.3)	0.37
Confirmed PO4 <2.0 mg/dL	3 (<1)	1 (<1)	1.00

Efficacy results are missing = failure;

aULN ≤43 U/L for males 18 to <69 years, and ≤ 35 U/L for males ≥ 69 years; ≤ 34

U/L for females 18 to < 69 years and ≤ 32 U/L for females ≥ 69 years;

bULN ≤30 U/L males, ≤19 U/L females;

csCr is serum creatinine;

deGFRCG is creatinine clearance (Cockcroft-Gault method);

eConfirmed upon retesting;

fPO4 is serum phosphorus.

At week 96 of this trial the mean age was 38 years, more than half were males (64%). The predominant genotype was C followed by D. A quarter had been previously treated with nucleos(t)ides.

The virologic response rates were similar in both treatment arms (TDF: 75% & TAF: 73%). A larger proportion of TAF patients achieved normalization of serum ALT values. The impact of TAF on bone metabolism was lesser than TDF. Fewer changes in hip and spine BMD was noted in TDF patients through 96 weeks. Similarly, renal changes were lower in TAF. Tubular markers remained the same from week 48 to week 96 in the TAF group. Serious adverse events and the rates of treatment discontinuations due to adverse events was similar in both the arms (≤6% & <1.5%).

TAF provides the same potent viral suppression as TDF with better bone and renal safety than TDF.

Abstract no. FRI-153, K. Agarwal et al. Presented at the International Liver Congress 2017, 19^th- 23^rd April, Amsterdam, The Netherlands.

Tenofovir Linked to Renal Toxicity in A Significant Number of Hepatitis B Patients

The two potent antivirals, entecavir and tenofovir have armed doctors against chronic hepatitis B. Tenofovir is used presently in its prodrug form of tenofovir disoproxil fumarate (TDF). TDF had been known to cause renal toxicities when used as a part of a combination to treat HIV. Some reports also showed an increase in renal toxicities when used long term for the treatment of chronic hepatitis B (CHB).

In a real-world cohort that followed 414 patients the risk factors and prevalence of renal toxicity was researched. This cohort included 76% of males and the average age was 62 years. Patients on an average had been treated with TDF for 82 months. The eGFRCG was 69 mL/min and around 36% had eGFR <60. One third patients were receiving alternate day dosing.

Most patients had HBeAg – CHB (91%) and the predominant genotype was D (79%). HBV DNA was undectable in 90% of the patients and ALT was normal in 92% of patients. Cirrhosis was present in 45% of patients, 38% had arterial hypertension, 10% had diabetes, 20% had high PTH levels and 6% had low vitamin D levels.

A significant proportion of patients had osteopenia (42%) and osteoporosis (14%) at the spine. While 37% had osteopenia and 4% had osteoporosis at the hip.

Renal examination found 37% of patients had low blood phosphate (<2.7 mg/dL, 10% <2.3), 59% had increased UBCR (>300 mg/g), 66% hyperphosphaturia (<0.80 TmPO4/GFR ratio) and 53% hypercalciuria (>0.11 UCA/Cr ratio).

There were atleast two markers of proximal tubular damage in 41% of the patients. These patients were generally older, had previously been treated with adefovir and had lower eGFR, diabetes and arterial hypertension.

Renal problems are present in a significant proportion of patients being treated with TDF. It would be beneficial for these patients to be shifted to tenofovir alafenamide.

Abstract no. SAT-156. P. Lampertico et al. Presented at the International Liver Congress 2017, 19^th-23^rd April, Amsterdam, Netherlands.