Long Term (96 Weeks) Adefovir in HBeAg Negative Chronic Hepatitis B Results in Significant Virological, Biochemical, and Histologic Improvement
--96 week results in HBeAg negative
--Drug resistance summary
--Liver Histology Improvements Regardless of Baseline Fibrosis in HBeAG-
--Lack of Ethnic Differences between Caucasians and Asians in Response to Adefovir in HbeAg+ and HbeAg- Patients with Chronic HBV
--Adefovir for 3 Years in Patients with Lamivudine Resistant HBV and HIV Co-infection
This study was presented by Stefanos Hadziyannis (Henry Dunant Hospital, Athens, Greece) and colleagues and Gilead Sciences.
Summary. Study authors concluded: Adefovir for 96 weeks resulted in significant and continued reduction in HBV DNA and ALT; and additional histologic improvement beyond that seen at week 48. Discontinuation of ADV resulted in loss of HBV DNA and ALT suppression. And reversion of histologic improvement. The safety profile at week 96 was similar to that seen at week 48. Adefovir has a distinct resistance profile from lamivudine. Emergence of adefovir resistance was delayed and infrequent. Resistance report below.
Adefovir dipivoxil (ADV) 10 mg has demonstrated significant histological, virological, and biochemical improvement as compared to placebo (PLB) through 48 weeks of therapy in HBeAg positive and HBeAg negative patients. The benefit of 96 weeks of continuous ADV 10 mg therapy was evaluated in this study.
Hadziyannis presented this background. Adefovir is a nucleotide analogue of adenosine monophosphate. It is a chain terminator of HBV DNA. It has activity against wild-type and lamivudine-resistant HBV. Its administered by one 10 mg tablet once daily orally. It has durable HBV DNA suppression with a high threshold for the development of resistance. The safety profile was good in 48 weeks studies and similar to placebo. Its approved for HBV treatment in the US, European Union, Canada, Australia, Singapore and Hong Kong.
For this study (study 438) patients were HbsAg+ for at least 6 months; HBeAg- and HBeAb+; had compensated liver disease; adequate renal function; HIV, HCV and HDV seronegative; had a liver biopsy; HBV DNA ≥105 copies/ml; ALT x ULN ≥1.5 to 15.
185 HBeAg negative CHB patients were randomised to receive ADV 10 mg or PLB for 48 weeks in a 2:1 ratio. At 48 weeks, the ADV group was re-randomized (2:1 ratio) to ADV 10 mg (n=80) or PLB (n=40). PLB patients received ADV 10 mg (n=60) in the second 48 weeks.
Median HBV DNA at baseline was 7.05 to 7.16 log10 copies/ml (>10 million). Median ALT was 2.1 to 2.4 >ULN. Median ALT was 86 to 99 IU/L. 10-15% of patients had cirrhosis. Median total Knodell HAI score 10 and Ishak fibrosis score 2.
Serum HBV DNA (Roche Amplicor Monitor PCR LLQ<1000 copies /mL) and ALT levels (upper limit normal (ULN) 43 IU/L) were evaluated every 4 weeks. Liver biopsy was performed at baseline and 48 weeks and was optional at 96 weeks. Scoring of biopsies was performed using the Knodell and Ishak scoring systems. Histological improvement was defined as a ≥ 2-point improvement in Knodell score with no worsening of fibrosis, with missing biopsies at week 48 considered as failures.
Resistance analysis was performed: The HBV polymerase RT domain was PCR amplified and sequenced for all isolates from patients with detectable HBV DNA at baseline and at week 96.
97% of study patients completed 48 weeks. 92% completed week 96; 125 patients will be followed for an additional 3 years. This will yield 5 year followup for patients originally randomized to receive adefovir.
80 patients received placebo followed by ADV. 79 patients received ADV and continued on ADV. 40 patients received ADV followed by placebo. Average age was 46-47 yrs. 82-83% were men. 25-33% were Asian. 65-70% were Caucasian. 2-5% were Black; 38-45% had prior interferon therapy; 7-9% had prior lamivudine therapy.
Patients receiving ADV 10 mg had immediate reductions in viral load (HBV DNA). Patients who switched off ADV to placebo at week 48 had immediate increases in HBV DNA. Patients who started ADV therapy & remained on it had sustained VL reductions. Patients who started on placebo had no VL reductions until week 48 when they started on ADV when they saw immediate VL reductions.
At week 96, 71% of patients who had been on ADV for the entire 96 weeks had undetectable serum HBV DNA (LLQ=1000 copies/ml). 80% of these patients had <10,000 copies/ml at week 96. 88% of these patients had <100,000 copies/ml at week 96. 76% of patients who started on placebo & switched to ADV had undetectable serum HBV DNA. 50% achieved an undetectable serum HBV DNA within 36 weeks of initiating therapy.
At week 96, median ALT was <40 IU/L (upper limit of normal, ULN) for patients on ADV (ADV-ADV, PLB-ADV) had. Patients who started on ADV had median ALT <40 but after switching to placebo median ALT increased above 40.
At week 96, 76% of patients who started & remained on ADV achieved normalization of ALT. 80% of patients who started on placebo & switched to ADV achieved normalization of ALT. 32% of patients who started on ADV & switched to placebo had normalized ALT at week 96. 83% had ALT < 1.2 x ULN and 87% had ALT levels < 1.5 x ULN, with 50% of patients having normalized ALT within 20 weeks of initiating therapy.
Median Change from Baseline in Total Knodell Score
In the subset of patients who started & remained on ADV with a third biopsy at week 96 (n= 19), histological improvement was seen in 79% at week 96; there was a 5 point median decline in total Knodell score and 53% had a ≥ 1 point decline in the Ishak fibrosis score. At week 48 median decrease in total Knodell score was 4 points. Median changes in total Knodell score showed increases for patients on placebo. Patients who started on placebo & switched to ADV and patients who started on ADV and switched to placebo showed improvements in total Knodell score but not as much as patients were on ADV for full 96 weeks. After patients who were on ADV switched to placebo the improvements in total Knodell score declined almost back to baseline by week 96, median decline from baseline was 4 points at week 48 and 1 point at week 96. Patients who started on placebo & switched at week 48 to ADV had median 2.5 decline in total Knodell score at week 96.
Assessment in Fibrosis at Week 48 and 96
For patients starting and remaining on ADV, 63% (n=19) showed improved fibrosis at week 48 and 74% at week 96. This shows it can take more than 1 year to achieve improvement in fibrosis of greater than 2 points. None of these patients showed worsening of fibrosis.
For patients who started on placebo (n=20), 30% showed improvement in fibrosis at week 48 and 35% at week 96 after switching to ADV. Patients switched from placebo to ADV at week 48. At week 48, 40% of patients had worsening of fibrosis; at week 96 25% had worsening of fibrosis, compared to baseline.
For patients who started on ADV and switched at week 48 to placebo (n=8), 50% showed improved fibrosis at week 48 and 38% at week 96, showing some decline after switching off ADV. At week 48 no patients showed worsened fibrosis and at week 96 13% showed worsened fibrosis, compared to baseline.
Safety Summary- 96 Weeks
Adverse events and lab abnormalities over 96 weeks was similar to that seen in the first 48 weeks. 2 of 492 patients with serum creatinine ≥0.5 mg/dL from baseline: 1 patient resolved with continued ADV; 1 patient resolved upon discontinuation of ADV.
25% of patients who switched from ADV to placebo had ALT elevations >10xULN. None were associated with liver decompensation. Careful monitoring following treatment discontinuation is recommended.
Drug Resistance Summary
Novel conserved site mutation rt N236T was identified:
--0% of patients had this mutation at week 48
--2.5% at week 96
In poster #1141 a detailed resistance report was provided. Here is a summary. 79 patients with HBeAg-negative chronic HBV received ADV 10 mg daily in this study (study 438) for 96 weeks. The entire HBV reverse transcriptase domain was sequenced. Phenotypic analysis was also performed. Conserved site mutations were identified in 5/79 patients after 96 weeks of ADV therapy Patients A, B, C, D and E). Gilead reported on 2 patients that developed the N236T mutation had serum HBV DNA rebound. Both patients responded to lamivudine therapy. BOne patient with the A181V mutation had serum HBV DNA rebound while the other continued to respond to ADV. The patient that developed the K241E and K318Q mutations continued to respond to ADV. Rebound defined as 1 log or greater increase in serum HBV DNA from nadir.
Patient A developed the N236T mutation and serum HBV DNA rebounded.
Patient B developed N236T+A181A/T and HBV DNA rebounded.
Patient C developed A181A/V and HBV DNA did not rebound
Patient D developed A181V and HBV DNA rebounded
Patient E developed K214E+K318Q and HBV DNA did not rebound.
Effect of Conserved Site HBV Mutations on Adefovir Susceptibility In Vitro
--The N236T mutation reduced ADV susceptibility by 7-14 fold in vitro.
--Addition of the A181T mutation to the N236T mutant HBV did not enhance ADV resistance in vitro.
--The A181T mutation remained susceptible to ADV in vitro.
--The A181V mutation reduced ADV susceptibility by 2-3 fold in vitro
--The K241E and K318Q mutations did not alter in vitro ADV susceptibility
In Vitro Susceptibility of N236T Mutant HBV to Lamivudine and Entecavir
--N236T mutant HBV remained susceptible to lamivudine with IC50 values shifted ≤3.5 fold
--N236T mutant HBV remained susceptible to entecavir with IC50 values shifted <1 fold
In Vivo Susceptibility of N236T Mutant HBV to Lamivudine in Patients A & B
--Patient A switched to lamivudine monotherapy after the development of N236T mutant HBV, seen at week 80. A181T was first observed at week 96. Patients A and B with the N236T mutation displayed suboptimal HBV DNA suppression at week 48 (<2 log reduction) and subsequent rebound (>1 log) from nadir. Emergence of N236T was associated with an ALT flare (10xULN at week 92) in patient A but not in patient B. Patient A began lamivudine monotherapy at week 104 and serum HBV DNA became undetectable by Digene hybridization assay (LLOQ=150,000 copies/ml) after 6 months. ALT normalized.
--Patient B experienced viral load rebound on ADV, the N236T mutation was seen at week 80, and at week 100 N236T/A181T mutation was seen and lamivudine therapy was started; whereupon HBV DNA started to decline.
Serum HBV DNA in 2 Patients with the A181V Mutation
One patient (C) had reduction in HBV DNA on ADV from 7 log at baseline to 3 log at week 80. He had viral load rebound at week 80 and A181V was observed at week 96. He was off ADV from week 96 to 104. Serum HBV DNA declined quickly to undetectable by PCR (<1000 copies/ml) when back on ADV.
Patient D saw HBV DNA decline on ADV from 8 log to 5.5 log on ADV. HBV DNA increased at week 64 and A181V was observed at week 80. HBV DNA continued to increase. Emergence of A181V was not associated with ALT flare in either patient. Clinical data are currently insufficient to link A181V with ADV resistance.
Serum HBV DNA Levels in Patient E with the K241E and K318Q Mutations
HBV replication in patient E was suppressed near the limit of detection (1000 copies/ml) through week 96, suggesting that K241E and K318Q do not confer resistance to ADV.
In studies of lamivudine, resistance to lamivudine developed in 24% after 1 year, 41% after 2 years, 53% after 3 years, and 70% after 4 years (studies 435, 412, and 460).
Long term resistance surveillance ongoing for up to 5 years.
Liver Histology Improvements Regardless of Baseline Fibrosis in HBeAG-
In Poster 1156 Patrick Marcellin reported that 48 weeks in study 438 of ADV resulted in consistent & significant improvement in liver histology and viral status regardless of baseline Knodell Fibrosis score in patients with HbeAg- chronic HBV.
Patients in the trial were randomized to treatment with ADV or placebo (PLB) for 48 weeks. Liver biopsies were performed at baseline, after 48 weeks in all patients. The primary efficacy endpoint was a ≥ two-point improvement in the inflammatory score of the Knodell Histology Activity Index (HAI) with no progression of the fibrosis score.
This was achieved by 64% (77/121) treated with ADV 10 mg QD and 33% (19/57) PLB treated patients (p<0.001) at 48 weeks.
The objective of this analysis is to compare the efficacy response between ADV 10 mg and PLB treated patients with regards to baseline Knodell fibrosis scores (F0/F1 = no/portal fibrosis and F3/F4 = bridging fibrosis/cirrhosis) at 48 weeks.
Evaluable paired baseline and week 48 biopsies were available from 167 patients (91%) enrolled in the study. The biopsies were assessed by a central histopathologist, blinded to treatment assignment and sequence. Biopsies were scored utilizing Knodell HAI scores comparing the baseline to the week 48 biopsy. Change in alanine aminotransferase (ALT), serum HBV DNA (Roche Amplicor, LLQ 400 copies/mL) and histology were evaluated in patients receiving ADV 10 mg and PLB.
ADV 10 mg results in a consistent and significant biochemical, virological and histological response compared to PLB (ALT normalization, change in ALT, HBV DNA < 400 copies/mL, HBV DNA reduction and histological improvement) regardless of the baseline Knodell fibrosis score.
At baseline, 0-1% of patients had F0, no fibrosis; 59-61% had FI portal fibrosis; 23-27% had F3 bridging fibrosis; and 10-11% had F4 cirrhosis. There was little difference between the placebo and ADV arms at baseline.
For patients with baseline Knodell Fibrosis scores of F0/1: ADV 10mg resulted in 64% of patients with histologic improvement and 27% of patients receiving placebo. For patients with baseline F3/4 Knodell Fibrosis score: 68% receiving ADV improved histology and 45% saw improvement on placebo.
The median change in HBV DNA at week 48 was the same regardless of baseline Knodell Fibrosis score (4.0 log for F0/1 vs 3.9 log for F3/4). Patients on placebo had 1 to 1.5 log HBV DNA reductions at week 48.
ALT was normalized at week 48 in 78% of patients on ADV with F0/F1 and by 64% for patients with F3/F4. 20-29% of patients receiving placebo had ALT normalization.
34% of patients on ADV saw regression of fibrosis from F3/4 to F1/0 and 22% saw this on placebo (the poster did not say whether this difference was significant). 0% of patients on ADV progressed from F0/1 to F3/4. 21% on placebo progressed from F0/1 to F3/4.
By Ishak Score: 34% of patients on ADV and 14% on placebo saw improved histology. 4% on ADV and 36% on placebo saw worsening of fibrosis by Ishak score.
Lack of Ethnic Differences in Response to Adefovir in HbeAg+ and HbeAg- Patients with Chronic HBV
SG Lim (National University Hospital, Singapore) and colleagues, and Gilead Sciences reported at AASLD on this study which evaluates response of asian and Caucasians patients with chronic HBV (CHB) in 2 international, multi-center phase 3 studies comparing adefovir (ADV) 10 mg to placebo for 48 weeks.
Summary. The authors concluded that in HBeAg+ and HBeAg- CHB patients, 48 weeks of ADV 10 mg once daily demonstrated significant histological, virological, and biochemical improvement compared to PLB, regardless of ethnicity (Asian or Caucasian). The similarity of response was consistent with the PK parameters in Asian and Caucasian patients. Safety was similar regardless of ethnicity. Reduction in serum HBV DNA was similar regardless of genotype.
522 CHB patients were treated for 48 weeks in two randomized, double-blind, placebo-controlled studies:
--338 HBeAg+ patients (HBV DNA ≥ 106 copies/mL, Roche AmplicorTM PCR, LLQ 400 copies/mL, ALT 1.2–10 x ULN) were randomized in a 1:1 ratio to ADV 10 mg or placebo (PLB)
--184 HbeAg- patients (HBeAg-/HBeAb+, HBV DNA ≥ 105 copies/mL, ALT 1.5–15 x ULN) were randomized in a 2:1 ratio to ADV or PLB.
Paired baseline and week 48 liver biopsies were assessed by a single histopathologist blind to treatment assignment and sequence. Improvement was defined as a ≥ 2 point decrease in Knodell necroinflammatory score from baseline at week 48 with no worsening of fibrosis, with missing biopsies considered as treatment failures.
Virological and biochemical assessments and adverse-event monitoring were conducted every 4 weeks. For this analysis, data from the two studies were integrated.
Additionally, two PK studies in healthy Asian patients were conducted and PK parameters were compared to data from four PK studies in healthy Caucasians and CHB patients. 12 Asian patients were randomized to receive a single dose of ADV 5 mg, ADV 10 mg, or ADV 30 mg in a cross-over design. In a second study, 24 Asian patients were randomized 5:1 to ADV 10 mg or PLB, respectively for 7 days. Single dose PK parameters for ADV 10 mg in Asian patients were then compared to single dose ADV 10 mg PKs parameters in 83 Caucasians healthy volunteers and 14 CHB patients.
At baseline, 50% of patients enrolled in the treatment studies were Asian and 46% Caucasian. All patient demographic and HBV disease characteristics were well matched. Assessable baseline and week 48 biopsies were available for 88% HBeAg+ and 91% HBeAg- patients.
At week 48, ADV 10 mg resulted in histological improvement in 60% ADV compared to 26% of PLB (p < 0.001) in Caucasian patients and in 56% ADV compared to 29% of PLB Asian patients (p < 0.001).
Change in serum HBV DNA from baseline at week 48 was of -3.9 and -3.7 log10 copies/mL in Caucasian and Asian patients, respectively while 34% of Causcasian patients and 39% of Asian patients had undetectable HBV DNA (< 400 copies/mL) at week 48. Consistently, the reduction in serum HBV DNA was similar across genotypes (A–D).
The percentage of patients achieving ALT normalization at week 48 was similar in both groups (Asian 63%, Caucasian 64%).
ADV was well tolerated by both ethnic groups with similar frequency of AEs and grade 3/4 lab abnormalities in the ADV and placebo groups. PK parameters (AUC, Cmax, Tmax, and T1/2) were similar in Asian and Caucasian patients in phase 1 clinical trials conducted in the United States and Asia.
The authors concluded that in HBeAg+ and HBeAg- CHB patients, 48 weeks of ADV 10 mg once daily demonstrated significant histological, virological, and biochemical improvement compared to PLB, regardless of ethnicity (Asian or Caucasian). The similarity of response was consistent with the PK parameters in Asian and Caucasian patients. Safety was similar regardless of ethnicity. Reduction in serum HBV DNA was similar regardless of genotype.
Long Term Treatment with Adefovir for 3 Years in Patients with Lamivudine Resistant HBV and HIV Co-infection
8-15% of HIV-infected are HBsAg+ and HBV is a major cause of morbidity and mortality. The purpose of this study was to evaluate 3 years treatment of ADV (10 mg once daily) in patients with LAM-R HBV and HIV co-infection. Yves Benhamou and colleagues and Gilead Sciences reported results at AASLD.
Summary. HBV DNA reduced 5.5 log copies/ml after 3 years. Median ALT reduced from 80 to 31 IU/L. 46% had <1000 copies/ml. ALT normalized in 64%. No adefovir HBV or HIV mutations seen. HIV remained stable. No evidence of nephrotoxicity. No ALT flares seen. Study authors reported no loss of suppression was seen.
Patients with LAM-R HBV, co-infected with HIV, who previously participated in a one-year pilot study of ADV, continued treatment for a further two years. ADV was added to the pre-existing anti-retroviral therapy including LAM (150 mg bid).
Patients were seen every 4 weeks in the first year and every 12 weeks in the 2nd and 3rd years. At each visit, serum ALT, serum HBV DNA (Amplicor Monitor™ Roche, LLQ 2.6 log10 copies/mL), HBV serological markers, plasma HIV RNA (LLQ 2.3 log10 copies/mL) and CD4 cell count were measured. HIV RNA was <2.3 log10 copies/ml. Gene sequencing for HBV and HIV were performed throughout the study.
35 patients were studied; mean age 39 yrs; 34 men; median prior 3TC 42 months. Baseline median HBV DNA was 8.75 log copies/ml. Mean ALT was 81 IU/L. 94% were HBeAg+. Liver histology n=23: Mean activity 1.52, mean fibrosis 2.04, cirrhosis 22%. Mean HIV RNA was 2.88 log copies/m. Mean Cd4 count was 422.
Median change in serum HBV DNA: -4.0 log c/ml at week 48; -4.8 log c/ml at week 96; -5.5 log c/ml at week 144.
Median serum ALT: 53 IU/L at week 48; 46 IU/L at week 96; 31 IU/L at week 144.
Percent with HBV DNA <1000 copies/ml: 0% at baseline; 6% at week 48; 27% at week 96; 46% at week 144.
ALT normalization: 3% at baseline; 19% at week 48; 37% at week 96; 64% at week 144.
HBeAg loss and HBeAb seroconversion was observed in 3 and 2 patients, respectively. Serum HIV RNA levels and CD4 counts were stable throughout 144 weeks.
No ADV-associated HBV resistance mutations (N236T) identified at weeks 48, 96, and 144.
No ADV-associated HIV resistance mutations (K65R, K70E) identified at weeks 48 and 96. Week 144 genotyping in progress.
There was no evidence of nephrotoxicity up to week 144. Two patients with transient grade 1 changes in serum creatinine (≥0.5 mg/dL increase from baseline) at weeks 28 and 32. Both resolved on treatment. No serum phosphorous <1.5 mg/dL.
No evidence of ALT flares on treatment up to 144 weeks. Transient ALT increase in the first 12 weeks followed by sustained ALT reduction and normalization.
3 serious adverse events were reported, study authors said were all unrelated to ADV. One patient developed HCC and died due to disease progression.
Patients will continue in long term followup.