Potential new treatment for HBV

[raja1972]

http://www.physorg.com/news/2010-12-potential-treatments-hepatitis-tuberculosis-underway.html

But human trials will be 3-5 years away :-(

[stef2011]

what do you think about the combo interferon+telbivudine or future combo interferon lambda+telbivudine

is the a way to prevent sides on this combo and does PN risk woth the try, at least staggered for short periods like:
6 months interferon+telbivudine
6 months interferon+tenofovir

[StephenCastlecrag]

Many thanks, again, for your answers.  We have heard of encouraging report about LB80380 from Hong Kong. Let's hope it will not have side effects like Clevudine.

I have posted your comments to the Chinese Forum. All the very best. Are you going to AASLD in November? We will await your expert comments.

[studyforhope]

These compounds are other nuceloside analogs, variants, as so many exist, that act principally like Tenofovir or Entecavir. The chance for any one of those to achieve practical standing at this time of historical development is extremely small.

The only drug currently in advanced development with a very realistic chance to join the established very selected antiviral HBV drug family is the following.
LB80380
(it possesses similar powers to Entecavir, has very little toxicity and is effective against LAM resistant strains).

it might be effective against ADF or ETV resistant strains also, but this needs to be shown clearly. Here are its latest data for the AASLD 2011:

WEEK 48 ANALYSIS OF A PHASE IIb STUDY OF THE EFFICACY AND SAFETY OF LB80380 vs. ENTECAVIR IN TREATMENT-NAÏVE PATIENTS WITH CHRONIC HEPATITIS B
C. Lai1; S. Ahn2; K. Lee2; S. Um3; M. Cho4; S. Yoon5; J. Lee6; N. Park7; Y. Kweon8; J. Sohn9; J. Lee10; J. Kim10; K. Han2; M. Yuen1
1. University of Hong Kong, Hong Kong, Hong Kong.
2. Yonsei University, Seoul, Korea, Republic of.
3. Korea University, Seoul, Korea, Republic of.
4. Pusan National University, Pusan, Korea, Republic of.
5. The Catholic University of Korea, Seoul, Korea, Republic of.
6. Inha University, Incheon, Korea, Republic of.
7. Ulsan University, Ulsan, Korea, Republic of.
8. Kyungpook National University, Daegu, Korea, Republic of.
9. Hanyang University, Seoul, Korea, Republic of.
10. LG Life Sciences, Ltd., Seoul, Korea, Republic of.

Background: LB80380, a novel nucleotide analogue, is effective and safe in chronic hepatitis B(CHB) patients with lamivudine-resistant mutations, with doses above 90 mg daily.

Aim: To compare the efficacy and safety of LB80380 with entecavir in treatment-naïve CHB patients up to week 48 of therapy.

Methods: 115 CHB patients fulfilling the following criteria were recruited from Hong Kong and Korea: (1) HBsAg positive for >6 months, (2) HBeAg-positive with HBV DNA ≥105 copies/mL or HBeAg-negative with HBV DNA ≥104 copies/mL, (3) elevated ALT levels (1.2-10 X ULN), (4) treatment-naïve and (5) compensated liver disease. They were randomized in the ratio of 1:1:1 to receive either LB80380 90 mg, 150 mg or entecavir 0.5 mg daily orally for 48 weeks. 102 patients who adhered to the protocol were analysed as per-protocol analysis set. The efficacy endpoint was the change in HBV DNA at week 48 from baseline. There is an extension study up to week 96 which is ongoing.

Results: The data up to week 48 of treatment are tabulated below.

All two doses of LB80380 showed comparable anti-viral activity with entecavir 0.5 mg daily after 48-week treatment.
Carnitine supplement 660 mg was given to the patients who developed low serum L-carnitine levels throughout the treatment period. The levels became normal in all patients after the carnitine supplements. No drug-related serious or significant adverse events were observed.
Full sequencing of the HBV polymerase region was performed at baseline, at week 48 and whenever there was virologic breakthrough for samples with HBV DNA > 103 copies/mL. No resistant mutations were found in any of the 3 groups of patients by week 48.

Conclusions: (1) At week 48, LB80380, 90 or 150 mg daily had comparable antiviral activity with entecavir 0.5 mg daily, and no resistant mutation was detected. (2) Low serum L-carnitine levels, though occurring in a significant proportion of patients, were normalized in all patients with carnitine supplement. (3) Other than lowering of serum L-carnitine levels, no LB80380-related serious or significant adverse events were not reported.

LB80380
90mg
(n=34) LB80380
150mg
(n=33) Entecavir
0.5mg
(n=35) p
M : F 20 : 14 28 : 5 28 : 7 0.035
Age (yrs) ± SD 42.4 ± 10.3 40.4 ± 10.7 41.4 ± 11.8 NS
HBeAg+ : HBeAg- 19 : 15 18 : 15 21 : 14 NS
Baseline HBV DNA (log10 c/mL) ± SD 7.65 ± 1.18 7.64 ± 1.43 7.92 ± 1.28 NS
Week 48 HBV DNA (log10 c/mL) ± SD 2.40 ± 0.53 2.41 ± 0.78 2.34 ± 0.59 NS
Log10 HBV DNA decrease at week 48 ± SD -5.26 ± 1.00 -5.23 ± 1.23 -5.59 ± 1.16 NS
HBV DNA < 300 copies/mL at week 48 (%) 67.7 81.8 80.0 NS
ALT normalized at week 48 (%) 88.2 78.8 91.4 NS
HBeAg loss for HBeAg+ pts 4/19 3/18 3/21 NS
Serum L-carnitine lower
than normal (%) 72.2 97.4 - 0.0025

[StephenCastlecrag]

Thank you for the abstract. I layman terms, how do these compounds work against HBV?

[studyforhope]

Here is the abstract:

Antiviral activity of various 1-(2'-deoxy-β-D-lyxofuranosyl), 1-(2'-fluoro-β-D-xylofuranosyl), 1-(3'-fluoro-β-D-arabinofuranosyl), and 2'-fluoro-2',3'-didehydro-2',3'-dideoxyribose pyrimidine nucleoside analogues against duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) replication.
Srivastav NC, Shakya N, Mak M, Agrawal B, Tyrrell DL, Kumar R.
SourceDepartment of Laboratory Medicine and Pathology, 1-71 Medical Sciences Building, Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.

Abstract
Despite the existence of successful vaccine and antiviral therapies, infection with hepatitis B virus (HBV) continues to be a major global cause of acute and chronic liver disease and high mortality. We synthesized and evaluated several lyxofuranosyl, 2'-fluoroxylofuranosyl, 3'-fluoroarabinofuranosyl, and 2'-fluoro-2',3'-didehydro-2',3'-dideoxyribose pyrimidine nucleoside analogues for antiviral activities against hepatitis B virus. Among the compounds examined, 1-(2-deoxy-β-d-lyxofuranosyl)thymine (23), 1-(2-deoxy-β-d-lyxofuranosyl)-5-trifluoromethyluracil (25), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)uracil (38), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)thymine (39), 2',3'-dideoxy-2',3'-didehydro-2'-fluorothymidine (48), and 2',3'-dideoxy-2',3'-didehydro-2'-fluoro-5-ethyluridine (49) were found to possess significant anti-HBV activity against DHBV in primary duck hepatocytes with EC(50) values of 4.1, 3.3, 40.6, 3.8, 0.2, and 39.0 μM, respectively. Compounds 23, 25, 39, 48, and 49 (EC(50) = 41.3, 33.7, 19.2, 2.0-4.1, and 39.0 μM, respectively) exhibited significant activity against wild-type human HBV in 2.2.15 cells. Intriguingly, 25, 39, 48, and 49 retained sensitivity against lamivudine-resistant HBV containing a single mutation (M204I) and 48 emerged as an effective inhibitor of drug-resistant HBV with an EC(50) of 4.1 μM. In contrast, 50% inhibition could not be achieved by lamivudine at 44 μM concentration in the drug-resistant strain. The compounds investigated did not show cytotoxicity to host cells up to the highest concentrations tested.