tenofovir, no resistance at 5 years (probably none at 10years too)

[stef2011]

No Detectable Resistance to Tenofovir Disoproxil Fumarate (TDF) Following up to 240 Weeks of Treatment in Patients with HBeAg+ and HBeAg- Chronic Hepatitis B Virus Infection
P. Marcellin1; E. Heathcote2; A. Corsa3; Y. Liu3; M. D. Miller3; K. M. Kitrinos3
1. Hopital Beaujon, University of Paris, Clichy, France.
2. Toronto General Hospital, Toronto, ON, Canada.
3. Gilead Sciences, Inc., Foster City, CA, United States.

Aim: To evaluate amino acid changes within HBV pol/RT after up to 240 weeks of tenofovir disoproxil fumarate (TDF) treatment and determine their potential association with resistance to TDF. No TDF resistance has been detected through 192 weeks of TDF treatment. Methods: Patients in Studies GS-US-174-0102 (HBeAg-) and GS-US-174-0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open-label TDF. Patients with HBV DNA >400 copies/mL at/after Week 72 could add emtricitabine (FTC) as a fixed-dose combination tablet upon investigator’s discretion. Virologic breakthrough was defined as confirmed HBV DNA either >1 log10 from nadir or HBV DNA ≥400 copies/mL after 77% retention). In the TDF arm, 9/323 (2.8%) patients were viremic at Week 240/last visit, with four patients on TDF and 5 patients on FTC/TDF. For the 4 TDF patients, 1 had no change in pol/RT with virologic breakthrough and 3 had unique polymorphic site changes (1 with virologic breakthrough). One patient had a resolution to wild-type from a baseline mixture at a conserved site (rtK/Q154K) in addition to a polymorphic site change. For the 5 FTC/TDF patients, 2 had no change in pol/RT (1 with virologic breakthrough), 1 was unable to be genotyped, and 2 had unique polymorphic site changes. In the ADV to open-label TDF arm, 3/171 (1.8%) patients were viremic at Week 240/last visit. Two patients were on TDF while 1 was on FTC/TDF. Both TDF patients were unable to be genotyped, likely due to low viral loads (~3.0 copies/mL) and 1 FTC/TDF patient developed a conserved site change (rtK168N) along with a unique polymorphic site change during virologic breakthrough coincident with transient nonadherence. Overall, 4/494 (0.8%) patients had virologic breakthrough defined during Year 5; 3 of these patients had documented nonadherence during breakthrough and HBV DNA began to return to <400 copies/mL in all 4 patients while continuing on study. Phenotypic analysis of HBV from these patients is currently underway. Conclusions: In these long term studies of TDF for chronic hepatitis B where patient retention has remained high, virologic breakthrough during Year 5 was rare (0.8%), transient, and typically associated with nonadherence. No cases of viral resistance to TDF have been documented to date. Resistance surveillance continues through Year 8 of both studies.

[vijik]

Yes. Lets Hope. It ll be available soon. Atleast we can use it for life time like diabetes or bp patients since it has no toxicity, if no cure is not on its way to clear us.

[4est]

hope so :)

[stef2011]

i dont think they will release that before patent expires, the human hiv trial should have data already but i dont think it will be public

the only data we have is in vtro 2.5folds more potency on hbv and no kidneys tox, who knows it may have some more effect on hbsag too

[4est]

how about new tenofovir ?
(if i understand correct the active substance is the same but only carry in in some other way and more powerful, at least in HIV - some news on HBV )

[stef2011]

it is not exactly like that because they found resistance mutations in vitro but in vivo tenofovir worked the same with just little reduced activity.

the fact that quantity and kinetics of tenofovir in the cells is very high makes it effective even to the resistance mutations found in vitro.chimerix has even a new formula with improved kinetics inside cells which is able to work even on hiv resistance mutations, on hbv is 2.5 folds more potent

there is only a clinical case i have found where all nucs were totally useless, no effect.
ths is a guy put on sequence monotherapy for years of lam, adv, etv and then tdf.
this patient ended up with so many primary and secondary mutations that no therapy works at all.this type of virus doosnt exsist naturally nad has just been created by crazy nucs use so if one never uses lam, adv and possibly etv too there should be no troubles to reach so many mutations

i think i posted this case a few days ago, it is a patient from south america

[StephenCastlecrag]

Tenofovir has high genetic barrier to mutation - I think you need to have mutation in two places in order to cause Tenofovir to be not effective. Secondly, Tenofovir has high potency, therefore  opportunities for mutations to occur and persist are reduced too.

Hope I got it right.

[stef2011]

it is my comment:
if it is none at first 5 years there is very little possibility of developping mutants while hbvdna is well suppressed in the following years.
this is the only drug with no resistance mutants at all on hbv, every other drugs has mutant resistance starting from 1 year, tnf none

the reason of no resistance is the way the drug is absorbed and used by liver cells, and the quantity and time the drugs stays in the cells (i dont remember exactly the pathway and names in english of the process) but all other nucs are different in this

anyway they ll keep monitoring for it but very very unlikly

[MiddleAge67]

probably none at 10years too?

i did not find it in the article??