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Stopping Long Term NUC therapy -successful in about 50% of patients!

The following presentation, among other things, summarises nicely few important points regarding the stopping of llong-term NUC therapy (in particular TDF therapy).

http://regist2.virology-education.com/2015/nlhepdag15/S3_2_Sonneveld.pdf

About 50% of people on TDF who stop TDF after being undetectable for long time go on without the relapse (without the need to restart the treatment - for at least a year after they stop)... Additionally and very interestingly, a number of these exhibit hbsag loss down the road.
A very good news indeed.
This brings to mind an advantage of TDF compared to ETV, namely, a possibility to stop it, with 50% of chance of not needing to continue it - at least not very soon. Stopping ETV would be a more risky in my understanding, due to a possible resistance development..or am I mistaken in this???

9 Responses
Avatar universal
Can you define a "long time"? Is this the one after 3-5 years on NUCS?
Avatar universal
Regarding the stopping NUCs, following articles are cited in the presentation, pertaining to hbeag negative carriers:


http://www.ncbi.nlm.nih.gov/pubmed/22659218
Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.
Hadziyannis SJ1, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E.
Abstract
BACKGROUND & AIMS:
Little is known about the biochemical and virological effects of stopping long-term nucleos(t)ide analogue therapy for hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB).
METHODS:
We performed a cohort observational study, following 33 HBeAg-negative patients with CHB, undetectable serum HBV DNA, and normal levels of aminotransferases after long-term (4 or 5 years) treatment with adefovir dipivoxil (ADV). All patients were followed for 5.5 years; follow-up visits included measurements of serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), and HBV DNA monthly for the first 6 months and every 3-6 months thereafter. Various factors were measured at baseline, the end of treatment (EOT), and following treatment to identify those associated with clearance of HBsAg.
RESULTS:
During the first few months of the postdiscontinuation period, all patients experienced virological and 25 (76%) had biochemical relapse. During the follow-up period, 18 patients (55%) who had discontinued antiviral therapy achieved sustained response (HBV DNA level 2000 IU/mL, ALT elevation above 1.25 × normal or doubling of ALT from cessation, and re-initiation of anti-viral therapy.
RESULTS:
We identified 33 patients with HBeAg-negative CHB who stopped treatment following viral suppression. Mean treatment duration was 5.28 ± 2.73 years. Patients were treated with lamivudine (3), adefovir (14), entecavir (4), and tenofovir (12). Eleven (33%) patients met the primary end point of composite relapse. For individual end points, 21 (63%) patients had a viral relapse, 16 (48%) had a biochemical relapse, and 16 (48%) restarted treatment, leaving 17 (52%) patients who remained treatment-free over a median 36 months of follow-up. Lower pre-treatment ALT and detectable HBV DNA within the first month after treatment discontinuation were associated with increased rates of composite relapse (HR 1.01; P = 0.022 for ALT and HR 1.01; P = 0.038 for HBV DNA).
CONCLUSION:
Patients with noncirrhotic HBeAg-negative CHB can stop treatment after greater than 4-5 years of suppressive therapy with nucleosides/nucleotides with more than 50% remaining treatment-free.


http://onlinelibrary.wiley.com/doi/10.1111/apt.13150/abstract
Reduced risk of relapse after long-term nucleos(t)ide analogue consolidation therapy for chronic hepatitis B
H. Chi1, B. E. Hansen1, C. Yim2, P. Arends1, M. Abu-Amara2, A. A. van der Eijk3, J. J. Feld2, R. J. de Knegt1, D. K. H. Wong2 andH. L. A. Janssen
Summary
Background
Before stopping nucleos(t)ide analogue (NA) treatment in chronic hepatitis B (CHB), 6–12 months of consolidation therapy is recommended.
Aim
To investigate the effect of consolidation therapy on off-treatment outcomes in CHB patients.
Methods
We included 94 patients who stopped NA after at least 1 year of therapy. Patients could be HBeAg-positive or HBeAg-negative at start-of-treatment, but were HBeAg-negative and had undetectable HBV DNA at time of discontinuation. Consolidation therapy was defined as treatment after the first undetectable HBV DNA (and HBeAg loss for HBeAg-positive patients) until NA cessation.
Results
At 3 years, 74% of the start-of-treatment HBeAg-positive and 75% of the start-of-treatment HBeAg-negative patients developed HBV DNA >2000 IU/mL at a single time point, whereas a persistent virological relapse (≥2 tests of HBV DNA >2000 IU/mL 6 months apart within 1 year) developed in 49% of the start-of-treatment HBeAg-positive and 53% of the start-of-treatment HBeAg-negative patients. For both HBeAg-positive and HBeAg-negative patients, consolidation therapy of ≥3 years was associated with lower persistent virological relapse rates compared to <1 year (1-year relapse rate: 25% vs. 54%; P = 0.063 and 24% vs. 57%; P = 0.036, respectively). At 3 years, 9% of the HBeAg-positive and 14% of the HBeAg-negative patients became HBsAg-negative. Prolonged consolidation therapy increased the likelihood of HBsAg loss. Two cirrhotic patients developed hepatic decompensation but both recovered.
Conclusions
After nucleos(t)ide analogue discontinuation, relapse was common in patients with chronic hepatitis B. Prolongation of consolidation therapy beyond 3 years decreased the risk of persistent virological relapse and increased the likelihood of HBsAg loss.

Avatar universal
Continuation...



http://gut.bmj.com/content/64/4/667.short
Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study
Wai-Kay Seto1, Aric Josun Hui2, Vincent Wai-Sun Wong3, Grace Lai-Hung Wong3, Kevin Sze-Hang Liu1, Ching-Lung Lai1, Man-Fung Yuen1, Henry Lik-Yuen Chan3
Abstract
Background and objective
The off-treatment durability of nucleos(t)ide analogue therapy in Asian hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) and the role of hepatitis B surface antigen (HBsAg) levels in predicting off-treatment durability has not been well investigated.
Methods
Following Asia-Pacific Association for the Study of the Liver guidelines, entecavir was stopped in Asian HBeAg negative patients treated for ≥2 years with undetectable HBV DNA levels on ≥3 separate occasions 6 months apart before treatment cessation. HBsAg and HBV DNA levels were prospectively monitored every 6–12 weeks for 48 weeks. Entecavir was restarted if there was virologic relapse (defined as HBV DNA >2000 IU/mL).
Result
184 patients (mean age 53.9 years, 67.9% male) were recruited. The cumulative rate of virologic relapse at 24 and 48 weeks was 74.2% and 91.4%, respectively. The median HBV DNA level at virologic relapse was 11 000 (range 2115 to >1.98×108) IU/mL. 42 (25.8%) patients had elevated alanine aminotransferase (median level 97 U/L, range 37–1058 U/L) during virologic relapse. Mean rate of off-treatment HBsAg decline was 0.018 (±0.456) log IU/mL/year. No patients cleared HBsAg. There was no correlation between off-treatment serial HBsAg and HBV DNA levels (r=−0.026, p=0.541). HBsAg levels at the time of entecavir commencement, entecavir cessation and the subsequent rate of HBsAg reduction were not associated with virologic relapse (all p>0.05).
Conclusions
Entecavir cessation in Asian HBeAg negative CHB resulted in high rates of virologic relapse, suggesting nucleos(t)ide analogue therapy should be continued indefinitely until the recognised treatment endpoint of HBsAg seroclearance.


http://www.ncbi.nlm.nih.gov/pubmed/23744454
Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients.
Jeng WJ1, Sheen IS, Chen YC, Hsu CW, Chien RN, Chu CM, Liaw YF.
Author information
Abstract
The optimal duration of nucelos(t)ide analog (Nuc) treatment in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B virus (HBV) infection is unknown. The Asian Pacific Association for the Study of the Liver (APASL) guidelines recommend that treatment can be discontinued if undetectable HBV-DNA has been documented on three occasions ≥ 6 months apart. This study aimed to test this stopping rule in HBeAg-negative chronic hepatitis B (CHB) patients treated with entecavir (ETV). Ninety-five patients (39 cirrhosis) were treated with ETV for a median of 721 (395-1,762) days before stopping therapy and were then monitored with serum HBV DNA and alanine aminotransferase (ALT) at least every 3 months. Within 1 year after stopping ETV therapy, "clinical relapse" (an episode of ALT elevation >2 × upper limit of normal plus HBV-DNA >2,000 IU/mL) occurred in 43 (45.3%) of the 95 patients. Of the 39 cirrhosis patients, 17 (43.6%) relapsed and one (2.6%) developed decompensation. The median duration until relapse was 230 days (74.4% >6 months). Logistic regression analysis showed that baseline HBV-DNA ≤ 2 × 10(5) IU/mL was the only significant independent factor for sustained response. The 1-year relapse rate was 29% in patients with a baseline HBV DNA ≤ 2 × 10(5) IU/mL versus 53% in those with HBV DNA >2 × 10(5) IU/mL (P = 0.027). For the latter, consolidation therapy >64 weeks reduced the relapse rate to 33.3% in patients without cirrhosis.
CONCLUSION:
With an overall 1-year relapse rate of 45% and 29% in those with a baseline serum HBV DNA ≤ 2 × 10(5) IU/mL, the APASL stopping rule for HBeAg-negative CHB patients with proper off-therapy monitoring is adequate even in patients with cirrhosis. Consolidation therapy >64 weeks seems more appropriate for those with higher baseline HBV DNA.


Avatar universal
Text of the first 2 abstract got scrambled/mixed. Those abstract can be found here:

http://www.ncbi.nlm.nih.gov/pubmed/25109610

http://www.ncbi.nlm.nih.gov/pubmed/22659218
Avatar universal
Asian-Pacific guidelines for HEP B state:

In HBeAg-positive CHB patients who achieve HBeAg seroconversion with undetectable HBV DNA, the relapse rates depend on the duration of consolidation therapy [242]. One recent study described 94 patients who stopped NA after at least 1 year of therapy. Patients could be HBeAg-positive or HBeAg-negative at the start of therapy, but all were HBeAg-negative and had undetectable HBV DNA (2000 IU/ml measured twice 6 months apart within 1 year, or retreatment after an initial HBV DNA elevation. At the start of therapy, 35 patients were HBeAg-positive and 59 were HBeAg-negative. The cumulative relapse rate was 33 % at 6 months, 42.7 % at 1 year, and 64.4 % at 5 years. Patients with at least 3 years of consolidation therapy (n = 37) had a 1-year relapse rate of 23.2 % compared to 57.2 % for 1–3 years of consolidation therapy (n = 32), and 55.5 % for <1 year of consolidation therapy (n = 20) (p = 0.002). For each additional year of consolidation therapy, patients were 1.3-fold more likely to lose HBsAg (hazard ratio 1.34; 95 % CI 1.02–1.75). Consolidation therapy of at least 3 years decreased the rate of relapse and increased the rate of HBsAg loss significantly [243].

Due to the high relapse rate after NA treatment discontinuation in patients with HBeAg-negative chronic hepatitis, treatment until HBsAg loss is generally recommended [218]. HBsAg levels may be a potential marker to guide treatment cessation. HBsAg levels of 2 log10 IU/ml at end of treatment) [244]. In one recent study to assess the outcome of patients withdrawing from NA therapy after HBsAg clearance, 27 (5 %) out of 520 CHB patients who received NA for prolonged periods ultimately lost serum HBsAg and were followed for 44 (12–117) months thereafter. It was concluded that patients reaching the therapeutic endpoint of HBsAg clearance can be safely withdrawn from NA following either anti-HBs seroconversion or at least 12 months of a post-clearance consolidation period [245]. However, in one recent meta-analysis including 22 studies with a total of 1732 HBeAg-negative patients (median duration of therapy, consolidation therapy and off-therapy follow-up ranged from 6 months to 8 years, 4–96 weeks and 6–80 months, respectively, and patients were monitored with serum ALT and HBV DNA monthly in the first 1–3 months and every 3–6 months thereafter in most studies), the 1-year off-therapy ‘virological relapse’ (HBV DNA >2000 IU/ml)and ‘clinical relapse’ (HBV DNA >2000 IU/ml + ALT elevation) occurred in <70 % and <50 % of the patients, respectively, and <40 % of the patients received re-treatment. These rates were higher in patients with shorter treatment, shorter consolidation therapy (<2 years) and those treated with less potent nucleos(t)ide analogues. Off-therapy severe flares were rare and hepatic decompensation was reported in only one patient with cirrhosis. Biochemical relapse reflecting enhanced immune-mediated hepatocyte killing may lead to a higher chance for off-therapy HBsAg seroclearance and possibly be desirable. Thus, with an appropriate stopping rule and a proper off-therapy monitoring plan, cessation of long-term nucleos(t)ide analogue therapy prior to HBsAg seroclearance in HBeAg-negative CHB is a feasible alternative to indefinite treatment [246].
Avatar universal
Long time would mean having at least 2-3 years of undetectable DNA, preferably even longer.

Factors that contribute to chance of SVR after discontinuation of the therapy are:
- lower pre-treatment DNA (and maybe also lower pre-treatment ALT values)
- length of undetectable DNA while on treatment (the longer the better)
- end of treatment HBsAg (the lower the better, preferably <200;  if higher then 1000 IU/ml it won't work almost certainly)
Avatar universal
i wud never advice anyone to stop tdf once started.. its a risky game. Plus continuing tdf itself suppresses hbsag and also gives a little chance of remission/cure.
Avatar universal
If it wouldn't be risky all doctors would get their patients of the nucs...and that is the reason that most of the guidelines recommend nucs to be continued until hbsag loss (indefinitely or until a cure or some other very hbv supressive medicine is found).

To me it appears that having undetectable DNA on nucs (preferably Tenofovir) for > 3 years, combined with fiibroscan < 6 and EITHER:
a) pre-treatment DNA of < 100.000 IU/ml and HBsAg < 400 IU/ml,
OR
b) HBsAg < 200 IU/ml
would be a relatively safe criteria for treatment stoppage, off course combined with regular and frequent monitoring in the first 12 months after treatment stoppage.

I, personally, based on my current knowledge, would be ok to stop Tenofovir (but probably not Entecavir) treatment after either:
a) being 4 years undetectable, provided having DNA <100.000 iu/ml at start of treatment and hbsag < 400 iu/ml with fibroscan =< 5.5 at the end of treatment
OR
b) being 4 years undetectable and having hbsag < 200 iu/ml and fibroscan =< 5.5
Avatar universal
For the sake of completeness, here is the last abstract that was discussed during the presentation slides posted in the first post of this topic:

STOPPING TENOFOVIR DISOPROXIL FUMARATE (TDF) TREATMENT AFTER LONG TERM VIROLOGIC SUPPRESSION IN HBeAg-NEGATIVE CHB: WEEK 48 INTERIM RESULTS FROM AN ONGOING RANDOMIZED, CONTROLLED TRIAL (“FINITE CHB”)
T. Berg1, K.-G. Simon2, S. Mauss3, E. Schott4, R. Heyne5,
D. Klass6, C. Eisenbach7, T.M. Welzel8, R. Zachoval9,
G. Felten10, J. Schulze zur Wiesch11, M. Cornberg12,
E.B. Martins13, L. Gallo13, T. Warger13, J. Petersen14. 1Innere Medizin, Sektion Hepatologie, Universita ̈tsklinikum, Leipzig, 2Gastroenterologische Gemeinschaftspraxis, Leverkusen, 3Zentrum HIV and Hepatogastroenterologie, Du ̈sseldorf, 4Charite, 5Leberzentrum Checkpoint, Berlin, 6Innere Medizin I, Universita ̈tsklinikum, Ulm, 7Universita ̈tsklinikum, Heidelberg, 8J.W.-Goethe Universita ̈t, Frankfurt a. Main, 9Klinikum der LMU, Mu ̈nchen, 10Gastroenterologische Gemeinschaftspraxis, Herne, 11University Hamburg Eppendorf, Hamburg, 12Medizinische Hochschule, Hannover, Germany; 13Gilead Sciences, Foster City, United States; 14IFI Institut, Hamburg, Germany E-mail: lothar.***@****
Background and Aims: Long-term effective NUC therapy may lead to partial restoration of HBV-specific T cell functions. Stopping therapy in HBV-DNA suppressed HBeAg-negative patients may lead to initial viral rebound and hepatic flare followed by HBsAg clearance. We investigated HBsAg kinetics after controlled stopping of long-term TDF therapy.
Methods: Subjects on effective TDF therapy for at least 4 years were randomized to either stop or to continue TDF therapy for 144 weeks (advanced fibrosis/ cirrhosis excluded). Primary endpoint is HBsAg loss at Week 144. TDF could be restarted in case of clinically significant hepatitis B flares.
Results: 45 subjects were randomized in this open-label study at 13 sites in Germany (median age 45 years, 79% male, 88% Caucasian). 21 Stop-TDF subjects and 21 Continue-TDF subjects completed Week 48 (3 subjects withdrew consent – data excluded). At W48, Continue-TDF subjects maintained viral suppression, stable ALT, none lost HBsAg. 19 of 21 Stop-TDF subjects had early (first 12 weeks) substantial HBVDNA rebound (median 205,380 IU/mL, [Q1 59,995 IU/mL; Q3 444,147 IU/mL]) accompanied by ALT elevations (median 106 IU/mL; [Q1 76 IU/ml; Q3 233 IU/mL]). 2 subjects had minimal HBVDNA rebound (max 259IU/mL) and normal ALT; both had HBsAg levels <500IU/ml at baseline (BL), while HBsAg levels in the other 19 subjects were substantially higher (median 52,640 IU/mL; [Q1 26,518 IU/mL; Q3 95,240 IU/mL; range 4,400–221,840 IU/mL]). At W48, 3 subjects had restarted TDF and all had returned to normal ALT and HBV DNA <LLQ, 18 subjects remained off TDF, 15/18 had normal ALT, 14/18 had HBVDNA 1 log (n = 5, median −1.62 log) compared those with decline <1log (n=13, median −0.23log); median BL HBsAg levels were 14,888IU/ml vs 52,280IU/ml, respectively. Continue- TDF subjects had only small declines in HBsAg (median: −0.09 log). Conclusions: Stopping TDF in chronic HBV HBeAg negative long- term suppressed subjects with defined restarting criteria appears to be safe and led to a significantly greater early HBsAg decline as compared to a continued TDF monotherapy. HBsAg loss was observed so far in two subjects (9.5%). If necessary, TDF can be effectively restarted. Lower HBsAg level at BL seems to be a predictive factor for HBsAg decline.

News publication relating to this research:

Thomas Berg from University Medical Center Leipzig and colleagues looked at outcomes after controlled discontinuation of prolonged tenofovir treatment.

Prior research indicates that long-term effective antiviral therapy may lead to partial restoration of HBV-specific T-cell function, the researchers noted as background. Stopping therapy usually results in disease reactivation with HBV DNA viral load rebound and sometimes hepatic flares, or sudden ALT (alanine aminotransferase) increases due to inflammation as the immune system attacks the resurgent virus. In some cases, however, this may be followed by HBsAg clearance.

The "Finite CHB" study included 45 chronic hepatitis B patients at 13 sites in Germany who had been on effective tenofovir treatment for at least 4 years, with HBV DNA <400 copies/mL for at least 3.5 years. A majority were men, most were white, and the median age was 45 years. At baseline all were HBsAg-positive, hepatitis B "e" antigen (HBeAg)-negative, had normal ALT (median 22 IU/mL; 40 IU/mL is considered the upper limit of normal), did not have cirrhosis, and had no history of decompensated liver disease.

Participants in this open-label study were randomly assigned to either stop tenofovir or continue therapy for 144 weeks. Tenofovir could be restarted if clinically significant hepatitis B flares occurred.

The primary endpoint was HBsAg loss at week 144, considered the closest approximation to a cure. Berg presented interim 48-week findings; 21 participants in the stop-tenofovir group and 21 in the continuous-tenofovir group completed 48 weeks and were included in this analysis.

Results

At 48 weeks, patients who remained on tenofovir maintained viral suppression, had stable ALT levels, and none experienced HBsAg loss.
3 people (14%) who stopped tenofovir restarted therapy by week 48 -- 2 due to early hepatitis B flares and 1 due to persistent high-level viremia; all returned to undetectable HBV DNA and normal ALT.
All patients who stopped tenofovir experienced HBV rebound, mostly within the first 12 weeks after discontinuation.
By 48 weeks, among the 18 patients who stopped and stayed off tenofovir, 16 (89%) had a viral load below 20,000 IU/mL, including 14 (78%) with HBV DNA <2000 IU/mL.
Most people who stopped tenofovir also experienced ALT elevations, with 12 (57%) reaching levels more than twice the upper limit of normal.
But by 48 weeks, among the 18 who stayed off tenofovir, all had ALT less than twice the upper limit of normal, including 15 (83%) with normal ALT.
Several patients who stopped tenofovir experienced substantial reductions in HBsAg; the median reduction was -0.28 log, compared with just -0.09 log in the continuous-tenofovir group.
2 patients who stopped tenofovir experienced HBsAg loss, 1 at week 20 and 1 after week 40.
Participants who experienced the largest HBsAg reductions -- including the 2 with HBsAg loss -- started out with lower baseline HBsAg levels (<25,000 IU/mL) than those with smaller or no HBsAg reductions.
The proportion of people with both low HBV DNA and near-normal ALT increased with longer time off tenofovir.
"Stopping [tenofovir] in HBeAg-negative patients with undetectable HBV DNA for at least 3.5 years appears to be safe," the researchers concluded, and tenofovir can be restarted if necessary.

"Stopping [tenofovir] was associated with a more profound decline in HBsAg levels compared to with continuous [tenofovir]," they continued. "These data support the concept of stopping antiviral therapy in long-term HBV DNA-suppressed subjects without cirrhosis."
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