hbv combination therapy newer advances
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hepatitis B , newer antiviral , drugs comparison, effectTRANSCRIPT
High Rate of Complete Viral Suppression With Combination Therapy in Patients With Chronic Hepatitis B
and Prior Treatment Failure
Carrie R. Wong. et al.(J Clin Gastroenterol. Nov-2011;45:900–905)
PRESENTED BYVINEET MISHRA
Introduction
Oral nucleos(t)ides are the most commonly used HBV antiviral agents for treatment of chronic hepatitis B
Nucleos(t)ides for HBV therapy belong to three classes
L-nucleosides -(lamivudine, telbivudine, and emtricitabine),
Deoxyguanosine analogues (entecavir)
Acyclic nucleoside phosphonates (adefovir and tenofovir)
RESPONSE RATE IN HBeAg POSITIVE PATIENTS
EASL GUIDELINE (JOURNAL OF HEPATOLOGY 2009 )
RESPONSE RATE IN HBeAg NEGATIVE PATIENTS
RESISTANCE RATE IN HEPATITIS B POSITIVE PATIENTS
Compensatory mutations may occur which restore viral fitness
Selective pressure favours resistant HBVa
Reduced population may include resistant HBV
Ongoing replication during antiviral therapy can lead to the emergence of resistance
Nucleos(t)ide analogue therapy
With ongoing replication
Continued therapy
Genetically diverse HBV population
Wild type HBV
HBV variants
Resistant HBV
Ghany M & Liang TJ. Gastroenterology 2007;132:1574-85.
Background Most common causes of treatment failure to oral
nucleos(t)ides are partial response (PR) and antiviral drug resistance (AVR)
Rescue therapy in these settings often requires combination therapy with a nucleoside and nucleotide
Although the literature on clinical outcomes of combination treatment is sparse
Recommendations for combination therapy from earlier studies have either been controversial or limited by small
sample size
Background
In fact, current guidelines discouraged the use of sequential monotherapy favoring combination therapy over sequential monotherapy, especially in the case of antiviral resistance
So, this study was retrospectively planned to find out efficacy and tolerability of various antiviral combination treatment regimens among patients with prior treatment failure for Chronic Hepatitis B
AIMS AND OBJECTIVES
The primary objective was to determine the rate of complete viral suppression (CVS) by using combination therapy
Secondary objective was to compare CVS(complete viral suppression) among different combination treatment regimens and indications
MATERIALS AND METHODS
A retrospective cohort of 109 consecutive patients with Chronic Hep B who were treated with combination HBV antiviral therapy at 3 gastroenterology and liver clinics in Northern California were analyzed
All patients began their current combination regimens between April 2004 and August 2009 and were treated for at least 6 months at the time of data analysis
ETV+TDF (n=41) ADV+ETV (n=22) TDF+emtricitabine (n=19) LAM+ADV (n=13) LAM+TDF (n=10) LdT+TDF (n=2) ADV+LdT (n=2)
MATERIALS AND METHODSThe AVR (antiviral drug resistance ) was defined as AVR indication for combination therapy was defined as
confirmed resistance based on genetic test results (n=25) or the presence of virologic breakthrough, defined as a documented rise in serum HBV DNA by ≥ 1 log10 IU/ mL from nadir during continuation of initial therapy (n=4)
The PR(partial response) was defined as detectable serum HBV DNA levels during prior therapy
without the development of AVR
Complete Viral Suppression was defined as having undetectable serum HBV-DNA as reported by local
laboratories (<29 to 100 IU/mL)
.
Standard doses of oral agents for treatment of Chronic Hepatitis B were used:
LAM 100 mg daily ADV 10 mg daily LdT 600 mg daily ETV 0.5 or 1.0 mg daily TDF 300 mg daily TRUVADA (TDF 300mg+FTC 200mg daily) Indications for combination therapy were grouped into 3 categories
AVR (antiviral drug resistance ) to prior treatment (n=29), PR (partial response) to prior therapy (n=60), and others (n=20, with 13 due to patients request for more potent regimens,
7 due to side effects)
Some of the patients in the PR group had prior LAM therapy with the development of resistance, but had PR to their second drug that led to the addition of an additional agent
RESULTS
Baseline Characteristics
Nearly all patients were Asian (99%), with the majority being Vietnamese and/or Chinese (82%)
The majority of patients had HBV genotype B (53%) or C (46%)
Detectable HBeAg in 60%
Of the 109 patients, 17 had cirrhosis
Treatment Outcomes The median treatment duration on the current
combination therapy was 21 months (range, 6 to 50 mo)
The majority of patients achieved Complete Viral Suppression by 6 months (77%) and continued to achieve or maintain Complete Viral Suppression at 12, 18, and 24 months
The median time to achieve Complete Viral Suppression was 6 months (range, 1 to 37 mo)
Only 11 patients did not have Complete Viral Suppression by the end of treatment or by their most recent follow-up
Treatment Outcomes….. Patients who did not achieve Complete Viral Suppression
were on the following combinations: LAM+ADV (n=4), ETV+TDF (n=4), ADV+ETV (n=2), and TDF+FTC (n=1).
Only 4 of these patients remained on their current combination therapies, whereas the other 7 were switched to another regimen of antiviral therapy
No patient had HBeAg loss or seroconversion with combination therapy
Over half of patients achieved normalization of ALT levels while receiving combination therapy
Treatment Outcomes
Comparison of Complete Viral Suppression by Combination Treatment Regimens
Two different groups of TDF-based combinations, that is, TDF+ETV and TDF+LAM or FTC or LdT, had a similar number of patients with detectable serum HBV DNA at baseline (83% and 81%, respectively)
The proportion of patients with Complete Viral Suppression at 6, 12, and 24 months (80%, 80%, 89% in TDF+ETV group and 76%, 96%, 100% in other group )
Comparison of Complete Viral Suppression by Combination Treatment Regimens
The comparison of Complete Viral Suppression rates among various ETV based combination treatments revealed insignificant differences
The TDF+ETV group had a faster rate of Complete Viral Suppression than the TDF+LAM or FTC or LdT group: median 5 versus 6 months, but this difference was not statistically significant
Comparison of Complete Viral Suppression by Indications for Combination Therapy
Analysis of patients by AVR and PR indications revealed no significant differences in Complete Viral Suppression rates between the 2 groups
Both groups had similar proportions of patients with Complete Viral Suppression at 6 months (72% vs. 74%)
Tolerability Side effects during combination treatment were
reported in 11 patients
Possible causal relationships with treatment were present in 4 of these patients.
Decrease in GFR occured in 5 patients who were on LAM+ADV (n=2), ETV+TDF (n=2), and TDF+FTC (n=1),
but none had GFR <65 mL/min or 20% lower than their pretreatment levels
Strength of the study
Evaluated clinical outcomes in a real-life clinical setting
Treatment outcomes were also observe in patients who received newer agents such as ETV and TDF
Due to lack of data on combination oral drugs therapy, this study will provide feasibility of further prospective study regarding combination in case of drugs resistance or partial response
Limitations of study
Retrospective design and
No standardized monitoring for nonadherence
Lack of routine viral resistance surveillance
Baseline laboratory data were not available for all patients and was considered baseline if available within 3 months before the initiation of combination therapy
Limitations of study
Didn’t provide the baseline characteristic detail of different groups of combination therapy
Didn’t reveal off treatment response of various combination
Didn’t compare combination therapy with monotherapy
ANSWERS STILL REQUIRED
How to diagnose antiviral resistance whether virological breakthrough is sufficient or genetic study are required ??
How to monitor for AVR ??
How to manage patients with a suboptimal response to therapy or the development of antiviral drug resistance ??.
Monitoring for Antiviral Resistance
Test serum HBV DNA prior to therapy and at 3 month intervals
Primary non-responders should be offered combination or alternative therapy
Enquire about medication compliance when virologic breakthrough is seen
Genotyping should be performed to confirm resistance and determine specific mutations
Lok AS, et al. Hepatology. 2007;46:254-265.
Summary: AASLD Guidelines for Management of Antiviral-Resistant HBV
Resistance Rescue Therapy
LamivudineTelbivudine
Add adefovir or tenofovir DFSwitch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (risk of entecavir resistance)
Adefovir Add lamivudineSwitch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (if no prior lamivudine resistance)
Entecavir Add adefovir or tenofovir DF
Multidrug Multidrug resistance to lamivudine + adefovir: Consider emtricitabine + tenofovir DF (fixed-dose combination), tenofovir DF, entecavirMultidrug resistance to lamivudine + entecavir: Consider tenofovir DF or emtricitabine + tenofovir DF (fixed-dose combination)
Lok AS, et al. Hepatology. 2007;46:254-265.
HBV genotypic resistance is common in HBV endemic area
Sequential therapy appears to raise the risk of resistance, combinations of NA can be effective in suppressing virus in these individuals
Combination of ADV/LAM is superior to ETV or ADV in rescuing those with LAM resistance
Combination of LAM+ADV is superior to ETV montotherapy for ADV-resistance
Addition of TDF to ETV gives the best response in those with partial response to ETV monotherapy, and was superior to ETV and TDF monotherapy
K
61st annual meeting of AASLD Hepatology 2010 Oct;52 Suppl:320A-1291A.
DISCUSSION Combination therapy with different cross-resistance
profiles were effective at achieving and maintaining CVS for the majority of patients for either AVR or PR
Overall, the median time to achieve CVS was 6 months
Rapid and complete suppression of serum HBV DNA is an important strategy to avoid the development of antiviral drug resistance and treatment failure
In particular, serum HBV DNA should generally be undetectable or <2000 IU/mL after 24 weeks of initial oral therapy with a nucleos(t)ide agent
Summary Combination therapy with 2 oral nucleos(t)ides is effective
and safe for patients with failure to earlier therapy.
No significant differences in the rate of CVS in patients with either AVR or PR
No significant differences whether TDF or ADV was used in combination with ETV whether ETV or one of the weaker nucleosides (LAM,
LdT, FTC) was used in combination with TDF
Summary…..Combination therapy with both of the 2 newer and more
expensive agents, ETV and TDF, may not be necessary when a combination strategy is used.
Further studies are needed to help define the optimal
selection of agents to be used in combination therapy for CHB in the setting of AVR or PR.
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