HBV combination therapy newer advances


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  • 4. There have been no studies addressing the issue ofwhether add-on (combination) therapy versus switchingto an alternative monotherapy is preferable in patientswith a suboptimal initial virological response to a singlenucleoside analog. Add-on therapy may be advisable if theinitial drug used has a low genetic barrier to resistance orif the duration of therapy has been prolonged becausethese factors increase the likelihood of drug-resistantHBV being present.
  • A related, but separate issue relates to the role of “addon” combination therapy in current treatment algorithms.For patients treated with nucleoside analogs, it isrecommended that antiviral response to treatment beevaluated at specific intervals and changes in therapymade in those with a “suboptimal” virological response.9,35 The guidelines indicate this change in drugtherapy can either be “add on” (i.e., adding the secondagent resulting in combination therapy) or a “switch”(i.e., switching to alternative single drug). There are norandomized studies that directly assess which strategy isbetter
  • defined as a documented rise in serum HBV DNA by >1 log10 IU/ mL from nadir during continuation of initial therapy
  • Ftc emtricitabine LdT telbivudine
  • Till recent little knowolefdge regarding combination
  • HBV combination therapy newer advances

    1. 1. Carrie R. Wong. et al. (J Clin Gastroenterol. Nov-2011;45:900–905) PRESENTED BY VINEET MISHRA
    2. 2. 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)
    6. 6. Ongoing replication during antiviral therapy can lead to the emergence of resistance Wild type HBV Genetically diverse HBV population HBV variants Resistant HBV Nucleos(t)ide analogue therapy Continued therapy Compensatory mutations may occur which restore viral fitness With ongoing replication Reduced population may include resistant HBV Selective pressure favours resistant HBVa Ghany M & Liang TJ. Gastroenterology 2007;132:1574-85.
    7. 7. 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
    8. 8. 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
    9. 9. 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
    10. 10. 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)
    11. 11. MATERIALS AND METHODS The 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)
    12. 12. 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
    13. 13. 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
    14. 14. 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
    15. 15. 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
    16. 16. Treatment Outcomes
    17. 17. 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 )
    18. 18. 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
    19. 19. 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%)
    20. 20. 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
    21. 21. 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
    22. 22. 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
    23. 23. 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
    24. 24. 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 ??.
    25. 25. 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.
    26. 26. Summary: AASLD Guidelines for Management of AntiviralResistant HBV Resistance Rescue Therapy Lamivudine Telbivudine Add adefovir or tenofovir DF Switch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (risk of entecavir resistance) Adefovir Add lamivudine Switch 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, entecavir Multidrug resistance to lamivudine + entecavir: Consider tenofovir DF or emtricitabine + tenofovir DF (fixed-dose combination) Lok AS, et al. Hepatology. 2007;46:254-265.
    27. 27.  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 K with partial response to ETV monotherapy, and was superior to ETV and TDF monotherapy 61st annual meeting of AASLD Hepatology 2010 Oct;52 Suppl:320A1291A.
    28. 28. 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
    29. 29. 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
    30. 30. 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.