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					Update on Management of
    HBV Resistance
               Prof.
    Abdel fattah Abdel salam
  Ain shams school of medicine
         Objectives/agenda
• What is HBV antiviral drug resistance?
• What are the clinical sequels of drug
  resistance?
• What is the mechanism of drug resistance?
• How can we detect drug resistance?
• How can we reduce the risk of drug
  resistance?
The Twin Pillars of HBV
       Therapy
    Viral       Avoidance
 suppression   of resistance
       Evolution of Approved HBV
          Therapy Over Time
                                  Peginterferon alfa-2a



                     Lamivudine                   Entecavir                 Tenofovir


1990                   1998       2002              2005         2006        2008


Interferon alfa-2b                Adefovir                    Telbivudine
       Summary of FDA Approved
         Oral HBV Treatments
Oral     Antiviral     Pharmacologic          Genetic             Adverse Events‡
Drug     Potency*         Barrier             Barrier†
LAM          ++                 +                 1                        --

ADV           +                 +                 1        Nephrotoxicity (≤1% per year)
ETV         ++++              ++++                3                        --
LdT          ++                ++                 1        Myalgia, myositis, neuropathy,
                                                             cardiac arrhythmia (rare)
TDF         ++++              ++++                ?                Nephrotoxicity§
*Approximate and relative.
†Number of mutations needed for primary antiviral drug resistance.
‡Only includes reported adverse events that may differ in historical incidence associated

with LAM and, therefore, potentially affecting selection vs other agents. Pancreatitis has
been reported as a class effect and all agents have to be dose adjusted for renal
insufficiency.
§ From HIV databases
Mechanism of Action of Antiviral Drugs


 Infectious
HBV virion                Antiviral drugs                Infectious
                                                        HBV virion




                                                                            HBsAg
                       DNA pol                                           envelopes
                    Partially            RT
                    double-
                                  (-)-
              stranded DNA
                                 DNA


                             A(n)
                                              Encapsidated
                                               pregenomic
                      mRNA                          mRNA
   cccDNA

                                                   Lai et al., J Med Virol 2000
1. Which of the following terms describes the detection
   of amino acid substitutions in the HBV polymerase
    gene that decrease sensitivity to antiviral drugs?

 A. Primary nonresponse
 B. Virologic breakthrough
 C. Biochemical breakthrough
 D. Genotypic resistance
 E. Phenotypic resistance
          Antiviral Resistance Terms
  • Genotypic resistance: detection of mutations that have been
    shown in in vitro studies to confer resistance to the nucleos(t)ide
    analogue that is being administered
  • Virologic breakthrough: increase in serum HBV DNA by > 1 log10
    (10-fold) above nadir after achieving virologic response, during
    continued treatment
  • Biochemical breakthrough: increase in ALT above upper limit of
    normal after achieving normalization, during continued treatment
  • Phenotypic resistance: in vitro confirmation that the mutation
    detected decreases susceptibility (as demonstrated by increase in
    inhibitory concentrations) to the nucleos(t)ide analogue administered
  • Cross-resistance: presence of mutants selected by one agent that
    also confer resistance to other antiviral agents



Lok AS, et al. Hepatology. 2007;45:507-539.
  Genotypic Resistance, Virologic Rebound
  and Biochemical Rebound: NIH Definitions
                                      Detection of
                                                         Virologic                Biochemical
                                       genotypic
                                                         rebound                    rebound
                                       resistance
          HBV DNA (log10 copies/mL)




                                                                                                 ALT (IU/L)
                                                                              1 log10
                                                Nadir
                                                                                                              1 x ULN

                                                        Antiviral drug

                                                        Time

Lok A et al. Program of the 2006 Management of Hepatitis B Virus Meeting; 2006, Bethesda, USA.
Antiviral Resistance Pathways in CHB
Pathway                                    Mutation          Associated Resistance
Nucleoside                                 rtM204V/I                  LAM
                                                                      FTC
                                                                      LdT
                                                                      CLV
Nucleotides                                rtN236T                    ADV
                                                                      TDF


Naive entecavir                 rtL180M + rtM204V with one           ETV
resistance                        of rtT184, S202, or M250




Yuen L, et al. AASLD 2007. Abstract 949.
    Factors affecting the development of
    drug resistance
                      Patient factors                                    Drug factors

                                                     Risk of antiviral
                                                     drug resistance


                                                                          Minimising resistance
                                                                          requires choosing an
                                                        Virus factors    antiviral to modify these
                                                                                risk factors




Adatped from: Zoulim F. Antivir Res. 2004;64:1-15.
  Incomplete suppression of viral replication
  allows the generation of resistant virus
                         Treatment begins                    Drug-susceptible virus

                                                             Drug-resistant variant
       HBV replication




                                                      Time
Fung SK and Lok ASF. Antivir Ther 2004 9:1013–1026.
Locarnini S, et al. Antivir Ther 2004;9:679–693.
    Reducing the risk of drug resistance
    through choice of a potent antiviral
     Choose a potent antiviral to achieve rapid and maximal viral
                           load suppression
                                          Treatment begins             Drug-susceptible virus
                        HBV replication




                                                     Maximal suppression = minimal resistance




Locarnini S. J Hepatol. 2003;39:S124-32.
                                                         Time
Fung SK & Lok ASF. Antivir Ther. 2004;9:1013-26.
Locarnini S, et al. Antivir Ther. 2004;9:679-93.
 HBV DNA Reduction With Oral Agents
 in HBeAg+ Chronic Hepatitis B*
                                ADV[1]   ADV[2]
                                10 mg    30 mg L-FMAU[3] LAM[4]   TDF[5]    LdT[4]      ETV[6]
                           0
       HBV DNA at 1 Year




                           -1
        Log10 Decrease




                           -2
                           -3
                           -4    -3.5
                           -5
                                          -4.8    -5.1
                           -6                             -5.5
                           -7                                      -6.2      -6.5
                                                                                         -6.9
 *Data from individual reports, not direct comparisons
 (different populations, baseline values, HBV DNA assays).
1. Hepsera [package insert]. 2. Marcellin P, et al. N Engl J Med. 2003;348:808-816. 3. Yoo BC, et al.
AASLD 2005. Abstract 186. 4. Tyzeka [package insert]. 5. Heathcote E, et al. AASLD 2007. Abstract LB6.
6. Baraclude [package insert].
               Lamivudine and wild-type HBV


                                              Lamivudine
                              Y           inhibition

Nucleotides                                               ss (-) DNA
              high affinity
                                  M
                                      D
                                          D        HBV polymerase (wild type)

     Y = Tyrosine
     M = Methionine
     D = Aspartate
   Lamivudine and YMDD variant HBV


                                     Lamivudine
                            Y       weak inhibition

Nucleotides
                            V                         ss (-) DNA
                reduced
                 affinity

                                D
                                      D       HBV polymerase (variant)
     Y = Tyrosine
     M = Methionine
     D = Aspartate
   A high genetic barrier occurs when antivirals
       require multiple resistance mutations
              Mutations associated with viral breakthrough in patients1-8




Lamivudine
                                                                                    Mutations sufficient for viral breakthrough
                                  M204I
Telbivudine                       only3

                                                                            OR
     Adefovir
                                                                                                          OR            OR                       * L180M and M204I/V +
 Entecavir*                                                                                                                                        T184, S202 or M250 are
                                                                         AND                                                                       required for viral rebound
                                                                                                                                                   to entecavir.4



 Adapted from: 1. Locarnini S. Monothematic Conference, October 6-8, 2005, Istanbul, Turkey. 2. Locarnini S, et al. Antivir Ther. 2004;9:679-93. 3. Yuen M-F & Lai C-
 L. Expert Rev Anti Infect Ther. 2005;3:489-94. 4. Colonno RJ, et al. 2006. 57th AASLD Meeting, October 27-31, 2006, Boston, USA. Oral presentation. Hepatology.
 2006;44(4, suppl 1):229A-30 (Abstract 110). 5. Zeffix® (lamivudine) Summary of Product Characteristics. Glaxo Group Ltd. August 2006. 6.Tyzeka™ (telbivudine)
 Prescribing Information (US FDA). Idenix Pharmaceuticals Inc. October 2006. 7.Hepsera® (adefovir) Summary of Product Characteristics. Gilead Sciences
 International Ltd. October 2006. 8. Baraclude® (entecavir) Summary of Product Characteristics. Bristol-Myers Squibb Pharma EEIG. June 2006.
          AASLD HBV Guidelines: An Update
          clinicaloptions.com/hepatitis



 Cumulative Rates of Resistance With Oral
 Agents in Nucleos(t)ide-Naive Patients
      Not head-to-head trials; different patient populations and trial designs
                 Yr 1         Yr 2         Yr 3         Yr 4        Yr 5    Yr 6
Drug
Generation



1st     LAM             24%               38%         49%               67%            70%



        ADV              0%               3%          11%               18%            29%
2nd
         LdT            4%                17%
         ETV           0.2%               0.5%        1.2%             1.2%            1.2%   1.2%
3rd
         TDF            0%                0%          0%


EASL. J Hepatol. 2009;50:227-242. Tenny DJ, et al. EASL 2009. Abstract 20.
Marcellin P, et al. AASLD 2009. Abstract 481. Heathcote E, et al. AASLD 2009. Abstract 483.
    Definitions of Primary Nonresponse
             With Oral Therapies
   • AASLD: decrease in serum HBV DNA by
     < 2 log10 IU/mL after at least 24 weeks of
     therapy
   • Other definition
           – HBV roadmap: failure to reduce HBV DNA by
             1 log10 IU/mL or more at Week 12



1. Lok AS, et al. Hepatology. 2007;45:507-539.
2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Nonresponse, Suboptimal Response,
and Virologic Breakthrough
                     1.0
                                                   Antiviral Drug
                       0                      Primary nonresponse
 Change in HBV DNA




                                                                                Virologic
                                                                            breakthrough
    (log10 IU/mL)




                     -1.0       2 log
                                              Suboptimal response
                     -2.0


                     -3.0

                                                                 1 log
                                                                   1 log
                     -4.0                      Nadir

                            0           6                   12             18
                                                  Months

Lok AS, et al. Hepatology. 2007;45:507-539.
      The clinical sequels of HBV resistance


          Virologic rebound1
          Flares in serum ALT2
          Histologic progression of liver disease3
          Reduced rate of HBeAg seroconversion4
          Increased recurrence of hepatitis post-orthoptic liver
            transplant5
          Decompensation and death in cirrhotic patients1
          Transmission of drug-resistant HBV6
          The emergence of drug-resistant HBV may compromise                                                       future treatment
           options7

1. Fung S and Lok ASF. Antivir Ther. 2004;9:1013-26.       2. Lok ASF, et al. Gastroenterology. 2003;125:1714-22.
3. Dienstag JL, et al. Gastroenterology 2003;124:105-17.   4.Leung NWY, et al. Hepatology. 2001.;33:1527-32.
5.Mutimer D, et al. Gut. 2000;46:107-13.                   6. Thibault V, et al. AIDS. 2001;16:131-33.
7. Lok AS-F. N Eng J Med. 2005;352:2743-46.
2. What is the optimal timing for initiating
rescue therapy for drug-resistant HBV?
A. At the first sign of biochemical breakthrough
B. At the first sign of virologic breakthrough
C. Only after virologic and biochemical breakthrough are
  both detected
 Management Roadmap According to
 Week 24 Virologic Response
                                  Patients with primary response
                                              Week 24
                                  Assess early predictors of efficacy


                                           Partial response
   Complete response                                                    Inadequate response
                                               HBV DNA
 HBV DNA negative by PCR                                                HBV DNA ≥ 2000 IU/mL
                                          60 to < 2000 IU/mL


     Continue therapy;                                                  Add a more potent drug;
   monitor every 6 months                                               monitor every 3 months




Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
 Management Roadmap According to
 Week 24 Virologic Response (cont’d)
                                  Patients with primary response
                                              Week 24
                                  Assess early predictors of efficacy


                                           Partial response
                                               HBV DNA
                                          60 to < 2000 IU/mL



  Antiviral: low genetic                                                   Antiviral: high genetic
          barrier                                                                  barrier
 Add a second drug without                                                 Monitor every 3 months;
     cross-resistance                                                      continue to ≥ 48 weeks

*If incomplete response at 48 weeks, add a more potent noncross-resistant antiviral.
                        Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Management of Virologic
Breakthrough
 Management options
   – “Switch to” another drug
   – “Add on” another drug
   – “Switch to” and “add on” another drug
 Choice of second drug generally dictated by lack of cross-
  resistance
3. Which of the following is the best approach for
managing a patient with lamivudine resistant
HBV?
A. Stop lamivudine
B. Stop lamivudine and switch to adefovir
C. Stop lamivudine and switch to entecavir
D. Continue lamivudine and add adefovir
E. Continue lamivudine and add entecavir
 AASLD Recommendations for
 Managing Virologic Breakthrough


Resistance                                   Rescue Therapy


                   Add adefovir (superior to adefovir switch)
Lamivudine        Add tenofovir* or switch to emtricitabine/tenofovir*
                  Switch to entecavir (increased risk of entecavir-R development)




  *Off label.


Lok A, et al. Hepatology. 2007;45:507-539.
EASL (2009) guidelines



   Management of antiviral resistance
   Treatment modification

   LVD-r           ADV-r                     ETV-r                       LdT-r                     TDF-r

 Add TDF (or •    If N236T •               Add TDF•                   Add TDF (or •               Resistance •
 ADV if TDF       substitution:                                       ADV if TDF                  not yet
 not available)   Switch to TDF                                       not available               described
                  and add ETV,                                                                    Cross •
                  LVD or LdT                                                                      resistance
                  OR switch to                                                                    profile
                  TDF and                                                                         determined by
                  emtricitabine                                                                   genotyping
                  If A181T/V •                                                                    and
                  substitution:                                                                   phenotyping
                  Switch to TDF                                                                   Any NA could •
                  and add ETV                                                                     potentially be
                  OR switch to                                                                    used
                  TDF and
                  emtricitabine



                   European Association for the Study of the Liver. J Hepatol 2009;50. In press
4. Which of the following is the best approach for
managing a patient with adefovir resistant HBV?

A. Switch to tenofovir
B. Switch to lamivudine
C. Switch to entecavir
D. Increase dose of adefovir to 30 mg/day
E. Add lamivudine
 AASLD Recommendations for
 Managing Virologic Breakthrough
 Resistance                                  Rescue Therapy

                    Add lamivudine (superior to lamivudine switch)
 Adefovir           Switch to or add entecavir (only in the absence of lamivudine-R)
                    Switch to emtricitabine/tenofovir*

 Entecavir          Add or switch to adefovir or tenofovir*

                    Add adefovir (superior to adefovir switch)
 Telbivudine        Switch to entecavir (increased risk of entecavir-R development)
                    Add tenofovir* or switch to emtricitabine/tenofovir*

  *Off label.


Lok A, et al. Hepatology. 2007;45:507-539.
EASL (2009) guidelines



   Management of antiviral resistance
   Treatment modification

   LVD-r           ADV-r                     ETV-r                       LdT-r                     TDF-r

 Add TDF (or •    If N236T •               Add TDF•                   Add TDF (or •               Resistance •
 ADV if TDF       substitution:                                       ADV if TDF                  not yet
 not available)   Switch to TDF                                       not available               described
                  and add ETV,                                                                    Cross •
                  LVD or LdT                                                                      resistance
                  OR switch to                                                                    profile
                  TDF and                                                                         determined by
                  emtricitabine                                                                   genotyping
                  If A181T/V •                                                                    and
                  substitution:                                                                   phenotyping
                  Switch to TDF                                                                   Any NA could •
                  and add ETV                                                                     potentially be
                  OR switch to                                                                    used
                  TDF and
                  emtricitabine



                   European Association for the Study of the Liver. J Hepatol 2009;50. In press
 Reasons for Concern About Sequential
 Monotherapy

  Multidrug-resistant mutants can be found on the same
   viral genome after sequential monotherapy[1,2]
  Poor virologic control with entecavir can follow lamivudine-
   pretreated patients[3]
  Entecavir resistance has been documented when rtL180M
   + rtM204V mutants preexist in treatment-naive patients in
   low concentrations[5]


1. Yim HJ, et al. Hepatology. 2006:43:S173-181. 2. Shaw T, et al. AASLD 2007. Abstract 986. 3. Schildgen O,
et al. N Engl J Med. 2006;354:1807-1812.
4. Reijnders JG, et al. AASLD 2007. Abstract 951. 5. Colonno R, et al. Hepatology. 2006;44:1656-1665.
How can we reduce the risk of
drug resistance?
 Strategies to Limit Resistance
  Use antiviral treatment only as needed
  Use drugs with optimal antiviral potency
  Use tolerable and convenient regimens to support
   adherence
  LAM/LdT monotherapy not advisable as first-line therapy
   because of high incidence of resistance




Keeffe EB, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
 Strategies to Limit Resistance
  Maximize genetic barriers to resistance
      – Choose drugs with a low incidence of resistance over time
      – Avoid sequential monotherapy and treatment interruptions




Keeffe EB, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Any Current Role for Combination
Therapy as Initial Treatment?
   No combination therapy has convincingly shown increased short-term efficacy
    in nucleos(t)ide-naive patients
     – LdT + LAM vs LdT vs LAM[1]
     – LAM + ADV vs LAM[2]
     – FTC + ADV vs ADV[3]
     – TDF + FTC vs TDF[4]
   Currently available drugs have excellent resistance profile
   Study to generate data sufficient for approval of combination treatment
    unlikely to be performed
     – Would have to be very large, very long, require shorter-term endpoints than
       resistance alone, and expensive


          1. Lai CL, et al. Gastroenterol. 2005;129:528-536. 2. Sung JJ, et al. J Hepatol. 2008;48:728-735.
                    3. Hui CK, et al. J Hepatol. 2008;48:714-720. 4. Berg T, et al. EASL 2009; Abstract 903.
Proposed Special Populations for
Combination Therapy
 Cirrhosis (especially decompensated)
   – High risk of hepatitis flare with emergence of resistance
 HIV/HBV coinfection
   – Drugs with dual antiviral activity must be used in
     combination to prevent drug resistance
 Preexisting resistance
   – Rates of infection with resistant virus low but increasing
 No data showing benefit of combination therapy vs
  monotherapy with newer more potent agents in treatment
  naïve patients
          Lok AS, et al. Hepatology. 2007;45:507-539. Jacobson IM. J Hepatol. 2008;48:687-691.
Case 1: Primary Nonresponse
Case 1: History
 52-year-old male
 HBV diagnosed 2004
 Laboratory results: March 2008
  – ALT: 179 IU/L
  – AST: 136 IU/L
  – INR, albumin, and bilirubin normal
  – HBeAg positive
  – Anti-HBe negative
  – HBV DNA: 2.0 x 108 IU/mL
Case 1: Management and Treatment
Decisions
 Patient treated with adefovir 10 mg/day
 Week 12 laboratory results
   – ALT decreased to 50 IU/L
   – HBV DNA declined to 2.5 x 107 IU/mL
   – Medication well tolerated, and he is adherent to dosing
     schedule
 Week 24 laboratory results
   – ALT: 48 IU/L
   – HBV DNA: 2.2 x 107 IU/mL
   – Remains HBeAg positive, anti-HBe negative
Case 1: Question
 What are the management options for this patient?
   – Continue adefovir monotherapy?
   – Switch to new oral agent as monotherapy?
   – Continue adefovir and add a second drug?
Case 1: Management and Treatment
Decisions
 Primary nonresponse suspected
 Switch from adefovir to Entecavir 0.5 mg/day


 Week 12 laboratory results*
     – Undetectable HBV DNA (< 300 copies/mL)
     – ALT: 27 IU/L
 Week 24 laboratory results*
     – Undetectable HBV DNA (< 300 copies/mL)
      – ALT: 22 IU/L
*Of telbivudine treatment.
Case 1: Conclusions and Summary
 Patient achieves HBeAg seroconversion 18 months after
  starting telbivudine
   – Undergoes consolidation before stopping treatment
 Case highlights importance of monitoring HBV DNA and
  preemptive switching in the face of nonresponse
Case 2: Preventing Resistance
Case 2: History
 38-year-old male                Laboratory results
 Employed as a software            – ALT: 44 U/L
  engineer                          – HBeAg positive and anti-
                                      HBe negative
 Uses no tobacco or alcohol
                                    – HBV DNA: 820,000 IU/mL
 HBV infection diagnosed           – Anti-HAV IgG positive
  6 years ago at time of blood
                                    – HCV/HDV/HIV negative
  donation
                                    – Liver ultrasound: normal
                                    – Alpha-fetoprotein: 3.2 ng/mL
                                    – Liver biopsy: grade 2, stage
                                      1
Case 2: Questions
 Would you treat this patient?
 If so, with which agent would you initiate therapy?
   – Adefovir 10 mg/day
   – Entecavir 0.5 mg/day
   – Lamivudine 100 mg/day
   – Telbivudine 600 mg/day
   – Tenofovir 300 mg/day
 Strategies to Prevent Antiviral Drug-
 Resistant HBV
  Judicious use of antiviral treatment; avoid unnecessary
   treatment
  Use most potent agent with highest genetic barrier to
   resistance
  Monitor viral response; switch therapy if response
   suboptimal




Lok AS, et al. Hepatology. 2007;45:507-539.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Case 2: Treatment and Follow-up
 Patient treated with entecavir 0.5 mg/day
 Week 12
   – ALT: 28 U/L
   – Serum HBV DNA: undetectable
   – HBeAg positive

 Week 24
   – ALT: 30 U/L
   – INR, albumin, and bilirubin normal
   – Serum HBV DNA: undetectable
   – HBeAg positive
Case 2: Question
 What are the management options if this patient remains
  HBeAg positive after 1 or 2 years of entecavir therapy?
   – Continue entecavir monotherapy at 0.5 mg/day?
   – Increased the dose of entecavir to 1.0 mg/day?
   – Switch to new oral agent as monotherapy?
   – Continue entecavir and add a second drug?
Case 2: Conclusion and Summary
 Continues to tolerate treatment, no ALT flares
 Patient remains HBeAg positive at Years 2 and 3
 Patient maintains undetectable HBV DNA
 Monitored for HBeAg seroconversion or signs of virologic
  breakthrough every 6 months
   – Liver tests
   – HBeAg, anti-HBe, and HBV DNA testing
   – Hepatocellular carcinoma surveillance
Case 3: Managing Resistance
Case 3: History
   42-year-old female                          Current laboratory results
   HBV infection diagnosed at                    – ALT: 88 IU/mL
    24 years of age                               – AST: 72 IU/mL
   Patient asymptomatic                          – HBeAg positive
   Lamivudine started 2 years ago                – Anti-HBe negative

   Review of previous records reveals            – HBV DNA: 3,000,000 IU/mL

     – Normal to mildly elevated ALT              – Anti-HAV total positive
       levels (45-80 U/L) for past 2 years        – Anti-HCV negative
     – Undetectable HBV DNA for first             – Alpha-fetoprotein: 4 µg/L
       18 months of therapy; then
       increased to 720,000 IU/mL
   Physical examination unremarkable
Case 3: Question 1
 Would you add an agent and continue lamivudine or
  switch to a new agent?
 Which of the following agents would you consider using?
   – Adefovir 10 mg/day
   – Entecavir 1 mg/day
   – Telbivudine 600 mg/day
   – Tenofovir 300 mg/day
 Options for Lamivudine Resistance in
 AASLD Guidelines
 Resistance                                  Rescue Therapy
                    Add adefovir (superior to adefovir switch)
 Lamivudine         Switch to entecavir (increased risk of entecavir-R development)
                    Add tenofovir* or switch to emtricitabine/tenofovir*
                    Add lamivudine (superior to lamivudine switch)
 Adefovir           Switch to or add entecavir (only in the absence of lamivudine-R)
                    Switch to emtricitabine/tenofovir*
 Entecavir          Add or switch to adefovir or tenofovir*
                    Add adefovir (superior to adefovir switch)
 Telbivudine        Switch to entecavir (increased risk of entecavir-R development)
                    Add tenofovir* or switch to emtricitabine/tenofovir*
  *Off label.


Lok A, et al. Hepatology. 2007;45:507-539.
Case 3: Conclusion and Summary
 Tenofovir 300 mg daily was added to continued
  lamivudine
 HBV DNA decreased to 2600 IU/mL at 6 months and
  became undetectable at 1 year
 Could this patient have been treated with tenofovir alone
  as add-on or monotherapy?
Resistance Summary
 HBV resistance can be delayed or avoided by
  – Using a highly potent antiviral agent
  – Improving adherence
  – Regular monitoring of serum HBV DNA, with change in therapy for
    nonresponse or suboptimal response to initial therapy

 When resistance occurs
  – Avoid use of cross-resistant drugs
  – Consider add-on therapy rather than switching to second
    monotherapy
  – Consider using the most potent available antiviral or combination

				
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