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.

THANK YOU FOR

PATIENT LISTENING