# Presentation: 444575

## FDA Advisory MeetingClinical Trial Design – Hepatitis B Treatment

**Anna S.F. Lok, M.D.**
**University of Michigan**
**Ann Arbor, M I**

## TREATMENT  OF CHRONIC HEPATITIS B

**Review of sentinel trials and meta-analysis of randomized controlled trials of Interferon (IFN) and Lamivudine (LAM)**
**Clinical Practice Guidelines**
**Issues for future clinical trials**

## Goals of Antiviral Treatment of Chronic Hepatitis B

**1.  Sustained suppression of HBV replication**
- 	**Decrease in serum HBV DNA to <10****5**** copies/ml**
**	****HBeAg to anti-HBe seroconversion**
**	****HBsAg to anti-HBs seroconversion**
**2.  Remission of liver disease**
- 	**Normalization of serum ALT levels**
**	****Decreased necroinflammation in liver**
**3.  Improvement in clinical outcome**
- 	**Decreased risks of developing cirrhosis, liver **
**	****failure and HCC**
**	****Increased survival****	**

## Review of Clinical Trials ofIFN and Lamivudine

**Study population**
**HBeAg+ CHB**
**HBeAg- CHB**
**Decompensated cirrhosis**
**Inclusion/exclusion criteria**
**Treatment regimen**
**Sample size**
**End-points, response rates**
**Ability of measurements of response to predict outcome**

## Sentinel Clinical Trials of IFN and LAM in HBeAg + CHB

|  | IFN * | LAM # |
| --- | --- | --- |
| Controls | No Rx | Placebo |
| No. of patients/arm | 10 – 101 | 66 – 143 |
| Sample Size | Not Discussed | Power for 1° end-point |
| 1° End Point | HBeAg & HBV DNA loss | Decrease in HAI
by >2 points |

**HBV DNA Assay    ------****	****dot-blot/liquid hybridization ***
**	****	****	****              ****liquid hybridization #**

## ‘Sentinel’ Clinical Trials of IFN and LAMin HBeAg- CHB

|  | IFN* | LAM# |
| --- | --- | --- |
| Entry Criteria | HBV DNA+,  ALT | HBV DNA+,  ALT |
| Controls | Some trials | 1 trial |
| Sample Size | Not discussed | Not discussed |
| Duration of Rx | 3-24 months | 12 months - infinity |
| 1° End Point | Normal ALT, HBV DNA- | Normal ALT, HBV DNA- |
|                 
                HBV DNA Assay – dot blot/liquid hybridization *
                                 liquid hybridization, bDNA, hybrid capture, PCR # |  |  |

## Meta-analysis of 24 RCTs of IFNin HBeAg+ CHB

**855 IFN R****x****, 444 no R****x**

| Response Parameters | Difference in Response Rate | 95% CI | P Value |
| --- | --- | --- | --- |
| ALT normalization | 26% | 18% - 34% | <0.00001 |
| Clearance of HBeAg | 24% | 8%-29% | <0.00001
 |
| Sustained loss of HBV DNA | 23% | 18% - 29% | <0.00001
 |
| Clearance of HBsAg | 6% | 4% - 8% | <0.00001
 |

**Craxi et al., J Hepatol (in press)**

## Meta-analysis of 12 Studies of IFN Rx on Long-Term Outcome of HBeAg+ Adults#

**765 IFN Rx, 1210 no R****x*******
**Mean FU 6·1 yr (2.1 – 8.9 yr)**

|  | IFN (95% CI) | No Rx (95% CI) |
| --- | --- | --- |
| Loss of HBsAg | 11.4% (9.1 - 13.7) | 2.6% (1.8 - 3.4) |
| Hepatic Decompensation | 9.8% (7.7 - 12.1) | 13.3% (10.1 - 16.4) |
| Development of HCC | 1.9% (0.8 - 3.0) | 3.2% (1.8 - 4.5) |
| Liver Related Death | 4.9% (3.3 - 6.5) |  8.7% (6.1 - 11.3) |

**# Significant heterogeneity of results**
*** Includes non-concurrent controls**

**Craxi et al., J Hepatol (In press)**

## IFN Rx of HBeAg+ CHB

|  | Pred | IFN Alone |  | Controls |
| --- | --- | --- | --- | --- |
|  | + IFN | 5 MU | 1 MU |  |
| No. of Patients | 44 | 41 | 41 | 43 |
| Loss of HBV DNA and HBeAg | 16(36) | 15(37) | 7(17) | 3(7) |
| Loss of HBV DNA only | 4(9) | 3(7) | 4(10) | 2(5) |
| Loss of HBsAg | 5(11) | 5(12) | 1(2) | 0 |
| ALT normal at Last FU | 19(43) | 18(44) | 11(27) | 8(19) |
| Reactivation during FU | 1(2) | 0 | 1(2) | 0 |

**Perrillo et al., NEJM 1990;323:295**

## IFN Treatment of HBeAg - CHB

**Type of Study****	****	****        # Studies****	****        # Treated     # Untreated**
**Randomized****	****	****             ****	****4****	****	****86****	****        84**
**  ****(IFN vs. no treatment)**
**Randomized****	****	****             ****	****2****	****	****110 ****	****        ******
**  ****(comparing different IFN schedule)**
**Randomized****	****	****             ****	****3****	****	****45****	****        ******
**  ****(IFN vs. other active compound)****	**
**Not Randomized****	****             ****	****9****	****  ****	****702****	****        ******
**	**
**ALL****	****	****	****             ****	****18****	****	****943****	****        84**

## IFN Treatment of HBeAg - CHBCumulative results of published studies

**44 -**
**69**

*Alberti, NIH, HBV 2000 Meeting*

*** HBV DNA by non-PCR assays**

**38 -**
**59**

**7 -**
**38**

**7 -**
**38**

## IFN Rx of HBeAg - CHB: Histologic Response

**Author,****	****        ****	**** Mean HAI Score                Mean Fibrosis Score**
**Year****	****	****   IFN          Control             IFN          Control**
**Lampertico, 1997**
**   ****Baseline****	****   10.3****	****	****9.3****	****      2.1****	****            2.2**
**	****	****	**** ****} p=.001**
**   ****End of Rx      ****	****     5.3****	****	****9.3****	****      1.8****	****            2.0**
**Fattovich, 1992**
**   ****Baseline****	****     8.1           ****	****9.0****	****      N/A****	****            N/A**
**	****	****              ****} p=.004**
**  ****12 mon post-Rx  5.5             ****	****7.5 ****	****      N/A             N/A**

## IFN Rx of HBeAg- CHB

**216 patients, FU median 7 yr**
**	****78 patients - median 5 months Rx**
**	****138 patients - median 12 months Rx**
**	****3 MU tiw**
**Response**
**	****End of R****x****	****54%**
**	****FU Yr. 1****	****44% of initial responders, 24% of all patients**
**	****End of FU****	****33% of initial responders, 18% of all patients**
**Predictors of Response**
**	****Duration of R****x**** > 6 months**
**	****Early response, within 4 months**

**Manesis & Hadziyannis, Gastroenterology 2001;121:101**

## Lamivudine Rx of HBeAg+ CHB

**Lamivudine R****x**** of HBeAg+ CHB**

-     **Placebo**
**     ****Lam x 52 wk**
**     ****IFN x 16 wk**
**     ****Lam x 24 wk                       **
**     ****+IFN x 16 wk**

**HBeAg seroconversion at week 52**

**Lai et al., NEJM 1998**

**Dienstag et al., NEJM 1999**

**Schalm et al., Gut 2000**

- 13

## Lamivudine Rx of HBeAg+ CHB

**Lamivudine R****x**** of HBeAg+ CHB**

**Histologic response at week 52**

-     **Placebo**
**     ****Lam x 52 wk**
**     ****IFN x 16 wk**
**     ****Lam x 24 wk               ****.****    +IFN x 16 wk**

**Dienstag et al., NEJM 1999**

**Schalm et al., Gut 2000**

**Lai et al., NEJM 1998**

- 14

## Lamivudine Rx of HBeAg+ CHB

**Normal ALT at Week 52**

## Lamivudine Rx of HBeAg+ CHB

**Lamivudine R****x**** of HBeAg+ CHB**

**%  of Patients**

*Multi-center Asian Study*

## Lamivudine Rx of HBeAg- CHB

**Lamivudine R****x**** of HBeAg- CHB**

**Lamivudine**

**Placebo**

**0**

**24**

**52**

*Tassopoulos et al., Hepatology 1999; 29:889*

****** ****HAI ******** 2 points**

**HBV DNA -**
** ****(PCR)**

**HBV DNA -**
** ****(bDNA) **
**ALT Normal**

**At wk 24**

**HBV DNA -**
**(bDNA) **
**ALT Normal**

**At wk 52**

## Lamivudine Rx of HBeAg- CHB

**Lamivudine Treatment (0-52 Weeks)**

**Lamivudine R****x**** of HBeAg- CHB**

**HBV DNA (pg/mL)**

**ALT (xULN)**

**Normal ALT**

*Tassopoulos et al., Hepatology 1999; 29:889*

**Notes:**
Median HBV DNA remained < 2.5 pg/ml (Chiron Quantiplex) from week 2 and throughout treatment until week 76
By week 12 the median ALT had fallen to 1.0 X ULN; and median of <= 1.0 x ULN was sustained from week 16 through to week 52.  Median ALT rose to 2.4 x ULN at week 60 and by week 76 had fallen back to 1.6 x ULN.  Median ALT remained below baseline (3.2 x ULN) throughout treatment and follow up).
At week 52, the proportion of lamivudine treated patients who were complete responders remained high (65%).  Seven percent were partial responders and 28% were non-responders.  The non responders comprised 10 patients with missing data and 5 patients with serum HBV DNA concentrations ranging from 3 - 170pg/ml. Three of these five patients had YMDD variant HBV.

Patient numbers (HBV DNA)

Patient numbers (ALT)

## Treatment of HBeAg - CHB

| Treatment | On-Therapy Response | Sustained Response |
| --- | --- | --- |
| IFN (3-6 MU tiw) |  |  |
| 6 months | 60 – 90% | 10 – 15% |
| > 12 months | 50 – 75% | 20 – 25% |
| Lamivudine (100-150mg) |  |  |
| 12 months | 65 – 80% | ~10% |
| 24 months | 50 – 60% | ? |
| > 36 months | 30 – 40% | ? |
| Adefovir |  |  |
| 12 months | 70% | ? |

## Treatment of Decompensated Cirrhosis

**Measurements of Response**
**Viral suppression****	****	****	**** ******
**Biochemical improvement****	****	**** ******
**Decrease in CTP score****	****	**** ******
**	****(Alb, bil, PT, ascites, encephalopathy)**
**Decrease clinical complications****	**** **_**+**_
**Decrease need for transplant****	**** **_**+**_
**Decrease HCC****	****	****	**** ****	**** ?**
**Improve survival****	****	****	**** **_**+**_

## Lamivudine Rx of Decompensated Cirrhosis

**35 patients**
**decomp cirrhosis**

**23 patients R****X**** ******** 6 months**

**22 patients**
****** ****CTP score ******** 2 points**

**20 patients alive at 19 ******** 2 months**
**3 with resistant mutants **

**5 deaths**
**7 OLT**

**1 no improvement**
****** ****OLT**

**2 deaths;**
**1 SBP, 1 HCC**

*Villeneuve et al., Hepatology 2000;31:207*

## Clinical Practice Guidelines

**Who to treat**
**What treatment**
**When to stop treatment**

## AASLD Practice Guidelines

**Current therapy has limited long-term efficacy**
**Careful balance of benefits and risks before treatment is initiated**
**patients’ age**
**severity of liver disease**
**likelihood of response**
**potential adverse events **
**	****	****	****Lok and McMahon, Hepatology 2001;34:1225**

## AASLD Practice Guidelines: Rx Strategies

**	****	****	****	****Observe**
**  ****+ ****	**** +****	****>2x ULN****	****IFN or Lam**
**	****	****	****	****IFN NR or contraindications ******** Lam**
**  –****	**** ****+****	****>2x ULN****	****IFN or Lam**
**	****	****	****	****Long-term R****x**** required****	**
**  –****	**** –****	****normal****	****No Rx required**
**  ****+/ –****	**** +****	****cirrhosis****	****Compensated: IFN low dose or Lam**
**	****	****	****	****Decompensated: Lam, optimal timing ****	****	****	****	****	****unknown**
**	****	****	****	****Transplant**
**   ****+/ –****	**** –****	****cirrhosis****	****Compensated: observe**
**	****	****	****	****Decompensated: Transplant**

- ***HBV DNA in serum >10****5**** copies/ml**

**AASLD Practice Guidelines: Rx Strategies**

**HBeAg****	****HBV DNA*   ALT****	****	****Treatment**

- Lok and McMahon, Hepatology 2001;34:1225

## Treatment of Chronic Hepatitis B

**  ****More durable response**
**  ****Resistant mutants not    **
**   ****reported**

**  ****Expensive**
**  ****Frequent side effects**

**  ****Long/indefinite duration of R****x**
**  ****Resistant mutants**

**  ****Oral administration**
**  ****Negligible side effects**
**  ****Lower costs?**

**Interferon**

**Lamivudine**

** **_**Pros**_

**  **_**Cons**_

**Treatment of Chronic Hepatitis B**

## AASLD Practice GuidelinesTreatment Regimen - IFN

_**Dose**_
**	****	****	****5 MU QD or 10 MU tiw SC**
_**Duration**_
**	****	****	****e + CHB   -  16 wk**
**	****	****	****e – CHB   -  12 months**

**Lok and McMahon, Hepatology 2001;34:1225**

## AASLD Practice GuidelinesTreatment Regimen - Lamivudine

_**Dose**_
**	****	****100mg daily po**
**	****	****HIV Coinfection – 150mg bid + other HIV R****x**
_**Duration**_
**	**_**e+ CHB**_** – 1yr...**
**	****	****HBeAg seroconversion – Stop R****x****?**
**	****	****DNA suppression, HBeAg+ - Continue R****x****?**
**	****	****Breakthrough infection – continue R****x ****if clinically stable?**
**	****	****	****	****	****   ****Stop R****x**** if clinical deterioration**
**	**_**e- CHB**_** > 1yr, optimal duration?**
**	****	**

- Lok and McMahon, Hepatology 2001;34:1225

## Issues for Future Clinical Trials

**Study population**
**Entry criteria**
**Treatment regimens**
**Indications for assessing treatment response**
**End-points for stopping treatment**
**Durability of response after treatment withdrawal**
**Short and long term safety and efficacy**

## Issues for Future Clinical Trials

**Study population**
**Adults with**** **
**e+ CHB (normal vs. elevated ALT)**
**e- CHB**
**decompensated cirrhosis**
**Coinfection (HIV, HCV)**
**Extrahepatic disease**
**Patients on immunosuppressive/chemo R****x**
**Children**

## Issues for Future Clinical Trials

|  | HBeAg+ | HBeAg- |
| --- | --- | --- |
| HBV DNA (copies/ml) | > 105, 106 | > 104, 105, 106 |
| ALT (ULN) | > 1.5, 2, 3, 5 | > 1.5, 2, 3, 5 |
| Histology | Required?
HAI >?
Fibrosis? | Required?
HAI >?
Fibrosis? |

_**Entry Criteria**_

## Issues for Future Clinical Trials

_**Treatment Regimens**_
**	****Study Design**
**Monotherapy – placebo vs. active control**
**Monotherapy vs. combination therapy**
**	****Duration of R****x**
**Finite duration – 1 or 2 years**
**Built in follow-up/follow-on **
**durability of response **
**long-term safety**
**drug resistance**
**additional response with extended R****x**

## Issues for Future Clinical Trials

_**	**__**End-points for Treatment Response - Liver Histology**_
**	**
**	**_**Pros**_
**	****Direct assessment of liver disease – inflammation and fibrosis**
**	**_**Cons**_
**	****Requires 2 biopsies**
**	****Risks of complications**
**	****Expensive**
**	****Sampling error**
**	****Intra and Inter observer variability**
**	****Scores not linear**
**	****Not applicable outside clinical trials**
**	****Clinical significance of a 2-point decrease in HAI uncertain**

## Issues for Future Clinical Trials

**End-points for treatment response**
**	****HBeAg+ CHB**
**	****	****HBeAg loss, **_**+**_** anti-HBe ****+**
**	****	****Decreased HBV DNA level, <10****5**** copies/ml ****+**
**	****	****ALT normal**
**	****HBeAg- CHB**
**	****	****Decreased HBV DNA level, <10****3**** copies/ml ****+**
**	****	****ALT normal range**
**	****Decompensated Cirrhosis**
**	****	****Decreased HBV DNA level ****+**
**	****	****CTP score decrease **_**>**_** 2 points and/or**
**	****	****MELD score (INR, bil, Cr) decrease**

## Issues for Future Clinical Trials

**	****Do proposed composite (virologic, serologic biochemical) end-points correlate with**
**Histologic response**
**Improved clinical outcome?**

## Ability of Surrogate Markersto Predict Clinical Outcome

**Limited data**
**Problems:**
**Prolonged natural course**
**Limited follow-up in prospective studies**
**Few RCTs, small sample size**
**Disease heterogeneity between treated and untreated controls (historical/non-concurrent) in retrospective studies**

## IFN Rx of HBeAg+ CHB

|  | Total HAI Score |  | Ranked
Assessment* |
| --- | --- | --- | --- |
|  | Initial | FU Mon 6 |  |
| Treated patients (90) |  |  |  |
| HBeAg& HBV DNA Loss (30)  | 8·0+3 | 6·2+3 | 18/9/3 |
| HBV DNA Loss only (9) | 8·9+4 | 5·0+2 | 7/2 |
| No Response (51) | 6·7+2 | 7·5+3 | 8/30/13 |
| Controls (24) | 8·0+3 | 7·0+3 | 8/14/2 |
| *Improved/same/worse |  |  |  |

**Perrillo et al., NEJM 1990;323:295**

## Impact of HBeAg Clearanceon Long-Term Clinical Outcome

**0       12       24       36       48        60       72       84       96**

**1.0**
**0.8**
**0.6**
**0.4**
**0.2**
**0.0**

**Month**

**Proportion with complication free survival**

- Niederau et al., NEJM 1996;334:1422-7

**IFN**
**No R****x**

**Clearance of HBeAg**

**No Clearance of HBeAg**

## Cumulative Transplant-Free Survival of Patients with HBeAg- Chronic Hepatitis

**Cumulative Transplant-Free Survival of Patients with HBeAg- Chronic Hepatitis**

*Papatheodoridis et al., J Hepatol 2001; 34:306-313*

**IFN-SR vs IFN-NR p=0.03**

**IFN-SR vs Un-R****x**** p=0.05**

## Correlation Between Week 52 HBV DNA Levels and HBeAg Seroconversion in Lamivudine TrialsNUCB 3009/NUCA 3010

**Log****10**** HBV DNA Levels**

- Dienstag et al., NEJM 1999, Lai et al., NEJM 1998
- Courtesy of GSK – L Condreay and S Gardner

## Correlation between Week 52 HBV DNA Levelsand ALT NormalizationLamivudine Trials NUCB 3009/NUCA 3010

**Log****10**** HBV DNA Levels**

- Dienstag et al., NEJM 1999, Lai et al., NEJM 1998
- Courtesy of GSK – L Condreay and S Gardner

## Correlation Between Week 52 HBV DNA Levelsand Histologic ResponseLamivudine Trials NUCB 3009/NUCA 3010

**Log****10**** HBV DNA Levels**

- Dienstag et al., NEJM 1999, Lai et al., NEJM 1998
- Courtesy of GSK – L Condreay and S Gardner

## Correlation Between Week 48 HBeAg Seroconversion,HBV DNA, ALT and Histologic ResponseAdefovir Trial GS-437 (e+ CHB)

_**HBeAg Seroconversion**_

_**No HBeAg Seroconversion**_

**Log****10**** HBV DNA Levels**

**Log****10**** HBV DNA Levels**

**ADV 10mg**

*Courtesy of J Fry, C Brosgart, Gillead*

## Correlation Between Week 48 HBV DNA, ALT and Histologic Response Adefovir Trial GS-438 (e-CHB)

_**ADV**_

_**PLA**_

**Log****10**** HBV DNA Levels**

**Log****10**** HBV DNA Levels**

**Courtesy of J Fry, C. Brosgart, Gilead**

## Issues for Future Clinical Trials

**Indications for stopping treatment**
**Achievement of on-treatment response**
**Maintenance of on-treatment response for defined duration**
**Indications may vary depending on severity of underlying liver disease and immune status of host**

## Correlation between Week 48HBeAg loss, HBV DNA,ALT and Histologic Response

**ADV 10 mg**

_**HBeAg Loss**_

_**No HBeAg Loss**_

**Log****10**** HBV DNA Levels**

**Log****10**** HBV DNA Levels**

## Treatment of Chronic Hepatitis B

**Role of IFN in Patients with Cirrhosis**

**IFN vs Pred + IFN in CHB - US multi-center trial**
** ****	****98/150 (65%) had cirrhosis**
** ****	****1 treated and 1 control patient died of liver failure**
**	****	****	****	****	****	****	****	****      ***Perrillo et al., NEJM 1990*

**	****         ****Low dose IFN in clinical cirrhosis**
**Child’s class****	****	****n****	****Response****	****R****x**** withdrawal**
**A****	****	****	****5****	****5****	****	****0**
**B****	****	****	****15****	****5****	****	****3**
**C****	****	****	****6****	****0****	****	****4**

*Perrillo et al., Gastro 1995*

## Effect of IFN on Survival and HCC Development

**Effect of IFN on Survival and HCC Development**

*Lin et al., Hepatology 1999;29:971*

**Survival**

**HCC**

## RCTs of IFN Treatment of HBeAg - CHB

**Author,****	****	****   IFN Dose,****	****Number****	****       Number****	****Follow**
**Year****	****	****   Duration****	****Treated****	****      Untreated****	****    Up**
**Hadziyannis,****	****   5 MU/m****2****,****	****25****	****	****25****	****12 mo.**
**   ****1990****	****	****   14-16 wks****	**
**Fattovich,****	****   5 MU/m****2****,****	****30****	****	****30****	****12 mo.**
**   ****1992****	****	****   6 mo.**
**Pastore,****	****   ****	****   5 MU/m****2****,****	****10****	****	****  8****	****24 mo.**
**   ****1992****	****	****   6 mo.**
**Lampertico,****	****   6 MU/m****2****,****	****21****	****	****21****	****22 mo.**
**   ****1997****	****	****   24 mo.**

## IFN Treatment of HBeAg-  Patients

**IFN Treatment of HBeAg-  Patients**

*Hadziyannis S, et al., J Hepatology 1990; 11(Suppl 1):513 *
*Fattovich G, Hepatology 1992; 15:584**	**	*
*Pastore G, J Hepatology 1992; 14;221 **	**	*
*Lampertico p, Hepatology 1997; 26:1621*

## Long-Term Follow-Up of HBeAg- Patients with End-of-Treatment Response to IFN

**Long-Term Follow-Up of HBeAg- Patients ****with End-of-Treatment Response to IFN**

*Papatheodoridis et al., J Hepatol 2001; 34:306-313*

## PLA

**Log****10**** HBV DNA Levels**

- Dienstag et al. Courtesy of L. Condreay and S. Gardner, GSK., NEJM 1999, Lai et al., NEJM 1998

## LAM

**Log****10**** HBV DNA Levels**

- Dienstag et al. Courtesy of L. Condreay and S. Gardner, GSK., NEJM 1999, Lai et al., NEJM 1998

## PLA

**PLA**

## LAM

**Log****10**** HBV DNA Levels**

## PLA

**Log****10**** HBV DNA Levels**

## LAM

**Log****10**** HBV DNA Levels**

## Correlation Between Week 48 HBeAg Seroconversion,

**Correlation Between Week 48 HBeAg Seroconversion,**
**HBV DNA, ALT and Histologic Response**
**GS-437 (e+ CHB)**

**Placebo**

_**HBeAg Seroconversion**_

_**No HBeAg Seroconversion**_

**Log****10**** HBV DNA Levels**

**Log****10**** HBV DNA Levels**