Tenofovir disoproxil fumarate, tablet, 300 mg, Viread®, July 2009
Public summary document for Tenofovir disoproxil fumarate, tablet, 300 mg, Viread®, July 2009
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Public Summary Document
Product:Tenofovir disoproxil fumarate, tablet, 300
mg, Viread®
Sponsor: Gilead Sciences Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
The submission sought to extend the Section 100 (Highly Specialised
Drugs Program) listing of tenofovir to include treatment of
HBeAg-negative, treatment-naïve patients and
treatment-experienced patients with chronic hepatitis B
(CHB).
Highly Specialised Drugs are medicines for the treatment of chronic
conditions, which, because of their clinical use or other special
features, are restricted to supply to public and private hospitals
having access to appropriate specialist facilities.
2. Background:
Tenofovir has been listed under Section 100 since 1 October 2002
for treatment of patients with HIV infection.
This was the second submission to the PBAC requesting listing of
tenofovir for treatment of CHB.
At its November 2008 meeting, the PBAC recommended extending the
listing of tenofovir to include treatment of patients with
HBeAg-positive chronic hepatitis B who are nucleoside analogue
naïve on a cost minimisation basis with entecavir 0.5 mg
tablets where the equi-effective doses are tenofovir 300 mg per day
and entecavir 0.5 mg per day.
The Committee rejected the application for listing of tenofovir in
HBeAg-negative nucleoside naïve CHB patients, considering
insufficient evidence had been present to support the claim of
non-inferiority to entecavir 0.5 mg. Based on the data provided,
the Committee did not accept the claim that tenofovir is equally
effective in nucleoside naïve HBeAg-negative patients to
entecavir because this conclusion relied on the assumption that
tenofovir is equally effective in nucleoside naïve
HBeAg-negative and HBeAg-positive patients.
The Committee also rejected the application for listing of
tenofovir for the treatment of CHB in nucleoside experienced
patients. The PBAC considered the methods used in the submission
for the direct comparison of tenofovir to adefovir to be
flawed.
3. Registration Status
Tenofovir was first registered by the TGA on 13 August 2002 for use
in combination with other antiretroviral agents for the treatment
of HIV-infected adults. Evidence to support this indication is
based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in
controlled studies of tenofovir in treatment-naïve adults and
in treatment-experienced adults.
On 30 July 2008, the TGA approved indications were extended to
include treatment of CHB in adults with evidence of active viral
replication and active liver inflammation.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drugs Program)
Private hospital authority required
Treatment-naïve chronic hepatitis B patients who satisfy all
of the following criteria:
- Histological evidence of chronic hepatitis on liver biopsy (except in patients for whom a liver biopsy is contraindicated).
- Elevated HBV DNA and/or abnormal serum ALT levels in conjunction with documented chronic hepatitis B infection.
Chronic hepatitis B in patients who have failed antihepadnaviral
therapy and who satisfy all of the following criteria:
- Persistently elevated HBV DNA levels despite prior antihepadnaviral therapy of greater than or equal to 6 months duration or failure to achieve a 1 log reduction in HBV DNA within 3 months of commencing antihepadnaviral therapy except in patients with evidence of poor compliance; or
- Repeatedly elevated serum ALT levels despite antihepadnaviral therapy of greater than or equal to 6 months duration with documented chronic hepatitis B infection.
NOTE:
Patients who have failed prior antihepadnaviral therapy may receive
tenofovir treatment in combination with lamivudine.
Patients should have undergone a liver biopsy at some point since
initial diagnosis to obtain histological evidence of chronic
hepatitis.
Persons with Child’s class B or C cirrhosis (ascites,
variceal bleeding, encephalopathy, albumin less than 30 g per L,
bilirubin greater than 30 micromoles per L) should have their
treatment discussed with a transplant unit prior to initiating
therapy.
Female patients who are of child-bearing age should not be
pregnant, should not be breast-feeding, and should be using an
effective form of contraception.
The PBAC agreed with the requested restriction but with minor
changes.
5. Clinical Place for the Proposed Therapy
Tenofovir will provide an alternative oral treatment for chronic
hepatitis B in both treatment-naïve and treatment-experienced
patients.
6. Comparator
As in the November 2008 submission, the re-submission nominated
entecavir 0.5 mg as the comparator for treatment-naïve
patients and adefovir as the comparator for treatment-experienced
patients. The PBAC previously considered these comparators to be
appropriate.
7. Clinical trials
Nucleos(t)ide naïve HBeAg negative patients
No new direct randomised trials comparing tenofovir with entecavir
were identified.
The basis of the re-submission for tenofovir in nucleos(t)ide
naïve HBeAg negative patients was a new comparison of the
tenofovir 300 mg arm of one randomised trial (trial 0102) and the
entecavir 0.5 mg arm of another randomised trial (Lai 2006).
Participants in both trials were HBeAg negative. The trials did not
have a common comparator on which to construct an indirect
comparison.
The re-submission also included the unpublished results of a post
hoc subgroup analysis of the results of a mixed treatment
comparison (MTC) meta-analysis as supplementary evidence.
For a list of the studies presented, refer to the November 2008
Public Summary Document.
Nucleos(t)ide experienced patients
The primary evidence presented in the re-submission for tenofovir
in nucleos(t)ide experienced patients was the same as in the
previous submission.
Please refer to the November 2008 Public Summary Document for a
list of these trials and studies.
The re-submission presented additional supplementary evidence. The
following table details those studies published or presented at the
time of submission:
| Trial/First author | Protocol title/Publication title | Publication citation |
| 0102 LTE HBeAg negative patients | Two year tenofovir disproxil fumarate (TDF) treatment and adefovir dipivoxil (ADV) switch data in HBeAg-negative patients with chronic hepatitis B (Study 102) | Marcellin P, Buti M, Krastev Z et al, 59th Meeting of the American Association for the Study of Liver Disease. San Francisco, California: 31 October–4 November 2008. Oral presentation #146 |
| Hann 2008 | Tenofovir (TDF) has stronger antiviral effect than adefovir (ADV) against lamivudine (LAM)-resistant hepatitis B virus (HBV). | Hann HW, Chae HB, Dunn SR, Hepatol Internat 2: 244–249 |
| Leemans 2008 | Switching patients with lamivudine resistant chronic hepatitis B virus from tenofovir to adefovir results in less potent HBV-DNA suppression. | Leemans WF, Janssen HLA, Niesters HGM et al, J Vir Hep 15 : 108–114 |
| van Bömmel 2004 | Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. | van Bömmel F, Wünsche T, Mauss S et al, Hepatol 40: 1421–1425 |
| van Bömmel 2005 | Tenofovir rescue for patients with lamivudine resistant HBV infection with suboptimal virologic response to adefovir. | van Bömmel F, Feucht HH, Möller B et al, Hepatol 42 (4 Suppl 1): 589A |
| van Bömmel 2006 | Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. | van Bömmel F, Zöllner B, Sarrazin C et al, Hepatol 44: 318–325 |
| van Bömmel 2007 | Efficacy of tenofovir DF for the treatment of adefovir resistance. | van Bömmel F, Trojan J, Wasmuth H et al, 58th Meeting of the American Association for the Study of Liver Diseases. Boston, Massachusetts, November 2–6 2007. Abstract 960 |
| Roberts 2009 | Prevalence & nature of viral mutations in CHB patients on antiviral therapy: the CHARM study. | Roberts SK, Ngu MC, Strasser SI et al, Australian Gastroenterology Week, Brisbane, 22–25 October 2008. Poster 24 |
| Dakin 2008 HBeAg positive patients (post hoc sub-group analysis) | Results of a mixed treatment comparison meta-analysis of nucleoside and nucleotide therapies for HBeAg-positive chronic hepatitis B. | Dakin HA, James ES, 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, April 23–27 2008. Abstract |
| Choe 2008 | Tenofovir plus lamivudine as rescue therapy for adefovir-resistant chronic hepatitis B in hepatitis B e antigen-positive patients with liver cirrhosis. | Choe WH, Kwon SY, Kim BK et al, Liver Internat 28: 814–820 |
8. Results of Trials
Nucleos(t)ide naïve HBeAg negative patients
The re-submission aimed to demonstrate the non-inferiority of tenofovir 300 mg to
entecavir 0.5 mg by comparing two treatment arms from two separate trials, with no
common comparator. The specified non-inferiority margin was 10-15 %. The results of
the key comparison of the tenofovir 300 mg arm of trial 0102 and the entecavir 0.5
mg arm of Lai (2006), both in HBeAg negative CHB patients, with no common comparator,
are presented in the following table.
Results of the common outcome measure across the two treatment arms from trials 0102
and Lai 2006
| Outcome | 0102 Tenofovir n with event/N (%) | Lai 2006 Entecavir n with event/N (%) |
| HBV DNA <300 copies/mL | 230/250 (92.0) | 293/325 (90.2) |
CI=confidence interval; DNA=deoxyribonucleic acid; HBV=hepatitis B virus; n = number
with event; N = number in group; OR=odds ratio; RD=risk difference; RR=relative risk.
Nucleos(t)ide experienced patients
The re-submission presented the same primary evidence as was presented in the previous
submission.
The results of the comparison for tenofovir versus adefovir in nucleos(t)ide-experienced
patients (combined analysis for studies 0102 and 0103) are shown below:
| Outcome | Tenofovir n with event/N (%) | Adefovir n with event/N (%) | ARD (95% CI) | RR (95% CI) | OR (95% CI) |
| Complete response a | 37/51 (72.5) | 15/24 (62.5) | 10.0% (-12.9%, 33.0%) | 1.16 (0.82, 1.65) | 1.59 (0.57, 4.44) |
| HBV DNA <400 copies/mL | 46/51 (90.2) | 17/24 (70.8) | 19.4% (-0.6%, 39.3%) | 1.27 (0.97, 1.67) | 3.79 (1.06,13.56) |
| Histologic response | 40/51 (78.4) | 21/24 (87.5) | -9.1% (-26.5%, 8.3%) | 0.90 (0.73, 1.10) | 0.52 (0.13, 2.07) |
ARD=absolute risk difference; CI=confidence interval; DNA=deoxyribonucleic acid; HBV=hepatitis
B virus; n = number with event; N = number in group; OR=odds ratio; RR=relative risk.
a Proportion of subjects with complete response at week 48, defined as HBV DNA levels
<400copies/mL and histologic improvement indicated by at least 2-point reduction in
Knodell necro-inflammatory score without worsening in Knodell fibrosis score.
For the purposes of this post hoc comparison, the definition of “treatment experienced”
CHB patients was any subject with greater than 12 weeks of prior nucleoside therapy.
The re-submission claimed that as the lower limits of the 95 % confidence intervals
(CIs) are -0.6 % for the risk difference and 0.97 for the relative risk, it can be
concluded that tenofovir is non-inferior to adefovir using either 15 % or 10 % non-inferiority
margins.
The results of the mixed treatment comparison meta-analysis (Dakin 2008) are presented
below:
Key results of the meta-analysis of outcomes after one year of treatment: All treatment-naïve
patients
| Treatment (number of trials) | % patients HBV DNA <300 copies/mL (95% CrI) | OR vs. LAM (95% CrI) |
| Nucleoside- and nucleotide-naïve HBV mono-infected patients – HBeAg-positive and HBeAg-negative patients combined | ||
| Tenofovir (1) | 94.65 (85.86, 99.03) | 33.29 (6.876, 116.4) |
| Entecavir (3) | 79.04 (68.22, 89.1) | 4.666 (2.464, 9.374) |
| Telbivudine (3) | 71.84 (58.64, 84.76) | 3.161 (1.59, 6.505) |
| Telbivudine + lamivudine (1) | 61.63 (29.56, 88.35) | 2.588 (0.461, 9.044) |
| Adefovir (4) | 62.17 (39.74, 84.73) | 2.274 (0.744, 6.431) |
| Lamivudine (9) | 46.88 (43.2, 50.43) | – |
| Adefovir + lamivudine (1) | 45.39 (17.73, 75.3) | 1.167 (0.246, 3.544) |
| Placebo (5) | 6.21 (1.37, 15.26) | 0.077 (0.016, 0.207) |
Crl=credible interval; DNA=deoxyribonucleic acid; HBV=hepatitis B virus; LAM=lamivudine;
OR=odds ratio
Relevant p values: Tenofovir is significantly better than lamivudine (p<0.05); tenofovir
is significantly better than placebo (p<0.05); tenofovir is significantly better than
adefovir (p<0.05); tenofovir is significantly better than telbivudine (p<0.05); tenofovir
is significantly better than entecavir (p<0.05); telbivudine+lamivudine is significantly
worse than tenofovir (p<0.05); adefovir+lamivudine is significantly worse than tenofovir
(p<0.05)
Abbreviations: CrI, credible (Bayesian probability) interval; OR, odds ratio showing
how many times higher the probability of this outcome is with the treatment in question,
compared with lamivudine
Resistance
The re-submission reported that, to date, no clinically relevant mutations associated
with tenofovir have been identified.
The re-submission provided the results of an updated safety review, performed during
the six months from May 2008 to October 2008. During this period, the sponsor reviewed
three key safety areas, and subsequently updated their company core safety information
to include angioedema as an undesirable event. No amendments were considered necessary
in the other two key safety areas reviewed, agranulocytosis and immune reconstitution
syndrome.
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
Nucleos(t)ide naïve HBeAg negative CHB patients
The re-submission described tenofovir as non-inferior in terms of
effectiveness and non-inferior in terms of safety compared to
entecavir 0.5mg in nucleos(t)ide naïve HBeAg negative CHB
patients.
Nucleos(t)ide experienced patients
The re-submission described tenofovir as non-inferior in terms of
effectiveness and non-inferior in terms of safety compared to
adefovir in nucleos(t)ide experienced CHB patients.
For PBAC’s views, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as tenofovir 300 mg once daily,
long-term therapy, entecavir 0.5 mg once daily, long-term therapy
in treatment naïve patients, and adefovir 10 mg once daily,
long term therapy in treatment experienced patients.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients/year to be
less than 10,000 in Year 5 of listing.
12. Recommendation and Reasons
The PBAC recommended extending the listing of tenofovir on a cost-minimisation basis compared with entecavir 0.5 mg for treatment of chronic hepatitis B in nucleoside analogue naïve and on a cost-minimisation basis compared with adefovir 10 mg for patients who have failed previous antihepadnaviral therapy. The equi-effective doses are entecavir 0.5 mg once daily and tenofovir 300 mg once daily for long-term therapy in treatment-naïve patients, and adefovir 10 mg and tenofovir 300 mg for long-term therapy for treatment-experienced patients. The PBAC considered the submission’s assumptions for a weighted price based on 50 % utilisation in each treatment group as reasonable.
.
The PBAC recognised there is a clinical need for an effective
additional treatment for chronic hepatitis B, particularly in
HBeAg-negative and treatment-experienced patients and noted that
tenofovir is widely listed in international guidelines as treatment
for hepatitis B. The clinician at the hearing indicated that to
date, there have been no signs of resistance to treatment with
tenofovir. The Pre-PBAC Response acknowledged that the data
presented are limited, but no new trials addressing the
PBAC’s concerns with appropriate comparators are
planned.
The basis of the re-submission for tenofovir in nucleos(t)ide
naïve HBeAg-negative patients is a comparison of the tenofovir
300 mg arm of one randomised trial (trial 0102) and the entecavir
0.5 mg arm of another randomised trial (Lai 2006). Participants in
both trials were HBeAg-negative. The trials did not have a common
comparator on which to construct an indirect comparison. In the
absence of a common reference, there is greater uncertainty with
this data-set than with the data presented previously in
treatment-naïve HBeAg-positive nucleoside patients, however
the unadjusted comparison approach is the only analysis possible
given the trial data available.
The PBAC previously considered that HBeAg status is both an effect
modifier and an independent predictor of outcome. Therefore, the
comparison of outcomes between HBeAg-positive patients from one
study and HBeAg negative patients from another study is subject to
considerable confounding with important differences between the
baseline characteristics of the patients in the trials, in addition
to HBeAg status, that may influence the outcome.
The PBAC considered that the approach used in the previous
submission for the direct comparison of tenofovir with adefovir, in
which the results of the subgroups of nucleoside experienced
patients from a trial in HBeAg-positive CHB patients and a trial in
HBeAg negative CHB patients were combined, was flawed. These data
were presented again and the methodological approach did not
address the PBAC’s concerns. Patient data from two separate
RCTs are combined, resulting in a loss of randomisation, an obvious
imbalance of HBeAg-positive patients between treatment arms and an
under-representation of HBeAg- positive patients in the data. The
Pre-Sub-Committee Response noted that the totality of the evidence
provides an overall picture of the clinical efficacy of tenofovir
in comparison with the appropriate comparators. The PBAC was
advised that the data support the fact that tenofovir is an
effective agent, but the performance against its comparators
remains uncertain because of the limitations of the data
available.
Other evidence presented in the submission, including the mixed
treatment comparison meta-analysis by Dakin et al (2008), supported
a finding that tenofovir is an effective treatment for chronic
hepatitis B. The PBAC noted that the re-submission states that the
Dakin 2008 meta-analysis shows that treatment with tenofovir is
more likely to result in a HBV DNA level < 300 copies/mL than
either entecavir or adefovir, and this result is statistically
significant. However, due to the under-representation of data in
HBeAg negative patients, the results of this post hoc analysis are
likely to be dominated by the treatment effect in HBeAg positive
patients.
Nevertheless, despite the deficiencies in the data, the PBAC
accepted overall that tenofovir is likely to be no worse than
entecavir 0.5 mg for treatment naïve patients and no worse
than adefovir 10 mg for treatment experienced patients and that it
represents an important alternative treatment option for patients
with chronic hepatitis B.
Recommendation
TENOFOVIR DISOPROXIL FUMARATE, tablet, 300 mg
Extend the current recommended restriction to include the
following:
Restriction:
Section 100 (Highly Specialised Drugs
Program)
Private hospital authority required
Treatment, as sole PBS-subsidised therapy, of chronic hepatitis B
In a patient who is nucleoside analogue naïve and satisfies
all of the following criteria:
- Histological evidence of chronic hepatitis on liver biopsy (except in patients with coagulation disorders considered severe enough to prevent liver biopsy);
- (a) Abnormal serum ALT levels in conjunction with documented chronic hepatitis B infection; or
- (b) Elevated HBV DNA levels in conjunction with documented chronic hepatitis B infection;
- (3) Female patients of child-bearing age are not pregnant, not breast-feeding, and are using an effective form of contraception.
Persons with Child’s class B or C cirrhosis (ascites,
variceal bleeding, encephalopathy, albumin less than 30 g per L,
bilirubin greater than 30 micromoles per L) should have their
treatment discussed with a transplant unit prior to initiating
therapy.
Chronic hepatitis B in a patient who has failed antihepadnaviral
therapy and who satisfies all of the following criteria:
- (a) Repeatedly elevated serum ALT levels while on concurrent antihepadnaviral therapy of greater than or equal to 6 months duration in conjunction with documented chronic hepatitis B infection; or
(b) Repeatedly elevated HBV DNA levels one log greater than the
nadir value or failure to achieve a 1 log reduction in HBV DNA
within 3 months, whilst on previous antihepadnaviral therapy except
in patients with evidence of poor compliance;
(2) Female patients of child-bearing age are not pregnant, not
breast-feeding, and are using an effective form of
contraception.
Persons with Child’s class B or C cirrhosis (ascites,
variceal bleeding, encephalopathy, albumin less than 30 g per L,
bilirubin greater than 30 micromoles per L) should have their
treatment discussed with a transplant unit prior to initiating
therapy.
NOTE:
Patients should have undergone a liver biopsy at some point since
initial diagnosis to obtain histological evidence of chronic
hepatitis.
Patients may receive tenofovir treatment in combination with
lamivudine but not with other PBS-subsidised antihepadnaviral
therapy.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Gilead Sciences welcomes the PBAC recommendation to extend the listing of Viread to include patients with chronic hepatitis B, both treatment naïve and treatment experienced patients, in accordance with the proposed S 100 restriction.
