Tenofovir with emtricitabine and rilpivirine, tablet containing tenofovir disoproxil fumarate 300 mg with emtricitabine 200 mg and rilpivirine hydrochloride 25 mg, Eviplera® - November 2011
Page last updated: 02 March 2012
Public Summary Document
Product: Tenofovir with emtricitabine and
rilpivirine, tablet containing tenofovir disoproxil fumarate 300 mg
with emtricitabine 200 mg and rilpivirine hydrochloride 25 mg,
Eviplera®
Sponsor: Gilead Sciences Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
The submission requested a S100 (Highly Specialised Drugs Program)
Authority Required listing for the treatment of human
immunodeficiency virus (HIV) infection in combination with other
antiretroviral agents in a patient with a CD4 count of less than
500 per cubic millimetre or symptomatic HIV disease.
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
The fixed combination drug had not previously been considered by
the PBAC.
3. Registration Status
Tenofovir with emtricitabine and rilpivirine, Eviplera®, was registered by the TGA on 23 January 2012 for the following indication:
- Treatment of HIV infection in treatment-naïve adult patients with plasma HIV-1 RNA ≤ 100,000 copies per mL at the start of therapy.
4. Listing Requested and PBAC’s View
Section 100 listing
Public Hospital Authority Required
(STREAMLINED)
Private Hospital Authority Required
Initial treatment of HIV infection in combination with other
antiretroviral agents in a patient with a CD4 count of less than
500 per cubic millimetre or symptomatic HIV disease;
Continuing treatment of HIV infection in combination with other
antiretroviral agents where the patient has previously received
PBS-subsidised therapy of HIV infection.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
HIV infection is a chronic, immunosuppressive infection that is
characterised by a continuous, high-level viral replication and a
slow, insidious, progressive destruction of the human immune
system. In the absence of effective antiretroviral treatment, HIV
infection leads to severe immune deficiency and the development of
the systemic opportunistic infections and cancers that define the
onset of the final stage of HIV infection, the acquired immune
deficiency syndrome (AIDS), and ultimately results in death.
Typically, standard medical management of HIV-1 infection consists
of combinations of different antiretroviral therapies (e.g.
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs),
non-nucleoside reverse transcriptase inhibitors (NNRTIs) and
protease inhibitors (PIs)).
The submission proposed that the place in therapy of tenofovir with
emtricitabine and rilpivirine is to provide an alternative
combination tablet for the treatment of HIV.
6. Comparator
The submission nominated the fixed dose combination product
tenofovir disoproxil fumarate (DF) (300 mg) with emtricitabine (200
mg) and efavirenz (600 mg), Atripla® as the
comparator. This was accepted by the PBAC.
7. Clinical Trials
The basis of the submission was two direct randomised comparative
trials, ECHO and THRIVE, comparing rilpivirine (25 mg) plus two
N(t)RTIs and efavirenz (600 mg) plus two N(t)RTIs in treatment
naïve HIV patients. Subjects enrolled in both the ECHO and
THRIVE trials were treatment naïve only. The THRIVE trial
included some patients who did not receive all three compounds in
Eviplera or Atripla, i.e. they received different N(t)RTIs.
The ECHO and THRIVE trials were both 96 weeks in duration, with the
primary outcome reported at 48 weeks. The primary outcome for both
the ECHO and THRIVE trials was the proportion of patients with
plasma viral load less than 50 HIV-1 RNA copies/mL at week 48. In
order to qualify as a virologic responder, using the time to loss
of virologic response (TLOVR) algorithm, a subject must have had
two consecutive values below the specified threshold. For loss of
response, two consecutive values above the threshold were required.
The threshold specified for the primary efficacy outcome in both
trials was 50 copies/mL. Both the ECHO and THRIVE trials used a
maximum allowable difference of 12% according to the TLOVR
algorithm as defined by the FDA.
Details of the studies published at the time of submission are
shown in the table below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Direct randomised trials | ||
| ECHO | ||
| Molina J et al 2011 | Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naïve adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. | The Lancet. 2011 Jul; 378:238-46. |
| THRIVE | ||
| Cohen C et al 2011 | Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naïve adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. | The Lancet. 2011 Jul; 378:229-37. |
| Pozniak AL et al 2010 | Efficacy and safety of TMC278 in antiretroviral-naïve HIV-1 patients: Week 96 results of a phase IIb randomized trial | AIDS 2010; 24(1): 55-65. |
| Wilkin A et al 2010 | TMC278 shows favourable tolerability and non-inferior efficacy compared to efavirenz over 192 weeks in HIV-1-infected treatment-naïve patients | Infection 2010; 38: S63-64. |
8. Results of Trials
Efficacy Trials
The results for the primary outcome of the ECHO and THRIVE trials,
proportion of virological responders, defined as a viral load less
than 50 copies/mL at week 48 showed both rilpivirine and efavirenz
(plus tenofovir DF with emtricitabine or plus two N(t)RTIs)
resulted in high virologic response rates (84.3% vs. 81.5%,
meta-analysis). As the lower limit of the 95% confidence interval
was above -12% in both the ECHO and THRIVE trials, the
non-inferiority criteria were met (p<0.0001).
Although not presented in the submission, it is evident that
statistically significantly more patients treated with two N(t)RTIs
plus rilpivirine, compared to efavirenz, had treatment failure due
to virologic failure (risk difference 4.2%, 95% CI: 1.5, 6.9).
Statistically significantly more patients treated with two N(t)RTIs
plus efavirenz, compared to rilpivirine, discontinued treatment due
to adverse events (risk difference 4.7%, 95% CI: 6.9, 2.5). As
patients in THRIVE were allowed N(t)RTIs other than tenofovir DF /
emtricitabine treatment, the results from ECHO may be more
relevant.
Across both ECHO and THRIVE trials, patients in the rilpivirine
plus two N(t)RTIs treatment groups had greater resistance to
lamivudine, abacavir and emtricitabine. Alternatively, patients in
the efavirenz plus two N(t)RTIs treatment groups had greater
resistance to zidovudine.
The cross-resistance to other NNRTIs and N(t)RTIs may have an
impact on the choice of NNRTI for first-line treatment.
Bio Equivalence Trial
The submission presented the results of pharmacokinetic parameters
for fixed dose versus free dose tenofovir
DF/emtricitabine/rilpivirine from Study 103.
For PBAC’s view of these results, see Recommendation and
Reasons.
A summary of the adverse events reported in the clinical trials
showed there was no statistically significant difference in the
incidence of adverse events (all grades) between rilpivirine plus
two N(t)RTIs and efavirenz plus two N(t)RTIs (ECHO - RR 0.95, 95%
CI:0.90, 1.00; THRIVE - RR 1.00, 95%CI 0.95, 1.05). In addition,
there was no statistically significant difference in the incidence
of any serious adverse events between rilpivirine plus two N(t)RTIs
and efavirenz plus two N(t)RTIs (ECHO - RR 0.74, 95% CI:0.44, 1.24;
THRIVE - RR 0.91, 95%CI 0.52, 1.59).
However, the rate of treatment-related adverse events was lower in
subjects treated with rilpivirine plus two N(t)RTIs (42.5% in ECHO
and 50.3% in THRIVE) than in subjects treated with efavirenz plus
two N(t)RTIs (62.2% in ECHO and 66.0% in THRIVE). Rilpivirine plus
two N(t)RTIs was statistically significantly associated with fewer
adverse events leading to discontinuation and fewer skin and
neurologic adverse events than efavirenz plus two N(t)RTIs across
both the ECHO and THRIVE trials.
The submission provided additional data on potential safety
concerns beyond those identified in the clinical trials. The
submission stated that the safety profile of Eviplera is likely to
be consistent with the safety profile of its component products and
that in general, treatment with two N(t)RTIs + rilpivirine was safe
and well-tolerated.
9. Clinical Claim
The submission described Eviplera as non-inferior in terms of
comparative effectiveness and superior in terms of comparative
safety over Atripla.
Based on the supporting data, the PBAC accepted the
submission’s claim that Eviplera is non-inferior in terms of
comparative effectiveness and superior in terms of comparative
safety over Atripla, with the caveat that treatment with
rilpivirine plus two N(t)RTIs is associated with more virological
failure and cross-resistance to other NNRTIs and N(t)RTIs than
efavirenz plus two N(t)RTIs.
10. Economic Analysis
The submission presented a cost-minimisation analysis.
Both the ECHO and THRIVE trials relied upon doses of 25 mg for
rilpivirine and 600 mg for efavirenz. In addition, the submission
presented evidence from an international Phase 2b randomised
dose-finding study of rilpivirine in treatment-naïve HIV-1
infected patients (Pozniak et al., 2010). Within this study, the
lowest assessed dose of rilpivirine (25 mg/day) demonstrated
sustained efficacy comparable with 600 mg of efavirenz and was
selected for further clinical development.
Based on this evidence, the PBAC considered that it is reasonable
to assume that 25 mg/day rilpivirine and 600 mg/day efavirenz are
equi-effective.
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients treated/year was estimated by the
submission to be less than 10,000 in Year 5. The estimate was
uncertain. The net financial cost to the PBS was estimated by the
submission to be between $10 and $30 million in Year 5. The
estimate was uncertain given the imprecision in the estimated
number of patients treated.
The net cost to the PBS in 2015 is estimated at less than $10
million where Eviplera is listed for treatment-naïve only
patients compared to an increased net cost though in the same range
if listed for all HIV-1 patients.
12. Recommendation and Reasons
The PBAC recommended listing of tenofovir disoproxil fumarate with emtricitabine and
rilpivirine hydrochloride (Eviplera®) in the Section 100 Highly Specialised Drugs (HSD) Program for the treatment of human
immunodeficiency virus (HIV) infection on a cost-minimisation basis compared with
the Atripla® (tenofovir disoproxil fumarate with emtricitabine and efavirenz). The doses of tenofovir
DF and emtricitabine included in Eviplera are identical to the doses of tenofovir
DF and emtricitabine. The PBAC considered the therapeutic relativity of Eviplera and
Atripla depended on the equi-effective doses of ripilvirine and efavirenz. The PBAC
considered the equi-effective doses to be 25 mg/day rilpivirine and 600 mg/day efavirenz.
The PBAC noted that the product meets the requirements of the Guidelines for the listing
of fixed combination products.
The PBAC noted that the TGA Delegate’s Summary had been received just prior to the
PBAC meeting and that the Delegate proposed to approve Eviplera for registration for
the treatment of HIV-1 infection in anti-retroviral treatment-naïve adult patients.
Therefore, the PBAC considered that that there was some uncertainty surrounding the
place of Eviplera therapy in practice as the data presented were from treatment naïve
patients only, but the requested restriction did not prevent patients using Eviplera
as a second line treatment. However, the PBAC was confident that prescribers treating
patients with HIV had the necessary expertise that would ensure the appropriate use
of Eviplera. Therefore, the PBAC considered that a restriction wording consistent
with that of the comparator Atripla (tenofovir with emtricitabine and efavirenz) was
appropriate.
However, the PBAC recommended amending the current restriction for both the triple
combination therapies, Eviplera and Atripla®, as highlighted by strikethrough above, for clarity. The PBAC considered that triple
therapy was unlikely to be used in combination with other anti-retrovirals and therefore
the wording “in combination with other antiretroviral agents” was redundant. It may
cause confusion as doctors may think they need to prescribe another agent as well
as the triple therapy agent to be eligible for PBS-subsidised treatment. This is also
consistent with the proposed TGA Delegate’s wording. The PBAC also requested the Secretariat
seek advice from the Australasian Society for HIV Medicine (ASHM) on the appropriateness
of this wording.
The PBAC accepted the fixed dose combination product tenofovir disoproxil fumarate
(DF) 300 mg with emtricitabine (200 mg) and efavirenz (600 mg) (Atripla®) is the appropriate comparator.
The submission presented a Phase 1, randomised, crossover bioequivalence trial (Study
103), and the PBAC considered that the pharmacokinetic results demonstrated that Eviplera
versus its individual components are within the pre-specified non-inferiority margin.
Therefore, bioequivalence can be accepted in healthy subjects without HIV infection.
For comparative efficacy, the submission presented two direct randomised comparative
trials, ECHO and THRIVE, comparing rilpivirine (25 mg) plus two non-nucleoside/tide
reverse transcriptase inhibitors (N(t)RTIs) and efavirenz (600 mg) plus two N(t)RTIs
in treatment naïve HIV patients. ECHO and THRIVE were both of 96 weeks duration of
treatment naïve patients only.
For the primary outcome of virologic response (plasma viral load < 50 HIV-1 RNA copies/mL)
at 48 weeks both rilpivirine and efavirenz (plus tenofovir DF with emtricitabine or
plus two N(t)RTIs) resulted in high virologic response rates (84.3% vs. 81.5%, meta-analysis).
As the lower limit of the 95% confidence interval was above -12% in both the ECHO
and THRIVE trials, the non-inferiority criteria were met (p<0.0001).
With regard to cross resistance, the PBAC noted of the patients with virologic failure
who were treated with rilpivirine plus two N(t)RTIs in the ECHO and THRIVE trials
51.3% and 47.6% were resistant to efavirenz. However, no patients with virologic failure
who were treated with efavirenz plus two N(t)RTIs were resistant to rilpivirine.
Based on the supporting data, the PBAC accepted the submission’s claim that Eviplera
is non-inferior in terms of comparative effectiveness and superior in terms of comparative
safety over Atripla, with the caveat that rilpivirine plus two N(t)RTIs is associated
with more virological failure and cross-resistance to other NNRTIs and N(t)RTIs than
efavirenz plus two N(t)RTIs.
The PBAC noted the advice of the Highly Specialised Drugs Working Party which supported
listing tenofovir with emtricitabine and rilpivirine as a HSD under Section 100.
Recommendation:
TENOFOVIR DISOPROXIL FUMARATE with EMTRICITABINE and RILPIVIRINE HYDROCHLORIDE, tablet,
300 mg-200 mg-25 mg
Restriction: Section 100 listing
Public Hospital Authority Required (STREAMLINED)
Private Hospital Authority Required
Initial treatment of HIV infection in combination with other antiretroviral agents in a patient with a CD4 count of less than 500 per cubic millimetre or symptomatic
HIV disease;
Continuing treatment of HIV infection in combination with other antiretroviral agents where the patient has previously received PBS-subsidised therapy of HIV infection.
Maximum qty: 60
Rpt: 5
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 list Eviplera (tenofovir DF/emtricitabine/rilpivirine hydrochloride) on the PBS for the treatment of patients with HIV infection.
