DARUNAVIR, tablet, 400 mg (as ethanolate), Prezista®, July 2010
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Public Summary Document
Product: DARUNAVIR, tablet, 400 mg (as
ethanolate), Prezista®
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
The submission requested a Section 100 (Highly Specialised Drugs Program) listing for the treatment in combination with other antiretroviral agents, and co-administered with 100 mg ritonavir once daily, of HIV infection in a protease inhibitor naïve patient with:
(a) evidence of HIV replication (viral load greater than 10,000 copies per mL); and/or
(b) CD4 cell counts of less than 500 per cubic millimetre.
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
This new strength and the extended therapeutic indication of
protease inhibitor-naïve HIV-1 patients had not previously
been considered by the PBAC.
3. Registration Status
Darunavir was first TGA registered on 15 March 2007 for the
treatment, in combination with other antiretroviral agents, of
HIV-1 infection in heavily pre-treated adults with evidence of
viral replication, who have HIV-1 strains resistant to multiple
protease inhibitors.
Its TGA registration was changed on 30 July 2009 to use (with low
dose ritonavir as a pharmacokinetic enhancer) in combination with
other antiretroviral agents for the treatment of human
immunodeficiency virus-1 (HIV) infection in adult patients.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drug Program)
Private Hospital Authority Required
Treatment, in combination with other antiretroviral agents, and co-administered with
100 mg ritonavir once daily, of HIV infection in a protease inhibitor naïve patient
with:
a) evidence of HIV replication (viral load greater than 10,000 copies per mL); and/or
b) CD4 cell counts of less than 500 per cubic millimetre.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Human immunodeficiency virus (HIV) infection is a chronic,
immunosuppressive infection characterised by continuous, high-level
viral replication and slow, progressive destruction of the human
immune system. Highly active antiretroviral therapy (HAART) has
reduced HIV-related morbidity and mortality, and increased the life
expectancy of HIV-infected individuals. HAART usually consists of
three to six different antiretroviral therapies (e.g.
nucleoside/nucleoside reverse transcriptase inhibitors,
non-nucleoside reverse transcriptase inhibitors and protease
inhibitors) and those which are restricted for use in salvage
patients (e.g. tipranavir and enfuvirtide).
Inclusion of darunavir 400 mg on the PBS would allow earlier access
to darunavir in a protease-inhibitor naïve patient who may be
infected with PI-resistant HIV virus or who is unsuitable for other
PIs.
6. Comparator
The submission nominated ritonavir boosted lopinavir (dosed at 800
mg/200 mg per day) as the comparator. The PBAC did not consider
ritonavir boosted lopinavir to be the appropriate comparator.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented one direct, multi-centre, open-label,
randomised, controlled trial of ritonavir boosted darunavir
(800/100 mg once daily) versus ritonavir boosted lopinavir (800/200
mg once daily) in treatment naïve patients with HIV infection
(ARTEMIS).
The key trial was published at the time of submission as
follows:
| Trial ID/First author | Protocol title/Publication title | Protocol title/Publication titlePublication citatio |
|---|---|---|
| ARTEMIS | ||
| Ortiz R et al (2008) | Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. | AIDS 2008: 22(12); 1389-97 |
| Mills A et al (2009) | Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-Week analysis. | AIDS (2009) 23:13; 1679-1688 |
| Cohen C. (2009) | The ARTEMIS trial: Once-daily darunavir/ritonavir in the management of treatment-naive, HIV-infected patients. | T Future HIV Therapy (2009) 3:2; 121-133 |
| Estrada V, Fuster M. (2008) | Darunavir in treatment-naïve patients. The ARTEMIS study. | Enfermedades Infecciosas y Microbiologia Clinica. 2008 Oct; 26 Suppl 10:10-3. Spanish |
8. Results of Trials
The primary outcome of the ARTEMIS trial was virologic response,
defined as a confirmed plasma viral load < 50 copies/mL at Week
48. The trial demonstrated non-inferiority of darunavir to
lopinavir against its pre-specified minimal difference of 12% in
viral load <50 copies/mL at 48 weeks.
At 96 weeks there was a significant difference favouring darunavir
in percentage of patients achieving a viral load of <50
copies/mL, a secondary outcome of the ARTEMIS trial. There were no
statistical differences in other secondary efficacy outcomes,
supporting the non-inferiority of darunavir to lopinavir.
For PBAC’s comments on these results, see Recommendation
and Reasons.
The comparative toxicity of darunavir and lopinavir mostly favoured
darunavir at 48 weeks but with no difference in adverse events at
96 weeks. Treatment with darunavir was associated with
significantly less episodes of diarrhoea. At both time points the
rates of Grade 3 and 4 adverse events were comparable between the
drugs with no occurrence of Grade 3 or 4 diarrhoea in either group
≥1%. No additional safety concerns were apparent for darunavir
over lopinavir.
9. Clinical Claim
The submission described darunavir as superior to lopinavir in
terms of efficacy, based upon the proportion of patients achieving
a viral load <50 copies/mL and superior in terms of safety and
tolerability.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost-minimisation analysis for ritonavir
boosted darunavir as compared with ritonavir boosted lopinavir. The
equi-effective doses were those administered in the ARTEMIS trial
(800/100 mg darunavir/ritonavir once daily and 800/200 mg
lopinavir/ritonavir once daily).
During the evaluation an additional analysis was conducted
comparing the cost of ritonavir boosted atazanavir to ritonavir
boosted darunavir.
The drug cost per patient per year estimated for ritonavir boosted
darunavir (800/100 mg once daily), ritonavir boosted lopinavir
(800/200 mg once daily), unboosted atazanavir (400 mg once daily)
and ritonavir boosted atazanavir (300/100 mg once daily) were all
less than $15,000.
Based on drug cost per patient per year, when ritonavir boosted
darunavir was compared with unboosted atazanavir, ritonavir boosted
darunavir was associated with cost savings to the PBS.
Alternatively, when ritonavir boosted darunavir was compared with
ritonavir boosted atazanavir there was a net cost to the PBS.
11. Estimated PBS Usage and Financial Implications
The net financial savings per year to the PBS were estimated by the submission to be less than $10 million
per year in the fifth year of listing. The submission’s estimate was uncertain as
it was derived from its uncertain forecast of patient numbers. A recalculated indicative
estimate undertaken during the evaluation which assumed an equal substitution of darunavir
for lopinavir, unboosted atazanavir and boosted atazanavir and gave a net cost of less than $10 million per year to the PBS in the fifth year. The evaluation considered
there was unlikely to be any use outside of the requested restriction.
12. Recommendation and Reasons
The PBAC agreed that the restriction wording suggested in the
submission is appropriate.
The PBAC did not agree with the submission’s nomination of
ritonavir boosted lopinavir (dosed at 800/200 mg daily) as the
appropriate comparator for ritonavir booster darunavir (dosed at
800/100 mg daily). Instead, the Committee considered ritonavir
boosted atazanavir (dosed at 300/100 mg daily) is the more
appropriate comparator for ritonavir boosted darunavir in treatment
naïve and protease inhibitor naïve patients, although
acknowledging that a proportion of the use of atazanavir in this
patient group will be unboosted (dosed at 400 mg daily), so that
using a weighted mix of boosted and unboosted atazanavir is the
most appropriate approach.
The Committee considered atazanavir to be the more appropriate
comparator because this is consistent with the most recent
treatment guidelines which nominate ritonavir boosted atazanavir
and ritonavir boosted darunavir as the preferred protease inhibitor
(PI) based regimens for treatment-naïve patients, with
ritonavir boosted lopinavir now listed as an alternative rather
than preferred regimen, except in pregnant women.
Additionally, the analysis of the Australian HIV Observation
Database (AHOD) data from 2006 onwards supports the use of
atazanavir as the comparator. Using data from 2006 and later,
atazanavir (not specified whether boosted or unboosted) accounts
for 22 (40%), lopinavir accounts for 16 (29%), and other PIs for 17
(31%) of the PI treatments in treatment naïve patients. AHOD
data also shows that the most commonly used PI for previously PI
naïve patients after 1 January 2006 was atazanavir at 53.3%
followed by boosted lopinavir at 35.6%.
The submission’s assertion that a significant proportion of
treatment naïve patients who received atazanavir are likely to
have received atazanavir unboosted (which was based upon the TGA
approved Product Information for atazanavir and the PBPA relativity
sheets), was not considered justified by PBAC as the most recent US
and Australian clinical guidelines recommend ritonavir boosted
atazanavir for this group of patients. Additionally, the current
PBS restriction for atazanavir does not restrict use to unboosted
atazanavir for naïve patients and boosted atazanavir for
treatment experienced patients. The Committee acknowledged that it
will be difficult to establish the exact proportions of use of
unboosted and boosted atazanavir in treatment naïve and PI
naïve patients for any future submission, but that this should
be justified using the best available evidence at the time.
The Committee noted the opinion of two clinical experts on the
issue of the appropriate comparator. The PBAC indicated it would
welcome the expert opinions of a wider sample of the
Australasian Society for HIV Medicine (ASHM) membership, if appropriate, in any future submission.
The Committee noted that the submission presented evidence from one
direct, multi-centre, open-label, randomised, controlled trial of
ritonavir boosted darunavir versus ritonavir boosted lopinavir in
treatment naïve patients with HIV infection (ARTEMIS). No
evidence from a direct or indirect comparison of atazanavir
(boosted or unboosted) with boosted darunavir was presented.
Although acknowledging that at the time the ARTEMIS study design
was developed, ritonavir boosted lopinavir was the appropriate
comparative treatment, this is no longer the case. In the absence
of data comparing the efficacy and safety of darunavir versus
atazanavir in treatment naïve and PI naïve patients, the
Committee was unable to form a view on the comparative
effectiveness and cost of these two treatments.
The PBAC therefore rejected the submission because of the
inappropriate choice of comparator and because there was no
clinical- or cost-effectiveness data provided to allow a comparison
against the appropriate comparator, atazanavir with or without
ritonavir.
The PBAC noted that the submission meets the criteria for an
independent review.
Recommendation:
Reject
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
Janssen-Cilag is committed to ongoing interaction with the PBAC
with a view to ensuring access to darunavir through the PBS for
patients with HIV.
