Darunavir, tablets, 150 mg and 300 mg (as ethanolate), Prezista®, November 2009
Public Summary Document for Darunavir, tablets, 150 mg and 300 mg (as ethanolate), Prezista®, November 2009
Page last updated: 05 March 2010
Public Summary Document
Product: Darunavir, tablets, 150 mg and 300 mg (as
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
The submission sought an extension to the current Section 100
(Highly Specialised Drugs Program) listing to include treatment, in
combination with other antiretrovirals, of human immunodeficiency
virus (HIV) infection in antiretroviral experienced patients who
have failed previous treatment with, or have resistance to, one
antiretroviral regimen, and who meet certain criteria.
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.
At the July 2007 meeting, the PBAC recommended a Section 100
(Highly Specialised Drugs Program) listing of darunavir for the
treatment of HIV infection in antiretroviral treatment experienced
patients who must have failed previous treatment with, or have
resistance to, three different antiretroviral regimens. This was on
the basis of a high but acceptable incremental cost-effectiveness
ratio compared with tipranavir. Full details are available in the
July 2007 Public Summary Document.
3. Registration Status
Darunavir was first TGA registered on 15 March 2007 and was
indicated for treatment of HIV-1 infection, in combination with
other antiretroviral agents, in heavily pre-treated adults with
evidence of viral replication, who have HIV-1 strains resistant to
multiple protease inhibitors.
On 30 July 2009, the TGA registration for darunavir was changed to use (with low dose ritonavir as a pharmacokinetic enhancer) in combination with other antiretroviral agents for the treatment of human immunodeficiency virus-1 infection in adult patients.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drugs Program)
Private hospital authority required
Treatment, in combination with other antiretroviral agents, and co-administered with
100 mg ritonavir twice daily, of HIV infection in an antiretroviral experienced 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.
A patient must have failed previous treatment with, or have resistance to, 1 antiretroviral regimen.
The PBAC had no objection to the requested wording of the restriction.
5. Clinical Place for the Proposed Therapy
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 combinations of different
antiretroviral therapies (e.g. nucleoside/nucleotide reverse
transcriptase inhibitors, non-nucleoside reverse transcriptase
inhibitors and protease inhibitors).
The change to the current PBS listing for darunavir would allow its use earlier in the clinical management of HIV-1 infection, after failure or resistance to one antiretroviral regimen.
The submission nominated lopinavir with ritonavir as the main
comparator. This was considered appropriate by the PBAC.
7. Clinical Trials
The submission presented one randomised trial (TITAN) comparing
darunavir 600 mg/ritonavir 100mg bd (twice daily) added to
optimised background regimen with lopinavir 400 mg/ritonavir 100 mg
bd added to optimised background regimen in patients with HIV that
are both early treatment (prior treatment with ≤1 protease
inhibitor) and treatment experienced (prior treatment with ≥ 2
The ITT results of the TITAN study were not directly applicable to the extension of listing sought, and the submission presented a post-hoc sub-group analysis from the TITAN study of the ITT results of patients that have previously been treated with ≤ 1 protease inhibitor (PI) as more representative of the extension to listing being sought, as well as a post-hoc subgroup analysis of highly treatment experienced patients (≥ 2 PIs).
Details of the published studies presented in the submission are in the table below.
|Trial ID / First author||Protocol title / Publication title||Publication citation|
|Madruga JV et al||Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial.||Lancet 2007: 370(9581); 49-58.|
|De Meyer S et al||Influence of baseline protease inhibitor resistance on the efficacy of darunavir/ritonavir or lopinavir/ritonavir in the TITAN trial.||J Acquir Immune Defic Syndr 2008: 49(5); 563-573|
|Bánhegyi D et al||Phase III TITAN Week 96 final analysis: efficacy/safety of darunavir/ritonavir versus lopinavir/ritonavir in lopinavir/ritonavir-naïve, treatment-experienced patients||Poster P22, 9th International Congress on HIV and Drug Therapy in HIV Infection, Glasgow, UK, 9–13 November 2008|
|De Meyer S et al||Resistance development in virological failures with DRV/r or LPV/r: 96-week analysis of the Phase III TITAN trial in treatment-experienced patients||Oral Presentation, 9th International Congress on HIV and Drug Therapy in HIV Infection, Glasgow, UK, 9–13 November 2008|
8. Results of Trials
The published results of the TITAN trial are summarised in the
Primary Outcome - Virological Response < 400copies/mL
Primary outcome - proportion of patients with virological response < 400 copies/mL in TITAN
|Darunavir/ rtv||Lopinavir/ rtv|
|Week 48 N (%)||228 (76.5)||199 (67.0)|
|Relative Risk (95% CI)||1.14 (1.03, 1.26)|
|Absolute Risk Difference (95% CI)||9.5 (2.3, 16.7)|
|Week 96 N (%)||199 (66.8)||175 (58.9)|
|Relative Risk (95% CI)||1.13 (1.001, 1.283)|
|Absolute Risk Difference (95% CI)||7.9 (0.1, 15.6)|
OBR=optimised background regimen rtv = ritonavir
The PBAC noted at 48 weeks and 96 weeks for both the ITT population and highly treatment experienced patient group (≥2 prior PIs), the relative risk and absolute risk difference in the proportion of patients with virological response <400 copies/mL were statistically significantly in favour of the darunavir/rtv arm. The results in the early treatment patients who had received ≤1 prior PI were not statistically significantly different at week 48 or week 96.
Secondary Outcome - Virological Response <50
Secondary outcome - proportion of patients with virological response <50 copies/mL in TITAN
|Week 48 N (%)||211 (70.8)||179 (60.3)|
|Relative Risk (95% CI)||1.17 (1.04, 1.32)|
|Absolute Risk Difference (95% CI)||10.5 (2.9, 18.1)|
|Week 96 N (%)||180 (60.4)||164 (55.2)|
|Relative Risk (95% CI)||1.09 (0.95, 1.26)|
|Absolute Risk Difference (95% CI)||5.2 (-2.8, 13.1)|
The ITT results from TITAN showed that the darunavir/rtv was superior to lopinavir/rtv at Week 48 for the secondary outcome of virological response defined as viral load < 50 Copies/mL. This superiority was not maintained at Week 96 and the submission described the two drugs as being not different at Week 96. The point estimate for the proportion of patients achieving a virological response measured by < 50 copies per mL remains higher with darunavir/rtv treatment than lopinavir/rtv treatment until just after week 48. For the post hoc sub groups by prior PI treatment darunavir/rtv was superior to lopinavir/rtv in the heavily pre-treated patients (treated with ≥2 prior PIs) at both time points, Week 48 and 96. Darunavir/rtv was not different to lopinavir/rtv in the early treatment experienced patients (treated with ≤1 prior PIs) at Week 48; and Week 96.
The number of virological failures by week 96 was lower in the darunavir/rtv ITT population (41/298 – 13.8%) than the lopinavir/rtv group (76/297 – 25.6%). Proportionally fewer virological failures in the darunavir/rtv arm developed mutations than in the lopinavir/rtv arm.
Fewer virological failures treated with darunavir/rtv than with lopinavir/rtv treatment lost susceptibility to other PIs.
However, no data were provided about the efficacy of lopinavir after a patient has been treated with darunavir. The PBAC considered the movement of darunavir towards earlier treatment could impact on the overall cost and outcomes of the treatment of HIV.
For the purpose of cost-minimisation the submission assumed that there was no difference in adverse events between darunavir/rtv and lopinavir/rtv, except for the incidence and prevalence of diarrhoea.
Summary of Incidence of key AEs in TITAN (Regardless of Severity and Causality >5% incidence)
|TMC114-C214 (TITAN)||48 Weeks||96 Weeks|
|Darunavir/rtv 600/100mg bd + OBR||Lopinavir/rtv 400/100mg bd + OBR||Risk Difference (95% CI)||Darunavir/rtv 600/100mg bd + OBR||Lopinavir/rtv 400/100mg bd + OBR||Risk Difference (95%CI)|
|Any AE n (%)||277 (93.0)||273 (91.9)||1.0(-3.2,5)||281 (94.3)||281 (94.6)||-0.3(-4.0, 3.4)|
|Gastrointestinal Disorders n (%)||176 (59.1)||177 (59.6)||-0.5 (-8.4, 7.4)||192 (64.4)||190 (64.0)||0.5 (-7.2, 8.2)|
|Diarrhoea||95 (31.9)||124 (41.8)||-9.9(-17.6,-2.2)||105 (35.2)||138 (46.5)||-11.2(-19.1,-3.4)|
|Nausea||55 (18.5)||62 (20.9)||-2.4 (-8.8, 4.0)||58 (19.5)||65 (21.9)||-2.4 (-8.9, 4.1)|
|Abdominal pain||29 (9.7)||21 (7.1)||2.7 (-1.8, 7.1)||35 (11.7)||24 (8.1)||3.7 (-1.1, 8.5)|
|Vomiting||26 (8.7)||21 (7.1)||1.7 (-2.7, 6.0)||31 (10.4)||23 (7.7)||2.7 (-2.0, 7.3)|
|Nervous System Disorders n (%)||82 (27.5)||50 (16.8)||10.7(4.1,173)||93 (31.2)||60 (20.2)||11.0(4.0,18.0)|
|Headache||33 (11.1)||22 (7.4)||3.7 (-1.0, 8.3)||36 (12.1)||26 (8.8)||3.3 (-1.6, 8.2)|
|Dizziness||14 (4.7)||10 (3.4)||1.3 (-2.2, 4.8)||17 (5.7)||13 (4.4)||1.3 (-2.1, 4.8)|
|Skin & Subcutaneous Tissue Disorders n (%)||94 (31.5)||72 (24.2)||7.3(0.1,14.5)||105 (35.2)||86 (29.0)||6.3 (-1.2, 13.8)|
|Rash||19 (6.4)||12 (4.0)||1.3 (-2.1, 4.7)||22 (7.4)||15 (5.1)||2.3 (-1.5, 6.2)|
|Pruritus||7 (2.3)||17 (5.7)||-3.4(-6.5,-0.2)||8 (2.7)||17 (5.7)||-3.0 (-6.3, 0.2)|
9. Clinical Claim
The submission claimed that darunavir is at least non-inferior to
lopinavir with superior tolerability and no additional toxicity for
the population for whom the extended PBS listing was
For PBAC’s view, see Recommendation and Reasons.
10. Economic Analysis
The submission presented a cost-minimisation analysis. The
equi-effective doses were darunavir 600 mg/ritonavir 100 mg twice
daily and lopinavir 400 mg/ritonavir 100 mg twice daily.
11. Estimated PBS Usage and Financial Implications
The estimated number of patients per year was less than 10,000 in
Year 5, with estimated cost savings per year to the PBS of less
than $10 million in Year 5.
The PBAC considered the submission’s estimates to be uncertain due to the uncertainty associated with the estimate of the uptake rate of darunavir in early treatment experienced patients.
12. Recommendation and Reasons
The PBAC recommended that darunavir co-administered with ritonavir
be listed for the treatment in combination with other
antiretroviral agents for patients who have failed previous
treatment with, or have resistance to, one antiretroviral treatment
regimen, on a cost minimisation basis compared with lopinavir with
The PBAC considered that the presentation of a post-hoc sub-group analysis from the TITAN study of the ITT results of patients that have previously been treated with ≤1 protease inhibitor (PI) was most representative of the extension to listing being sought. The Committee noted the results in this early treatment experienced patient (ETEP) group was not statistically significantly different at week 48 or week 96 for the primary outcome of proportion of patients with virological response < 400 copies per mL. With respect to virological response defined as viral load, the point estimate for the proportion of patients achieving a response remains higher with darunavir/ritonavir treatment that with lopinavir/ritonavir treatment until approximately week 48. For the secondary outcome, virological response < 50 copies per mL, the ITT results from TITAN show for the early treatment group show that darunavir/ ritonavir was not different to lopinavir/ritonavir at week 48, and week 96.
The number of virological failures (ITT) by week 96 was lower in the darunavir/ ritonavir population that in the lopinavir/ritonavir group (13.8% compared with 25.6%). Fewer virological failures treated with darunavir/ritonavir than with lopinavir/ritonavir lost susceptibility to other PIs. No separate data were available for the ETEP group.
The PBAC noted that the submission claimed that in the TITAN study “the only consistent and clinically meaningful difference at both week 48 and week 96 was diarrhoea” which favours darunavir. However, the Committee noted the data also showed significant differences in toxicity in favour of lopinavir for nervous systems disorders (at weeks 48 and 96) and overall skin and subcutaneous tissue disorders (at week 48 only).
The PBAC concluded that for effectiveness darunavir/ritonavir was non-inferior to lopinavir/ritonavir, and that, while the toxicity profiles were different, the overall impact in terms of cost of management would be similar.
There was uncertainty associated with the place of darunavir in the early treatment of HIV. Advice from expert clinicians confirmed that the clinical algorithm for early treatment HIV is rapidly evolving, and factors such as the availability of resistance testing, new drug classes, new formulations and pill burden would all impact treatment choice.
DARUNAVIR, tablets, 150 and 300 mg (as ethanolate).
Amend the current restriction to read as follows:
Restriction: Section 100 (Highly Specialised Drugs Program)
Private hospital authority required
Treatment, in combination with other antiretroviral agents, and co-administered with 100 mg ritonavir twice daily, of HIV infection in an antiretroviral experienced 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. A patient must have failed previous treatment with, or have resistance to, 1 antiretroviral regimen.
Pack size: 120 (300 mg), 240 (150 mg)
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 welcomes this decision by the PBAC to provide earlier
access to darunavir for Australians living with HIV/AIDS.