Raltegravir Potassium, tablet 400 mg (base), Isentress® - March 2010
Public Summary Document for Raltegravir Potassium, tablet 400 mg (base), Isentress® - March 2010
Page last updated: 02 July 2010
PDF printable version for RALTEGRAVIR POTASSIUM, tablet 400 mg (base), Isentress® (PDF 46 KB)
Public Summary Document
Product: RALTEGRAVIR POTASSIUM, tablet 400 mg
(base), Isentress®
Sponsor: Merck Sharp & Dohme (Australia) Pty
Ltd
Date of PBAC Consideration: March 2010
1. Purpose of Application:
The submission sought an extension to the current Section 100
(Highly Specialised Drugs Program) listing for the treatment
naïve patients with human immunodeficiency virus (HIV)
infection, 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.
2. Background:
This was the first time raltegravir had been considered by the PBAC
for use in treatment naïve patients with HIV infection.
3. Registration Status:
Raltegravir was TGA registered on 28 October 2008. Raltegravir is
currently registered for use in combination with other
antiretroviral agents, and is indicated for the treatment of human
immunodeficiency virus (HIV-1) infection in adult patients. This
indication is based on analyses of plasma HIV-1 RNA levels in
controlled studies of raltegravir. The use of other active
antiretroviral agents in combination with raltegravir is associated
with a greater likelihood of treatment response. There are no study
results demonstrating the effect of raltegravir on clinical
progression of HIV-1 infection.
4. Listing Requested and PBAC’s View:
SECTION 100 (HIGHLY SPECIALISED DRUGS PROGRAM)
Private hospital Authority required
Treatment, in combination with other antiretroviral agents, of HIV
infection in patients 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:
Raltegravir is an integrase strand transfer inhibitor (ISTI).
Raltegravir would provide an alternate treatment option for
treatment naïve patients with HIV infection.
6. Comparator:
The submission nominated the comparator as a mix of non-nucleoside
reverse transcriptase inhibitors (NNRTl’s) efavirenz and
nevirapine, and protease inhibitors (PIs) atazanavir, lopinavir and
darunavir (boosted with the PI ritonavir as a pharmacokinetic
enhancer). The PBAC considered that as efavirenz is the drug most
likely to be replaced in practice, the comparison of raltegravir
and efavirenz is the most important one.
7. Clinical trials
The submission presented two direct non-inferiority randomised
trials (STARTMRK and P004) comparing raltegravir and efavirenz; and
an indirect mixed treatment comparison (MCT) including three
nevirapine versus efavirenz trials, one atazanavir versus efavirenz
trial, two lopinavir/ritonavir versus efavirenz trials and one
darunavir versus lopinavir/ritonavir trial.
STARTMRK is a multicenter, double-blind, randomized,
active-controlled study which evaluated the safety and
antiretroviral activity of raltegravir versus efavirenz in
treatment naïve HIV-infected patients, each in combination
with tenofovir disoproxil fumarate with emtricitabine. P004 is a
multicenter, double-blind, randomized, dose-ranging study to
compare the safety and activity of raltegravir plus tenofovir and
lamivudine (3TC) versus efavirenz plus tenofovir and lamivudine
(3TC) in antiretroviral therapy (ART)- naïve HIV-infected
patients.
All trials were conducted in patients who were diagnosed with HIV
and were naïve to antiretroviral therapy. The drugs under
investigation in the trials were administered in combination with a
range of optimised background therapies (OBTs).
Both of the direct randomised trials had been published at the time
of submission.
Seven of the studies included in the indirect comparison published
at the time of submission are as follows:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Direct – raltegravir vs. efavirenz | ||
| Indirect – nevirapine vs. efavirenz | ||
| Indirect – atazanavir vs. efavirenz | ||
| Indirect – lopinavir/ritonavir vs. efavirenz | ||
| Indirect (2 nd degree) – darunavir vs. lopinavir/ritonavir | ||
| Lennox et al 2009 (STARTMRK) | Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. | Lennox JL, De Jesus E, et al. Lancet 374 (9692) pp796-806 |
| Markowitz et al 2006 (P004) | Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. | Markowitz M, Morales-Ramirez JO, et al Journal of Acquired Immune Deficiency Syndromes 43(5) pp 509-515 |
| Markowitz et al 2007 (P004) | Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: Results of a 48-week controlled study. | Markowitz M, Nguyen B-Y, et al. Journal of Acquired Immune Deficiency Syndromes 46(2): pp 125-133 |
| Gaytan JJA et al 2004 | Nevirapine or efavirenz in combination with two nucleoside analogues in HIV-infected antiretroviral-naive patients. | Gaytan JJA, Zapata de la Garza ER, et al, Medicina Interna de Mexico, 2004; 20: 24-33 |
| Nunez M et al 2002 | SENC trial: a randomized, open-label study in HIV-infected naive individuals. | Nunez M, Soriano V, et, al, HIV Clinical Trials 2002; 3: 186-94 |
| Van Leth F et al 2004 | Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. | Van Leth F, Phanuphak P et al, Lancet, 2004; 363: 1253-63 |
| Squires K, et al 2004 | Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. | Squires K, Lazzarin A et al, J Acq Immun Defic Synd 2004; 36: 1011-19 |
| Riddler SA et al 2008 | Class-sparing regimens for initial treatment of HIV-1 infection. | Riddler SA, Haubrich R et al, NEJM 2008; 358(20): 2095-2106 |
| Madero J et al, 2008 | A prospective, randomized, open label trial of efavirenz versus lopinavir/ritonavir based HAART among antiretroviral therapy naive HIV infected individuals presenting for care with CD4 cell counts <200mm3 in Mexico. | Madero J, Villasis A et al, AIDS 2008 XVII International AIDS Conference; 3-8 August 2008, Mexico City |
| 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. | Ortiz R, Dejesus E et al, AIDS 2008; 22(12): 1389-97 |
8. Results of trials
The comparison of the proportion of patients with HIV RNA less than
50 copies per mL at weeks 24, 48 and 96 in both the STARTMRK and
P004 trials showed raltegravir was numerically superior to
efavirenz on this outcome but the results did not reach statistical
significance. The submission based its assessment of
non-inferiority on the STARTMRK trial alone. At both weeks 48 and
96 the lower bound of the confidence interval was greater than
-12%, which satisfied the criteria for establishing non-inferiority
of raltegravir and efavirenz.
The submission provided individual trial results for the trials
comparing nevirapine, atazanavir, and lopinavir/ritonavir versus
efavirenz, and darunavir versus lopinavir/ritonavir. In the absence
of the necessary head to head trials against nevirapine and the
three PIs, the submission undertook a Mixed Treatment Comparison
(MTC) based on one or more common comparators. The MTC was a
Bayesian analysis using Markov chain Monte Carlo (MCMC)
methods.
The submission claimed that the results of the MTC suggested that
at week 48 there were statistically significant advantages for
raltegravir compared to atazanavir, lopinavir/ritonavir, nevirapine
and lopinavir/ritonavir plus efavirenz. However, the PBAC noted
that this statistically significant advantage for raltegravir over
nevirapine, atazanavir and lopinavir/ritonavir in the MTC did not
concur with the individual trial evidence presented by the
submission, which indicated no statistically significant
differences between nevirapine, atazanavir or lopinavir/ritonavir
and efavirenz.
The submission also provided results for ranking of treatment based
on the MTC. These indicated that raltegravir had an 86.5%
probability of being the best treatment at week 24 and a 70.7%
probability of being the best treatment at week 48. Efavirenz,
which the direct trial evidence indicated was non-inferior to
raltegravir, had a 12.5% probability of being the best treatment at
week 24 and a 2.7% chance at week 48. The submission claimed that
the MTC ranking results indicated a clear advantage for raltegravir
compared with all other drugs.
To test the stability of the MTC results, the analysis was rerun by
removing the Ortiz et al 2008 trial from the analysis, as darunavir
is not PBS listed for treatment naïve patients. (The Ortiz
trial constituted 689 treatment naïve patients randomised to
either darunavir/ritonavir or lopinavir/ritonavir). The revised
results comparing the results presented in the submission is shown
in the table below.
MTC – proportion of patients with HIV RNA less than
50 copies per mL at week 48
| Trial ID | MTC – fixed effects model | ||
|---|---|---|---|
| OR Median (95% CrI) | RD Median (95% CrI) | RR Median (95% CrI) | |
| Presented in the submission | |||
| RAL vs. ATZ | 1.81 (1.06, 3.08) | 0.11 (0.01, 0.23) | 1.15 (1.01, 1.38) |
| RAL vs. LPN/r | 1.86 (1.04, 3.36) | 0.11 (0.01, 0.24) | 1.16 (1.01, 1.42) |
| RAL vs. LPN/r + EFV | 2.79 (1.49, 5.28) | 0.21 (0.07, 0.36) | 1.34 (1.10, 1.78) |
| RAL vs. NVP | 1.74 (1.03, 2.95) | 0.10 (0.004, 0.21) | 1.14 (1.01, 1.35) |
| RAL vs. ATZ | 1.76 (1.02, 2.85) | 0.10 (0.00, 0.23) | 1.26 (1.00, 1.93) |
| RAL vs. LPN/r | 2.19 (1.24, 3.62) | 0.14 (0.02, 0.28) | 1.40 (1.02, 2.34) |
| RAL vs. NVP | 1.78 (1.03, 2.91) | 0.10 (0.00, 0.23) | 1.26 (1.00, 1.95) |
| RAL vs RAL | 1.00 | 0.00 | 1.00 |
| RAL vs EFV | 1.37 (0.89, 2.12) | 0.05 (-0.02, 0.14) | 1.07 (0.98, 1.21) |
| RAL vs. DRV | 1.25 (0.62, 2.51) | 0.04 (-0.07, 0.17) | 1.05 (0.92, 1.27) |
| Recalculateda | |||
| RAL vs RAL | 1.00 | 0.00 | 1.00 |
| RAL vs EFV | 1.35 (0.89,2.10) | 0.06 (-0.02, 0.16) | 1.13 (0.97, 1.54) |
| RAL vs. LPN/r + EFV | 1.52 (0.83, 2.58) | 0.07 (-0.03, 0.20) | 1.17 (0.94, 1.75) |
RAL = raltegravir; ATZ = atazanavir; EFV = efavirenz; LPN/r =
lopinavir + ritonavir; NVP = nevirapine; DRV = darunavir. Values in
bold are statistically significant.
a Includes exclusion of the Ortiz trial.
The PBAC noted that when the darunavir trial was removed from the
MTC, raltegravir no longer had a statistical advantage over
lopinavir/ritonavir plus efavirenz.
The PBAC noted that there is only limited experience to date of
using a MTC approach for the purpose of an initial decision to list
a drug on the PBS and that given that it is based on indirect
comparisons, the results were considered less reliable than those
of the head to head trials.
The PBAC noted the individual trial results for the trials
comparing nevirapine, atazanavir, and lopinavir/ritonavir versus
efavirenz, and darunavir versus lopinavir/ritonavir generally
supported the conclusion that there were no significant differences
between the other comparators and efavirenz. By inference, these
trial results would suggest that raltegravir is similar in efficacy
to all of the comparators, despite the results of the MTC
indicating that raltegravir is superior to atazanavir, nevirapine
and lopinavir/ritonavir.
The PBAC accepted that the results of the two direct
non-inferiority randomised trials comparing raltegravir and
efavirenz as part of first line anti-retroviral therapy indicate
that raltegravir is similar in efficacy to efavirenz; and that the
equi-effective doses are 800 mg raltegravir per day and 600 mg
efavirenz per day.
The sponsor advised that in the pivotal STARTMRK trial, the rate of
discontinuations due (only) to drug-related adverse experiences was
significantly lower in the raltegravir arm compared to the
efavirenz arm (RAL, n = 3 (1.1%) versus EFV, n = 12 (4.3%);
difference = -3.2% 95% CI (-6.4, -0.6), P=0.0189).
The TGA-approved Product Information states that the STARTMRK
clinical trial experience found that the numbers (%) of patients
with adverse experiences and with drug-related adverse experiences
in the group receiving raltegravir, were less frequent than in the
group receiving efavirenz. In the study, the rates of
discontinuation of therapy due to adverse experiences were 3.2% in
patients receiving raltegravir + emtricitabine (+) tenofovir and
6.4% in patients receiving efavirenz + emtricitabine (+) tenofovir.
Drug-related clinical adverse reactions of moderate to severe
intensity occurring in greater than or equal to 2% of
treatment-naïve adult patients in each of the STARTMRK
treatment groups included diarrhoea, nausea, fatigue, dizziness,
headache, insomnia, rash including maculo papular rash.
There were statistically significantly fewer CNS related AEs in
patients treated with raltegravir compared with those treated with
efavirenz. The submission used this difference in the modelled
evaluation and an analysis comparing the type, timing and severity
of these events was provided. Efavirenz was associated with the
occurrence of CNS related events including dizziness, sleep
disturbance, mood swings, impaired concentration which were
generally considered mild and short-term, beginning on the first or
second day of the therapy and which resolved within two to four
weeks.
The results of the MTC indicated significantly fewer
discontinuations due to all causes for raltegravir compared with
nevirapine and significantly fewer discontinuations due to adverse
events or lack of efficacy for raltegravir compared with
lopinavir/ritonavir. The discontinuation outcomes presented by the
submission for the MTC included discontinuation due to reasons
other than adverse events and it cannot be determined what
proportion of discontinuations were due to adverse events and what
proportion were due to other reasons. It was noted that the
differences identified by the analyses might not provide an
accurate picture of discontinuations due to adverse events and any
potential advantages associated with raltegravir for that outcome.
The PBAC noted that during the reporting period of the Periodic
Safety Update Report (PSUR) from September 2008 to March 2009,
safety-related updates were made to the drug interactions, side
effects and laboratory test findings sections of the Company Core
Data Sheet (CCDS) for raltegravir. The side effects section was
updated based on post-marketing surveillance with regard to
depression and suicidal ideation and behaviours. The PSUR stated
that depression, suicidal ideation and suicidal behaviours and
related events are to be monitored for three years following the
addition of this potential risk to the Risk Management Plan (RMP).
It appeared that additional potential risks had been associated
with raltegravir.
The submission claimed that the ranking of raltegravir as the best
treatment in terms of discontinuation for all causes and
discontinuations due to adverse events or lack of efficacy in the
MTC, was a main source of safety evidence. However, the
discontinuation outcomes presented by the submission allowed for
discontinuation due to other reasons than adverse events and as
such comparisons based on these outcomes did not directly address
comparative toxicity.
The PBAC did not accept that reduced incidence of CNS adverse
events were sufficient to support a claim of superiority in safety
for raltegravir over efavirenz or to support a cost-effectiveness
analysis. The PBAC noted that CNS toxicity with efavirenz is
generally mild and usually of relatively short duration, beginning
on the first or second day of the therapy and resolving within two
to four weeks and can be minimised by administration at
night.
9. Clinical Claim
The submission claimed raltegravir was non-inferior in terms of
efficacy and superior in terms of toxicity to efavirenz; and
superior in terms of efficacy and similar in terms of toxicity to
atazanavir, lopinavir/ritonavir and nevirapine.
The PBAC did not consider the claim of superior efficacy and
similar toxicity in comparison with nevirapine and the PIs to be
reasonable as the submission claim was based on indirect
comparisons, which are open to bias from a variety of sources. The
PBAC noted that the individual trial results generally indicated no
statistically significant differences between nevirapine,
atazanavir or lopinavir/ritonavir and efavirenz. Given the direct
trial evidence presented by the submission demonstrated
non-inferiority of raltegravir and efavirenz, it was anticipated
that an indirect comparison of raltegravir and other comparators
using efavirenz as the common comparator would suggest similar
efficacy between the drugs. Furthermore, the PBAC noted that it was
not clear on what evidence the claim of similar toxicity of
raltegravir to nevirapine, atazanavir and lopinavir/ritonavir was
based. The PBAC noted that the MTC assessed discontinuations due to
all causes and discontinuations due to adverse events or lack of
efficacy – and that neither of these analyses assessed
adverse events solely; therefore, discontinuations might be due to
other events.
10. Economic Analysis
The submission presented a stepped economic evaluation using a
cost-utility model.
The health outcomes used in the economic model were virologic
response (HIV RNA less than 50 copies per mL), CD4 cell count and
CNS related adverse events.
The PBAC considered the cost-utility analysis to be inappropriate,
given the direct trial evidence comparing raltegravir and efavirenz
demonstrates non-inferiority between the two drugs and the indirect
mixed treatment comparison does not conclusively demonstrate the
superiority of raltegravir to nevirapine, atazanavir or
lopinavir/ritonavir.
The PBAC noted a number of other issues raised in relation to the
economic model, including uncertainties about utility decrement
assigned to CNS events, the mortality rates and risk of AIDS
events, the assumption used in the model that the probability of
maintaining level of response across therapies beyond 96 weeks is
equal to the maintenance of response seen in the last 24 week
period of the trial and cost offsets.
Hence, the uncertainty in the model was reflected in the large
variation of the ICER from the base case of $10,000 to $50,000 per
year per quality adjusted life year (QALY) to $50,000 to $100,000
per QALY when the lower 95 % confidence limit of treatment effect
is used. The PBAC also considered that modelling across all lines
of therapy may not be appropriate, particularly as the treatment
algorithm for HIV is rapidly evolving.
11. Estimated PBS Usage and Financial Implications:
The submission estimated that the likely number of patients per
year was estimated to be less than 10,000 treatment-naïve
patients at listing date and in Year 5 and. The net financial cost
per year to the PBS was estimated to be up to less than $10 million
in Year 5.
Recommendation and Reasons:
The PBAC recommended the listing as a pharmaceutical benefit of
raltegravir as a section 100 (Highly Specialised Drugs Program) on
a cost minimisation basis compared with efavirenz. The
equi-effective doses are 800 mg raltegravir per day and 600 mg
efavirenz per day.
The PBAC accepted that the results of the two direct
non-inferiority randomised trials comparing raltegravir and
efavirenz as part of first line anti-retroviral therapy indicate
that raltegravir is similar in efficacy to efavirenz. However, the
PBAC did not accept that reduced incidence of CNS adverse events
were sufficient to support a claim of superiority in safety for
raltegravir over efavirenz or to support a cost-effectiveness
analysis. The PBAC noted that CNS toxicity with efavirenz is
generally mild and usually of relatively short duration, beginning
on the first or second day of the therapy and resolving within two
to four weeks and can be minimised by administration at
night.
The PBAC noted the individual trial results for the trials
comparing nevirapine, atazanavir, and lopinavir/ritonavir versus
efavirenz, and darunavir versus lopinavir/ritonavir generally
supported the conclusion that there were no significant differences
between the other comparators and efavirenz. By inference, these
trial results would suggest that raltegravir is similar in efficacy
to all of the comparators, despite the results of the Mixed
Treatment Comparison (MTC) indicating that raltegravir is superior
to atazanavir, nevirapine and lopinavir/ritonavir.
The PBAC noted that there is only limited experience to date of
using a MTC approach for the purpose of an initial decision to list
a drug on the PBS and that given that it is based on indirect
comparisons, the results were considered less reliable than those
of the head to head trials.
The PBAC considered the cost-utility analysis to be inappropriate,
given the direct trial evidence comparing raltegravir and efavirenz
demonstrates non-inferiority between the two drugs and the indirect
mixed treatment comparison does not conclusively demonstrate the
superiority of raltegravir to nevirapine, atazanavir or
lopinavir/ritonavir. Hence, the treatment effect modelled for
raltegravir relative to efavirenz likely overstates the incremental
effect and cost effectiveness of raltegravir. The uncertainty in
the model was reflected in the large variation of the ICER from the
base case in the range of $10,000 to $50,000 per year per quality
adjusted life year (QALY) to a range of $50,000 to $100,000 per
QALY when the lower 95 % confidence limit of treatment effect is
used. The PBAC also considered that modelling across all lines of
therapy may not be appropriate, particularly as the treatment
algorithm for HIV is rapidly evolving.
The PBAC agreed with a number of other issues raised in relation to
the economic model, including uncertainties about utility decrement
assigned to CNS events, the mortality rates and risk of AIDS
events, the assumption used in the model that the probability of
maintaining level of response across therapies beyond 96 weeks is
equal to the maintenance of response seen in the last 24 week
period of the trial and cost offsets.
The PBAC noted that the price requested was based on weighting
utilisation for first line therapy with current fourth line use,
which was reasonable but that the price for first line therapy
should be based on that for efavirenz and that the Drug Utilisation
Subcommittee (DUSC) of the PBAC should monitor utilisation once
listing eventuates. The PBAC also considered that the
Pharmaceutical Benefits Pricing Authority should review the price
following the DUSC review.
Recommendation:
RALTEGRAVIR POTASSIUM, tablet 400 mg (base)
Section 100 listing
(Highly Specialised Drug)
Private hospital authority required
Treatment, in combination with other antiretroviral agents, of HIV infection in patients with:
(a) CD4 cell counts of less than 500 per cubic millimetre; or(b) viral load of greater than 10,000 copies per mL.
Pack size: 60
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
Merck, Sharp & Dohme (Australia) Pty Ltd welcomes the PBAC decision to recommend raltegravir as an option for treatment naïve HIV patients. The Sponsor maintains that the use of an MTC is an appropriate way of assessing relative efficacy and safety of a drug versus multiple comparators in the absence of direct head to head trial evidence. The Sponsor stands by the MTC results as being consistent with the individual head to head trials.
