Transcript A-Antinorix

Terapia antiretrovirale: coniugare efficienza
terapeutica e contenimento della spesa?
Andrea Antinori
INMI Lazzaro Spallanzani IRCCS, Roma
Simposio SIMIT
Sostenibilità delle cure complesse e aspetti gestionali in malattie infettive, 11 Novembre 2015
Andrea Antinori
Disclosure statement
•
Personal fees for consultancy and lectures from Abbvie,
Bristol Myers Squibb, Gilead, Janssen, Merck, ViiV.
•
Travel grants from Abbvie, ViiV.
•
Research grants from Bristol Myers Squibb, Gilead,
Janssen, ViiV.
START: 57% Reduced Risk of Serious Events or
Death With Immediate ART
Cumulative Percent With Event
• 4.1% vs 1.8% in deferred vs immediate arms experienced serious AIDS or non-AIDS–related event
or death (HR: 0.43; 95% CI: 0.30-0.62; P < .001)
10
8
Deferred ART
6
4
Immediate ART
2
0
0
6
12
18
24
30
Mo
36
42
48
54
60
INSIGHT START Group. N Engl J Med. 2015;[Epub ahead of print]. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
Expanding access to HAART is a cost effective
approach for treating and preventing HIV
Over 30 years, the HAART expansion scenario was associated with a net benefit of US$ 900 million (95% confidence interval
US$ 493 million to 1.45 billion).
Increasing the HAART treatment rate from 50 to 75% of clinically eligible individuals in British Columbia appears to be a costeffective strategy based on this model. These cost-effectiveness results are consistent with public health objectives: all
individuals who are eligible for an established life-saving treatment should receive it.
Johnston KM, et al. AIDS, 2010
DHHS 2015
Cost Considerations and Antiretroviral Therapy
(Last updated May 1, 2014; last reviewed May 1, 2014)
Potential Cost Containment Strategies from a Societal Perspective
Given resource constraints, it is important to maximize the use of resources without sacrificing
clinical outcomes.
Data suggest that continued CD4 monitoring yields no clinical benefit for patients whose viral loads are
suppressed and CD4 counts exceed 200 cells/mm3 after 48 weeks of therapy. A reduction in
laboratory use from biannual to annual CD4 monitoring could save ~$10 million per year in the United
States (see the Laboratory Monitoring section). Although this is a small proportion of the overall costs
associated with HIV care, such a strategy could reduce patients’ personal expenses if they have
deductibles for laboratory tests.
The present and future availability of generic formulations of certain ARV drugs, despite the potential
caveats of increased pill burden and reduced adherence, offers other money-saving possibilities on a
much greater scale. One analysis suggests the possibility of saving approximately $900 million
nationally in the first year of switching from a branded fixed-dose combination product to a three-pill
regimen containing generic efavirenz.
Reducing CD4 monitoring to once per year could result in
annual savings of $10.2 million. Decreasing CD4 frequency
could result in a population savings of $225.7 to $615.1
million over the lifetime of patients in care, depending on life
expectancy and CD4 test cost.
Cost-effectiveness analysis of 2015
GESIDA/Spanish AIDS National Plan
recommended guidelines for initial antiretroviral
therapy in HIV-infected adults
Of all the ART regimens recommended by GESIDA/PNS in their 2015 consensus paper as
preferred regimens for naive patients, ABC/3TC + DTG emerged as the least expensive
whether considering the ART cost alone or considering all the additional costs derived from the
decision of initiating treatment with an ART regimen and most efficient.
When taking into account recommended and alternative regimens, TDF/FTC/RPV turned out
to be the most efficient regimen in terms of cost/efficacy.
Considering all the regimens, 3TC + LPV/r, classified as “other” by the GESIDA/PNS
consensus group, was the least expensive, one of the most efficacious (88%of response rate)
and the most efficient (5,280 Euros in the base-case scenario).
Regimens including integrase inhibitors (DTG, RAL and EVG/c) present a high efficacy, but
these regimens are also less efficient due to their high cost.
Other low efficient regimens are ABC/3TC + ATV/r and ABC/3TC + LPV/r due to their low
efficacy.
The GESIDA/PNS panel stratified the recommended regimens in PR, AR and OR. Lack of
experience, pill burden and toxicity issues in real life may be among the reasons to qualify
LPV/r + 3TC as OR despite being the less costly and the most efficient.
Berenguer J, et al. EIMC, 2015
Registrational Treatment-Naive Clinical Trials:
Cross-Study Comparison
HIV RNA <50 c/mL at Week 48
90
90
FLAMINGO DTG (n=242)
GS-103 STB (n=353)
SINGLE DTG (n=414)
SPRING-2 DTG (n=411)
GS-102 STB (n=348)
GS-103 ATV+RTV (n=355)
STARTMRK RAL (n=281)
SPRING-2 RAL (n=411)
GS-102 Atripla (n=352)
ARTEMIS DRV+RTV (n=343)
ECHO/THRIVE RPV (n=550)
FLAMINGO ATV+RTV (n=242)
ECHO/THRIVE EFV (n=546)
STARTMRK EFV (n=282)
SINGLE Atripla (n=419)
GS 934 EFV (n=244)
88
88
88
87
86
85
84
84
83
83
82
82
81
80
78
78
77
76
76
76
ARTEMIS LPV/r (n=346)
CASTLE ATV+RTV (n=440)
ABT 730 LPV/r qd (n=333)
CASTLE LPV/r (n=443)
ABT 730 LPV/r bid (n=331)5
GS-903 EFV (n=299)
KLEAN FPV/r (n=434)
KLEAN LPV/r (n=444)
GS 934 EFV (n=243)
CNA 30024 EFV (n=324)
CNA 30024 EFV (n=325)
SOLO FPV/r (n=322)
MERIT ES MVC (n=311)
MERIT ES EFV (n=303)
SOLO NFV (n=327)
CNA 30021 EFV (n=386)
CNA 30021 EFV (n=384)
73
71
70
70
69
69
68
68
68
68
Third drug class
NNRTI
PI-PI/r
INSTI
CCR5-Inhib
66
0
10
20
30
40
50
60
% of Patients with HIV-1 RNA <50 copies/mL at Week 48
70
80
90
100
BHIVA and EACS 2015 Guidelines
Preferred and Recommended Regimens
London ARV algorithm: First line therapy
5
Patient requires ARV therapy for the first time:
Commence Kivexa + efavirenz where clinically appropriate
Efavirenz not suitable [1, 3]
Kivexa® not suitable [2, 3]
HIV resistance [4]?
HIV resistance?
No resistance:
Alternative first line options:
2 NRTI + raltegravir
If raltegravir not suitable, refer to
virtual clinic [3] and consider:
2 NRTI + atazanavir/ritonavir
2 NRTI + darunavir/ritonavir
Eviplera® [6]
Yes, refer to virtual clinic
[3] and consider:
Atazanavir/ritonavir or
Darunavir/ritonavir based
ART
If no resistance, alternative
first line backbone option if
appropriate:
Truvada®
If PI/r or Eviplera® are not suitable,
consider Stribild® [5, 7]
See NEXT slide for key
Incremental costs of adverse event (AE) per episode
compared with matched patients without an AE.
Of the 2548 NNRTI-treated patients, 29.3% experienced AEs.
The mean incremental cost per episode ranged from $1580 for rash to $2032 for lipid disorder, $8307 for sleep-related symptoms and $12 833 for
nausea/vomiting.
During the 12 months following NNRTI initiation, the mean annual total health care cost was $27 299 (efavirenz: $26 185; other NNRTIs: $34 993) and AEassociated costs were $608 (efavirenz: $554; other NNRTIs: $979) among all NNRTI users.
With treatment increasing patient survival, comparisons of therapeutic regimens should consider treatmentassociated AEs.
Simpson KN, et al. HIV Med, 2014
Budget impact analysis of antiretroviral less drug
regimen simplification in HIV-positive patients on the
Italian National Health Service
Scenario one
Each cycle, one-third of the patients in PI-based triple therapy addressed as eligible for PI-based monotherapy and PI-based dual therapy are moved to PI-based
monotherapy and PI-based dual therapy.
Scenario two
In the first cycle, all patients in PI-based triple therapy addressed as eligible for PI-based monotherapy and PI-based dual therapy are moved to PI-based monotherapy and
PI-based dual therapy.
Scenario three
Each cycle, one-third of the patients in PI-based triple therapy and on TDF/FTC + EFV or TDF/FTC/EFV addressed as eligible for PI-based monotherapy and PI-based dual
therapy are moved to PI-based monotherapy and PI-based dual therapy.
Scenario four
In the first cycle, all patients in PI-based triple therapy and on TDF/FTC + EFV or TDF/FTC/EFV addressed as eligible for PI-based monotherapy and PI-based dual therapy
are moved to PI-based monotherapy and PI-based dual therapy.
Restelli U, et al. Clinicoecon Outcomes Res, 2014
PROTEA: Virologic Response at Wk
48
Nadir CD4+ Count
< 200 cells/mm3
ITT: -8.7% (-1.8% to -15.5%)
94.9
86.1
80
60
40
20
n/N =
0
118/
137
129/
136
100
HIV-1 RNA < 50 c/mL (%)
HIV-1 RNA < 50 c/mL (%)
100
Nadir CD4+ Count
≥ 200 cells/mm3
96.7
94.8
94.3
29/
30
91/
96
100/
106
80
65.9
60
40
20
n/N =
0
27/
41
DRV/RTV
DRV/RTV +
DRV/RTV DRV/RTV + DRV/RTV DRV/RTV +
2 NRTIs
2 NRTIs
2 NRTIs
• No difference in efficacy between treatment arms in “switch included” analysis that classified pts with
viral suppression at Wk 48 after reintensification or second switch as virologic responders.
Antinori A, et al. Glasgow HIV 2014. Abstract O423A. Clarke A, et al. Glasgow HIV 2014. Abstract O423B;
Antinori A, et al. AIDS, 2015
Distribution of costs spent in an average
lifetime
Base case analysis and if patented drugs are replaced by
generic versions
Nakagawa F, et al. PLoS One, 2015
• Eligibility: either initiating ART on EFV-based
regimen, or on EFV/TDF/FTC ≥ 1 yr before
switch to multicomponent regimen; with no
known adherence problems
• Conclusion: in a well-organized healthcare
setting with free access to ART, switch from
EFV/TDF/FTC to multicomponent regimen
had no impact on virologic response
• Caveat: results may not be generalizable to
other populations or settings
Engsig FN, et al. J Acquir Immune Defic Syndr. 2014;66:407-413.
100
ART-Naive Pts Initiating
Therapy
80
60
40
20
0
-24 -12
0
12
24
36
48
Wks Before and After Inclusion Date
Pts at Risk, n
STR-TEE 47
TTR-TEL 22
Fraction With VL ≥ 50
(copies/mL)
• 467 pts on STR (EFV/TDF/FTC); 512 pt
switched to EFV+ TDF + 3TC
Fraction With VL ≥ 50
(copies/mL)
Switch From STR to Multicomponent Regimen After
Virologic Suppression
100
49
29
111
56
105
47
79
34
58
23
43
12
Pts on STR-TEE Who
Continued or Switched
80
60
40
20
0
-24 -12
0
12
24
36
48
Wks Before and After Inclusion Date
Pts at Risk, n
STR-TEE 351
TTR-TEL 510
353
511
356
512
349
504
343
478
329
422
274
322
Perception of Antiretroviral Generic Medicines
One-Day Survey of HIV-Infected Patients and Their Physicians in
France
Acceptability of antiretroviral generics in
this French population was mostly dictated
by the patient’s and physician’s knowledge
and use of generics overall.
It should be improved with an efficient
information of both patients and
physicians.
Jacomet C, et al. PLoS One, 2015
Cost-effectiveness of generic-based cART
Sensitivity analysis by failure rate and drug price reduction
Compared with a slightly less effective generic-based regimen, the cost-effectiveness of first-line branded ART exceeds
$100,000/QALY. Generic-based ART in the United States could yield substantial budgetary savings to HIV programs.
Compared with no ART, generic-based ART
has an ICER of $21 100/QALY.
Compared with generic-based ART, branded
ART increases lifetime costs by $42 500 and
per-person survival gains by 0.37 QALYs for
an ICER of $114 800 QALY.
Estimated first-year savings, if all eligible
U.S. patients start or switch to generic-based
ART, are $920 million.
Walensky RP, et al. Ann Intern Med, 2012
Impact of changes in treatment guidelines and introduction of
generic ARVs on projected average annual population costs
(million €)
Lazio region 2012-2016
Angeletti C, et al. HIV Med, 2014
Predicted savings to the UK NHS from switching to
generic antiretrovirals:2015-2019
• If all people with HIV infection in the UK switched
from patented to generic ARVs they become
available, there is the potential to save in the region
of £1.25 billion in NHS drug costs over the next 5
years (2015-2019).
• This switch in treatment would involve the average
treated person increasing their pill count from 2.3 to
3.5 pills per day.
• This money could be used to fund other much
needed HIV programmes, such as HIV prevention or
the treatment of HIV/HCV co-infection.
• The benefit of patented fixed dose combinations over
individual generic pills has not been proved in
randomised clinical trials, despite large differences in
costs.
Hill A, et al. HIV Drug Therapy, Glasgow, UK, 2014.Abst.#O216
Mean lifetime costs according with different
scenarios
Assuming that the current standards of care remain as they are, the mean lifetime healthcare cost of an MSM infected with HIV in
2013 at age 30 is estimated to be £360,800.
If 3,000 MSM had been infected in 2013 (but diagnosed in later years) and all were aged 30 years at infection then the future direct
lifetime costs relating to HIV care amounts to approximately £1.1 billion.
Nakagawa F, et al. PLoS One, 2015
GS-US-292-0109
Renal Safety Results
Tubular Proteinuria
UPCR
UACR
RBP:Cr
β-2-m:Cr
E/C/F/TAF
TDF-Based
Regimen
Each difference between treatment arms
was statistically significant (p <0.001).
•
•
Statistically significant improvements for participants who switched from either E/C/F/TDF or from boosted ATV + FTC/TDF

Serum creatinine (p <0.001); eGFR (p <0.001)

Fractional excretion of phosphate, FEPO4 (p=0.05); fractional excretion of uric acid, FEUA (p <0.001)
Changes began by Week 2 and persisted to Week 48
UPCR: urine protein: creatinine ratio; UACR: urine albumin: creatinine ratio; RBP, retinol-binding protein; β-2-m:Cr , beta-2 microglobulin.
Mills A, et al. IAS 2015. Vancouver, CA; #TUAB0102.
Use of newer antiretroviral agents can be costeffective
Substituting newer antiretroviral drugs increased expected survival by 3.9
years in advanced HIV disease.
The incremental cost-effectiveness ratio of newer, compared with
conventional, antiretroviral drugs was $75,556/QALY gained. Sensitivity
analyses showed that substituting only one newer ARV drug cost $54,559 to
$68,732/QALY, depending on assumptions about efficacy.
Sensitivity to virologic efficacy and intolerance of
newer antiretroviral therapy.
Sensitivity analysis of the odds ratio of achieving virologic
suppression under assumptions of high discontinuation (49%, equal
to conventional therapy, solid line) or low discontinuation (24.5%,
dashed line) of newer antiretroviral drug therapies.
Bayoumi AM, et al. J Acquir Immune Defic Syndr, 2013
New Highly Active Antiretroviral drugs and
generic drugs for the treatment of HIV
infection
A budget impact analysis on the Italian National Health Service
Restelli U, et al. BMC Infect Dis, 2015
The cumulative use of generic drugs and new
drugs would lead to annual savings of 4.6 million
€ (-0.6 %) in 2015; 16.9 million € (-2.1 %) in
2016; 19.4 million € (-2.4 %) in 2017; 51.1
million € (-6.1 %) in 2018 and -110.3 million € (12.8 %) in 2019.
The sensitivity analysis showed annual mean
savings for the Italian NHS ranging from 12.6
million € , -1.5 % compared to the base case
scenario (decreasing all the rates of transition
used in the simulation, and increasing the cost of
generic drugs) to 76.0 million € , -9.1 %
(increasing all the rates of transition used in the
simulation, and decreasing the cost of generic
and new drugs).
Conclusions: The use of antiretroviral generic
drugs may lead to savings that would
compensate the expenditure increase due to
new, innovative drugs available on the market.
Summary
• Early universal ART access could increase lifetime costs, despite a more
favourable cost-effectiveness
• Maximizing resources use without limitation of clinical outcome
• Cost-effectiveness of recommended ARV regimens for initial therapy can be
affected by ranking efficacy according with RCT results
• Incremental costs due to adverse events and cost efficacy of simplification
strategies should be implemented in farmacoeconomic models
• Replacing patented drugs by generic version could have a great impact over
saving costs, even though it could be affected by several bias (perception,
disruption, overweighting for improved efficacy and side effects)
• Compensation of innovative drugs approach by combining generic replacement
should be explored as cost-saving strategy