COST-EFFICIENCY VERSUS POTENCYPROFESSOR ADRIAN STREINU-CERCELMD, PHD

2nd CEE MEETING on Viral Hepatitis and Co-infection with HIV6-7 OCTOBER 2016BUCHAREST ROMANIA

Efficiency in Health

Efficiency is a relationship of value:

How much output of value (health benefit) perinput of value (resource cost)

Focus on efficiency forces consideration of both sides of the value proposition:Benefits and costs

EFFICIENCY =

BENEFITSRESOURCE

COSTS

Efficiency, Quality and Cost

Efficiency, in terms of eliminating waste, is one dimension of quality in health care.

Quality, in terms of net benefits to health,is part of the equation for health efficiency.

Cost, in terms of resource costs, is theother part of the equation for efficiency.

Potency ≠ Efficacy ≠ Efficiency

Drug Potency HCV = drug`s capacity to suppress viral replication in the first 72h at undetectable level

Drug Efficacy HCV = drug`s capacity to clear the virus from infected cells

Factors explaining IFN-α and ribavirin treatment f il

The new DAA`s era of SVR

HCV is unique amongst viruses in that it is curable, with the goal of treatment being the attainment of SVR, resulting in the cessation of disease progression in approximately 99% of patients

Another problem: Cost-effectiveness of novel direct-acting antiviral; DAAs treatments in patients co-infected with hepatitis C and HIV

Compared to infection with chronic hepatitis C virus (HCV) alone, patients co-infected with human immunodeficiency virus (HIV) have an increased rate of disease progression, shorter survival, worse transplant outcomes and decreased treatment effectiveness

These newly available HCV treatments have shown a propensity to achieve high rates of sustained virologic response (SVR) also amongst HIV co-infected patients

Driving factors underlying liver disease pathogenesis in HCV-HIV co-infection.

The main differences of the viral response to treatment is “definitive clearance” for HCV

Talha Burki Elimination on the agenda for hepatitis CLancet Infect. Dis. 2014, 14, 542-543

HCV Cure Reduces All-Cause Mortality Long-term follow-up study of

530 pts with chronic HCV infection and advanced fibrosis or cirrhosis HCV treatment 1990-2003 Follow-up median 8.4 yrs

(IQR: 6.4-11.4) Main outcome: all-cause

mortality Secondary outcomes: liver

failure, HCC, liver-related mortality, transplantation

10-year cumulative incidence of all outcome measures decreased with SVR

van der Meer AJ, et al. JAMA. 2012;308:2584-2593.

10-Yr Cumulative Incidence

50

40

30

20

10

0

Perc

ent

SVRNo SVR

All-C

ause

M

orta

lity

Live

r-R

elat

edM

orta

lity

HC

C

8.9

26.0

1.9

27.4

5.1

21.8

Markov state transition model simulating the naturalhistory of hepatitis C.

Note. Transition probabilities derivedfrom recent population-based studies. F0-2, F3, and F4 represent METAVIR stages of hepatic fibrosis.

F3- and F4- treated states involve reduced risks of liver-relatedmorbidity and mortality compared with untreated states.

Economic and Public Health Impacts of Policies Restricting Access to Hepatitis C Treatment Alexis P. Chidi, PhD, MSPH, Cindy L. Bryce, PhD3V A L U E IN HE A L T H 1 9 ( 2 0 1 6 ) 3 2 6 – 3 3 4

75kPa

F4

9.0/11.0

PPV: 38–57%NPV: 98–99%

F3

8.1/8.4

PPV: 65–77%NPV: 84–95%

Cut-off points for liver stiffness in chronic hepatitis

F2

2.5

7.2

PPV*: 80%NPV†: 73%

Marcellin P et al., Liver Int. 2008; In press. Chan HLY et al., J Viral Hepat. 2008; In press

* PPV=positive predictive value† NPV=negative predictive value

Monitoring of disease progression, complications of cirrhosis using FibroScan

Oesophageal varices grade II/III

27

Ascites

49

HCC

54

Bleeding

63 kPa75

Foucher J, et al., Gut 2006;55:403-8.

711 patients with liver diseasesF3F4 144

Life Expectancy Gain at Various SVR According to Liver Fibrosis Stage

Zhou K, DDW, 2014, Su1035

• Model demonstrates greatest life expectancy benefit of treatment derived from treatment of younger patients with higher levels of fibrosis

• Older cohorts did not realize substantial improvement in life expectancy gain despite increases of SVR up to 90% when they had no fibrosis

F0 F4

0,0

0,5

1,0

1,5

2,0

2,5

3,0

50% 60% 70% 80% 90%0,0

2,0

4,0

6,0

8,0

10,0

12,0

50% 60% 70% 80% 90%

60M

65M

70M

60F75M65F70F80F80M75F

60F60M65F65M70F70M75F75M80F80M

LE G

aine

d (y

ears

)

LE G

aine

d (y

ears

)SVR (%)SVR (%)

Translating improvements of SVR into cure requires consideration of several factors

SVR

Fibrosis stage

Patient Factors

Access

Policy

OPTIMIST-2: SMV + SOF for 12 weeks in GT1 Naive/Experienced Patients With Cirrhosis

Lawitz E, et al. EASL-ILC 2015; Poster presentation LP04.

88 79

020406080

100

Treatment-naive

Treatment-experienced

44/50 42/53

83 7492 84

020406080

100

GT1a GT1a withQ80K

GT1a withoutQ80K

GT1b

60/72 35/3825/34 26/31

Prop

ortio

n of

pat

ient

s w

ith S

VR (%

)

68 87 7494 80 100

020406080

100

Platelets<90,000/mm

Platelets ≥90,000/mm

Albumin<4 g/dL

Albumin≥4 g/dL

Fibroscan score>20 kPa

Fibroscan score >12.5–≤20 kPa

13/19 73/84 39/53 47/50 12/15 11/11

Presence of Q80K influences response in patients with GT1aSVR12 rates <75% achieved in patients with a low platelet count or low albumin

levels

Factors That Influence HCV Treatment Decisions

Category Factors

Viral HCV GT Viral load

Treatment

HCV treatment history

– PegIFN + RBV– Protease

inhibitor

RBV eligibility Resistance

Fibrosis stage

Child-Pugh score If cirrhotic, any history of

decompensation? Transplant evaluation if necessary

Coinfection/comor HIV coinfection Cardiovascular renal metabolic etc

Preventing future costs at minimal costs … Patient with fibrosis>F3:

Calculate CTP Score Calculate MELD Score fibromax fibroscan Standard : Hem Biochemistry – including ionogram Coagulation Test

At NO COSTS!

Minimal Costs

Minimal Costs

Factors which influence viral load drop/cure of infected cells

Factors which cannot be modifiedHost geneticsDisease characteristics (extensive fibrosis,

cirrhosis)HCV Genotype

Factors which can be modified:DAAs potency (Phase I)Ribavirin +/-Lengths of treatment

Potency/ SVRTreatment

Phase I

InfectedCell cure

HC

V R

NA

leve

l

LLD

Target not detected

End of treatment Start

therapyW4

Phase II

Efficacy

Potency No resistance; EC50 >EC50WT

=

Viral drop- DAAs

NS5A NS5B NS3/4A NS5A NS5B NS3/4A

Daclatasvir N/A Asunaprevir Ombitasvir Dasabuvir Paritaprevir/rDuration 1 day 3 days Duration 3 days 2 days 3 days

Viral Drop -3.2 0 -3.3 Viral Drop -3.1 -1.5 -4.1

-6.5 -8.7

NS5A NS5B NS3/4A NS5A NS5B NS3/4ADaclatasvir Sofosbuvir N/A N/A Sofosbuvir Simeprevir

Duration 1 day 3 days Duration 3 days 7 daysViral Drop -3.2 -3.7 0 Viral Drop 0 -3.7 -4.1

-6.9 -7.8

NS5A NS5B NS3/4ASofosbuvir N/A Ledipasvir

Duration 3 days 3 daysViral Drop -3.7 0 -3.3

-7

General characteristics of different classes of DAAs

Efficacy Genotype dependency

Barrier to resistance

NS3/4A (protease inhibitors) +++ +++ ++

NS5A +++ +++ ++NS5B (nucleos(t)ides) +++ +++ +++

NS5B (nonnucleosides) ++ + +

DAA RAVs vs Fold change

Minimum Costs for HCV treatment, Diagnostics, Genotyping and Monitoring

$121

$242

$129 $193

$149

$298

$118

$56

$56

$56

$56 $56

$56

$56

$90

$90

$90

$90 $90

$90

$90

050

100150200250300350400450500 HCV Genotyping Diagnostic monitoring

Treatment

$275

$339$295

$444

$264

Pred

icte

d co

st, U

S$

$267

$388

Consequences of inaccurate hepatitis C virus genotyping on the costs of prescription of direct antiviral agents

The cost-effectiveness results show an overall increase in terms of efficacy due to the use of sequence analysis of HCV genotype along with a slight increase in terms of costs.The cost per unit of efficacy gained is difficult to interpret due to the lack of

S f C f

Treatment of chronic hepatitis C virus genotype 1 infection: comparison of health-economic outcomes for naïve patients

Range and mean values of treatment costs per SVR for non-cirrhotic patients

Range and mean values of treatment costs per SVR for cirrhotic patients

ISPOR 21st Annual International Meeting; 21-25 May 2016 W hi t DC USA

Best strategies for rapid SVR and costs reduction

We could compare two strategies for managing hepatitis C infection in

1) Current Practice – only patients with advanced fibrosis or cirrhosis are treated for hepatitis C. Before becoming eligible for treatment patients with early-stage disease are deferred until disease progression

and 2) Full Access – patients with early-stage disease, advanced fibrosis, and cirrhosis to be treated before becoming eligible

Strategies to Increase Efficiency

ACCESS

COSTQUALITY

EFFICIENCY

Issues and Challenges in Using Cost –Efficiency in Developing Clinical Guidelines

In thinking about clinical guidelines - important to recognize heterogenityamong patients: they differ !!

not only clinically

but in terms of their assessments of different health outcomes and their preferences for risk.

There is no single ICER that applies to all patients in a given clinical situation.

Expected effectiveness will vary among people even within a clinical subpopulation, and thus it may make sense for the physician to recommend different

treatment pathways for patients who appear to be clinically identical while still recognizing the importance of cost and the need for a range of appropriate care in any given clinical situation.

Cost-Effectiveness and Clinical Practice Guidelines: Have We Reached a Tipping Point?—An OverviewL i P G i J PhD*

Treatment availability

We assumed that all patients would be treated with one of two currently available interferon-free hepatitis C drug regimens:

A multidose three-drug combination of ombitasvir, paritaprevir, and ritonavir with dasabuvir (3D)

or A single-dose two-drug combination of

sofosbuvir/ledipasvir (SOF/ LDV)

Ledipasvir/Sofosbuvir for GT1 Tx-Naive Non-cirrhotics with HCV RNA < 6 M IU/mL:

Are 8 wks sufficient? Or are 12 wks better? Established by retrospective analysis of ION-3

Many clinicians were initially uncomfortable

What do “real-world” data show?

8 vs 12 Wks of LDV/SOF in Pts With GT1 HCV: HCV-TARGET and TRIO Network

Treatment-naïve, noncirrhotic pts with GT1 HCV HCV RNA < 6 M IU/mL in HCV-TARGET

1. Terrault N, et al. AASLD 2015. Abstract 94. 2. Curry M, et al. AASLD 2015. Abstract 1046.

251/263 604/632SV

R12

(%)

127/131 187/192

SVR

12 (%

)

n/N =

HCV-TARGET[1] TRIO Network[2]

100

8 Wks

97 97 95 96

8 Wks 8 Wks 12 Wks

80

604020

0

10080

604020

0

Romania SVR – W12 post-therapy

69/ 97%

0 2/ 3%

No of pts SVR12 = 71

ND<15 UI/ml<150 UI/ml

Source: INBIMB 2016

Incidence of AEs – week of therapy

138/ 82%

27/ 16%

2/ 1% 1,2

Total AEs W1-W12 = 169 Out of 550 pts

S2S4S10S12

Source: INBIMB 2016

Treatment for Hepatitis C VirusMoving Towards a Public Health Agenda

The characteristics of an ideal regimen include safety and universal efficacy: cure rate of ≥ 85% across all populations - including pregnancy and

nursing, in pediatrics and people with cirrhosis; HIV coinfection – and other common comorbidities Treatment must be:

Simple with minimal safety and efficacy monitoring and convenient – preferably one single tablet – easy to administer and

undergo

Data is needed on DAAs during pregnancy Pediatric studies are underway Despite gaps in knowledge and limitations of currently available DAAs,

they have many of the characteristics needed to address HCV globally

HCV All-Oral Regimens Currently and Soon to Be AvailableRegimen Component Classes Dosing Approved

Genotypes

Sofosbuvir + ribavirin

Nucleotide polymerase inhibitor + nucleoside

analogue

Sofosbuvir: 400 mg QDRibavirin: dosed

according to weight/GT1, 2, 3, 4

Sofosbuvir + simeprevir

Nucleotide polymerase inhibitor + protease

inhibitor

Simeprevir: 150 mg QDSofosbuvir: 400 mg QD 1, 4

Sofosbuvir/ ledipasvir

Nucleotide polymerase inhibitor + NS5A inhibitor

Sofosbuvir/ledipasvir: 400/90 mg QD 1, 4, 5, 6

Paritaprevir/RTV/ ombitasvir + dasabuvir

Protease inhibitor + NS5A inhibitor +

polymerase inhibitor

Paritaprevir/RTV/ombitasvir: 150/100/25 mg† QDDasabuvir: 250 mg BID

1

Sofosbuvir + daclatasvir

Nucleotide polymerase inhibitor + NS5A inhibitor

Sofosbuvir: 400 mg QDDaclatasvir: 60 mg QD 1, 3

Grazoprevir/elbasvir

Protease inhibitor + NS5A inhibitor

Grazoprevir/elbasvir: 100/50 mg QD 1, 4

Sofosbuvir/velpatasvir*

Nucleotide polymerase inhibitor + NS5A inhibitor

Sofosbuvir/velpatasvir: 400/100 mg QD NA: clinicaloptions.com

“Curing” HCV requires sometimes more than SVR

SVR is usually considered as “Cure” for HCVIt is time to go beyond this

Toward Improved Health Care

[Efficiency = Outcome per Cost] Value

[Quality and Safety] Performance

[Use and Non-Use] Practice

Standards [Guidelines]

Evidence [Clinical Research]

Opinion [Personal experience]Efficiency, Quality and Cost in Health Care Harvey V. Fineberg, M. D., Ph. D.

International Society for Pharmacoeconomics and Outcomes

Strategies to Increase Efficiency Enhance “value-based competition” for health

care

Payment for covered life, health condition, orepisode of illness rather than for units of service

Equitable distribution of high-risk group of patients

Universal coverage

Scaling up global HCV treatment access is challenging

Offers the opportunity to leverage the lesson learned from HIV, where research has been invaluable.

In HIV, prevention, treatment and testing programs were established years before effective treatment was available.

With HCV we have the cure – but lack an independent research agenda for DAAs and their implementation.

A coordinate plan to provide care and treatment while seeking to optimize it – and asses the impact of doing

During 2015, a majority of the risk-shares concerned hepatitis C treatments as well as cancer treatments

IHS - Life Sciences: Article Risk-Sharing DatabPUBLISHED: 26 JAN 2016

Conclusions

“Pay-per-cure” - the payment is made for the drugs only in cases where the patient achieves SVR

a good solution for health providers to mitigate their risks and answer to high prices of new therapies.

What we have to do

1. Affordable price for tailored treatmentsa. Lobby to:

governants politicians local authorities

b. R&D reimbursement to the pharma-industry for the innovative medicines

c. Special policy of the UE governance for innovative medicines

2. Special medical training for those involved in HCV cure program (including GPs)