Regimen Selection to Support a “Public Health” Approach

Anthony Amoroso, MDAssistant Professor of Medicine

University of Maryland School of Medicine

Institute of Human Virology

Slide 2

Can a regimen be the cornerstone to support a public health approach?

Challenge: • Enable mid- and low-level providers to

deliver quality HIV treatment• to 100,000’s of patients • in community health clinics and dispensaries

Simplify clinical decision-making protocols centered on “four Ss”. 1. When to start2. When and what to substitute to3. When to switch for treatment failure4. When to stop

Gilks C, et al. Lancet Aug 5, 2006

Slide 3

Characteristics of an ideal public health regimen

Simple and convenient dosing

Durable and efficacious• Low rate of dose limiting toxicities • Predictable degree of viral suppression across different viral

populations

Superior safety profile • not exacerbated by prevalent co-morbidities, • avoids common drug-drug interactions.• easily diagnosable toxicities.

Predictable resistance pattern

• mutational pattern which simplifies switching therapy decisions• rational second line treatment options after clinical failure

Accessible pricing

Slide 4

Cost of Access

• Only $109,843,477 million spent directly on the purchase of ARV drugs within the 3rd year of PEPFAR (2006)

• ARV drug related costs are estimated to be less than 7% of total care, treatment and prevention package to 15 focus countries $1,601,986,513.

• “Drug costs are no longer the fundamental obstacle for treatment”

3rd OGAC to report to congress

Slide 5

Simple Dosing

• Durable viral suppression is absolutely linked to extraordinary tight adherence. • Lack of viral load monitoring amplifies the need

to ensure adherence.

• Availability of once a day therapy supports patients and adherence programs.

• 3TC and FTC • ABC, TDF, and DDI• EFV, NVP • Kaletra, Atazanavir, fosamprenavir• FTC/TNF, 3TC/ABC• FTC/TNF/EFV

Slide 6

Regimen Durability

• Intolerance and toxicities are the most common reasons for treatment failure and have important cost and safety ramifications : 1. Degree of complexity necessary for safe

and appropriate medication change. 2. Degree of complexity required for the

appropriate management of the side effects

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19Time

D4T/3TC/NVP or EFV AZT/3TC/NVP or EFV

TRUVADA/NVP or EFV

Uganda, Zambia and Kenya data combined

Medical Quality Assurance and Improvement AIDSRelief, 2006Continuation of using initial HAART regimen

N=349

N=331N=485

N= 1265

Slide 8

All Clinical Reasons for Therapy Switch

N (%)

Clinical Failure 240 (3.6)

Drug Interaction 324 (4.9)

Patient Preference 31 (0.4)

Poor Adherence 40 (0.6)

Pregnancy 94 (1.4)

Toxicity 1164 (17.5)Unlisted 495 (7.6)

Total 2388 (36.6)

Amoroso et al. 14th CROI. Los Angeles, 2007. Abstract 789

Causes of ART Switch1/08/2004 - 01/08/2006 : Kenya, Uganda, Zambia N=6520

Slide 9

Drugs Total Started Observed % SwitchedDue to Toxicity

Median time to toxicity (days)

D4T 2149 24.6% 141

AZT 1433 13.2% 81

TDF 2938 0.7% 58

NVP 4288 6.6% 83

EFV 3657 3.4% 119

LPV/r 622 2.0% 25

Amoroso et al. 14th CROI. Los Angeles, 2007. Abstract 789

Slide 10

SUMMARY Recent Abstracts

Country/study Date DrugObservedToxicity

S. Africa/MSF 2006 D4T

Neuropathy8.5% switch

Uganda/Forna 2006 D4T

Neuropathy31% / 8% grade 3-4

Kenya/Kim 2006 D4T 

Neuropathy23% / 3% grade 3-4

Rwanda/MSF 2006 D4T

Lipoatrophy 23%

Uganda/Zimbabwe/DART 2005 AZT

Anemia22% / 5.5% <6.5 Hb

S. Africa/MSF 2006 AZT

Anemia8.9% switch

Slide 11

Study 903 – Week 144 Patients (%) with Lipodystrophy†

Gallant et al. JAMA 2004

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TDF+3TC+EFVd4T+3TC+EFV

Week 48 Week 96 Week 144†Investigator-defined*p value < 0.001

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TDF+3TC+EFVd4T+3TC+EFV

Week 48 Week 96 Week 144†Investigator-defined*p value < 0.001

*

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Slide 12

TDF Attributable Toxicity N (%)

Renal Toxicity 3 (13.6)

Other/Not documented 19 (86.0)

Total 22

Slide 13

DART Trial: Toxicity Profile mismatch with targeted population

Anemia22.4% anemia by Wk 24

• 6.6% grade 4

Risk factors: • Female; • low baseline BMI; • low baseline Hb;

• low baseline CD4+;

(Ssali F, et al. Abstract 24)

Slide 14

Zidovudine and Severe AnemiaFinancial Implications at one hospital

• 15 consecutive cases of Hb <= 6.5 g/dl• Range 2.4-6.5, median 5.4

• 9 admissions• 14 units of blood transfused

• 3 deaths• 1 directly attributable to anemia

• Combined hospital bill = $1264 • Hospital left with $720 USD unpaid by

patients• 1.3% of 2004 hospital operating deficit

Slide 15

The Difficulty of Late Treatment Failure

• There are few specific treatment strategies which have clinical evidence once patients have clinically failed recommended 1st line regimens

• Broad cross-resistance among drugs within a class

Slide 16

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Example of virologic failure in relation to CD4 decline

Accumulation of mutations

Slide 17

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Example of in Subjects With Virologic Rebound on AZT/ABC/3TC

CNA3005

WT

50 c/mL

400 c/mL

28 weeks of M184V only

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3 3 4 411

1 1

0

M184V onlyM184V plus other mutations

Melby T, et al. 8th CROI, 2001: Abst. 448.

Stepwise Accumulation of Mutations

Slide 18

Resistance Patterns after Initial Failure of Common NRTI Backbones

AZT/3TC D4T/3TC

TIME TO DEVELOPMENT

M184V Multiple TAMS

ABC/3TC M184V

TDF/FTC M184V K65R

74V > K65R

19

Predicted NRTI activity based on median Predicted NRTI activity based on median phenotypes by genotype*phenotypes by genotype*

# Mutations RT genotype ZDV d4T ddI 3TC/FTC

ABC TDF

1 184V/I

65R

2 65R + 184V/I74V/I + 184V/I

41L + 184V/I

3 67N + 70R + 184V/I

215Y/F* +184V/I

4 67N + 70R +219E/Q + 184V/I

41L + 215Y/F* + 184V/I

5 41L + 210W + 215Y/F* + 184V/I

*215Y and 215F both require 2 mutations from wild type Resistant

SusceptibleLanier R, et al. 10th CROI, Boston 2003, #586

Partial

Slide 20

Rational Second Line Therapy

PhenoSense Results for K65R + M184V (n=58)

Above cutoffBelow cutoff

0

20

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% of viruses

ZDV TDF ABC ddI ddC 3TC

100% 90% 55% 42% 18% 3%

Miller et al. (2003) 43rd ICAAC, #H-904

AZT Remains Susceptible in K65R+M184V Viruses

Slide 21

Clinical and cost implications of first line therapies

AZT/D4T+3TC• Risk of accumulation of resistance mutations

over time • Switching patients at time of clinical failure will

limits second line options for many • Necessitate the use of viral load measurements for the

“four Ss” decision making process. • viral load measurements and genotype assays are costly

to set-up, train, quality assure, and provide logistical access to.

TDF+3TC/FTC• No additional “mutational costs” with allowing

patients to present with clinical failure as the indication for switch to second line.

• Eliminates the need for viral load measurements in most cases

22

Cost of maintaining 100 pts on 1st and 2nd line regimens

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Proportion on 1st vs 2nd line

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Combivir+EFV

Truvada+EFV

1st line NRTI

2nd lineLPV/r+ABC+TDF

2nd line

LPV/r+CBV

Slide 23

Good medical outcomes should drive treatment strategies

Strongly recommend implementing current WHO guidelines to move away from D4T (and AZT) which carry significant toxicities and complicate care delivery• Supports the accepted knowledge and

practice within the HIV treating community.

• Aligns 1st line treatment recommendations with guidelines in the U.S. and Europe• Ends the endorsement of substandard ART to

the poor of the world