ARV THERAPY IN 2009:Successes and Challenges

Pedro Cahn

5th IAS CONFERENCE ON PATHOGENESIS, TREATMENT AND BIOMEDICAL PREVENTION

CAPE TOWN, 2009

Thank you for your input• Quarraisha Abdool-

Karim• Andrew Beelen• Andrew Cheng• Andrew Clark• Alexandra Calmy • Joe Eron• Nathan Ford• Jose Gattell• Diana Gibb• Scott Hammer• Charles Hicks• Martin Hirsch• Jeff Jacobs• Alejandro Krolewiecki

• Michel Kazatchkine• N Kumarasamy• Louise Martin-Carpenter• Julio Montaner• Peter Reiss• Doug Richman• Mauro Schechter• Chip Schooley• Hernan Valdez• Marco Vitoria• Robin Wood• Bach-Yen Nguyen• Patrick Yeni

Successes and Challenges

• At the individual level

• At the Public Health level

• When to start

• Safety of 1st line and monitoring : Two standards of care?

• New data on existing drugs and new drugs and classes, new strategies

• The Public health approach in 2009

FACTS• HAART reduces VL by 6 orders of magnitude

• VL reduction drives to immune recovery

• Immune recovery reduces morbidity, need for hospitalization and mortality due to AIDS

• HAART impacts on “non-AIDS”associated mortality

• HAART save lives, with impact at individual and population level

• HAART impacts on vertical and sexual transmission

• Mathematical models show possibility of dramatic reduction on incidence, driving to potential control of the epidemic

 

0

5

10

15

20

25

30

35

1999 2000 2001 2002 2003 2004

%

Non HIV associated

TB

Causes of Death According to Death Certificates, Brazil 1999-2004Pacheco, 2008

69

15

24

35

47

65 66

81

91

58

64 65

58 5860

51

4340

28

0102030405060708090100 ARGENTINA:AIDS INCIDENCE RATE per million

IAS July 2009

SurvivalSurvival

0.90

0.87

0.08

0.92

0.90

0.18

0.95

0.94

0.55

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion

aliv

e

Years from enrolment

Entebbe Cohort(Uganda):pre-ART 1996-2000, median CD4 75 at enrolment:57.7/100 PY

164 eventsLCM: 2.2/100 PYCDM: 2.9/100 PY

218 events

About 26 fold reduction in mortality

When to start ART

NA cohort1

• In theoretical model, deferred ART and older age (per 10 years) 60% higher risk of all-cause mortality

• History of IDU and HCV were independent risk factors for mortality

ART cohort collaboration2

• Delaying ART in patients with CD4+ <250 cells/mm3 and <350 cells/mm3 associated with risk of AIDS and death

• For CD4+ ≥350 cells/mm3, differences in absolute risks were small

1. Kitahata M, et al. 16th CROI, Montreal 2009, #71; 2. Sterne J, et al. ibid, #72LB

Cumulative mortality estimates1

Calculated using extended Kaplan-Meier survival estimates

0

0.10

0.05

0

0.20

0.15

2 4 6 8 10Years after 1996

CD4+ >500 & initiate ART(n=2,616)

CD4+ >500 & defer ART(n=6,539)

Mortality hazard ratios, adjusted for lead times and unseen events2

4

500

1

0.5

2

400 300 0CD4+ threshold (cells/mm3)

Mo

rtal

ity

haz

ard

rat

io

200 100

Risk of opportunistic disease or death by latest CD4 count (ESPRIT/SILCAAT pooled data)

Latest CD4

cells/mm3

IL-2 No IL-2 Risk Ratio for

IL-2: No IL-2

Events PY Rate* Events PY Rate*

< 200 81 1437 5.64 109 1746 6.24 0.90

200-349 59 3286 1.80 73 4207 1.74 1.03

350-499 52 3983 1.31 50 5299 0.94 1.38

500-699 38 4426 0.86 33 4701 0.70 1.22

700 37 6525 0.57 16 3252 0.49 1.15

* Per 100 person-years

Babiker: 5th IAS

“… the DSMB found overwhelming evidence that

starting ART at CD4 counts between 200-350

cells/mm3 improves survival compared with

deferring treatment until CD4 cells drop <200

cells/mm3. Mortality in the standard-of-care group

was four times higher. Among participants without

baseline TB infection, twice as much developed TB

in the deferred group. Many resource-limited

countries have standards for HIV treatment similar

to Haiti so the results of could be applicable

elsewhere.”

CIPRA HT 001

Pape J: Unpublished data, reported by NIAID, June 8, 2009

Mortality During First Year of HAART in Latin America & Caribbean (CCASANet)

Death rates vary widely among Latin American, Caribbean countries• Probability of death higher in Haiti, Honduras, and Peru*

*Adjusting for BL CD4+ cell count at HAART initiation decreased probability of death, but rate remained higher in Haiti and Honduras.

Tuboi SH: J Acquir Immune Defic Syndr. 2009 May 6

0.00

0.02

0.04

0.06

0.08

0.10

0 3 6 12Months

Pro

bab

ility

of

Dea

th 0.12

9

0.14

Argentina (n = 794)

Brazil (n = 522)Chile (n = 547)

Haiti (n = 1672)Honduras (n = 329)

Mexico (n = 416)

Peru (n = 873)Overall (n = 5152)

Initiation of HAART at Higher CD4 Cell Counts IsAssociated With a Lower Frequency of Antiretroviral

Drug Resistance Mutations at Virologic Failure

Uy: J Acquir Immune Defic Syndr , 2009;51:450–453

Goals of HAART: A story of three eras

1996-2001: To reduce the incidence of opportunistic infections and AIDS-related deaths by stopping and reversing immunologic failure

2002-2007: To avoid emergence of resistance mutations by keeping viral load below 50 copies/mL at all stages

2008-…..: To reduce non-AIDS morbidity and mortality and HIV transmission

FACTS ON ARV ROLLOUT

• About 4 million people on ART

• About 6 million still in need (with current WHO guidelines)

• Western guidelines call for earlier start

• Current guidelines for LMIC still calling for relatively late start. Last update circa 3 years ago.

HIV Testing Rates and Outcomes in a South AfricanCommunity, 2001–2006: Implications for Expanded

Screening Policies

April M: J Acquir Immune Defic Syndr 2009;51:310–316

*Eligibility by current guidelines

*

Limitations and obstacles: Lost to follow-up

• Over 20% LTFU in LMIC1

• Main reasons: Advanced disease and payment for services2

• Poverty and logistics3 : ART interruption driven by stock shortages (OR 3.25), binge drinking (2.87), slimming symptoms (1.23). Conclusion: “Food supply programs and minimization of ARV shortage may reduce ART interruptions”

• Hidden costs in health care delivery might jeopardize success of “free services”4 Over 50% of the delivery costs in rural Tanzania was for transport.

1 Bull World Health Organ 2008

2. Morris K:www.thelancet.com/infection; 2008

3. Marcellin F: Tropical Medicine and Int. Health, 2008

4. Kruk M: Tropical Medicine and Int. Health, 2008

First-Line regimens in low resource settingsFirst-Line regimens in low resource settings

Challenges: The need for a safer start

• d4T based regimens: Issues with toxicity, and

lipoatrophy affect adherence and discourages

naïve patients to enter treatment programs

• Updated guidelines will recommend earlier

start, Nevirapine may not be safe with higher

CD4 counts

• d4T may select K65R in Clade C viruses

Global distribution of HIV-1 subtypes

1.3 million1.3 million

4.8 million4.8 million

2 million2 million

B 10%B 10%

A 12%

A 12%

URF 4.2%URF 4.2%

AG

6.7%

AG

6.7%

AE 3.1%AE 3.1%

G 5%G 5%

DD 3.6%3.6%

0 5 10 15 200

10

20

Subtype B

Subtype C

K65R

wt (wk 34-78)

Week

[TD

F]

(M

)Rapid Selection of K65R Resistance in Subtype C Isolates

Courtesy M. Wainberg

Only the subtype C sequence triggers a pausing site that increases the probability of a nucleotide misincorporation event which in turn leads to the K65R mutation.

%

NNRTI mutations +/-184V containing virus + additional mutations

TAM Containing Virus 56%

Tenofovir mutations (K65R or K70E) 23%

Tenofovir & TAM 7%

Q151M Complex 19%

Pan-Nucleoside Mutation Combinations

Q151M Complex & Tenofovir mutations 16%

69 insertion 1%

Pan-Nucleoside

(Q151 & TDF associated mutations or 69 insertion)

17%

Resistance Patterns (94 samples, patients failing d4T/3TC/NVP (1/3 switched to ZDV due to toxicity)

Hosseinipour : XVII IAC Abstract TUAB0105Abstract TUAB0105

OPTIMIZATION: The need for monitoring

Poor coverage of 2nd line ART in LIC

Misclassification of ART failure by clinical and

CD4 criteria can be as high as 45%1 resulting in

unnecessary switch of ART

Prolonged treatment with a failing regimen has

consequences on future drug choice and

efficacy

A feasible strategy is needed to avoid loosing

the benefits of the “first wave” of ARV rollout

1: Hosseinipour M: 4th IAS, Sydney, 2007

138 patients genotyped at treatment failure (WHO

criteria)“Overall > 50% have multiple

treatment-limiting mutations”

3TC resistance: 80.5% vs 40.3% (p<0・ 001); at least one TAM: 27.8% and

12.1%, “ Lack of viral monitoring

associated with resistance in the vast majority of those with

viral failure after the 1st year of HAART”.

Kantor R:

N: 149 patients, 58% misclassified.

“Immunological monitoring would lead to a premature

switch to 2nd line regimens”

Kantor R:Kantor R:

Kumarasamy N:

Uncontrolled Viral Replication as a Risk Factor for

Non-AIDS Severe Clinical Events in HIV-Infected

Patients on Long-Term Antiretroviral Therapy:APROCO/COPILOTE (ANRS CO8) Cohort Study

Ferry T: J Acquir Immune Defic Syndr 2009;51:407–415

Age > 60 years, a low CD4 cell count, and a moderate level of HIV replication

were independently associated with the occurrence of non-AIDS events

during the prolonged follow-up. “Our results…underline the need to avoid virological rebound…particularly in

older patients and/or those with a low CD4 cell count”

“Viral load testing needs to be introduced with the same sense of

urgency and commitment as the world approached ART access. To do less is to abandon ART to an early collapse”

Monitoring HIV Antiretroviral Therapy in Resource-Limited Settings: Time to Avoid Costly Outcomes

Editorial by Sawe and McIntyre; CID 2009:49

• Improve outcomes

• Protect 1st and 2nd -line regimens by avoiding

unnecessary switches

• Delay initiation of 2nd line ART

• Resolve discordant cases of clinical and/or

immunological failure

• Improve and monitor adherence

• Reduce resistance risk

• Reduce MTCT identifying viral failures

Strategic use of viral load: Expected benefits

UNITAID Expert Consensus, 2009

Antiretroviral Treatment: What’s new?

The 96 week landmark with newer drugs:Naive patients

Drug Outcome: Study drug/comparator

Phase

DARUNAVIR QD

Artemis

Non-inferior to LPV/r 3

MARAVIROC

Merit-ES

Non-inferior to EFV 3

RALTEGRAVIR

(004)

Non-inferior to EFV 2

(144 weeks data)

RILPIVIRINE Non-inferior to EFV 2

The 96 week landmark with newer drugs:Experienced patients

Drug Outcome: Study drug/comparator

Phase

ETRAVIRINE

(Duet)57 vs 36% 2

DARUNAVIR

(Titan)67 vs 59% 3

DARUNAVIR

(Power)40 vs 21% 3

MARAVIROC

(MOTIVATE)40 vs 6% 3

RALTEGRAVIR

(BENCHMRK)65 vs 21% 3

VICRIVIROC

(Victor E-1)59 vs 25% 2

(48 weeks data)

Good news with good old drugs at IAS 2009

• DART: Triple nucleoside (ZDV/3TC/ABC) not inferior

to ZDV/3TC/NVP regarding AIDS/death after 5 years1

• STAR and Stella cohorts: No difference in virologic

response in naïve patients (TDF/FTC vs ABC/3TC)2

• RECOMB: Switching from ZDV/3TC to TDF/FTC

significantly improves limb fat3

•HEAT:Similar VL slopes for TDF and ABC4

5th IAS- 1:Walker; 2: Koegl; 3: Ribera; 4: Yau

Good news with good old drugs at IAS 2009

• Swiss cohort: EFV based HAART lower risk of virological failure compared to LPV/r1

• German Truvada Cohort (n 523) 2: EFV advantage, OR: 2.142

• CASTLE: ATV/r non-inferior to LPV/r in naives at 96 weeks3

• M06-802: LPV/r QD non inferior to BID in experienced px4

•ARTEN: Nevirapine non inferior to ATV/r, better lipid

profile, more discontinuations5

1: Bucher; 2: Zoufaly; 3: Uy 4: Badai-Faesen; 5: Soriano

● NRTI & RTV sparing regimen in naïve patients

1. Raltegravir - Atazanavir (BMS, N = 90)

● NRTI sparing in naïve patients

1. Raltegravir - Lopinavir/r (Abbott P092, N = 200: 8 wk interim data - BHIVA-Apr09)

2. Raltegravir - darunavir/rtv (ACTG 5262, N = 111)

3. Raltegravir - darunavir/rtv (NEAT study, N = 800)

4. Vicriviroc-Atazanavir/r (N:215)

New Treatment Paradigms: Drug sparing (Selected studies)

New Treatment Paradigms: Drug sparing (Selected studies)

● NRTI sparing in patients with NNRTI / 1st ART failure:

1. Raltegravir – Lopinavir/r (Collaborative study, N = 540)

2. Raltegravir – Lopinavir/r (MRC - 3 arms, 2nd step exploring LPV/r monotherapy maintenance: N = 1000)

● NRTI sparing salvage regimen 1. Trio trial (ANRS): Darunavir-Etravirine-Raltegravir 2. NIAID Optimization Trial (N:577)

3. Maraviroc –Raltegravir – Darunavir (F. Huesped pilot study, N: 60)

NRTI-Sparing strategy: Proportion of subjects with HIV-1 RNA <40 copies/mL (observed data analysis)

0

10

20

30

40

50

60

70

80

90

0 2 4 6 8Week

Pro

po

rtio

n o

f su

bje

cts

wit

h H

IV-1

RN

A

<40

cop

ies/

mL

LPV/r + RAL

LPV/r + FTC/TDF

a-comparison between treatment groups based on Fisher’s exact test

LPV/r + RAL, % (n/N) 37.0 (37/100) 65.3 (66/101) 80.8 (80/99)

LPV/r + TDF/FTC, % (n/N) 8.8 (9/102) 18.8 (19/101) 42.6 (43/101)

P-valuea <0.001 <0.001 <0.001

Podsadecki :15th BHIVA, 2009 Poster #P31

Trying to make it simple in Cape town…

● ANRS 136: Maintenance with DRV/r monotherapy vs

ongoing 2 NRTIs + DRV/r: 87.5 vs 92%; 3 vs 1 SAE1

● MONET: DRV/r monotherapy 1% difference vs. triple

combo2

● ARIES: ATV/r+ ABC/3TC, rtv discontinued at week 36 vs

ongoing regimen: 86 vs 81% < 50 copies3

1: Katlama WBLB 102; 2 Arribas :TUABLB 106; 3:Squires: WBLB 103

Integrase inhibitors: Good news in the new class

● Raltegravir in naïve - 004: (n: 198) VL < 50 copies 78% vs

76% EFV; less AEs 54 vs 76%1

● Switch to RAL impacts on CD4 count: (n: 51) RAL + 119

cells vs. ongoing regimen + 39 cells2

● EASIER: Switch T-20 to RAL (n:170) Non inferior, no

difference in CD4 recovery

● ACTG 5244: Intensification: (n:53) No difference on VL,

cross-over design. Trend towards > CD4 increase with RAL

● Elvitegravir: High trough concentrations maintained w/ GS-

9350 150 mg, with low within-subject variability. QUAD

tablet in clinical trials5th IAS-1: Gottuzzo 5th IAS – 2: Garrido 3: De Castro – 4: Gandhi

S/GSK1349572: The new kid on the block

Dosing period Follow-up period

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1(BL)

2 3 4 7 8 9 10 11 14 21(FU)

Day

Mea

n C

ha

ng

e fr

om

Bas

elin

e i

n H

IV-1

RN

A

(lo

g1

0 c

op

ies/

mL

)

2 mg10 mg50 mgPBO

Well tolerated, QD, linear PK/PD. Mean decrease on Day 11 in pVL of 1.51 to 2.46 log10copies/mL was observed across doses tested (2mg - 50mg)5

Newer ART Agents: The pipeline is still active (partial list)

RTI PI EI II MI

Phase 3 Rilpivirine* (FDC

in progress)

Vicriviroc Elvitegravir

Phase 2 Apricitabine

Dexelvucitabine

Bilr 355*

Lersivirine*

Ibalizumab

PRO 140

GSK/SHINOGI

1349572

MPC-

4326

(Bevirimat)

Phase 1/2 Amdoxovir

IDX899*

Elvucitabine

TMC

310911

Hgs004

Pro 542

MPC-

9055

Phase 1 OBP-601 RDEA

806*

*=NNRTI

PPL-100

SPI-256

PF232798

SCH

532706

TBR 652

TRI-1144

INH-1001MPC-0461359

Day

HIV

-1 R

NA

ch

ang

e fr

om

bas

elin

e (l

og

10 c

op

ies/

mL

)

-2.0

-1.5

-1.0

-0.5

0.0

0.5

0 5 10 15 20 25 28

Placebo 10mg BID

30mg BID100mg BID

500mg BID100mg QD500mg QD

750mg QD

LERSIVIRINELERSIVIRINE ( A5271010) : Mean Reduction in Viral Load over Time (Monotherapy)

Last dayof dosing

Pfizer Confidential

• In vitro activity against clinically significant NNRTI mutations: K103N, Y181C/I & G190A/S• DDI profile: can be co-administered with antacids, PPIs, H2 blockers, atazanavir, darunavir, raltegravir, maraviroc, NRTIs

SUCCESSES (Individual level)

• Remarkable reversal of morbidity & mortality

• Capacity to resume a normal life for decades, with near normal QOL.

• Steady improvement on quantity and quality of drugs

• Capacity to suppress viral replication even in front of drug resistance

• Impact on MTCT

CHALLENGES (Individual level)

• Optimizing ARV in ageing population with increasing comorbidities

• Keeping drug development active and robust, to identify better long-term tolerated, user friendly and forgiving regimens to foster adherence

• Managing long term toxicity

• Pediatric formulations

SUCCESSES (Public health level)• 1st disease in history producing mobilization

in an effort to treat people, defeating the “too complex-too costly” paradigm

• From policy to programmatic roll-out: From 0% to almost 40% coverage in about 7 years,

• Partnership between scientists, activists and policy makers

• Putting human rights at the forefront, inclusion of marginalized groups

• Increasing evidence of role of ART as prevention

Number of People Receiving ARV in Low and Middle-Income Countries, 2002-2008Number of People Receiving ARV in Low and Middle-Income Countries, 2002-2008

0

0,5

1

1,5

2

2,5

3

3,5

4

2002 2003 2004 2005 2006 2007 2008

1: Souteyrand: IAS 2009 – WELBD 105At the end of 2008 3.8-4.3 million on ART 1

> 6 million still excluded…

Challenges to the Public Health Approach in 2009

• Expand testing and start ARV timely, with safer regimens

• Reduce high pre treatment and early on treatment

mortality

• Identify cheap monitoring and adherence support tools,

as well as strategies to confront loss to follow up

• Identify simple, low-cost 2nd and 3rd line strategies

• Integrate treatment and prevention

• Train and retain HCW

• Integrate HIV services to scale up to better health care

• Context: donor fatigue, competing priorities, global crisis

CONCLUSIONS• HAART works both at the individual and the

Public health level• By reducing morbidity, mortality and

transmission the concept of ART as prevention has to be redefined as HAART is prevention, of avoidable disease, deaths and new infections

• To make it happen we need to reach our patients timely, retain them in the health care system, which needs to be strengthened not against HIV programs, but in synergy with it.

      

MDGs decided by UN to be reached in 2015, aiming to reduce global poverty and improve life standards

0 10000 20000 30000 40000

Known HIVcommitments

Commitmentproportional to

GDP

Canada (184, 1590

Germany (*720, 3720

Italy (200, 2380

Japan (318, 4940

Russia (120, 1400

UK (*537, 3110

US (19430, 15500

Known G8 HIV commitments 2008-2010 compared with “fair share” commitments as a proportion of world GDP

(in millions) given US$ 61 billion needs

•Figures are mostly based on the Toyako Framework for Health Report of the Health Experts Group Annex. Note that due to different methodologies for reporting HIV contributions and their focus on health systems strengthening, the United Kingdom figure is the specific amount earmarked for the Global Fund for 2008 to 2010, and figure for Germany is an estimate based on funds intended for the Global Fund and 2007 HIV funding levels. *Global GDP proportions are based on International Monetary Fund values for 2007

Economy is in recession, HIV is not!