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!
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