Transcript STDs and HIV - XVIII International AIDS Conference, 2010

ART Advances-into the Next
Decade
James Hakim MB MMed MSc FRCP
Professor of Medicine, University of Zimbabwe
AIDS 2010
Vienna-Austria
18-23 July 2010
Antiretroviral Therapy Into the
Next Decade
Current
Status of
ART
Historical
perspectives
ART Into
the Next
Decade
Historical Perspectives
ART Milestones
Vancouver
Durban
Vancouver Durban
1996
2000
Barcelona
2002
Key ART Initiatives
National & Regional Initiatives
UNGASS
WHO
UNAIDS
GFATM
PEPFAR
NGO & Other Initiatives
CHAI
UNITAID
When/What
is the next Milestone
• ? Universal Access
Status of ART Roll-Out 2009
• 5.2m PLH on ART
– Most - MLIC
• Infection outstrips
Treatment by 5:2
• 5m more need
treatment
• 2010 WHO
Guidelines takes
this to 10 Mill
Achievements of ART
Kim J, Farmer P. NEJM 2006
• Improved survival
• Decreased
opportunistic
infections
• Improved quality of
life
Restores Hope & Dignity
Mortality RLS vs RRS
Braitstein P. Lancet 2006;367;817
• ART-LINC vs ART-CC comparisons
Low-INC HighINC
Female
51%
25%
CD4
108
235
CD4 gain 106
103
(base)
(6mths)
VL (6mths) 76%
77%
<500c/ml
Mortality
Adjusted HR
1-6 mths - 4.3 (95%CI 1.6-11.8)
7-12 mths-1.5 (95% CI 0.7-3.0)
Mortality in RRS
• Resource rich
settings
– Increasing
importance of nonAIDS illnesses
beyond second year
ART-CC CID 2010;50:1387
Mortality in RLS
Lawn S. AIDS 2008;22:1897
Lawn S. AIDS 2009;23:335
•  High early mortality
after initiation of ART
– Causes
•
•
•
•
•
•
Tuberculosis
Acute sepsis
Cryptococcal disease
Malignancy (KS)
P jiroveci
Impact of time spent on various
Others
CD4 strata on mortality
Other Achievements of ART
• Impact:
–  Tuberculosis
– Maternal and child mortality
» Hogan M, et al. Lancet 2010;375:1609
– Improves school attendance & workforce
» Zivin J, et al. J Publ Econ 2009;93:1008
» Thirumurthy H, et al. J Hum Res 2008;43:511
– HIV transmission
» Donnell D, et al. Lancet 2010;375:2092
Impact on Tuberculosis
Middelkoop K, et al. IAS C Town 2009;
Am J Resp Crit Care 2010; Jun 25
Severe P, et al. NEJM 2010;363:257
• Ecological analysis
• RCT
– Early vs Delayed
• Fall in TB
ART
prevalence in HIV
– 816 participants
patients
– TB cases:
• 1,250 pts in S. Africa
• 18 vs 36 p=0.0125
2005
2008
P-value
3.2%
1.6%
P=0.02
Early ART
Delayed ART
p-value
HIV+ve 9.2%
3.6%
p=0.003
18
36
P=0.0125
Rxd TB 4%
2.3%
p=0.06
All
ART in the Developing World
• Implementation has
been greatly helped
by WHO guidelines
–
–
–
–
2002
2003
2006
2010
2010 WHO ART Guidelines for
Adults & Adolescents Guidelines
Early Initiation of ART
CD4 threshold 350c/mm3
• CIPRA-HT-001
– Severe P, et al. NEJM
2010;363:257
– 816 participants
– Deaths:
• 6 vs 23 p=0.0011
• Cohort Analysis
– Even higher
thresholds
– 350-500
– >500
– Kitahata MM, et al.
NEJM 2009;360:1815
Guidelines-CD4 Thresholds
Guidelines
CD4-Asymptomatic Pts
DHHS (2010)
<350 (consider 500)
IAS (2010)
<500
EACS (2008)
<350 (consider >350)
BHIVA (2008
<350 (consider >350)
WHO EURO (2007/8)
200-350
WHO (2006)
<200 (consider 200-350)
WHO (2010)
<350
Treat Earlier-2010 WHO
Guidelines
To start earlier is the right thing to do
“Harmonize treatment guidelines”
CD4<350 c/mm3
Seek and Treat (earlier diagnosis)
Public Health Approach
DART
CIPRA
S. Africa
Jinja
Uganda
Survival
Proportion alive
1.0
0.8
0.95
0.92
0.90
0.94
0.90
0.87
164 events
LCM: 2.2/100 PY
CDM:2.9/100 PY
218 events
0.55
0.6
0.4
0.18
0.2
0.08
0.0
0
1
2
3
4
Years from enrolment
5
Entebbe Cohort
(Uganda):
pre-ART 19962000, median
CD4 75 at
enrolment:
57.7/100 PY
Survival at 5 yrs: LCM-90%, CDM-87%
IAS July 2009
18
Trained Lay Workersmonitoring ART
• Home-based vs
Facility based care
Jaffar S, et al. Lancet 2009;374:2080
– End point-Virologic
Failure (RNA >500c/ml)
• 859 participants
– (HBC-729 vs FBC-483)
• Rate Ratio:
– 1.04 (95%CI 0.78-1.4)
HBC is as effective as FBC
CIPRA South Africa
Sanne I, et al. Lancet 2010;376:33
• Nurse monitored vs
Doctor monitored
– Randomized noninferiority trial
• Follow up-120 wks
Doctor
monitored
n=408
Nurse
monitored
n=404
Total
Failure
179(44%)
192(48%)
Deaths
10
11
Virol Fail
44
39
Toxicity
68
66
LTFU
70
63
Nurse vs Doctor monitoring is non-inferior
HR 1.09 (95% CI 0.89-1.33)
Antiretroviral Drugs
• NRTIs
–
–
–
–
–
–
–
Zidovudine
Lamuvudine
Stavudine
Didanosine
abacavir
Tenofovir
Emtricitabine
• NNRTIs
–
–
–
Nevirapine
Efavirenz
Etraverine
• Integrase Inhibitors
– Raltegravir
• Protease inhibitors
–
–
–
–
–
–
–
–
–
–
Lopinavir
Atazanvir
Tipranavir
Darunavir
Indinavir
Ritonavir
Nelfinavir
Saquinavir
Amprenavir
Fosamprenavir
• Fusion Inhibitors
–
Enfuvertide
• CCR5 antagonists
–
Maraviroc
First-Line ART
• Harmonized to include TB and pregnant
women
• ART to all TB and HBV patients
• Preferred-NNRTI based regimen
• Preferred use of TDF or AZT
• d4T withdrawal and elimination
WHO 2010 Guidelines
Second-Line ART
• Boosted PI-based regimens
– Poor evidence of efficacy of NRTI
backbone in public health approach
– High resistance mutations when failure is
clinically or immunologically diagnosed
» Hosseinipour M, et al. AIDS 2009;23:1127
– ? Immediate use of new classes/drugs
immediately (RAL, ETV, Darunavir)
Second-Line ART
• Need for studies to provide evidence for
public health approach to second line
regimens
– EDCTP trial-EARNEST (enrolling)
– ACTG trial
– Other
• The place of PI/r monotherapy
Third-Line ART
• Real need to treat those failing secondline ART
• Can this be addressed with public health
approach principles?
– ? Need for resistance testing
– WHO 2010 recommends drugs eg DRV,
ETV, RLV
– Does this obviate resistance testing?
Monitoring
• Issues
– Efficacy tests (CD4, RNA VL)
•
•
•
•
Cost
Lab capacity
Impact on pace of roll-out
Need for evidence-based monitoring
– Evidence for RNA VL monitoring is good-but
availability to date is limited
• Need for roll-out of low-cost point-of-care tests
– CD4, RNA VL, resistance testing
Monitoring
• Toxicity tests
– CBC
• Chronic illness, AZT, malignancies,
malnutrition, etc
– Renal function test (which? creatinine,
urine)
• TDF
• Other
– Tropism tests, HLAB5701 (ABC)
Into the Next Decade
• Pipeline for new
antiretroviral drugs
• The pace of
development has
slowed in this area
Into the Next Decade
Treatment 2.0
• Current drugs are efficacious with good
safety and tolerance
– But there is still need for drugs that are:
•
•
•
•
•
More efficacious
Better tolerated (Better adherence)
More safe (Less monitoring)
More forgiving (Less resistance)
Compatible with TB, pregnancy, hepatitis,
malaria, etc...
Into the Next Decade
SMART. NEJM 2006;355:2283
DAD NEJM 2007;356:1723
Bone
Cardiovascular
Address longterm non-AIDS
complications
Renal
Neuro-congnitive
Hepatic
Into the Next Decade
• Non-AIDS outcomes
– unmitigated HIV replication or ART
• cardiovascular, hepatic, renal, bone, neurocognitive effects, cancer
• Aging/senescence
Limited data from RLS
More research required
Into the Next Decade
Laboratory Monitoring
• Accelerate roll-out of
Point-of-care
technology
–
–
–
–
CD4 counts
RNA Viral Load
Resistance
Other
HIV Eradication
• A preventive HIV
vaccine is an important
intermediate step
• The eradication and
cure of HIV remains the
only victory that we can
celebrate
• The science and
strategy required to
achieve this is of the
highest priority
• Granich R. Lancet 2009;373:48
• Hütter G. NEJM 2009;360:692
• Carter C. Nature Med 2010;16:446
Conclusions-Current
• The last decade has seen a momentous
expansion of ART in LMIC
• We continue to see the benefits of ART
in improved survival, reduction in
disease progression & improved quality
of life
• ART impacts non-AIDS conditions in
both negative and positive ways. This
must continue to be a focus of research
Conclusions
Into the Next Decade
• The quest for more efficacious, better
tolerated, safer and more forgiving
antiretroviral drugs must continue
• Better delivery modes of ART are
needed to improve access to all
• Preventive value of ART has come of
age-pMTCT and beyond...
• HIV cure remains the ultimate prize in
the response to AIDS
Acknowledgements
• UCSF
– Diana Havlir
• ARASA
– Michaela Clayton
• Univ of Zimbabwe
– Anthony Chisada
– Nehemiah Nhando
– Wadzanai Samaneka
– Mike Chirenje
• YRG-Care
– Kumar Kumarasamy
• University of Denver
– Thomas Campbell
• WHO
– Marco Vitoria
• Slides & Comments
– Many
Thank You