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A GLOBAL PERSPECTIVE
Pedro Cahn
Outline: ARV Therapy in 2008
When to start
When to switch
What to use as cART
The global perspective
Research questions
Initial Reports
USE OF ART
30 75
25 DEATHS
20 50
15
10 25
5
0 0
1995 1996 1997 1998 1999 2000 2001
39+/9 years
200 15 000
10 858
10 000
100
3 515 5 000
0 0
1994 1996 1997 1999 2000 2001 2002 2003 2004 2005
a2005 deaths annualized on basis of deaths until June 2005, reported by November 2005; ART programme data reported
.until September 2005
42
40 39
40
34
31
Patients With
30
30
25
20
10
0
1996 1997 1998 1999 2000 2001 2002
Lampe F, et al. CROI 2005. Abstract 593.
Clinical Outcome Improved by Starting
Therapy at Higher CD4+ Cell Count
Timing of antiretroviral initiation Cumulative Probability of AIDS/Death by
in treatment-naive subjects CD4+ Cell Count at HAART Initiation
(N = 10,885) in Antiretroviral 101-200 cells/mm3
Cohort Collaboration
201-350 cells/mm3
HR for progression to AIDS or death 351-500 cells/mm3
0.75
Late HAART
0.5 (2000-2005)
Pre-HAART (1995-1996)
0
25 30 35 40 45 50 55 60 65 70
Age, y
Adapted from Lohse N, et al. Ann Intern Med 2007;146:87-95
SMART Substudy: Clinical Impact of
Continuous vs Interrupted Therapy
Patients who initiated and remained on antiretroviral therapy at higher CD4+ cell counts
(> 350 cells/mm³) had better outcomes vs those who deferred and interrupted HAART
Caveat: small number of patients analyzed and not all treatment naive
0.1 1 5
Favors Interruption Favors Continuous
El-Sadr W, et al. CROI 2008. Abstract 36.
A Major Reason to Treat Earlier: Risk
of Non-AIDS Diseases and Death
Higher risk of CV, neoplastic, hepatic, renal diseases in
HIV-infected vs HIV-uninfected people
Lower CD4+ cell count and/or higher HIV-1 RNA may
increase the risk of serious non-AIDS events
SMART study: being off antiretroviral therapy raises risk of
serious non-AIDS diseases—even when CD4+ cell count
> 250 cells/mm3
FIRST: More Non-AIDS Than AIDS
Events at Higher CD4+ Cell Counts
Rates decline at higher CD4 counts
Non-OD > OD at CD4+ cell counts > 200 cells/mm3
18
16
100 Patient-Yrs)
12
10
8
6
4
2
0
< 200 200-349 350-499 ≥ 500
Latest CD4+ Cell Count (cells/mm3)
Patient-years: 1288 | 1442 1324 | 1343 1238 | 1232 1940 | 1900
Baker J, et al. CROI 2007. Abstract 37.
Immunosuppression Increases Risk of
HIV- and Non-HIV–Related Mortality
Cohort study of > 23,000 Overall
100
patients in Europe, Australia, HIV
Malignancy
and US Heart
Liver
– 76,577 patient-years of
follow-up
10
1248 (5.3%) deaths from
2000-2004
RR
Both HIV- and non-HIV–
1.0
related mortality associated
< 50 50-99 100- 200- 350- 500
with CD4+ cell count 199 349 499
depletion
CD4+ Cell Count (cells/mm3)
0.1
Weber R, et al. CROI 2005. Abstract 595.
AIDS risk at 6 months
< 200
800 800
(cells/mm3)
600 600
400 400
BL CD4+ Cell Count
200 200 201-350 > 500
51-200 351-500
< 50
0 0
0 1 2 3 4 5 6 0 48 96 144 192 240 288 336
Years on HAART Weeks From Starting HAART
Moore RD, et al. Clin Infect Dis. 2007;44:441-446.
Gras L, et al. J Acquir Immune Defic Syndr. 2007;45:183-192.
Virologic Control Associated With
Lower Risk of Lymphoma
Retrospective cohort analysis (N = 6458)
Inclusion criteria: initiation of antiretroviral therapy until development of lymphoma or December 31, 2006
94 lymphomas: 78 NHL and 16 primary CNS lymphoma
Independent risks for lymphoma: MSM, older age, CD4+ cell count < 200 cells/mm3, ≥ 75% of HIV-1 RNA
> 500 copies/mL
.975
1. Tuyama A, et al. CROI 2008. Abstract 57. 2. Letendre S. CROI 2008. Abstract 68.
Treatment to Prevent
HIV Transmission
The case for expanding access to HAART
to curb the growth of the HIV epidemic
HAART
Coverage
Julio SG Montaner, Robert Hogg, Evan Wood, Thomas Kerr, Mark Tyndall,
Adrian R Levy, P Richard Harrigan – Lancet 2006;368:531-36
HIV Treatment Reduces Heterosexual
Transmission
174 discordant, monogamous couples 393 steady heterosexual couples[2]
in Raiki, Uganda, retrospectively
analyzed for factors associated with HIV prevalence among partners declined
transmission[1] from 10.3% during
pre-HAART period to 1.9% during
30 late HAART period (P = .0061)
Transmission/Coital Act
Adjusted Rate Ratio of
ZDV
+ 3TC = ZDV/3TC
ABC
= ABC/3TC
EFV
+ TDF
+ =
FTC
EFV/
TDF/
FTC
LPV
+ RTV
= LPV/RTV
When to Start: 2008 vs. 2006
164
200 179
187 163 192
123 157 206
102
86 103 53 95
125
122 100 72 134
97 97
87 239
181
ZDV
’87 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07
Timeline of ARV Development
DLV
ETV
NVP TDF
ddC ABC
ZDV d4T RTGV
ddI 3TC EFV FTC
’87 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07 08
Reverse
transcriptase
inhibitors
ZDV NVP
ddI DLV
TDF EFV
d4T ABC
FTC 3TC Protease
ETV TMC 278 inhibitors
RCV APC SQV IDV
RTV NFV
Integrase
FPV LPV
inhibitors ATV TPV
GS9137 DRV
Raltegravir
others
Recommended Regimens for
Treatment-Naïve Patients: DHHS 2008
Column A Column B
PI or NNRTI + 2 NRTIs
Preferred Lopinavir/ritonavir bid* Efavirenz† Tenofovir DF/emtricitabine‡
Fosamprenavir + ritonavir Abacavir/lamivudine
Atazanavir + ritonavir ‡
subjects (n=106)
PI-treated
0.50
subjects (n=71)
days 0
0 4 8 12 16 20 24
Time (months)
– HIV RNA >1000 c/mL
1.00 Time to loss of 1 drug
– >1 resistance mutation equivalent
0.75
– Resistance testing Q4
months until ART
0.50
modification 0.25
Number of available antiretrovirals from the following: ZDV, 3TC,
ddI, ABC, TDF, EFV, IDV, NFV, SQV, RTV, APV, LPV.
0
0 4 8 12 16 20 24
Hatano H, CROI 2006, #615 Time (months)
UK CHIC Study
NNRTI
30 3-class resistance
Extensive 3-class resistance
20
10
0
2 4 6 8 10
Time Since Starting HAART (Years)
Virologic failure: HIV RNA >400 copies/mL despite >4 months on HAART.
Extensive failure by drug class:
NRTI: virologic failure of >1 subclass: ZDV and d4T, 3TC and FTC, ddI and TDF and ABC.
PI: virologic failure of >1 ritonavir-boosted PI.
NNRTI: virologic failure of EFV or NVP.
Phillips A, et al. 14th CROI, 2007. Abstract 532.
55
Relationship Between Viral Suppression
and Mortality
Proportion of Detectable Viral Loads Over
• Prospective, population-based Danish
6-18 Months After Initiation of HAART
HIV Cohort Study
– N = 3919 HIV-infected patients
100% (all values VL ≥ 400)
– On HAART ≥ 18 months
1%-99% (of values VL ≥ 400)
0% (all values VL < 400)
• Stratified based on proportion of 0.25
Cumulative Mortality
0.20
during the period 6 to 18 months after
0.15
initiation of HAART
0.10
• Higher risk of death with transient or
lack of viral suppression 0.05
# Triple NRTI should be considered as an alternative strategy for first-line in situations where NNRTI
options provide additional complications and to preserve the PI class for second line(e.g., pregnancy, viral
hepatitis co-infection, TB confection, women who wish to fall pregnant or who have CD4 count > 250
cells /mm3; severe reactions to NVP or EFV and HIV-2 infection).
Response to HIV therapy in resource-poor
and resource-rich regions
Virologic responses after initiating therapy
• Virologic response to first ART: Switzerland vs South Africa:
– 967 pts in Swiss HIV Cohort (median CD4+ = 212 cells/mm3)
– 1856 pts in Cape Town (median CD4+ = 81 cells/mm3)
• Similar virologic responses when adjusted for age, gender, CD4+ cell
count, year of starting therapy, and disease stage
• More ART modifications among Swiss, often to improve convenience and
tolerability
• Qualitative:
Ageing population
Stigma, discrimination and denialism
Pediatric formulations
Co-infected patients
Chronic toxicity
Late detection
Wrong approach to budget allocation
The World Bank
Table 1. Estimated number of people receiving antiretroviral therapy, people needing antiretroviral therapy and
percentage coverage in low- and middle-income countries according to region, December 2006
d
Geographical region Estimated number Estimated Coverage
e
of people receiving need
ARV therapy
l ud
c
ex
Sub-Saharan Africa 1 340 000 4 800 000 28%
s
East, South and South-East Asia 280 000 1 500 000 19%
0%
North Africa and the Middle East 4 000 77 000 6%
6
2 015 000 7 100 000
>
Total
28%
[1.8 – 2.2 [6.0 – 8.4
[24 – 34%]
million] million]
APRIL NOVEMBER
Courtesy Joep Lange
ONE WORLD
TWO STANDARDS OF CARE