STATE OF THE ART-

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

 June 5, 1981: 5 cases of PCP in

gay men from UCLA (MMWR)

 July 3, 1981: 26 additional cases

 Dec 10, 1981: 3 NEJM papers
describe cases

Gottlieb MS NEJM 2001;344:1788-91

AIDS Mortality Rates: 1996-2001

Mortality vs. ART utilization

40 100

Percentage of patient-days on ART

35
Deaths per 100 person-years

USE OF ART
30 75

25 DEATHS

20 50

15

10 25

5
0 0
1995 1996 1997 1998 1999 2000 2001

Palella F et al. 8th CROI 2001; abstract 268b.

The Survival Benefits of AIDS Treatment in the United States

39+/9 years

Walensky et al: JID 2006;194:11-19

Institutional deaths per 100 000 population and programmatic data: patients currently receiving antiretroviral therapy and deaths on
therapy, Botswana 1994-2005aa

700 Patients receiving antiretroviral therapy 50 000

Deaths of those on therapy 45 120
Deaths per 100 000 population 45 000
600

People currently receiving antiretroviral therapy

40 000
estimated from 2002
Deaths per 100 000 population

500 mortality reports 35 000

30 600
30 000
400
25 000
300
20 000

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

8| Progress Report | April 2007

 AIDS 2008

10 | Progress Report | April 2007

Antiretroviral Efficacy Rates Are
Improving in Clinical Practice
 Virologic failure of initial HAART in previously treatment-naive patients from
5 observational cohorts (N = 4143)
50
HIV-1 RNA > 500 copies/mL (%)

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

Probability of AIDS or Death

0.12
by CD4+ cell count at initiation of
therapy 0.10
– < 200 vs 201-350 cells/mm3 0.08
HR: 2.93 (95% CI: 2.41-3.57)
0.06
– < 350 vs 351-500 cells/mm3
HR: 1.26 (95% CI: 0.94-1.68) 0.04
 Results suggest a lower risk of 0.02
disease progression/death when
0.00
starting between 351-500 cells/mm3
1 2 3 4 5
Years Since Initiation of HAART
Sterne J, et al. CROI 2006. Abstract 525.
 ACTG A5164: Immediate vs Deferred
ART in Patients With Acute OIs
Stratified by CD4+ cell count
< or  50 cells/mm3,
PCP, BI, or other OI

Immediate Antiretroviral Therapy

HIV-infected Initiation within 48 hours of randomization and
48 weeks
patients receiving within 14 days of starting OI treatment
treatment for (n = 141)
presumed or
confirmed acute
OI/BI* Deferred Antiretroviral Therapy
Initiation between Weeks 4 and 32 48 weeks
(N = 282) (n = 141)

*Patients with TB excluded.

Zolopa A, et al. CROI 2008. Abstract 142.

85.8%
75.9%
HIV-Infected Patients in the HAART Era Have a
10-Year Shorter Expected Survival than Age and
Gender-Matched Controls
Survival from age 25 years
1
Population controls
Probability of Survival

0.75

Late HAART
0.5 (2000-2005)

0.25 Early HAART

(1997-1999)

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

Event, n (Rate per 100 Person-Years)

Interrupted HAART Continuous HAART HR P Value
OI/death
 Overall 15 (4.8) 4 (1.1) 4.4 .009
OI
 Overall 11 (3.5) 3 (0.8) 4.4 .02
Serious non-AIDS
 Overall 12 (3.9) 2 (0.5) 7.1 .01
Composite*
 Overall 21 (7.0) 5 (1.3) 5.1 .001
*Includes OI and serious non-AIDS events.
Emery S, et al. IAS 2007. Abstract WEPEB018.
 SMART: Effects of Therapy Reinitiation
on Morbidity and Mortality
 Significant decrease in excess risk Premodification (n = 639)
of OI/death in interruption arm after Postmodification (n = 195)
study modification
2.5
OI or Death P = .03
 Persistence of excess risk for 1.4
OI/death in interruption arm vs
continuous therapy arm related to: 1.8
Death
– Lower mean CD4+ cell count 1.3
– Higher proportion with HIV-1 RNA
> 400 copies/mL OI 3.3
1.7
 Antiretroviral therapy interruption
associated with long-term Major CVD, 1.7
consequences Renal, or
Hepatic Disease 1.1

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)

14 OD events Non-OD events

Rate (Events/

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

CASCADE Collaboration 2003

 CASCADE: Nadir CD4+ Cell Count
Predicts AIDS and Non-AIDS Events
 CASCADE collaboration cohort (N = 9858)
 Several clinical markers of HIV progression correlated with death due to AIDS-related
causes, non-AIDS–related severe infection, liver diseases, and non-AIDS–related
malignancies including
– Latest and nadir CD4+ cell counts
– Time spent with CD4+ cell count < 350 cells/mm3
AIDS-Related Death Non-AIDS–Related Death
Nadir CD4+ Cell Count
200-349 vs ≥ 350 200-349 vs ≥ 350
50-199 vs ≥ 350 50-199 vs ≥ 350
< 50 vs ≥ 350 < 50 vs ≥ 350
0.01 1.00 100.00 0.01 1.00 100.00
Liver Disease Death Non-AIDS Cancer Death
200-349 vs ≥ 350 200-349 vs ≥ 350
50-199 vs ≥ 350 50-199 vs ≥ 350
< 50 vs ≥ 350 < 50 vs ≥ 350
0.01 1.00 100.00 0.01 1.00 100.00
Marin B, et al. IAS 2007. Abstract WEPEB019.
 Association Between Current CD4+
Cell Count & Non-AIDS Complications
Study Lower Current CD4+ Cell Count Significantly
Associated With Increased Risk?
Non-AIDS Renal CVD Liver
malignancies disease/death events/death disease/death
FIRST Yes Yes Trend, NS No
D:A:D Yes Yes Trend, NS Yes
CASCADE Yes NA Yes Yes
SMART Trend, NS Trend, NS Trend, NS Yes

Phillips A, et al. CROI 2008. Abstract 8.

 Likelihood of Achieving Normal
CD4+ Cell Count Depends on BL Level
Johns Hopkins HIV Clinical Cohort ATHENA National Cohort
BL CD4+ Cell Count
> 350 1000
1000
201-350
Mean CD4+ Cell Count

< 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

Influence of Cumulative log10 HIV-1 RNA

1
Survival Probability
Without Lymphoma

.975

Viremia < 75% of time

Viremia ≥ 75% of time
.95
1000 0 2000 3000 4000
Days Since HAART Begun
Zoufaly A, et al. CROI 2008. Abstract 16.
 Other Risks of Ongoing Virus
Replication
 Accelerated fibrosis in patients with HIV/HCV-coinfection[1]
– HSC mediate fibrosis in patients with HCV
– HIV infects HSC in vitro by CD4-independent pathways
– Result: activation of HSC by HIV increases collagen gene expression,
potentially explaining the rate of fibrosis in HIV/HCV coinfection

 Increased HIV-associated dementia[2]

– In patients with neurocognitive dysfunction starting or changing ART,
60% fail to normalize neuropsychiatric function after 24 weeks
– Factors associated with incomplete recovery: CD4+ cell count nadir
≤ 350 cells/mm3, higher pre-ART HIV RNA level in CSF, lower pre-ART
HIV-1 RNA level in blood

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

20 Enrollment OR (95% CI) P Value

Period
10 Pre-HAART 1
(1991-1995)
1.0 Early HAART 0.55 .2763
< 1700 1700- 12,500- > 38,500 (1996-1998) (0.19-1.61)
12,499 38,499 Late HAART 0.14 .0127
0.1 HIV-1 RNA (copies/mL) (1999-2003) (0.03-0.66)

1. Gray RH, et al. Lancet. 2001;40:1149-1153.

2. Castilla J, et al. J Acquir Immune Defic Syndr. 2005;40:96-101.
 Toxicity Is a Major Reason for
Discontinuation of First-Line HAART
 ICONA study group Cause of Discontinuation
Toxicity Nonadherence
– Median follow-up: Failure Other
45 weeks
– Study population: 8%
862 ARV-naive patients
– 84.3% receiving 20%
unboosted PI + NRTIs
58%
– Discontinuations:
n = 312 (36%) 14%

d’Arminio Monforte A, et al. AIDS. 2000;14:499-507.

 Safety and Tolerability of Select
Current Regimens Are Excellent
Study Length Drug regimen Discontinuations Due to AEs,* %
AI424-089[1] 96 weeks ATV + d4T + 3TC 3
ATV/RTV + d4T + 3TC 8
GS934[2] 48 weeks EFV + TDF + FTC 5
EFV + ZDV/3TC 11
KLEAN[3] 48 weeks FPV/RTV + ABC/3TC 12
LPV/RTV + ABC/3TC 10
ARTEMIS[4] 48 weeks DRV/RTV + TDF/FTC 3
LPV/RTV + TDF/FTC 7
CASTLE[5] 48 weeks ATV/RTV + TDF/FTC 2
LPV/RTV + TDF/FTC 3
HEAT[6] 48 weeks ABC/3TC + LPV/RTV 4
TDF/FTC + LPV/RTV 6
GEMINI[7] 48 weeks SQV/RTV + TDF/FTC 4
LPV/RTV + TDF/FTC 7
1. Malan N, et al. IAS 2007. Abstract WEPEB024. 2. Arribas JR, et al. IAS 2007. Abstract WEPEB029. 3. Eron J Jr, et al.
Lancet. 2006;368:476-482. 4. DeJesus E, et al. ICAAC 2007. Abstract 718-b. 5. Molina JM, et al. CROI 2008. Abstract
37. 6. Smith K, et al. CROI 2008. Abstract 774. 7. Walmsley SL, et al. EACS 2007. Abstract PS1.4.
 Fixed-Dose Combinations

Individual Agents Fixed-dose combinations

ZDV
+ 3TC = ZDV/3TC

ABC
= ABC/3TC

TDF + FTC TDF/FTC

EFV
+ TDF
+ =
FTC
EFV/
TDF/
FTC

LPV
+ RTV
= LPV/RTV
 When to Start: 2008 vs. 2006

Guideline Recommendation to Begin Optimal Time Not Well Defined or

Immediate Therapy Recommendation to Delay Therapy
DHHS CD4+ cell count < 350 cells/mm3 CD4+ cell count > 350 cells/mm3
2008[1] Previous AIDS-defining illness
Pregnant women
HIV-associated nephropathy
HBV-coinfection, when HBV
treatment indicated
EACS CD4+ cell count < 350 cells/mm3 CD4+ cell count > 500 cells/mm3
2007[2] CD4+ cell count from 350-
500 cells/mm3 with high HIV-1 RNA
Opportunistic infection
IAS-USA Active AIDS No history of active AIDS, but CD4+
No history of active AIDS, but cell count from 200-350 cells/mm3
2006[3]*
CD4+ cell count ≤ 200 cells/mm3 CD4+ cell count > 350 cells/mm3

1. US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Default.aspx.

2. European AIDS Clinical Society.
Available at: http://www.eacs.eu/guide/1_Treatment_of_HIV_Infected_Adults.pdf.
3. Hammer SM, et al. JAMA. 2006;296:827-843.
*See updated version in JAMA Aug 2008
 When Is Antiretroviral Therapy
Started?
 Review of data from 2003-2005 from 176 sites in 42 countries (N = 33,008)
 Since 2000, CD4+ cell count at initiation in developed countries stable at
approximately 150-200 cells/mm3, increasing in sub-Saharan Africa from
50-100 cells/mm3

164
200 179
187 163 192
123 157 206
102
86 103 53 95
125
122 100 72 134
97 97
87 239
181

Egger M, et al. CROI 2007. Abstract 62.

 Summary: Why should we start earlier

 Treatment reduces AIDS-related morbidity and mortality

 Treatment reduces markers of systemic inflammation and immune
activation
 Treatment reduces non-AIDS–related complications—all of them
increasing in an aging HIV population
– Cardiovascular disease
– Malignancies
– Hepatic disease
– Renal disease
 Treatment reduces risk of transmission to others
 Treatment is more user friendly, more effective and better tolerated
now than in years past
Timeline of ARV Development

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

NRTI SQR NFV LPV/r ATV

NNRTI FPV DRV
PI RTV APV TPV
Entry
inhibitor IDV T-20 MVC

Integrase 25 unique ARV agents, at the first year of FDA approval

inhibitor
 Retrovirus life cycle
Maturation
Entry inhibitors inhibitor
ENF MRV Bevirimat
VCV TNX355
AMD11070

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 ‡

Alternative Lopinavir/ritonavir qd Nevirapine§ Zidovudine/lamivudine

Fosamprenavir (unboosted) Didanosine + lamivudine
Atazanavir (unboosted)║
Fosamprenavir + ritonavir qd
Choose a PI or NNRTI plus 2 NRTIs.
*The pivotal study that led to the recommendation of lopinavir/ritonavir as a preferred component was based
on twice-daily dosing. A smaller study has shown similar efficacy with once-daily dosing but also showed
a higher incidence of moderate-to-severe diarrhea with the once-daily regimen (16% vs 5%).
†
Efavirenz is not recommended for use in the first trimester of pregnancy or in sexually active women
with childbearing potential who are not using effective contraception.
‡
Emtricitabine may be used in place of lamivudine and vice versa.
§
Nevirapine should not be initiated in women with CD4 cell count >250 cells/mm 3 or in men with CD4 cell
count >400 cells/mm3 because of increased risk of symptomatic hepatic events in these patients.
║
Atazanavir must be boosted with ritonavir if used in combination with tenofovir DF.

Adapted from: http://aidsinfo.nih.gov/Default.aspx.

 Risks of deferring switch in
failing patients
• SCOPE cohort of 1.00 Time to development of
new mutation

% without new mutation

ART-experienced 0.75
*
Data are for

subjects (n=106)
PI-treated
0.50
subjects (n=71)

0.25 1 new major PI mutation*

– Stable ART for >120 1 new NRTI mutation
Any new mutation

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

Cumulative Risk of Extensive Failure

40
NRTI
PI
Cumulative Risk (%)

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

detectable VL (> 400 copies/mL)

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

– Consistent with shorter-term studies 0.00

0 18 36 54 72
Months After Baseline
Lohse N, et al. ICAAC 2005. Abstract H-515 (baseline = 18 months after HAART initiation)
CID2006;42:136-144
.
 BENCHMRK-1 & 2 Combined Efficacy†
Percent of Patients With HIV RNA <50 copies/mL at
Week 48 by Selected ARTs in OBT

CROI 2008 Abstract # J-117 Poster #789

 CONFRONTING FAILURE:
NEW DRUGS, HOW TO USE IT

• Goal: Virological supression < 50 copies

• How: Use at least 2 active drugs, one new class if possible
• When: Switch as early as possible
• Why:
 Avoid accumulation of resistance mutations (GSS)
 Avoid increases in fold changes (PSS)
 Preserve active drugs for OBR
 Preserve CD4 levels
 WHO - Recommendations for initiating ART in
adults and adolescents based on clinical stage and
availability of immunological markers
WHO Clinical CD4 testing
CD4 testing available
Staging not available
Do not treat
1 [A-III] Treat if CD4 cell count < 200/mm3 a

Do not treat c [A-III]

2 [B-III]
Treat irrespective of CD4 cell count, with
Treat
3 [A-III]
consideration of CD4< 350/mm3 in
some situations b [A-III]
Treat Treat irrespective of CD4 cell count
4 [A-III] [A-III]
a
The precise CD4 cell level above 200/mm3 at which ARV treatment should be started has not been
established.
b
CD4 cell count advisable to assist with determining need for immediate therapy for situations as
pulmonary TB and severe bacterial infections, which may occur at any CD4 level.
c
A total lymphocyte count of ≤ 1200/mm3 can be substituted for the CD4 count when the latter is
unavailable and mild HIV disease exist. It is not useful in the asymptomatic patients. Thus, in the
absence of CD4 cell count and TLC, patients with WHO Adult Clinical Stage 2 should not be treated.
 WHO: First Line ARV Drugs in Adults and Adolescents

Preferential 2 NRTI/NNRTI approach

AZT* or d4T EFV

3TC or FTC
TDF* or ABC NVP
Triple NRTI alternative approach#

* Preferential NRTI to be combined with 3TC or FTC.

# 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

Mortality during the first year of HAART

• Estimated mortality of 15% in sub-Saharan Africa vs 5% in Europe and
North America
• Early mortality seen after initiation of ART possibly due to pre-existing
condition or immune restoration

Egger M, et al. 14th CROI, Los Angeles 2007, #62

 Suboptimal Initial Response/First Failure
in Resource Unconstrained Settings
• Typically picked up early through VL monitoring
• All potential reasons evaluated
• Goal of therapy remains maximal virologic suppression
– i.e., VL <50 copies/ml, achievable in ~90% of patients
• Tailoring regimens to individual needs
– Resistance testing used to assist with choice recognizing its
limitations [amplification at low virus loads, mixtures (importance of
low-frequency variants)
– TDM
Treatment Failure
in Resource Limited Settings

• Lack of widespread availability of CD4 and VL testing

implies that completeness of response to any line of
therapy may not be fully assessed and treatment failure
will be picked up later
– Greater degree of drug resistance will occur

• Lack of individualized drug resistance testing

• Need for a public health approach, while pushing for
wider availabilty of appropriate monitoring tools

• Goal of therapy is to reduce morbidity and

mortality, so CD4 conservation and maximal
virologic suppression should be persued
 Limited use of second-line
• Only 40,000 (2%) on 2nd line at
end 2006
– limited provision in public sector
– high cost: $1000 – 2500 pa 900'000
– only some countries have 800'000 Total number of
universal access 700'000 people needing
2nd line ARVs
– HIV-TB co-management 600'000
(high estimate)
– ?? switch rates (4% annual in 500'000
DART) 400'000
300'000 Total number of
people needing
200'000
• Much more focus on scaling 100'000
2nd line ARVs
(low estimate)
up first-line -
– Clear what to use; many FDCs 2006 2007 2008 2009 2010
– Price competition: d4T/3TC/NVP
for $121 pa
Challenges in HAART in 2008 and Onwards
• Quantitative:
 Earlier initiation
 Wider roll-out without matching monitoring capacity
 > life expectancy
 Evidence for treating upfront newborns
 CART for pregnant women

• 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%

Latin America and the Caribbean

ti l l 355 000   490 000 72%

s
East, South and South-East Asia 280 000 1 500 000 19%

Europe and Central Asia 32 000   230 000 15%

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]

80 | Progress Report | April 2007

HAART MAKES THE DIFFERENCE

APRIL NOVEMBER
Courtesy Joep Lange
 ONE WORLD
TWO STANDARDS OF CARE

• FDC (TDF/EMT/EFV) • FDC (d4T/3TC/NVP)

• Resistance testing • Not available
• Baseline check-up • Limited
• Frequent CD4 & VL • CD4 in some
monitoring settings, VL low %
• Rtv-boosted PI’s • Limited availability
• 3rd and 4th line • Almost not availble
regimens
 ONE WORLD
TWO STANDARDS OF CARE

• ARV can be delivered all over the world

• Success rates comparable to 1st world
• Early mortality higher, due to late start
• Guidelines compromised by cost, procurement,
lack of political will and stigmatization of
vulnerable populations
• The majority of patients in need still lack access
to WHO recommended ARVs
• While expanding access to 1st line, push for
proven 2nd line therapies
• We know how to prevent and how to treat HIV/AIDS
• The epidemic can be curbed
• There is enough money around
• Poverty and uneven distribution of wealth is a major
driving force of the epidemic
• Lack of political will is killing 2.8 million people a year

The best moment to plant a tree was 20 years ago.

The second best option is today…