Feedback from 15th IAS Conference
13-18 August 2006
Simon Collins
HIV i-Base
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Feedback from 15th IAS Conference
1.Treatment access
2. New drugs
3. New strategies: boosted-PI monotherapy
4. Other issues
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Feedback from 15th IAS Conference
1.Treatment access
• many smaller studies including long-term data
• working in all countries, access for women and
children, TB coinfection, late diagnosis, adherence,
side effects
• funding - now 1.6 million on treatment, but dependent
on funding increasing every year, if this is to expand
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Number of people on antiretroviral therapy in low- and
middle-income countries, 2002‒2005
1400
North Africa and
the Middle East
1200
Europe and
Central Asia
1000
People
receiving
therapy
800
(thousands)
600
East, South and
South-East Asia
Latin America and
the Caribbean
400
Sub-Saharan
Africa
200
0
End Mid- End Mid- End Mid- End
2002 2003 2003 2004 2004 2005 2005
2006 Report on the global AIDS epidemic (UNAIDS, 2006)
Simon Collins: Toronto feedback: HIV I-Base
Piot WESS0102
UK-CAB September 2006
Scale up of treatment in the Elizabeth Glaser
Pediatric AIDS Foundation “Project HEART”
Initiating Care and ARV Treatment for over 68,000 people in 28 months at
95 sites in four African countries
100
Number of Sites
90
80
70
Cote d'Ivoire
60
South Africa
50
Tanzania
40
Zambia
30
Total
20
Côte d’Ivoire: 57
sites
10
0
Q1-04
Q2-04
Q3-04
Q4-04
Q1-05
Q2-05
Q3-05
Q4-05
Q1-06
Q2-06
South Africa: 3
sites
Quarters
Marlink THAB0201
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Women's access to HIV treatment, June 2006 - Piot
Mozambique
Uganda
Nigeria
Malawi
Zimbabwe
Zambia
Central African Republic
Botswana
Kenya
Côte d'Ivoire
Namibia
Rwanda
United Republic of Tanzania
Burundi
South Africa
10%
20%
Percentage of adults on ART who are women
Simon Collins: Toronto feedback: HIV I-Base
30%
40%
50%
60%
70%
Percentage of HIV-infected persons who are women
UK-CAB September 2006
“Refuting the Afro-pessimists”
• Adherence to ART is better in African programmes than in North
America
• A meta-analysis of 27 studies in sub-Saharan African countries
and 31 North American studies showed that adequate
adherence was observed in 77% of patients in Africa and 55% of
patients in North America.
• It is important to ensure that these reassuring initial rates of
adherence will be sustained over time.
• Data from Senegal suggest that the involvement of communities
may be the key to maintaining adherence in the long term.
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Stephen Lewis: closing ceremony
“... we are on the cusp of a huge financial crisis... and have been lulled into a
damaging false security (we jumped from $300 million a year… in the late
1990's, to $8.3 billion in 2005. It sounds impressive. But we need $15 billion in
2006, and $18 billion in 2007, and $22 billion in 2008. This will take us to $30
billion in 2010 … the moment of universal access to treatment, prevention and
care.”
“We're billions and billions short of those targets. If these circumstances
continue, universal access is doomed. The financial promises made at the G8
Summit in Gleneagles one year ago, are already unraveling. We will never
accumulate the extra $25 billion for Africa by 2010 as was committed.”
“PEPFAR has not yet announced its extension beyond 2008; when it does (as
it surely will), the annual contribution, given the other demands on the US
Treasury, will probably remain at $3 billion a year. That large amount was a
very significant percentage of the total expenditure on AIDS back in 2003/2004.
But as a percentage of what is needed for global AIDS programmes in 2008 $22 billion - $3 billion seems pretty paltry from the world's superpower.”
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Feedback from 15th IAS Conference
2. New drugs
• MK-0518
• maraviroc
• etravirine
• TNX-355
• atripla, T-1144, T-999, PL-100 etc
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
MK-0518 Merck’s integrase inhibitor: great promise
• MK-0518 is a strand transfer inhibitor of HIV integrase
(integrase is 3-step process and K-0518 block the final
step, where the viral DNA is spliced into the CD4-cell DNA)
• In treatment naïve patients with HIV RNA ≥ 5000 copies/ml
and CD4 ≥ 100/mm3, MK-0518 studied at four dose levels
for 24 weeks:
• had potent antiretroviral activity
• 85-95% with HIV RNA < 50 copies/mL
• achieved viral suppression faster than EFV
• was generally well tolerated
Markowitz THLB0214
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Protocol 004: Study Design
Part I
Part II
Integrase Monotherapy
Combination Therapy
for 10 days
4 doses 0518 vs EFV,
All plus TDF/FTC
Part I: 40 Rx-naïve pts
randomised to 100, 200,
400, or 600mg 0518 twice
daily, or placebo.
Part II: 150 Rx-naïve pts
randomised to 100, 200,
400, or 600mg 0518 twice
daily, or efavirenz, all
+TDF/FTCfor 48 weeks
8 patients in each arm
HIV RNA  of 1.7 – 2.2 log10 copies/mL
Morales-Ramirez et al, EACS 2005
30 new patients in each
arm
IAC 2006 Abs# THLB0214
*TDF = tenofovir
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Protocol 004: Baseline Characteristics
MK-0518 mg bid*
100
N=39
200
N=40
400
N=41
600
N=40
Efavirenz *
600mg qd
N=38
Age-mean (yrs)
37
34
36
37
36
%Male
85
73
90
73
76
%Non-White
82
65
66
65
68
HIV RNA
copies/ml**
(log10cp/ml)
58206
(4.8)
64715
(4.8)
43083
(4.6)
57919
(4.8)
67554
(4.8)
CD4 – mean
(cells/ul)
314
296
338
271
280
% with AIDS
31
33
29
43
37
* With TFV/3TC ** = geometric mean
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Change From Baseline
in HIV RNA (Log
10 Copies/mL)
Protocol 004: HIV RNA Change from Baseline*
(log10 copies/mL) (95% CI)
0
-1
-2
-3
0
MK-0518 100mg
MK-0518 200mg
MK-0518 400mg
MK-0518 600mg
Efavirenz
2
4
8
12
W eek
16
24
38
40
40
39
37
39
40
41
38
38
39
40
41
38
38
39
40
41
38
37
39
40
41
38
38
39
40
41
38
37
*assay LoQ 400 copies/mL
m518p4rna6 Aug. 10, 2006
IAC 2006 Abs# THLB0214
Markowitz THLB0214
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
25
27
27
28
26
Percent of Patients with
HIV RNA <50 copies/mL
Protocol 004: Percent (95% CI) of Patients
with HIV RNA < 50 copies/mL (NC=F)
100
80
60
*
40
*
20
0
0
MK-0518 100mg
MK-0518 200mg
MK-0518 400mg
MK-0518 600mg
Efavirenz
2
4
8
12
Week
16
24
39
40
41
40
38
39
40
41
40
38
39
40
41
40
38
39
40
41
40
38
39
40
41
40
38
39
40
41
40
37
* P < 0.001 for MK-0518 at each dose vs. EFV
m518p4.r50.5 Aug. 3, 2006
IAC 2006 Abs# THLB0214
Markowitz THLB0214
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Common (≥5%) drug related side effects
MK 0518 (all doses)
+TDF/FTC
N=160 (%)
Efavirenz
+TDF/FTC
N=38 (%)
Nausea
11
13
Headache
9
24
Dizziness
8
26
Diarrhea
7
11
Insomnia
7
11
Abnormal
dreams
6
18
Flatulence
6
-
Additional AEs seen at ≥ 5% in efavirenz group:
Fatigue (5%)
Nightmare (11%)
Disturbance in attention (5%)
Vomiting (8%)
Lethargy (5%)
Malaise (8%)
Anxiety (5%)
Simon Collins: Toronto feedback: HIV I-Base
* With TFV/3TC
UK-CAB September 2006
Maraviroc
• Double-blind placebo controlled study in 190 mixed/dual tropic patients
• Randomised to optimised background regimen (OBT) including at least one
sensitive drug, plus either maraviroc once-daily (n=63), vs maraviroc twice daily (n61) or placebo (n-60). [1]
• Over 90% patients were PI-experienced
• 50-60% currently using T-20
• Baseline CD4 count <100 cells/mm3
• Baseline viral load > 5logs respectively
• >95% patients had dual/mixed tropism.
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Maraviroc
Table 1: Virologic and immunologic responses at week 24
All treated patients with D/M-tropic HIV-1
Mean decrease in HIV-1 RNA (log10c/mL)*
Placebo
OBT
+
MVC
OBT
QD
+
MVC BID + OBT
n = 52
n = 58
n = 57
-0.97
-0.91
-1.20
+0.06
(-0.53, +0.64)
-0.23
(-0.83, +0.36)
Treatment diff (MVC-OBT) in HIV-1 RNA decrease
(log10c/mL) (97.5% CI
HIV RNA < 400 c/mL (%)
24.1
24.6
30.8
HIV RNA < 50 c/mL (%)
15.5
21.1
26.9
-0.89
-1.26
-1.44
+36 (n=58)
+60 (n=57)
+62 (n=52)
-104 (n=2)
+48 (n=12)
+33 (n=12)
Mean decrease in HIV-1 RNA in pts using T-20
Mean CD4 change (cells/mm3, mean)
All treated patients with D/M-tropic HIV-1
Mean CD4 change (cells/mm3, mean)
Pts with only X4-tropic HIV-1 detectable at time of
virologic failure
As no progression of HIV, questions importance of tropism test???
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Etravirine (TMC-125)
Phase II study in 199 treatment experienced patients with documented NNRTI
resistance and 3 or more primary PI mutations.
Randomised to TMC125 (400 mg or 800 mg bid) with an investigator selected
background, or standard-of-care control regimen.
Median baseline CD4 - 100 cells/mm3; viral load 4.7 log copies/mL
Table 1: Results of etravirine (TMC-125) at 48-weeks
400mg
800mg
control
Mean VL change (log)
-0.88 *
-1.01 *
-0.14
Mean CD4 change
+58
+61
+13
VL failure
9%
9%
78%
Med. duration of Rx (wks)
48 wks
48 wks
18 wks
* P <0.05 compared to control
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
TNX-355
Table 1: Baseline characteristics and ITT responses to TNX-355
15mg/kg +OBR
10mg/kg+OBR
placebo+OBR
N
28
27
27
Age
47
44
46
% male/female
78/22
93/7
89/11
Baseline CD4 (%<200)
299 (26%)
223 (51%)
245 (43%)
Baseline VL (%>5log)
4.8 (26%)
5.0 (57%)
4.8 (33%)
Mean change in CD4+
+51 (p=0.016)
+48 (p=0.031)
+1
Mean VL change wk-48
-0.71 (p<0.010)
-0.96 (p<0.001)
-0.14
N (%) >/= 1.0 log
9 (32)
10 (37)
3 (11)
N (%) >/= 0.5 log
11 (39) (p=0.029)
12 (44) (p=0.014)
3 (11)
% <400 (%<50) c/mL
7 (4)
4 (0)
0 (0)
Median TLVR (days)
253 (p=0.003)
230 (p=0.003)
0
Ref: Norris D, Morales J, Godofsky E et al. TNX-355, in combination with optimized background regimen (OBR), achieves statistically significant viral
load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 Weeks. Late breaker abstract THLB0218.
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Treatment Simplification* - 1996 - 2006
1996: d4T/3TC/IDV
10 pills, TID
1998: ZDV/3TC/EFZ
5 pills, BID
2002: ZDV/3TC/EFV
3 pills, BID
2004: TVD or EPZ /EFV
2 pills, QD
2006: ATRIPLA
1 pill, QD
* Selected regimens
Simon Collins: Toronto feedback: HIV I-Base
Montaner WEPL0101
UK-CAB September 2006
Early data on long-release entry
inhibitors - ‘2nd generation T-20’
Plasma Concentration
(mg/mL)
100
Subcutaneous Dose
Cynomolgus monkey
Normalized to 3 mg/Kg
10
1
TRI-1144
ENF
0.1
TRI-999
0.01
0
1
2
3
4
5
6
7
Time (days)
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
PL-100 and Its Prodrug, PPL-100
• Potent, specific and non-cytotoxic HIV-1 protease inhibitor
• Favorable cross-resistance profile: MDR HIV
• PPL-100, prodrug of PL-100, is an oral HIV drug in clinical trials
• Safety in animal models
– No observed adverse effect levels in rats and dogs
equivalent to ≥ 10g per day in man
– Favorable cardiovascular safety pharmacology and
genotoxicity results
• Inexpensive and easy to manufacture: 5 synthesis steps
• PPL-100 has a favorable formulation: capsules, water soluble
and bioavailable, co-formulation with other anti-virals
• PPL-100 is IP protected through 2023
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Feedback from 15th IAS Conference
3. New strategies:
•
Kaletra monotherapy
•
Fosamprenavir/r vs Lopinavir/r
•
tenofovir/FTC vs AZT/3TC
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Kaletra monotherapy
Three randomised trials using different study
designs came to similar conclusions:
“For the majority of patients who have never
failed on a Protease Inhibitor containing regimen,
including naïve patients,
Kaletra (LPV/r) monotherapy may be an
effective, virologically suppressive and well
tolerated regimen characterised by a high
genetic barrier and by very low incidences of viral
resistance.”
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Time from LPV/r monotherapy to 1st of 2 VL > 50 c/mL
LPV/r maintenance versus corresponding EFV subjects
% Maintaining Response
100%
90%
80%
62%
60%
40%
P<0.001 (log-rank test)
20%
LPV/r Arm
EFV Arm
0%
0
3rd
No. at risk
LPV/r Arm
EFV Arm
8
16
24
32
40
48
56
64
72
Weeks since switch to maintenance (LPV/r arm) or
consecutive HIV-1 RNA value <50 copies/mL (EFV arm)
92
43
67
36
48
31
Cameron THLB0201
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Time from LPV/r monotherapy to 1st of 2 VL > 500 c/mL
LPV/r maintenance versus corresponding EFV subjects
% Maintaining Response
100%
95%
84%
80%
60%
40%
p=0.18 (log-rank test)
20%
LPV/r Arm
EFV Arm
0%
0
No. at risk
LPV/r Arm
EFV Arm
8
16
24
32
40
48
56
64
72
Weeks since switch to maintenance (LPV/r arm) or
3rd consecutive HIV-1 RNA value <50 copies/mL (EFV arm)
92
43
83
36
63
31
Cameron THLB0201
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Kaletra monotherapy
3 posters including 2 from UK
Examples of individual cases: tolerability, adherence etc
• In developed countries: treatment naïve, reduction NOT
treatment experienced, or individualised:
Higher viral load rebound, viral failure, resistance
• In access countries: as second-line therapy
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Fosamprenavir/r vs lopinavir/r
Median baseline CD4 ~ 200 cells/mm3 (with 15-18% < 50 cells/mm3) and viral load 5.1 log
copies/mL (with 50% over 100,000 copies/mL). Median age was 37 years; 78% were male; 58%
were white/Caucasian; and 11% were CDC Class C.
Fosamprenavir/r vs lopinavir/r in treatment-naive patients: 48-week results
FPV/r
LPV/r
N
434
444
% VL <400 c/mL, (%) *
73%
71%
% VL <50 c/mL (%)
66%
65%
Median CD4 change c/mm3 (IQR)
+176 (106-281)
+191 (124-287)
Virological failure; n (%)
16 (4%)
24 (5%)
Drug-related Grade 2-4 AEs; n (%)
55 (13%)
46 (10%)
Discontinuations due to AEs; n (%)
53 (12%)
43 (10%)
• (95% CI -3.26, 5.47)
•very high adherence rates (calculated by percentage of returned pills) of >/= 98% for the
protease inhibitors and 99.4% for abacavir/3TC.
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
TDF/FTC/EFV vs AZT/3TC/EFV
Baseline median age 37, 14% female, 59% white, median viral load 5.0
copies/mL, median CD4 237 cells/mm3
ITT, n=509, (n=22) with baseline NNRTI mutations
Week 96 results
TDF+FTC arm (n=244) CBV arm (n=243)
HIV RNA<400 c/mL
76%
64%
(p=0.004)
HIV RNA<50 c/mL
69%
63%
(p=0.15)
CD4 cell incease
270
237
(p=0.036)
A/e discont.
5%
11%
(p<0.001)
(most common: anemia, nausea, fatigue, vomiting, rash)
Renal safety profile was also similar (serum creatinine, Cockcroft-Gault GFR (p=0.05).
Weight increase
2.7kg
0.5kg
(p<0.001)
DEXA, median limb fat
7.7 kg, n=144
5.5 kg, n=136
(p<0.001)
No patient developed the K65R mutation.
Significantly more patients on AZT/3TC developed M184V/I (9 vs 2, p=0.037).
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Feedback from 15th IAS Conference
4.Other issues
• Prevention: circumcision, PrEP, ARV treatment, HSV
treatment
• European resistance data
• UK studies: late diagnosis, use of STARHS,
complementary medicine and ARV interactions, UAI
behavioural 5 cities study
• Global: TB, HCV coinfection, children
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Feedback from 15th IAS Conference
•
Circumcision studies 3-4 oral presentations, 5+ posters
•
PrEP
•
European resistance - SPREAD - 1083 newly diagnosed individuals from 17
countries (20% recent infections <1 year): 44% gay/bi, 42% heterosexual. 9%
IVDU; 34% outside Western Europe. From 13 sub-types, ~9% had IASdefined resistance - slightly higher in recent infections vs undefined
infections. RTI -5-5% (30% >1 mutation); PI - 3%, NNRTI 2.6%; <1% dualclass resistance. TUAB 0101.
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Feedback from 15th IAS Conference
•
Use of complementary alternative medicine - 10% - Cross sectional multiple choice
questionnaire of ~250 patients: 154 (60%) using herbal remedies, 88 (34%) using
physical treatment and 67 (25%) using both. 25 pts (10%) were asked to stop CAM
because of potential interaction with ARVs, and slightly higher proportion (n=30) asked to
be cautious. Only 50% had discussed CAM with their HIV doctor. - MOPE 0219
•
UK late diagnosis and mortality - MOPE 0067, MOPE0296;
•
STARHS use - Brighton - 80/665 diagnoses identified as recent infections increasing
from 20% in 1996 to 50% in 2004 - MOPE 0504
•
UK UAI and behaviour of gay men in 5 UK cities ~ 4380 questionnaires and 3660 swabs.
HIV prevalence - 12-14% in London and Brighton, 9% in Manchester, 3% in Glasgow and
5% in Edinburgh. 41% (range 33/48%, Manchester/Glasgow) HIV+ men were
undiagnosed, and 50% (n=70) reported most recent result as HIV-negative (therefore
believing they were HIV-negative). MOPE 0517 A second behaviour study reported
higher rates of serosorting in heterosexual African HIV+ individuals - WEPDC05
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
The overlapping challenges of two epidemics: HIV and TB
• TB is a leading cause of death in
Africa and, in some settings, the
leading cause of death among
people with HIV
• First 3-6 months after starting
HAART may even have increase in
TB followed by decline
• Early diagnosis is required to further
decrease this risk
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
High prevalence and mortality from extensively-drug resistant
(XDR) TB in TB/HIV co-infected patients in rural South Africa
Survival from
time of Sputum
Collection
1.1
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
-.1
0
30
60
90
120
150
180
210
240
Days since Sputum Collected
Gandhi THLB0210
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Hepatitis C/HIV co-infection in IDUs is a major issue in Europe
<20%
11%
20-40%
0%
40-60%
25.5%
60-80%
>80%
20%
17%
15%
16%
9%
6%
6%
6%
12%
22%
20%
49%
66%
87%
95%
34%
79%
83%
82%
68%
81
5% %
71%
2%
29%
29%
16%
69%
32% 7% 1%
11%
<1%
15% 49%
59%
14% 5%
3%
5%
8%
80%
16%
82%
86%
68%
57%61%
16%
2%
16%
IDU as % of all HIV/AIDS cases with known transmission route
NOTE: % of AIDS cases in countries not reporting HIV
Sources: EuroHIV; national reports;
Kruk WEAX0101
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Children need to be on the global agenda
Children make up –
• 14% of new global infections,
• 18% of HIV related deaths
• 5.6% of persons living with
HIV
KLINE WESY0104
UNICEF estimates that 660,000 children urgently require
antiretroviral treatment, most of them in sub-Saharan Africa
“Care of the infected and uninfected child must include treatment
of their mothers and families”
Ruth Nduati
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Successful clinical outcomes in children
Before
2 mo
12 mo
18 mo
Puthanakit, WESY0102
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
“Open your purses, we need more nurses”,
• The issue of nursing staff needs was a
common theme through many
presentations in Track B.
• In sub Saharan Africa alone, more than
600,000 nurses are needed to deliver
HIV care and other services
• Nurses staff need to be supported and
appropriately utilised
“If I’d wanted to be an undertaker, I wouldn’t have trained as a nurse”
South African nurse, quoted by Alta Van Dyke
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006
Thanks
Slides:
• Rapporteur summary of Track B: James McIntyre
• New drugs from Late Breaker abstracts online
http://www.ias.se
(Follow link to conference, then conference programme, then
related session link)
Simon Collins: Toronto feedback: HIV I-Base
UK-CAB September 2006