TRACK B RAPPORTEUR
REPORT
Jürgen Rockstroh
on behalf of…
Sharon Walmsley
Jintanat Ananworanich
www.ias2013.org
Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Mark Bloch
Jason Brophy
Jan van Lunzen
David Hardy
www.ias2013.org
Kuala Lumpur, Malaysia , 30 June - 3 July 2013
WHEN TO START
WHAT TO START
www.ias2013.org
Kuala Lumpur, Malaysia , 30 June - 3 July 2013
When to start in adults: what is new in the 2013 Guidelines
Considering both the individual and the Public Health benefit….
• Threshold moved to < 500 CD4
• Priority for reaching all HIV+ symptomatic persons
and those with CD4 ≤ 350
• More CD4-independent situations for ART initiation (in
addition to HIV/TB coinfection and HBV advanced liver
disease):
– HIV serodiscordant couples,
– Pregnancy
– Children less than 5 years of age
GL are a “tool” for countries to produce their own guidelines:
they will adapt the new threshold(s) with operational / programmatic local context
Vella S IAS 2013
www.ias2013.org
Kuala Lumpur, Malaysia , 30 June - 3 July 2013
2013 WHO ART Guidelines in Adults: summary
Topic
When to
start
2002
CD4 ≤200
2003
CD4 ≤ 200
2006
2010
CD4 ≤ 200
CD4 ≤ 350
CD4 ≤ 500
- Consider 350
- CD4 ≤ 350 for TB
-Irrespective CD4 for TB
and HBV
-Irrespective CD4 for TB,
HBV, PW and SDC
- CD4 ≤ 350 as priority
Earlier initiation
1st Line
2013
8 options
4 options
8 options
6 options &FDCs
2 options & FDCs
- AZT preferred
- AZT preferred
- AZT or TDFpreferred
- d4T dose reduction
- AZT or TDF preferred
- d4T phase out
- TDF and EFV preferred
across all populations
Simpler treatment
2nd Line
Boosted and
non-boosted
PIs
Boosted PIs
Boosted PI
Boosted PI
Boosted PIs
-IDV/r LPV/r,
SQV/r
- ATV/r, DRV/r, FPV/r
LPV/r, SQV/r
- Heat stable FDC:
ATV/r, LPV/r
- Heat stable FDC:
ATV/r, LPV/r
Less toxic, more robust regimens
3rd Line
None
None
None
DRV/r, RAL, ETV
DRV/r, RAL, ETV
Viral Load
Testing
No
No
Yes
Yes
Yes
(Desirable)
(Tertiary centers)
(Phase in approach)
(preferred for monitoring,
use of PoC, DBS)
Better monitoring
An important step towards the global alignment
HIV/AIDS
Department
17 April
2013
of the HIV standard of care
New Recommendations in 2013 Guidelines for
Pregnant Women
All pregnant and breastfeeding women infected with HIV should initiate triple
ARVs (ART), which should be maintained at least for the duration of mother-tochild transmission risk. Women meeting treatment eligibility criteria should
continue lifelong ART .
(strong recommendation, moderate-quality evidence)
“Option B+”
“Option B”
For programmatic and operational
reasons, particularly in generalized
epidemics, all pregnant and
breastfeeding women infected with
HIV should initiate ART as lifelong
treatment.
In some countries, for women who
are not eligible for ART for their
own health, consideration can be
given to stopping the ARV regimen
after the period of mother-to-child
transmission risk has ceased.
(conditional recommendation, low-quality
evidence)
(conditional recommendation, low-quality
evidence)
TDF + 3TC
(or FTC) + EFV as a fixed-dose
combination
(FDC)
is recommended
Pregnancy/Breast
Feeding
warrants
ART
initiation as the
preferred option to initiate ART
Major issue now
not “when moderate-quality
to start” butevidence)
“whether to stop”
(strongisrecommendation,
New guidelines increase ART eligibility to up to
25.9 million people
9.7 million
16.2 million
Is ART becoming more
successful?
www.ias2013.org
Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Efficacy: all studies from 1994 to 2010
Frederick J. Lee, Janaki Amin, Andrew Carr, IAS 2013; WEAB0104
www.ias2013.org
Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Is there room for better ART (more
efficacious, less toxic, easier to
take)
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Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Encore1 study design
A randomized, double-blind, placebo-controlled, non-inferiority clinical trial
to compare the safety and efficacy of reduced dose EFV with standard dose
EFV plus 2N(t)RTI in ART-naïve HIV-infected individuals over 96 weeks
Patient population
ART-naïve HIV-infected adults with no prior AIDS, plasma HIV-1 RNA (pVL)
>1,000 copies/mL, 50 <CD4+ T cells/µL <500, creatinine clearance ≥50
mL/min, no pregnancy or nursing mothers
Randomisation
I. TDF/FTC + 400 mg EFV qd
(2 x 200 mg EFV + 1 x 200 mg matched placebo)
II. TDF/FTC + 600 mg EFV qd
(3 x 200 mg EFV)
1:1 (400mg:600mg), stratified by clinical site and screening pVL
Puls R for the ENCORE1 Study Group, AS 2013; WELBB01
Primary endpoint: non inferiority at week 48
EFV400 EFV600
%
%
Difference (95%CI)
p
ITT
94.1
92.2
1.8 (-2.1, 5.8) 0.36
<105 strata
94.9
92.9
2.0 (-2.7, 6.8) 0.40
≥105
92.7
91.1
1.7 (-5.3, 8.6) 0.64
NC=F
90.0
85.8
4.3 (-0.8, 9.4) 0.10
<105 strata
90.4
84.8
5.6 (-0.9, 12.1) 0.09
≥105
89.5
87.5
2.0 (-6.1, 10.2) 0.63
PP
98.3
97.4
0.9 (-1.5, 3.3) 0.47
<105 strata
≥105
98.9
97.4
97.6
97.0
1.2 (-1.5, 4.0) 0.70
0.3 (-4.1, 4.8) 1.00
favours
EFV600
-15
-10
-5
0
5
10
15
Difference in percentage of participants with pVL <200 copies/mL
Puls R for the ENCORE1 Study Group, AS 2013; WELBB01
favours
EFV400
Study design
HIV-infected children age < 18 yrs with VL < 50 copies/ml
(n=200)
Randomize 1:1
Stratify by research sites and body weight
Standard dose of LPV/r
Low dose of LPV/r
(FDA recommended dose)
(70% of standard dose)
Body weight
25-35 kg
Standard LPV/r
300/75 mg
Low dose LPV/r
200/50 mg
35-50 kg
400/100 mg
300/75 mg
Sample size calculation: Rate of failure in standard arm 12%,
Non-inferiority 95% CI within -12%, power 80%, alpha 0.05, one-sided
Puthanakit T et al., IAS 2013; MOAB0101
HN152 – PEARL Study
Virological efficacy at week 48
• Intention to treat (ITT) analysis (missing = failure)
HIV-RNA
Standard dose
n/N(%)
Low dose
n/N(%)
Difference
( 95%CI)
Pvalue
<50 copies/mL
90/98(91.8)
89/101(88.1)
-3.7(-12.0 to 4.6)
0.38
<400 copies/mL
92/98(93.9)
93/101(92.1)
-1.8(-8.9 to 5.4)
0.62
• Per protocol (PP) analysis (missing = censored)
HIV-RNA
Standard dose
n/N(%)
Low dose
n/N(%)
Difference
( 95%CI)
Pvalue
<50 copies/mL
89/95(93.7)
89/97(91.8)
-1.9(-9.4 to 5.5 )
0.61
<400 copies/mL
91/95(95.8)
93/97(95.9)
-0.1(-5.6 to 5.8)
0.98
At week 48; 8 patients had HIV HIV RNA > 400 copies/ml
Factors related to virological failure
Poor adherence (aOR =3.3) and Weight 35-50 kg (aOR 3.6)
Puthanakit T et al., IAS 2013; MOAB0101
HN152 – PEARL Study
New drugs
www.ias2013.org
Kuala Lumpur, Malaysia , 30 June - 3 July 2013
SAILING (ING111762) Study Design
HIV ART-experienced,
INI-naive
HIV-1 RNA >400 c/mLa
1:1 Randomization
stratified by HIV-1 RNA
(≤ or >50,000),
DRV/r use and # of fully
active drugs
Randomization
DTG 50 mg QD +
RAL PBO + BR
RAL 400 mg BID +
DTG PBO + BR
Week 24
planned interim
Week 48
primary analysis
a
At Screening and a second consecutive test >400 c/mL within 4 months prior to Screening (if Screening HIV-1 RNA >1000 c/mL,
no additional HIV-1 RNA assessment was needed).
PBO, placebo; BR, background regimen comprising at least 1 and no more than 2 active agents.
Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.
Primary Endpoint: HIV-1 RNA <50 c/mL at
Week 48
95% CI for difference
Favors
RAL
Favors
DTG
0.7 7.4
-20% -12%
0
Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.
14.2
20%
First study of repeat dose co-administration of
GSK1265744 and TMC278 long-acting parenteral
nanosuspensions
• GSK744 LAP and TMC278 LA formulations were generally safe and well
tolerated
• Mild-moderate injection site reactions occurred in a majority of study
participants; the overall tolerability profile supports evaluation in
longer-term clinical studies
• GSK744 LAP pharmacokinetics indicate q 4 weekly or less frequent
injections will maintain plasma drug levels well above 4x PA-IC90
• TMC278 LA pharmacokinetics suggest q 4 weekly injections give
plasma levels comparable to approved oral dose of rilpivirine
25mg/daily
• These results, along with an ongoing study of GSK744 + rilpivirine as an
oral two-drug maintenance regimen in HIV-infected patients, will
enable a similar study using the two-drug, long-acting injectable
regimen
Spreen W et al., IAS 2013; WEAB0103
18
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Kuala Lumpur, Malaysia , 30 June - 3 July 2013
What to learn about second-line
therapy?
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Kuala Lumpur, Malaysia , 30 June - 3 July 2013
EARNEST Trial design
HIV positive adolescents / adults (n=1200)
1st line NNRTI-based regimen >12m; > 90% adherence last 1m
Failure by WHO (2010) clinical, CD4 (VL-confirmed) or VL criteria
RANDOMIZE
PI + 2-3 NRTIs
PI + RAL
(NRTIs according to
local standard of
care)
PI + RAL
(12 wk induction)
PI
(Monotherapy)
FOLLOW-UP FOR 144 WEEKS
Primary outcome at week 96:
Good HIV disease control – defined as all of:
 Alive and no new WHO4 events from 0-96 weeks AND
 CD4 cell count > 250 cells/mm3 at 96 weeks AND
 VL<10,000 c/ml OR >10,000 c/ml without PI res. mutations at 96 weeks
Paton N et al., IAS 2013; WELBB02
Primary endpoint at 96 weeks
Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96
• Good disease control: PI/NRTI: 60% PI/RAL: 64% PI mono+: 56%
• Risk diff (95% CI): PI/RAL – PI/NRTI:
+4.2% (-2.4%,+10.8%;
P=0.21)
• Risk diff (95% CI): PImono+
– PI/NRTI:
-4.1% (-10.8%, +2.6%;
P<0.0001
P=0.23)
P=0.08
Paton N et al., IAS 2013; WELBB02
Mean % change in BMD
Proximal Femur
Lumbar Spine
Mean % change (SE) in BMD
from week 0 to 48
0
r/LPV+2-3NtRTI
r/LPV+RAL
-1
Mean difference
between arms
-2
-3
-2.0%
-4
-2.9%
-5
-4.2%
-6
-5.2%
All analyses are adjusted for baseline imbalances in
sex, BMI and smoking status
Hoy J et al., IAS 2013; WELBB05
Proximal femur
-2.4% (-3.5 to -1.2)
p=0.0001
Lumbar spine
-2.1% (-3.3 to-0.6)
p=0.0006
Long-term complications
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Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Hazard Ratio (HR) for hip, and all clinical fractures for
HIV infected VS uninfected patients.
Number of
fractures
Fracture IR/1,000
py [95%CI]
Age & Genderadjusted HR [95%CI];
p-val
Multivariate
adjusted HR*
[95%CI]; p-val
HIP FRACTURES
HIV
Uninfected
HIV
Infected
7,299
2.37 [2.31-2.42]
12
2.03 [1.15-3.57]
REF
6.16 [3.49-10.86];
p<0.001
REF
4.72 [2.35-9.47];
p<0.001
ALL CLINICAL FRACTURES
HIV
Uninfected
HIV
Infected
24,408
7.93 [7.83-8.03]
49
8.03 [6.07-10.62]
REF
2.67 [2.01-3.53];
p<0.001
REF
1.75 [1.24-2.48];
p=0.002
IR = incidence rate; py = person-years at risk; CI = confidence interval.
aFurther adjusted for body mass index, smoking, alcohol use, oral corticosteroid use, and the following comorbid conditions (as listed in the
Charlson comorbidity index): type 2 diabetes, chronic obstructive pulmonary disease, heart failure, myocardial infarction, rheumatoid
arthritis, cardiovascular disease, peripheral vascular disease, renal failure, liver disease, malignancy, paraplegia, ulcer, and dementia.
Knobel H et al., IAS 2013; WEABO205
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Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Hepatitis
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Kuala Lumpur, Malaysia , 30 June - 3 July 2013
New HCV /HIV epidemiological data. Center
for Disease Analysis 2013
Andrieux-Meyer I, IAS 2013
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Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Study to compare the prognostic performance of liver biopsy with
that of liver stiffness measurement to predict survival and liver
decompensations
Median (IQR) follow-up: 5 (4.2-5.4) years. Lost to follow-up: 26 (8.8%) patients.
Decompensations: 21 (7.1%, 95%CI: 4.1%-10%).
- Ascites: 12 (57%)
- Portal hypertensive gastrointestinal bleeding: 4 (19%).
- Hepatic encephalopathy: 2 (9.5%).
p<0.0001
F0
F1
F2
F3
F4
Macias J et al., IAS 2013, Kula Lumpur, Malaysia, TUABO1
According to LSM category
Probability of remaining free of decompensation
Probability of remaining free of decompensation
According to fibrosis stage (LB)
www.ias2013.org
p<0.0001
LSM ≤6 KPa
LSM 6.1-8.9 KPa
LSM 9-14.6 KPa
LSM 14.6-21 KPa
LSM ≥21 KPa
Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Early virological response (n=80)
70% previous non-responders, 30% cirrhotics
80
80%
60
40
20
60
20
40
69%
74%
80
100
Boceprevir
100
Telaprevir
28/38
W4
W12
W24
60%
2/10
6/10
6/10
W4
W12
W24
20%
0
40/50
0
41/59
60%
Salmon D et al., IAS 2013, Kula Lumpur, Malaysia, TUABO1
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Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Overcoming the cost barrier
http://www.medicinespatentpool.org
Lacombe K, IAS 2013, plenary
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Kuala Lumpur, Malaysia , 30 June - 3 July 2013
48
Patient B (2.6 years post-HSCT)
PBMC DNA
CD4+ T Cell Count
Sample
Input
Assay
Result / Detection Limit
PBMC DNA
50 x 106 PBMC
qPCR for
LTR/gag
Not Detected*
< 0.04 copies/106 PBMC
Peripheral
CD4+ T Cells
150 x 106 CD4+ T Co-culture
cells
Not Detected
< 0.01 IU/106 CD4+ cells
Rectal Biopsies
DNA from
1.3 x 106 cells
Not Detected
< 2 copies/106 cells
qPCR for
LTR/gag
Minimum 3.5 - 4 log10 reduction of PBMC DNA after alloHSCT, CCR5 wildtype
T et ,al.
WELBA05
No RNA and/or DNA detectable after www.ias2013.org
15 weeks off ART
KualaHenrich
Lumpur, Malaysia
30 June
- 3 July 2013
Track B Team
www.ias2013.org
Kuala Lumpur, Malaysia , 30 June - 3 July 2013