TRACK B RAPPORTEUR REPORT
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Transcript of TRACK B RAPPORTEUR REPORT
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
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
David Hardy Jan van Lunzen
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WHEN TO STARTWHAT TO START
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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
17 April 2013
2013 WHO ART Guidelines in Adults: summary 2013 WHO ART Guidelines in Adults: summary
Topic 2002 2003 2006 2010 2013When to start
CD4 ≤200 CD4 ≤ 200 CD4 ≤ 200- Consider 350 - CD4 ≤ 350 for TB
CD4 ≤ 350-Irrespective CD4 for TB and HBV
CD4 ≤ 500-Irrespective CD4 for TB, HBV, PW and SDC- CD4 ≤ 350 as priority
1st Line 8 options- AZT preferred
4 options- AZT preferred
8 options- AZT or TDFpreferred- d4T dose reduction
6 options &FDCs- AZT or TDF preferred- d4T phase out
2 options & FDCs- TDF and EFV preferred
across all populations
2nd Line Boosted and non-boosted PIs
Boosted PIs-IDV/r LPV/r, SQV/r
Boosted PI- ATV/r, DRV/r, FPV/r LPV/r, SQV/r
Boosted PI - Heat stable FDC: ATV/r, LPV/r
Boosted PIs - Heat stable FDC: ATV/r, LPV/r
3rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV
Viral LoadTesting
No No (Desirable)
Yes(Tertiary centers)
Yes(Phase in approach)
Yes(preferred for monitoring, use of PoC, DBS)
Earlier initiation
Simpler treatment
Less toxic, more robust regimens
Better monitoring
HIV/AIDS Department An important step towards the global alignment
of the HIV standard of care
“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.
(conditional recommendation, low-quality evidence)
All pregnant and breastfeeding women infected with HIV should initiate triple ARVs (ART), which should be maintained at least for the duration of mother-to-child transmission risk. Women meeting treatment eligibility criteria should continue lifelong ART .(strong recommendation, moderate-quality evidence)
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)
New Recommendations in 2013 Guidelines forPregnant Women
“Option B”
TDF + 3TC (or FTC) + EFV as a fixed-dose combination (FDC) is recommended as the preferred option to initiate ART
(strong recommendation, moderate-quality evidence)
Pregnancy/Breast Feeding warrants ART initiationMajor issue now is not “when to start” but “whether to stop”
New guidelines increase ART eligibility to up to 25.9 million people
9.7 million
16.2 million
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Is ART becoming more successful?
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Efficacy: all studies from 1994 to 2010
Frederick J. Lee, Janaki Amin, Andrew Carr, IAS 2013; WEAB0104
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Is there room for better ART (more efficacious, less toxic, easier to take)
Encore1 study designA 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 populationART-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
RandomisationI. 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 98.9 97.6 1.2 (-1.5, 4.0) 0.70
≥105 97.4 97.0 0.3 (-4.1, 4.8) 1.00
-15 -10 -5 0 5 10 15favours EFV600
favours EFV400
Difference in percentage of participants with pVL <200 copies/mL
Puls R for the ENCORE1 Study Group, AS 2013; WELBB01
HN152 – PEARL Study
Study designHIV-infected children age < 18 yrs with VL < 50 copies/ml
(n=200)
Standard dose of LPV/r(FDA recommended dose)
Low dose of LPV/r(70% of standard dose)
Randomize 1:1
Sample size calculation: Rate of failure in standard arm 12%, Non-inferiority 95% CI within -12%, power 80%, alpha 0.05, one-sided
Body weight Standard LPV/r Low dose LPV/r25-35 kg 300/75 mg 200/50 mg35-50 kg 400/100 mg 300/75 mg
Stratify by research sites and body weight
Puthanakit T et al., IAS 2013; MOAB0101
HN152 – PEARL Study
Virological efficacy at week 48HIV-RNA Standard dose
n/N(%)Low dose
n/N(%)Difference
( 95%CI)P-
value
<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
• Intention to treat (ITT) analysis (missing = failure)
• Per protocol (PP) analysis (missing = censored)HIV-RNA Standard dose
n/N(%)Low dose
n/N(%)Difference ( 95%CI)
P-value
<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/mlFactors related to virological failure
Poor adherence (aOR =3.3) and Weight 35-50 kg (aOR 3.6) Puthanakit T et al., IAS 2013; MOAB0101
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New drugs
Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.
SAILING (ING111762) Study Design
Week 48primary analysis
Randomization Week 24planned interim
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.
HIV ART-experienced, INI-naive
HIV-1 RNA >400 c/mLa
1:1 Randomizationstratified by HIV-1 RNA
(≤ or >50,000), DRV/r use and # of fully
active drugs
DTG 50 mg QD + RAL PBO + BR
RAL 400 mg BID + DTG PBO + BR
Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.
Primary Endpoint: HIV-1 RNA <50 c/mL at Week 48
95% CI for differenceFavors
RALFavors
DTG
-20% 0 20%
7.40.7 14.2
-12%
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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
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Spreen W et al., IAS 2013; WEAB0103
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What to learn about second-line therapy?
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 (NRTIs according to
local standard of care)
PI + RAL
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
• 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=0.23)
Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96
P=0.08P<0.0001
Paton N et al., IAS 2013; WELBB02
Mean % change in BMD
-6
-5
-4
-3
-2
-1
0
Proximal Femur Lumbar Spiner/LPV+2-3NtRTIr/LPV+RAL
Mea
n %
ch
ang
e (S
E)
in B
MD
fr
om
wee
k 0
to 4
8 Mean difference between arms
Proximal femur-2.4% (-3.5 to -1.2) p=0.0001
Lumbar spine-2.1% (-3.3 to-0.6)
p=0.0006
All analyses are adjusted for baseline imbalances in sex, BMI and smoking status
-5.2%
-4.2%
-2.9%
-2.0%
Hoy J et al., IAS 2013; WELBB05
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Long-term complications
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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 & Gender-adjusted HR [95%CI];
p-val
Multivariate adjusted HR* [95%CI]; p-val
HIP FRACTURESHIV Uninfected 7,299 2.37 [2.31-2.42] REF REFHIV Infected 12 2.03 [1.15-3.57]
6.16 [3.49-10.86]; p<0.001
4.72 [2.35-9.47]; p<0.001
ALL CLINICAL FRACTURESHIV Uninfected 24,408 7.93 [7.83-8.03] REF REFHIV Infected 49 8.03 [6.07-10.62]
2.67 [2.01-3.53]; p<0.001
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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Hepatitis
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New HCV /HIV epidemiological data. Center for Disease Analysis 2013
Andrieux-Meyer I, IAS 2013
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Study to compare the prognostic performance of liver biopsy with that of liver stiffness measurement to predict survival and liver
decompensations
p<0.0001 p<0.0001Prob
abili
ty o
f rem
aini
ng fr
ee o
f dec
ompe
nsati
on
F0F1F2F3F4
LSM ≤6 KPaLSM 6.1-8.9 KPaLSM 9-14.6 KPaLSM 14.6-21 KPaLSM ≥21 KPa
According to fibrosis stage (LB) According to LSM category
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%).
Prob
abili
ty o
f rem
aini
ng fr
ee o
f dec
ompe
nsati
on
Macias J et al., IAS 2013, Kula Lumpur, Malaysia, TUABO1
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W4 W12 W24 W4 W12 W24
Telaprevir Boceprevir
020
4060
8010
0
2/10 6/10 6/10
20%
60% 60%
020
4060
8010
0
41/59 40/50 28/38
69%80%
74%
Early virological response (n=80)70% previous non-responders, 30% cirrhotics
Salmon D et al., IAS 2013, Kula Lumpur, Malaysia, TUABO1
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Overcoming the cost barrier
http://www.medicinespatentpool.org
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Lacombe K, IAS 2013, plenary
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Patient B (2.6 years post-HSCT)
Sample Input Assay Result / Detection Limit
PBMC DNA 50 x 106 PBMC qPCR for LTR/gag
Not Detected*< 0.04 copies/106 PBMC
PeripheralCD4+ T Cells
150 x 106 CD4+ T cells
Co-culture Not Detected< 0.01 IU/106 CD4+ cells
Rectal Biopsies DNA from1.3 x 106 cells
qPCR for LTR/gag
Not Detected< 2 copies/106 cells
Minimum 3.5 - 4 log10 reduction of PBMC DNA after alloHSCT, CCR5 wildtypeNo RNA and/or DNA detectable after 15 weeks off ART
PBMC DNA CD4+ T Cell Count
Henrich T et al. WELBA05
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Track B Team