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


Mark Bloch Jason Brophy

David Hardy Jan van Lunzen


WHEN TO STARTWHAT TO START


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


Is ART becoming more successful?


Efficacy: all studies from 1994 to 2010

Frederick J. Lee, Janaki Amin, Andrew Carr, IAS 2013; WEAB0104


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


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%


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

18

Spreen W et al., IAS 2013; WEAB0103


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


Long-term complications


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


Hepatitis


New HCV /HIV epidemiological data. Center for Disease Analysis 2013

Andrieux-Meyer I, IAS 2013


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


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


Overcoming the cost barrier

http://www.medicinespatentpool.org

48

Lacombe K, IAS 2013, plenary


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


Track B Team

track b rapporteur report

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