Kuala Lumpur, Malaysia, 30 June - 3 July 2013 TRACK B RAPPORTEUR REPORT Jürgen Rockstroh on behalf of… Sharon Walmsley Jintanat Ananworanich

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Mark BlochJason Brophy David Hardy Jan van Lunzen

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 WHEN TO START WHAT TO START

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

17 April WHO ART Guidelines in Adults: summary Topic When to start CD4 ≤200 - Consider 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 1 st 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 2 nd 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 3 rd Line None DRV/r, RAL, ETV Viral Load Testing 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) 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) 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) 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 for Pregnant 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 initiation Major issue now is not “when to start” but “whether to stop” Pregnancy/Breast Feeding warrants ART initiation Major 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

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Is ART becoming more successful?

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

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Is there room for better ART (more efficacious, less toxic, easier to take)

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 mg EFV qd (2 x 200 mg EFV + 1 x 200 mg matched placebo) II. TDF/FTC 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 (-2.1, 5.8)0.36 <10 5 strata (-2.7, 6.8)0.40 ≥ (-5.3, 8.6)0.64 NC=F (-0.8, 9.4)0.10 <10 5 strata (-0.9, 12.1)0.09 ≥ (-6.1, 10.2)0.63 PP (-1.5, 3.3)0.47 <10 5 strata (-1.5, 4.0)0.70 ≥ (-4.1, 4.8)1.00 favours 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 design HIV-infected children age < 18 yrs with VL < 50 copies/ml (n=200) HIV-infected children age < 18 yrs with VL < 50 copies/ml (n=200) Standard dose of LPV/r (FDA recommended dose) Standard dose of LPV/r (FDA recommended dose) Low dose of LPV/r (70% of standard 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 Sample size calculation: Rate of failure in standard arm 12%, Non-inferiority 95% CI within -12%, power 80%, alpha 0.05, one-sided Body weightStandard LPV/rLow dose LPV/r kg300/75 mg200/50 mg kg400/100 mg300/75 mg Stratify by research sites and body weight Puthanakit T et al., IAS 2013; MOAB0101

HN152 – PEARL Study Virological efficacy at week 48 HIV-RNAStandard dose n/N(%) Low dose n/N(%) Difference ( 95%CI) P- value <50 copies/mL90/98(91.8)89/101(88.1)-3.7(-12.0 to 4.6)0.38 <400 copies/mL92/98(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-RNAStandard dose n/N(%) Low dose n/N(%) Difference ( 95%CI) P- value <50 copies/mL89/95(93.7)89/97(91.8)-1.9(-9.4 to 5.5 )0.61 <400 copies/mL91/95(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 kg (aOR 3.6) At week 48; 8 patients had HIV HIV RNA > 400 copies/ml Factors related to virological failure Poor adherence (aOR =3.3) and Weight kg (aOR 3.6) Puthanakit T et al., IAS 2013; MOAB0101

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 New drugs

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03. SAILING (ING111762) Study Design Week 48 primary analysis Randomization Week 24 planned 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/mL a 1:1 Randomization stratified by HIV-1 RNA (≤ or >50,000), DRV/r use and # of fully active drugs HIV ART-experienced, INI-naive HIV-1 RNA >400 c/mL a 1:1 Randomization stratified by HIV-1 RNA (≤ or >50,000), DRV/r use and # of fully active drugs DTG 50 mg QD + RAL PBO + BR DTG 50 mg QD + RAL PBO + BR RAL 400 mg BID + DTG 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 difference Favors RAL Favors DTG -20%020% %

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 First study of repeat dose co-administration of GSK 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

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 What to learn about second-line therapy?

EARNEST Trial design HIV positive adolescents / adults (n=1200) 1 st line NNRTI-based regimen >12m; > 90% adherence last 1m Failure by WHO (2010) clinical, CD4 (VL-confirmed) or VL criteria RANDOMIZE PI NRTIs (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/mm 3 at 96 weeks AND  VL 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=0.08 P< Paton N et al., IAS 2013; WELBB02

Mean % change in BMD 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

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Long-term complications

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 & Gender- adjusted HR [95%CI]; p-val Multivariate adjusted HR* [95%CI]; p-val HIP FRACTURES HIV Uninfected7, [ ]REF HIV Infected [ ] 6.16 [ ]; p< [ ]; p<0.001 ALL CLINICAL FRACTURES HIV Uninfected24, [ ]REF HIV Infected [ ] 2.67 [ ]; p< [ ]; p=0.002 IR = incidence rate; py = person-years at risk; CI = confidence interval. a Further 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

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Hepatitis

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 New HCV /HIV epidemiological data. Center for Disease Analysis 2013 Andrieux-Meyer I, IAS 2013

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 p< Probability of remaining free of decompensation F0 F1 F2 F3 F4 LSM ≤6 KPa LSM KPa LSM KPa LSM KPa LSM ≥21 KPa According to fibrosis stage (LB)According to LSM category Median (IQR) follow-up: 5 ( ) 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%). Probability of remaining free of decompensation Macias J et al., IAS 2013, Kula Lumpur, Malaysia, TUABO1

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 W4 W12 W24 W4 W12 W24 TelaprevirBoceprevir Early virological response (n=80) 70% previous non-responders, 30% cirrhotics Salmon D et al., IAS 2013, Kula Lumpur, Malaysia, TUABO1

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Overcoming the cost barrier 48 Lacombe K, IAS 2013, plenary

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Patient B (2.6 years post-HSCT) SampleInputAssayResult / Detection Limit PBMC DNA50 x 10 6 PBMCqPCR for LTR/gag Not Detected* < 0.04 copies/10 6 PBMC Peripheral CD4+ T Cells 150 x 10 6 CD4+ T cells Co-cultureNot Detected < 0.01 IU/10 6 CD4+ cells Rectal BiopsiesDNA from 1.3 x 10 6 cells qPCR for LTR/gag Not Detected < 2 copies/10 6 cells Minimum log 10 reduction of PBMC DNA after alloHSCT, CCR5 wildtype No RNA and/or DNA detectable after 15 weeks off ART PBMC DNACD4+ T Cell Count Henrich T et al. WELBA05

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Track B Team