Track B Summary Jeff Lennox Emory University Atlanta

Special thanks to my fellow Track B Rapporteurs: Annie Luetkemeyer San Francisco Trip Gulick New York Juergen Rockstroh Bonn And to the wonderful people of Rome for their hospitality!

When to Start ART

Risk of progression to AIDS or death in relation to CD4 cell levels in patients with sustained viral response to ART: COHERE cohort Results - event rates per 1000 years suppressed Most recent CD4 cell count (cells/µL) First new AIDS event or death from any cause (no. of events) Death from any cause (no. of events) <5094.9(54)64.8(38) 50-< (489)20.0(325) 200-< (548)6.9(318) 350-<5007.9(487)3.8(240)  (679)2.4(315) Similar results in an analysis of 27,108 patients in 4 M.S.F. programs in Africa- Patients who achieved a CD4 of had 1.69 AHR for mortality compared to those who achieved CD4 >500 WELB05 Heiner; TUBDP0106 Maman

Delayed Immediate Delayed Immediate HR: 0.6 [ 0.4, 0.9 ], P=0.01 Number at risk HPTN 052: Effects of early versus delayed initiation of ART on HIV clinical outcomes 1763 HIV-infected individuals were randomized to receive ART at a CD4 count of (immediate arm) or after two consecutive CD4 counts 200 (delayed arm). Death, WHO stage 4 clinical event, pulmonary TB or severe bacterial infection

New Drugs and New Strategies

7 Efficacy and safety of lersivirine vs efavirenz in antiretroviral treatment-naïve HIV-1-infected patients: Week 48 primary analysis results Randomized, double-blind Selection criteria –ARV naïve, HIV-1 RNA ≥1000 c/mL, CD4+ >200 cells/mm 3 –No RT mutations by standard genotyping Stratified by viral load (<100,000 or ≥100,000 c/mL) & geographic region (A & B) Randomization 1:1:1 EFV 600 mg QD + TDF/FTC LRV 750 mg QD + TDF/FTC 048 wk96 wk 6 weeks 24 wk Primary endpoint: Patients achieving HIV-1 RNA <50 c/mL LRV 500 mg QD + TDF/FTC TUAB0101, Pozniak

/63 (86%) 51/65 (79%) Lersivirine vs efavirenz- Efficacy results through Week 48 (plasma HIV-1 RNA <50 c/mL, ITT, NC=F) Number of Subjects with AE, n (%)LRV 500 mg N = 65 LRV 750 mg N = 65 EFV 600 mg N = 63 Nausea15 (23)27 (42) 8 (13) Headache15 (23)11 (17) 9 (14) Abnormal dreams 5 (8) 12 (19) Dizziness 5 (8)4 (6) 13 (21) Rash 3 (5)1 (2) 7 (11) TUAB0101, Pozniak

Once-daily Dolutegravir, a Next Generation Integrase Inhibitor in in Antiretroviral-naïve Adults 48 Week Results from SPRING-1 (ING112276) ●Phase IIb dose-ranging, partially-blinded, N~200 ART-naïve patients ●All arms include 2 NRTI backbone given once daily ●Primary endpoint: % <50 c/mL at 16 weeks (TLOVR) ●Planned interim analysis: % <50 c/mL at 48 weeks (TLOVR) HIV-1 RNA >1000 c/mL CD4 ≥200 cells/mm 3 1:1:1:1 Randomization HIV-1 RNA >1000 c/mL CD4 ≥200 cells/mm 3 1:1:1:1 Randomization EFV 600 mg DTG 50 mg DTG 25 mg DTG 10 mg Wk 48 interim analysis Stratified by HIV RNA >100,000 or ≤ 100,000 Epzicom/Kivexa or Truvada *Post hoc analysis using bioMONTR HIV-1 EQ SuperLow Assay LLOD=2 c/mL at Weeks 16, 24 and 48 Wk 96 TUAB0102 Van Lunzen

DTG: Rapid and Sustained Antiviral Activity Week 48 Efficacy Analysis (%<50 c/mL) Proportion (%) <50 c/mL (TLOVR) 91% 88% 90% 82% DTG 10mg DTG 25mg DTG 50mg EFV 600mg 95% confidence intervals are derived using the normal approximation

Laboratory Findings ●> Grade 3 lab abnormalities were rare (DTG 12% vs. EFV 14%) ●No Grade 3 or 4 ALT elevations in any subject ●Changes (+/- SD) in serum creatinine over time Note: no clinically relevant events nor discontinuations related to creatinine See also abstract TUPE238 (Min et. al.)

QD maraviroc 150 mg in combination with ATV/r vs. FTC/TDF + ATV/r in treatment-naïve patients infected with R5 HIV-1 (Study A ): 48 week results Patient eligibility criteria – R5 HIV at screening – HIV-1 RNA ≥1000 copies/mL – CD4 ≥100 cells/mm 3 – No evidence of resistance to ATV/r, TDF, or FTC – Study is not powered to show a treatment difference and no formal comparative statistics will be performed Randomization 1:1 N=121 MVC (150 mg QD) + ATV/r (300/100 mg QD) FTC/TDF + ATV/r (300/100 mg QD) 024 wk 48 wk Screening (6 weeks) 16 wk Interim analysesPrimary analysis TUAB0103, Mills

HIV-1 RNA <50 copies/mL at Week 24 and Week 48 according to baseline viral load Week 24Week 48Week 24Week 48 Patients with HIV-1 RNA <50 copies/mL (%) <100,000 copies/mL≥100,000 copies/mL Baseline HIV-1 RNA 34/39 33/43 17/22 11/ /39 35/4313/16 17/ Intent-to-treat. Missing=failure MVC + ATV/r FTC/TDF + ATV/r TUAB0103, Mills

Elvitegravir QD is non-inferior to raltegravir BID in treatment experienced patients:48 week results WELBB05, Molina 702 Treatment-experienced patients, double blind, randomized Background regimen (BR) based on resistance testing: 2 nd Agent: fully active PI/r 3 rd Agent: NRTI, ETR, MVC, T-20; If M184V/I, may add 3TC or FTC Non Inferiority Study with lower limit 95% CI at -10%

2011- The Year of (val)Acyclovir? MOAC0201- Valacyclovir suppression reduces breast milk and plasma HIV-1 RNA postpartum: -results of a randomized clinical trial TUAB0104- Impact of HSV-2 suppressive therapy with daily acyclovir on HIV-1 disease progression: a randomized placebo-controlled trial in Rakai, Uganda TUAB0202- Peripartum valacyclovir improves markers of HIV-1 disease progression in women co-infected with HSV-2: a randomized trial WEPDB0106- High-dose valacyclovir suppressive therapy results in greater reduction in plasma HIV-1 levels compared to standard dose acyclovir suppression among HIV- 1/HSV-2 co-infected persons: a randomized, open-label, crossover trial

Complications

US VA Database- ARV Exposure and Risk of Osteoporotic Fractures : >900 fractures in >56,000 patients MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs. Hazard Ratio MAOB0101, Bedimo

HIV-Related Predictors and Outcomes in 125 Liver and 150 Kidney Transplant Recipients MOAB0105, Beatty Studied rates and predictors of Patient survival AIDS-related opportunistic infections (OI) and neoplasms Other serious infections with hospitalization (SI) 1 & 3 year patient survival Kidney: 95% (90%, 98%) & 91% (84%, 95%) Liver: 80% (72%, 86%) & 67% (56%, 75%) Predictors of Mortality Liver: Dual organ HR 4.86 (1.93, 12.2) Pre-TX BMI<21 HR 2.74 (1.25, 5.98) Age >40 HR 2.23 (1.07, 4.64) Kidney: HCV HR 3.17 (1.10, 9.09) Age HR 1.06 (1.01,1.11)

Infections

CARINEMO ANRS ART + RMPART alone 2NRTI + NVP 200mg BID vs EFV begun at 4-6 weeks of Rifampin containing therapy for TB No difference in incidence of hepatitis or grade >2 rash between arms Bhatt WELBX05

21 Risk factors for TB-IRIS Adjusted HR95% CIp Early ART Late ART –3.27 <0.001 CD4 ≤100 CD – Extra-pulmonary Disseminated Pulmonary – – CAMELIA- ART initiation ‘‘early’’ (at 2 weeks) vs. ‘‘late’’ (at 8 weeks) after TB treatment onset in 661 naïve HIV-infected adults with CD4 cell count ≤ 200/µL 26% of patients developed TB IRIS a median of 2 weeks after ART WEAX0104 Laureillard, WEPDB0202 Marcy CAMELIA Causes of Death- 149/661 (22%) patients died, mortality was highest in the first 6 months. -TB was the most common cause of death, occurring early in therapy. - Drug Toxicity was the second most common cause of death, with a majority being due to D4T and occurring after 50 weeks

Evaluation of a Point of Care Cryptococcal Antigen Test on Serum, Plasma and Urine from Patients with HIV-associated Cryptococcal Meningitis