CROI Review: ARV and Other Issues of Interest

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Richard Haubrich, M.D., of UC San Diego AntiViral Research Center, presents "CROI Review: ARV and other Issues of Interest" at AIDS Clinical Rounds

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CROI Review: ARV and Other Issues of Interest

  1. 1. CROI 2014: ARV and other issues of interest Richard Haubrich, MD Professor of Medicine Division of Infectious Diseases Director, California Collaborative Treatment Group University of California, San Diego
  2. 2. OUTLINE • Epidemiology – TDR (CDC and Margott) • ARV treatment naïve studies – ACTG 5257: three EFV sparing regimens – Neat 001: DRV with NRTI or RAL – DTG 96 weeks – Prelude to long acting therapy: LATTE 1 • ARV complications? – DAD (again), Kaiser to block? – ACTG 5280- save the bones? • PrEP – long acting 744, proof of concept
  3. 3. Is there a difference in efficacy between ATVr and DRVr 1. Yes 2. No
  4. 4. Are all DHHS guidelines preferred regimens equivalent? 1. Yes 2. No 3. I don’t read the guidelines, so who cares!
  5. 5. Do you think there is adequate evidence to suggest ABC has increased CV risk (all other factors equal) 1. Yes 2. No 3. I am agnostic
  6. 6. Calcium and vitamin D can prevent ART related bone loss 1. yes 2. no 3. stop the @$#^! questions and tell me the answers
  7. 7. TDR EPIDEMIOLOGY
  8. 8. Sensitive Screening Reveals Widespread Underestimation of Transmitted HIV Drug Resistance • 2009-2011; 895 samples • Allele specific PCR: RT mutations – M41L, K103N, Y181C, M184V and K65R. • Prevalence – Bulk: 7.9% – Sensitive: 13.6% Jonson, et al. 21st CROI. Boston, 2014. Abstract 87.
  9. 9. Demographics • Age: < 20 5%; 20-40 63%; > 40 32% • Race/ Ethnicity – Black- 54% – White- 29% – Hispanic- 14% • Sex- 86% male • Risk: MSM 71% Jonson, et al. 21st CROI. Boston, 2014. Abstract 87.
  10. 10. Black: 15%, Hispanic 6%. White 16%
  11. 11. TDR: Naïve Gilead Studies (2000-2013) • Retrospective analysis – 4 studies: prior to treatment • IN (n=1617, 100 from early studies) • PR-RT (n=2531) • Subtype B: 92% – Enrollment years • 2000 (study 903), 2003 (study 934), 2013 (studies 104 and 111) • Transmitted resistance trends – INST: 1 T66T/I mixture 2000, 0 in 2003, 1.4% T97A – NNRTI and PI: increased presence – NRTI: stable presence of NRTI Margot NA, et al. 21st CROI. Boston, 2014. Abstract 578. Resistance-Associated Mutation 0 1 2 3 4 5 6 7 8 9 10 NNRTI PIINSTI Patients(%) 8.7% 2.4% 3.2% 1.0% 1.4% 0% 0.5% 4.2% 1.2% NRTI 2.9% 2.6% 2000 2003 2013
  12. 12. HPTN 061: “TDR” Black MSMs • Longitudinal cohort black MSM in 6 US cities – HIV uninfected (n=1167) – HIV infected (n=348) • Genotyped with resistance results (n=169 with HIV RNA >200 copies/mL) • ART drug resistance: 28% – In 3 cities, >40% had drug- resistance HIV – Multiclass resistance: 11% – 23% of newly infected had drug- resistant Chen I, et al. 21st CROI. Boston, 2014. Abstract 581. ART Drug Resistance in Black MSM (2009-2011) 0 10 20 30 40 50 60 70 Boston (n=14) LA (n=41) Atlanta (n=30) Patients(%) 50% 30% 17%17% 10% 20% 7% 41% 4% Any resistance Multi-class resistance 50% 8% 20% SF (n=10) DC (n=24) NYC (n=50) ‘some’ on arv based on drug levels
  13. 13. ARV Treatment: Naïve
  14. 14. Efficacy and Tolerability of Atazanavir, Raltegravir, or Darunavir with FTC/TDF: ACTG A5257 Landovitz RJ, Ribaudo HJ, Ofotokun I, Wang H, Baugh BP, Leavitt RY, Rooney JF, Seekins D, Currier JS, and Lennox JL for the A5257 Study Team
  15. 15. Background • DHHS Guidance for initial treatment of HIV-1 infection includes TDF/FTC with EFV, ATV/r, DRV/r, INI’s* • Globally, EFV most commonly prescribed, following WHO guidelines • Patients with transmitted drug resistance, psychiatric disorders, and women who are contemplating pregnancy** are not good EFV candidates • A5257 designed to provide a comprehensive comparison of non-EFV based regimens *ABC/3TC may be used with DTG; ** If other options are available
  16. 16. ACTG A5257 Study • Open-label, naïve, n=1809 – HIV RNA >1000 – Any CD4 count • Randomized to TDF/FTC plus: – ATVr (n=605) – RAL bid (n=603) – DRVr QD (n=601) • Primary endpoints – Time to HIV RNA >1000 at weeks 16-24, or >200 at or after week 24 – Time to discontinuation for toxicity Landovitz RJ, et al. 21st CROI. Boston, 2014. Abstract 85. BASELINE Patients (n=1809) Age (years) 37 Male (%) 76 Race/ethnicity (%) Black Hispanic 42 42 CD4 Median % <200 308 30 HIV RNA Median % >100K % >500K 4.6 30 7
  17. 17. Cumulative Incidence of Virologic Failure Difference in 96 wk cumulative incidence (97.5% CI) -20 0-10 10 20 3.4% (-0.7%, 7.4%) 5.6% (1.3%, 9.9%) -2.2% (-6.7%, 2.3%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r
  18. 18. Cumulative Incidence of Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) -20 0-10 10 20 13% (9.4%, 16%) 3.6% (1.4%, 5.8%) 9.2% (5.5%, 13%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r Favors RAL Favors DRV/r
  19. 19. Cumulative Incidence of Virologic or Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) -20 0-10 10 20 15% (10%, 20%) 7.5% (3.2%, 12%) 7.5% (2.3%, 13%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r Favors RAL Favors RAL Favors DRV/r *Consistent results seen with TLOVR at a 200 copies/ml threshold
  20. 20. Tolerability Failure Toxicity Associated Discontinuation of randomized ART * ATV/r (N=605) RAL (N=603) DRV/r (N=601) Any toxicity discontinuation 95 (16%) 8 (1%) 32 (5%) Gastrointestinal toxicity 25 2 14 Jaundice/Hyperbilirubinemia 47 0 0 Other hepatic toxicity 4 1 5 Skin toxicity 7 2 5 Metabolic toxicity 6 0 2 Renal toxicity (all nephrolithiasis) 4 0 0 Abnormal chem/heme (excl. LFTs) 0 0 2 Other toxicity 2 3 4 *Participants allowed to switch therapy for intolerable toxicity
  21. 21. Proportion VL ≤50 copies/mL ITT, regardless of ART change ITT, off-ART=failure (SNAPSHOT) 96 ATV/r 88% RAL 94% DRV/r 89% 96 ATV/r 63% RAL 80% DRV/r 73%
  22. 22. Resistance to Study Agents* 75/94 VF Available RAL 99/115 VF Available 9 Any Resistance (1.5% of ATV/r) 18 Any Resistance (3% of RAL) 4 Any Resistance (<1% of DRV/r) ATV/r DRV/r 295 Virologic Failures 1 Baseline Missing 56 VF Failed to Amplify 1809 Participants 65/85 VF Available *Stanford University Genotypic Resistance Interpretation Algorithm V 6.3.1
  23. 23. Resistance to Study Agents 75/94 VF Available RAL 99/115 VF Available 9 Any Resistance (1.5% of ATV/r) 18 Any Resistance (3% of RAL) 4 Any Resistance (<1% of DRV/r) ATV/r DRV/r 295 Virologic Failures 1 Baseline Missing 56 VF Failed to Amplify 1809 Participants 65/85 VF Available 5 isolated M184V 1 integrase mutation 2 T69D/T215A/T 1 K70N + M184V 7 isolated M184V 1 isolated integrase mutation 7 integrase + M184V 3 integrase + M184V + K65R 3 isolated M184V 1 integrase mutation *Stanford University Genotypic Resistance Interpretation Algorithm V 6.3.1
  24. 24. Additional Clinical Outcomes Mean change in CD4 count from baseline • CD4 increase at week 96 • ATV/r: 284 • RAL: 288 • DRV/r: 256 • Both PI/r arms had greater increases in LDL and triglycerides than the RAL-arm (p<0.001)
  25. 25. Conclusions • ATV/r, RAL, and DRV/r were equivalent for virologic efficacy • ATV/r was less well tolerated than DRV/r or RAL – Largely due to cosmetic hyperbilirubinemia • RAL was superior to both PI/r regimens for combined tolerability and virologic efficacy – DRV/r was superior to ATV/r • VF with resistance was rare – More frequently observed with RAL • Analyses are ongoing to evaluate: – Cardiovascular, metabolic, skeletal, fat, inflammatory biomarkers, behavior, adherence, and key subgroup differences
  26. 26. either with DRVr QD NEAT 001/ARNS 143: Raltegravir + Darunavir/r in Treatment-Naïve Patients Randomization 1:1 TDF + FTC (n=404) RAL bid (n=401)Phase 3 study (96 weeks) Treatment-naïve Open-label, non-inferiority HIV RNA >1000 copies/mL CD4 <500 cells/mm3 No major IAS-USA resistance mutations No HBV Primary endpoint: time to virologic or clinical failure (any of the following): • Viral failure • Death due to any cause. • Any new or recurrent AIDS-defining event. • Any new serious non-AIDS-defining event. Raffi F, et al. 21st CROI. Boston, 2014. Abstract
  27. 27. NEAT 001/ARNS 143: Raltegravir + Darunavir/r in Treatment-Naïve Patients • DRVr + RAL – Non-inferior at week 96 (adjusted difference 3.7% [-1.1%, 8.6%]; P=0.12) – Inferior to TDF/ FTC with CD4 <200 cells/mm3 • Similar safety between the 2 arms • Treatment-emergent resistance with available genotype at failure – RAL: 18% (5/28) • 4/5 with baseline HIV RNA >500K copies/mL – FTC/TDF: 0% (0/16) Raffi F, et al. 21st CROI. Boston, 2014. Abstract 84LB. Key Week 96 Outcomes RAL (n=401) TDF/ FTC (n=404) Virologic/clinical failure (%) Overall Baseline CD4 <200 Baseline HIV RNA >100K 17 39 36 14 21 27 Secondary HIV RNA <50 (%) CD4 gain Lipid changes (%) Total cholesterol LDL-C HDL-C Triglycerides Change in eGFR (mL/min) 89 267 +0.9 +0.5 +0.2 +0.3 +0.9 93 266 +0.5* +0.4* +0.1* +0.2 -3.8* Raffi F, et al. 21st CROI. Boston, 2014. Abstract
  28. 28. Walmsley et al. CROI 2014: 543 DTG vs EFV (Single)- WEEK 96 • Randomized, PC, double blind • Treatment naïve, HLA-B*5701 negative • Randomized to: – DTG + ABC/3TC – EFV/TDF/FTC
  29. 29. Walmsley et al. CROI 2014: 543 CD4 increase: 325 DTG vs 281, p = 0.004 Viral failure: 6% (25 subjects) in each arm HIV RNA < 50 (FDA snapshot)
  30. 30. HIV RNA < 50: snapshot by VL subgroup Walmsley et al. CROI 2014: 543
  31. 31. Treatment related adverse events Walmsley et al. CROI 2014: 543
  32. 32. • HIV-1 integrase inhibitor, dolutegravir analogue • Oral drug (t½ = 40 hours) • Long-acting SC or IM injection (apparent t½ ≈ 40 days) • Good virologic response at 5 and 30 mg/day as oral 10-day monotherapy GSK1265744 (744) Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.Spreen et al. HIV Clin Trials. 2013;14:192-203.
  33. 33. LATTE Study: 744 + Rilpivirine as 2-Drug Oral Maintenance Therapy Margolis D, et al. 21st CROI. Boston, 2014. Abstract 91LB. Efavirenz + 2 NRTIs* 744 (10, 30, 60 mg) + 2 NRTIs* Phase 2b study (96 weeks) Treatment-naïve Open-label HIV RNA >1000 copies/mL CD4 >200 cells/mm3 Stratified by HIV RNA and NRTI Week 0 24 48 96 Primary Endpoint HIV RNA <50 copies/mL (FDA “Snapshot”) 744 (10, 30, 60 mg) + Rilpivirine Induction (24 weeks) Maintenance (72 weeks) Patients in the 744 arm with HIV RNA <50 copies/mL at week 20 were switched to maintenance regimen at week 24. Baseline: CD4 ~ 400; HIV RNA ~ 4.2
  34. 34. Primary Endpoint Virologic Success: HIV-1 RNA <50 c/mL by FDA Snapshot (ITT-E) Week 744 overall response W48 82% EFV response W48 71% 744 overall response W24 87% EFV response W24 74% Median (IQR) change from baseline CD4+ cell count (cells/mm3) Week 48 744 overall +219 (141,343) EFV +227 (134,369) Proportion,% 242 4 8 12 16 4032 48362628BL 0 20 40 60 80 100 744 10 mg (N=60) 744 30 mg (N=60) 744 60 mg (N=61) EFV 600 mg (N=62) Induction Phase Maintenance Phase Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
  35. 35. Secondary Endpoint – Maintenance Population Virologic Success: HIV-1 RNA <50 c/mL by Snapshot (ITT-ME) 24 Week Proportion,% 2 4 8 12 16 4032 48362628BL *EFV patients with a week 24 visit 0 20 40 60 80 100 744 10 mg (N=52) 744 30 mg (N=53) 744 60 mg (N=55) EFV 600 mg (N=47) Induction Phase Maintenance Phase Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
  36. 36. Treatment Outcomes - Maintenance Population HIV-1 RNA <50 c/mL by Snapshot (ITT-ME) Outcome at Week 48 744 total n=160 EFV 600 mg n=47* Virologic success 149 (93%) 44 (94%) Virologic failure 9 (6%) 2 (4%) Data in window not <50 c/mL 7 (4%) 1 (2%) Discontinued for lack of efficacy 0 1 (2%) Change in ART 2 (1%) 0 No virologic data at Week 48 2 (1%) 1 (2%) Discontinued due to AE‡ 2 (1%) 1 (2%) *EFV patients with a W24 visit †Carried forward from Induction Phase ‡Abnormal ECG (10 mg); anxiety (60 mg); colitis (EFV) Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
  37. 37. LATTE Study – Week 48 Analysis Conclusions Margolis et al. CROI 2014; Boston, MA. Abstract 91LB. • Following induction therapy, oral 744+RPV maintained virologic suppression at a rate similar to EFV+NRTIs • Primary Endpoint: 82% of 744+RPV and 71% of EFV+NRTIs subjects had HIV-1 RNA <50 copies/mL • Secondary Endpoint (ITT-ME): 93% of 744+RPV and 94% of EFV+NRTIs subjects had HIV-1 RNA <50 copies/mL • Similar response rate across 744 10mg, 30mg, and 60mg arms • One subject, with persistently low 744 and RPV drug concentrations, developed treatment emergent INI and NNRTI mutations • 744+RPV was well tolerated, with few drug related AEs leading to withdrawal • Long-term data needed, however, these regimen POC results support evaluation of long-acting injectable regimen of 744 LA + TMC278 LA as maintenance therapy
  38. 38. Based on A5257 would you use ATVr: 1. More 2. Less 3. The same 4. I don’t use ATVr
  39. 39. When would you use a two drug regimen (i.e. PIr + INSTI or NNRTI)? 1. Never 2. For maintenance in patients that develop NRTI toxicity 3. For patients with high CD4 and low HIV RNA
  40. 40. ARV Complications?
  41. 41. D:A:D Study: Update on MI Risk and Abacavir Exposure • Prospective cohort (2000-2013) – >49,000 HIV-positive patients from 11 cohorts in Europe, Australia, US • Current abacavir use was associated with a 98% increase in MI rate – No difference between pre- and post-2008 – Results unchanged after stratifying by Framingham risk group, as well as by other factors (eg, renal function, dyslipidemia, hypertension) • Current findings argue against channeling bias Sabin CA, et al. 21st CROI. Boston, 2014. Abstract 747LB. PY: person-years. Adjusted Relative MI Rate and Current Abacavir Use 1.98 Reference No Abacavir 5 4 3 2 1 0.7 1.97 1.97 Overall Pre 3/2008 Post 3/2008 No ABC Events/PYs Rate/PYs (95% CI) 600/2,95,642 0.20 (0.19, 0.22) 425/169,417 0.25 (0.23, 0.28) 175/126,225 0.14 (0.12, 0.16) On ABC Events/PYs Rate/PYs (95% CI) 341/71,917 0.47 (0.42, 0.52) 247/40,833 0.61 (0.53, 0.68) 94/31,084 0.30 (0.24, 0.36)
  42. 42. Kaiser Permanente, Northern California: MI Risk and HIV Infection Status • Population-based cohort (1996-2011) – Male: 91% – HIV negative (n=257,600) • MI events: 2483 • Follow-up: 1,506,676 person-years – HIV positive (n=24,768) • MI events: 320 • Follow-up: 119,587 • Higher risk of MI among HIV-positive adults is no longer observed in more recent years – Reduced risk likely due to cardiovascular risk reduction, more lipid-friendly ART, and reduced immunodeficiency Klein DB, et al. 21st CROI. Boston, 2014. Abstract 737. MI Rate Ratios for HIV-infected vs negative 0 0.5 1.0 1.5 2.0 2.5 3.0 Adjusted Rate Ratio (95% CI) 1996-1999 2000-2003 2004-2007 2008-2009 2010-2011 1.8 1.7 1.3 Reference HIV- 1.3 1.0
  43. 43. ACTG A5280: Impact of High-Dose Vitamin D and Calcium on Bone Loss With ART • Double-blind, prospective, 48-week trial in treatment-naïve patients initiating efavirenz/ emtricitabine/tenofovir DF – Vitamin D level <75 to >10 ng/mL • Randomized arms – Vitamin D3 4000 IU/ calcium 1000 mg – Placebo • Primary endpoint – Percent change from baseline in total hip BMD at week 96 Baseline Characteristics Overton ET, et al. 21st CROI. Boston, 2014. Abstract 133. Vitamin D Calcium (n=79) Placebo (n=86) Age (years) 36 31 Male (%) 91 90 Race/ethnicity (%) White Black Hispanic 35 30 29 38 35 21 BMI (kg/m2) 25.0 24.0 HIV RNA (log10 copies/mL) 4.5 4.5 CD4 (cells/mm3) 339 342 Estimated daily intake Calcium (mg) Vitamin D (IU) 813 120 811 137
  44. 44. ACTG A5280: Impact of High-Dose Vitamin D and Calcium on Bone Loss With ART • HIV outcomes – HIV RNA <50 copies/mL: 90% – Similar CD4 gains in both arms • Change in 25(OH) vitamin D3 levels – Vitamin D/calcium arm • Increased from 26.7 ng/mL at baseline to 55.6 and 56.4 ng/mL at weeks 24 and 48, respectively – Placebo arm: no change from baseline levels (25.1 ng/mL) • Vitamin D3 and calcium – Reduced hip and spine BMD loss by 50% with ART – Attenuated bone turnover • Adverse events – Kidney stone (n=1, placebo) – No hypercalcemia, hypophosphatemia Overton ET, et al. 21st CROI. Boston, 2014. Abstract 133. Week 96 Change in BMD -4 -3 -2 -1 0 1 Lumbar Spine Total Hip Week48Change(%) -1.4% -2.9% -1.4% -3.2% Vitamin D and calcium (n=79) Placebo (n=86) P<0.001 P<0.08
  45. 45. ACTG A5257 Substudy: Impact of Raltegravir- and PI-Based Regimens on BMD • Open-label, treatment-naïve patients (n=328) – HIV RNA >1000 copies/mL • Randomized groups – Raltegravir + FTC/TDF (n=106) – Atazanavir/r + FTC/TDF (n=109) – Darunavir/r + FTC/TDF (n=113) • Week 96 change in BMD – Reduced BMD with all 3 arms – Raltegravir arm had significantly less BMD loss at lumbar spine and total hip versus PI-based arms (P<0.01) – Less loss in total body BMD • Raltegravir versus atazanavir/r (P=0.004) • Darunavir/r versus atazanavir/r (P=0.001) Brown TT, et al. 21st CROI. Boston, 2014. Abstract 779LB. Week 96 Change in BMD -5 -4 -3 -2 -1 0 1 Lumbar Spine Total Body Total Hip Week96Change(%) -3.6% -2.9% -1.6% -2.4% -3.4% -3.9% -1.8% -4.0% -1.7% Raltegravir (n=106) Atazanavir/r (n=109) Darunavir/r (n=113)
  46. 46. When would you use vitamin D and Ca++? 1. For post menopausal women 2. For all patients on EFV 3. For high-risk patients on EFV 4. After a fracture 5. Never- not enough data
  47. 47. Do you consider ABC-related CV effects in selection of regimens for naïve patients? 1. Never 2. In a patient with moderate CV risk 3. In a patient with high CV risk 4. I don’t use ABC
  48. 48. PrEP
  49. 49. US PrEP Demonstration Project: Implementation of PrEP (2012-2014) • STD clinics in San Francisco, Miami, Washington, DC (n=831) – MSM, transgender women (1.4%) – Clinic referrals (63%) – Self-referrals (37%): more likely to be white, higher education level, higher sexual risk behaviors and risk perception versus clinic referrals • Offered up to 48 weeks of open-label emtricitabine/tenofovir DF – Accepted PrEP: 60.4% • 77% had TDF-DP levels consistent with taking >4 doses/week • PrEP uptake associated with – Self-referral, prior PrEP awareness, higher-risk sexual behaviors BLD: below limit of detection. Cohen SE, et al. 21st CROI. Boston, 2014. Abstract 954. Tenofovir-DP Levels (Week 4) 0 10 20 30 40 50 60 <250 250-550 >550-950BLD Samples(%) 18% 43% 14% 5% 2% >950 2% 11% 27% 4% 4% 52% 43% 40% 35% Miami (n=157) Washington, DC (n=100) San Francisco (n=300) Doses/Week: <2 <2 2 4 >4 Tenofovir-DP (fmol/punch)* 0% *femtomole/punch: measure of flux density.
  50. 50. Partners PrEP Study: Low Frequency Resistance Testing Among Seroconverters • Double-blind, phase 3 study of serodiscordant, heterosexual couples – PrEP significantly reduced the risk of HIV infection by 67% to 75% (P<0.0001) – Ultra-deep versus standard sequencing • Detect drug resistance at frequencies >1% versus >20%, respectively • Ultra-deep sequencing on samples from 121 seroconverters • Overall resistance: 7.4% (9/121) – HIV positive at enrollment (n=3) – Acquired HIV after enrollment (n=6) • TDF (2/38): 1 M184V, 1 K65R/M184V • TDF/FTC (5/25): 4 M184V, 1K65R/K70E • Detection of PrEP drug in blood plasma was associated with an increased risk of resistance (P=0.0009) Lehman DA, et al. 21st CROI. Boston, 2014. Abstract 590LB. 0 20 40 60 80 100 Resistance Detected Above Frequencies of 1% in 121 Seroconverters Seroconverters(%) Overall (n=25/38/58) 20% 3.5%5.3% Before (n=4/8/6) After (n=21/30/52) Found to Be HIV Positive Before or After Study Enrollment Emtricitabine/tenofovir DF Tenofovir DF Placebo 50% 0% 12.5% 14.3% 3.8%3.3%
  51. 51. 0 20 40 60 80 100 0 20 40 60 80 100 PrEP Proof-of-Concept: Long-Acting Integrase Inhibitor in Nanosuspension for Injection • Macaque model of SHIV transmission • Study 1 (vaginal transmission) – Low-dose SHIV (50 TCID50) twice a week – GSK744 LA (50 mg/kg) 3 injections at week 0, 4, 8 – 6 of 6 pigtail macaques (lunar menstrual cycles) protected against SHIV infection • Study 2 (rectal transmission) – Weekly SHIV (50 TCID50) until systemic infection detected – One GSK744 LA (50 mg/kg) injection at week 0 – After 1 to 2 challenges, placebo macaques became infected – With a single GSK744 injection, infection was delayed by 5 to 10 challenges with SHIV Radzlo J, et al. 21st CROI. Boston, 2014. Abstract 40LB. Andrews CD, et al. 21st CROI. Boston, 2014. Abstract 39. Andrews CD, et al. Science. 2014;343:1151-1154. P=0.0005 Week Aviremic(%) GSK744 LA (n=6) Placebo (n=6) Week 0 2 4 6 8 10 12 14 16 30 Vaginal SHIV Exposure Aviremic(%) GSK744 LA (n=12) Placebo (n=4) Rectal SHIV Exposure 0 2 4 6 8 10 12 14 16 18 20 22 24 P<0.0001
  52. 52. Summary of Clinically Relevant Points • TDR still alive and well – Can find more using sensitive techniques – Little evidence of transmitted INSTI • ARV for naïve – ATV has more tolerability issues than RAL or DRV (mostly bilirubin) – RAL best tolerated – DTG with ABC/ 3TC superior to EFV/TDF/FTC (tolerability)
  53. 53. Summary of Clinically Relevant Points • ARV for naïve – Bone loss can be prevented with Ca and vitamin D – ABC cv risk still controversial • Long acting ART promising for – Maintenance – PrEP

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