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Antiretroviral Therapy: Challenging Patients and Difficult Problems

Antiretroviral Therapy: Challenging Patients and Difficult Problems. Joel E. Gallant, MD, MPH Professor of Medicine and Epidemiology The Johns Hopkins University School of Medicine Baltimore, Maryland. From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA. . Slide 2 of 47.

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Antiretroviral Therapy: Challenging Patients and Difficult Problems

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  1. Antiretroviral Therapy: Challenging Patients and Difficult Problems Joel E. Gallant, MD, MPHProfessor of Medicine and EpidemiologyThe Johns Hopkins UniversitySchool of MedicineBaltimore, Maryland From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  2. Slide 2 of 47 ACTG 5202: Time to Virologic Failure by Baseline Viral Load and CD4 Count ABC/3TC TDF/FTC 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 Probability of Remaining free of Virologic Failure Probability of Remaining free of Virologic Failure CD4<50, RNA≥100K (n=98, 35 VF) CD4<50, RNA<100K (n=78, 23 VF) CD4 50 to <200, RNA≥100K (n=80, 19 VF) CD4 50 to <200, RNA<100K (n=153, 10 VF) CD4 200 to <350, RNA≥100K (n=39, 6 VF) CD4 200 to <350, RNA<100K (n=273, 28 VF) CD4≥350, RNA≥100K (n=23, 5 VF) CD4≥350, RNA<100K (n=184, 29 VF) CD4<50, RNA≥100K (n=80, 6 VF) CD4<50, RNA<100K (n=83, 17 VF) CD4 50 to <200, RNA≥100K (n=70, 9 VF) CD4 50 to <200, RNA<100K (n=158, 19 VF) CD4 200 to <350, RNA≥100K (n=55, 8 VF) CD4 200 to <350, RNA<100K (n=289, 29 VF) CD4≥350, RNA≥100K (n=20, 2 VF) CD4≥350, RNA<100K (n=173, 24 VF) 0 24 48 72 96 120 144 168 192 216 0 24 48 72 96 120 144 168 192 216 Weeks from Randomization Weeks from Randomization From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA. Grant P, et al. CROI 2011. Abstract 535.

  3. Slide 3 of 47 Abacavir and MI Risk • Conflicting data from observational and prospective studies • Proposed pathogenic models: • Inflammation (higher hsCRP1) • Increased platelet reactivity/adhesion2 • Impaired endothelial function3 • Guidelines: use “with caution” in patients with high CV risk • McComsey G, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 835. • 2. Baum PD, et al. AIDS 2011, 25:2243–2248. • Hsue PY, et al. AIDS 2009;23:2021-7. From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  4. Slide 4 of 47 VA Study: TDF and risk of kidney disease • 10,841 HIV+ pts at VA • Time to first occurrence of 1) proteinuria 2) rapid decline in kidney function and 3) CKD (eGFR rate < 60 ) • Each year of exposure to TDF associated with: • 34% increased risk of proteinuria (p < 0.0001) • 11% increased risk of rapid decline (p = 0.0033) • 33% increased risk of CKD (p < 0.0001). • Pre-existing renal risk factors did not appear to worsen the effects of tenofovir. Scherzer R, et al. AIDS 2012 [Epub ahead of print] From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  5. Slide 5 of 47 NRTI-sparing regimens 1. Riddler S, et al. New Engl J Med 2008;358:2179-2. 2. Huang J, et al. WAIDS 2010. Vienna. WEAB0304 3. Goicoechea M, J et al. WAIDS 2010. Vienna. WEAB0304 4. Reynes J, et al. WAIDS 2010; Vienna. MOAB0101 5. Goicoechea M, J et al. WAIDS 2010. Vienna. THPE0068 6. Kozal MJ, et al. WAIDS 2010; Vienna. THLBB204 7. Portsmouth S, et al. WAIDS 2010; Vienna. THLBB203 8. Rieger A, et al. WAIDS 2010; Vienna. THLBB209 9. Taiwo B, et al. CROI 2011; Boston. Poster 551 From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  6. 43% failure by week 48 Slide 6 of 47 ACTG 5262: DRV/r + RAL Time to Virologic Failure (VF) Time to VF by Baseline HIV-1 RNA 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 Probability of not having a VF Probability of not having a VF HIV-1 RNA ≤ 100,000 copies/mL HIV-1 RNA > 100,000 copies/mL Log Rank Test p=0.0002 1 4 12 24 36 48 1 4 12 24 36 48 Time (weeks) Time (weeks) n with VF: 0 0 3 14 5 6 n at risk: 112 111 110 105 89 81 VL ≤ 100,000 n with VF: 0 0 1 4 1 1 n at risk: 63 63 62 59 54 50 VL > 100,000 n with VF: 0 0 2 10 4 5 n at risk: 40 45 45 45 39 31 Taiwo B, et al. AIDS 2011, ePub.

  7. Slide 7 of 47 ARVs and HCV PIs *↑TVR dose to 1125 mg q8h †Monitor for TDF toxicity 1. Telaprevir [package insert]. 2011. 2. Sulkowski M, et al. CROI 2011. Abstract 146LB. 3Boceprevir [package insert]. 2011.4. Sulkowski M, et al. IDSA 2011. Abstract LB-37. 5. Van Heeswijk R, et al. ICAAC 2011. Abstract A-1738a. 6. Dear HCP letter 3 Feb 2012.

  8. GS 103: Drug resistance through week 48 DeJesus E, et al. Lancet 2012;379:2429-38

  9. Slide 9 of 47 Evolution of Integrase Resistance With Increased Time After VF • SCOPE cohort: genotypic and phenotypic resistance increased over time on INSTI therapy[2] • More pts with multiple resistance mutations at later time points • Q148H/K/R or Y143R/H/C associated with high-level phenotypic resistance • Change in IC50 > 100-fold • N155H associated with low-level phenotypic resistance • Change in IC50 < 50-fold Evolution of Viral Clones After Failure of RAL Regimens BENCHMRK[1] 100 Other Other 80 Q148H/K/R* 19% Q148H/K/R 53% 60 Clones (%) Y143R/H/C 6% 40 N155H/R† 45% 20 N155H/R 18% 0 Later time points Early after failure *2° mutations with Q148H/K/R: G140S(A) , E138K †2° mutations with N155H/R: L74M, E92Q, T97A, V151I, G163R 1. Fransen S, et al. J Virol. 2009;83:11440–11446. 2. Hatano H, et al J Acquir Immune DeficSyndr. 2010;54:389-393. From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  10. Slide 10 of 47 VIKING: Dolutegravir “Functional Monotherapy” in Pts With RAL Resistance • DTG BID more effective than QD through Day 11 in pts with Q148 100 100 96 DTG 50 mg QD (n = 27) 100 92 78 80 DTG 50 mg BID (n = 24) 60 Primary Endpoint* (%) 40 33 20 0 All Patients Q148 + ≥ 1Other Mutationat Baseline OtherMutations *VL < 400 or ≥ 0.7 log10 reduction from baseline at Day 11. Eron J, et al. CROI 2011. Abstract 151LB. From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  11. Slide 11 of 47 Prevalence of Transmitted HIV Drug Resistance in US, 2006-2009 • Genotypic analysis of samples from newly diagnosed patients in CDC National HIV Surveillance System (N = 12,668) 20 All cases with sequencesCases classified as recent infectionsCases classified as long-standing infections 15.6 16 12 7.8 6.8 8 4.1 4 0 1 or more 1-class 2-class 3-class NNRTI NRTI PI Transmitted Drug Resistance Mutations (TDRMs) • Ocfemia MCB, et al. CROI 2012. Abstract 730. From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  12. Slide 12 of 47 Weighted Scores for ETR Susceptibility Monogram 4: 100I, 101P, 181C/I 3: 138A/G, 179E, 190Q, 230L, 238N 2: 101E, 106A, 138K, 179L, 188L 1: 90I, 101H, 106M, 138Q, 179D/F/M, 181F, 190E/T, 221Y, 225H, 238T Tibotec 3: 181I/V 2.5: 101P, 100I, 181C, 230L 1.5: 138A, 106I, 190S, 179F 1: 90I, 179D, 101E, 101H, 98G, 179T, 190A 0-2: 74% response 2.5-3.5: 52% response > 4: 38% response > 4 = reduced susceptibility From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  13. Slide 13 of 47 DHHS Perinatal Guidelines, 2011 • HIV-infected pregnant women who meet criteria for ART per adult guidelines should receive ART as recommended for nonpregnant adults, taking into account what is known about specific drugs in pregnancy and risk of teratogenicity (AI) • For women who require immediate initiation of ART for their own health, treatment should be started as soon as possible, including in first trimester (AII) DHHS Perinatal Guidelines, September 2011. From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

  14. Slide 14 of 47 Antiretroviral Therapy Safety During Pregnancy DHHS Perinatal Guidelines, September 2011. From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

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