1 / 45

Antiretroviral Therapy: A Case-Based Panel Discussion (Part I)

Antiretroviral Therapy: A Case-Based Panel Discussion (Part I). Michael S. Saag , MD Eric S. Daar , MD. From MS Saag , MD and ES Daar , MD at San Francisco, CA: March 29, 2013, IAS-USA. MERGED: 03-21-13. 30 yo white man Diagnosed on routine insurance examination

jabari
Télécharger la présentation

Antiretroviral Therapy: A Case-Based Panel Discussion (Part I)

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Antiretroviral Therapy:A Case-Based Panel Discussion(Part I) Michael S. Saag, MD Eric S. Daar, MD From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29, 2013, IAS-USA. MERGED: 03-21-13

  2. 30 yo white man Diagnosed on routine insurance examination PMHx remarkable for HTN, diet controlled No medications Understands treatment issues and wants to begin therapy if you think it is appropriate Case 1

  3. 30 yo white man Diagnosed on admission to jail for disorderly conduct PMHx remarkable for HTN, diet controlled and paranoid schizophrenia Doesn’t take any medications and doesn’t want to Case 1b

  4. Latently Infected CD4+ Lymphocytes HIV Infected Cells HIV virions Antiretroviral Rx Uninfected Activated CD4+ Lymphocytes Uninfected Resting CD4+ Lymphocytes M Saag, UAB

  5. Effect on inflammation in predicting mortality higher in HIV disease than the general population (SOCA/SCOPE) Hunt et al CROI 12

  6. T cell “activation” is lower in treated than untreated adults, but consistently higher than “normal” HIV + Untreated (n=82) HIV + ART (n=65) HIV – (n=132) Hunt et al JID 2003, PLoS ONE 2011 and unpublished

  7. Permanent Loss of CD4 if Wait to Start CD4-count increases on sustained suppressive (<400 c/mL) ARV treatment (n=655) by baseline count >350 cells/mm3: CD4 counts return to near-normal levels ≤350 cells/mm3: CD4 counts significantly increased but plateau after 4 years below normal range Differences in CD4 counts associated with differences in morbidity and mortality 900 800 700 CD4 Count (cells/mm3) 500 500 400 <200 201–350 >350 300 200 100 Years After Starting HAART 0 0 1 2 3 4 5 6 Median CD4 Counts Over 6 YearsStratified by Baseline CD4 Count Moore RD, Keruly JC. Clin Infect Dis 2007;44:441-446. From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29, 2013, IAS-USA.

  8. Major mutations 50% less likely in pts starting with CD4+ >350 vs <200 cells/mm3, despite greater treatment exposure GT mutations and virologic failure1 p=0.076 p=0.007 p=0.051 p=0.103 50 50 40 Patients (%) 30 20 10 0 Any mutation (n=78) NRTI mut. among NRTI-exp (n=50) NNRTI mut. among NNRTI-exp (n=37) PI mut. among PI-exp (n=48) 0-199 cells/mm3 200-349 cells/mm3 >350 cells/mm3 HOPS Cohort: Resistance Development 1. Uy JP, et al. 4th IAS, Sydney 2007, #WEPEB017; 2. van Sighem B, et al. ibid, #WEPEB016

  9. Most New Infections Transmitted by Persons who Do Not Know Their Status account for… ~25% Unaware of Infection ~54% New Infections ~75% Aware of Infection ~46% of New Infections Source: G. Marks et al. AIDS 2006 From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29, 2013, IAS-USA.

  10. Reasons to Start Early: The Biology Association of Inflammation and Disease Better Tolerated Medications Today Randomized Controlled Trial Data Cohort Data Public Health Common Sense!

  11. Slide 16 of 50 From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29, 2013, IAS-USA.

  12. Relative Time on Treatment… 40 years on Rx CD4 650/ul 35 years on Rx 5 years CD4 500/ul 30 35 40 45 50 55 50 65 70 AGE (years)

  13. Relative Time on Treatment… 40 years on Rx HARM? CD4 650/ul 35 years on Rx 5 years CD4 500/ul 30 35 40 45 50 55 50 65 70 AGE (years)

  14. So ….what is the harm? • Destruction of Lymphoid Tissue • Inflammation • Increased Cardiovascular Events • Increased incidence of certain malignancies • Increased ‘Aging’ • Accelerated Cognitive Decline

  15. Balance of data support starting Rx in ~ all individuals regardless of CD4+ T cell counts Understanding of HIV pathogenesis Cohort data Public health implications No randomized clinical trial data for higher CD4 counts (START study is enrolling) Waiting until RCT data could well lead to harm that likely will not be reversible Conclusions

  16. Case 2 • 42 year old man diagnosed with HIV in 1999; several OIs • Has ‘taken’ most existing antiretroviral drugs available, on and off, for years • Currently on TDF / FTC / DRV / rit • CD4 count is 33 /µL (nadir CD4 = 6) • CD4 count 3 months ago was 76 cells/µL • HIV RNA 128,000 c/mL (max VL 167,000) • Phenotype: Pan-sensitive

  17. Case 3 • 34 yo woman is diagnosed with TB • As part of evaluation she is found to be HIV+ • Initial lab values • CD4 82 cells/µL • VL 76,000 c/mL • No other significant medical condition • She is started on 4-drug anti-TB therapy (including INH and rifabutin) • Virus is wild-type virus

  18. Case 1 • 30 yo white man • Diagnosed on routine insurance examination • PMHx remarkable for HTN, diet controlled • No medications • Understands treatment issues and wants to begin therapy if you think it is appropriate

  19. A 49 year old asymptomatic man presents to your clinic after recently being diagnosed with HIV • History of HTN with CrCl ~75 mL/min • HBsAb+, HCV antibody negative • CD4 cells repeatedly 500-700 cells/uL • Plasma HIV RNA 30-50,000 copies/mL • Not anxious to start antiretrovirals but willing if you think it is necessary

  20. Factors to consider in choosing first-line therapy • Patient’s willingness to commit to therapy • Baseline resistance • Efficacy data • Tolerability • Convenience • Comorbid conditions • Consequences of failure (resistance) • Since the introduction of potent ARV therapy preferred regimens all include NRTIs + third drug

  21. Boosted-Protease Inhibitors KLEAN1 (ITT-E, TLOVR) 48 weeks CASTLE3 (ITT, NC=F) 96 weeks ARTEMIS2 (ITT, TLOVR) 96 weeks 100 100 100 79 66 80 80 74 80 71 65 68 50 50 50 40 40 40 20 20 20 n=346 n=343 n=443 n=440 n=434 N=444 0 0 0 LPV/r QD or BID DRV/r 800/100 QD LPV/r 400/100 BID ATV/r 300/100 QD LPV/r 400/100 BID FPV/r 700/100 BID Adapted from: 1. Eron J, et al. Lancet 2006; 368:476-482; 2. Mills A, et al. AIDS May 29, 2009 3. Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d

  22. ATV/r vs. EFVPrimary Endpoint Daar ES, et al. Ann Intern Med 2011; 154:445-456.

  23. STARTMRK: RAL vs. EFV ITT, NC=F 86 81 76 75 71 100 82 79 80 69 67 61 50 Percentage of Patients withHIV RNA Levels <50 Copies/mL 40 CD4 Change: RAL +374 vs. EFV +312 20 0 0 12 24 48 72 96 120 144 168 192 216 240 Weeks Number of Contributing Patients Raltegravir 400 mg BID 281 278 279 280 281 281 250 280 281 281 250 279 Efavirenz500 mg QHS 282 282 281 282 282 281 281 282 282 282 279 282 Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. LBPE19.

  24. Pooled ECHO and THRIVE: Virologic Response (ITT-TLOVR) 84.3% 82.3% Rimsky L, et al. 50th ICAAC 2010, Boston, MA. Abst. H-1810

  25. Pooled ECHO and THRIVE: Virologic Response (ITT-TLOVR) Rimsky L, et al. 50th ICAAC 2010, Boston, MA. Abst. H-1810

  26. GS102 & GS103: EVG/COBI/TDF/FTC vs. EFV/TDF/FTC or ATV/RTV + TDF/FTC Randomized, Phase III, Double-blind, Double Dummy, Active-controlled, International Studies GS 102 ~89% men 33% >105 c/mL CD4= ~385 c/uL Quad QD EFV/FTC/TDF Placebo QD EFV/FTC/TDF QD Quad Placebo QD Treatment Naïve HIV-1 RNA ≥5,000 c/mL Any CD4 cell count eGFR ≥70 mL/min Quad QD ATV/r +TDF/FTC Placebo QD GS 103 ~90% men ~41% >105 c/mL CD4= ~370 c/uL QUAD Placebo QD ATV/r +TD/FTC QD 48 weeks 192 weeks Sax P, et al, Lancet 2012: 379::2439-48; DeJesusE, et al, Lancet 2012; 379: 2429-38

  27. Study 236-102: Primary Endpoint:HIV-1 RNA < 50 copies/mL +3.6%, 95% CI 3.6 (-1.6% to +8.8%) CD4+ change: Quad +239vs. EFV +206 c/mm3 (p=0.009) No difference by baseline characteristics Sax P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 101.

  28. Study 236-102:Common Adverse Events * p<0.05; ^ p<0.001; # p=0.009 Sax P, et al, Lancet 2012: 379::2439-48

  29. Study 236-103: ATV/r vs. TDF/FTC/COBI/EVG HIV-1 RNA < 50 c/mL 100 90 80 70 50 50 40 30 20 10 0 92% 88% Diff: 3.5% (95% CI: -1.0 to 8.0) QUAD ATV/r Percent with HIV RNA <50 c/mL (ITT, M=F) BL 2 4 8 12 16 24 32 40 48 Changes in CD4+ count: Quad +207 vs. ATV/r +211 cells/mm3 (p=0.61) No difference by baseline characteristics Week DeJesusE, et al, Lancet 2012; 379: 2429-38

  30. Study 236-103: Adverse Events Adverse Events > 10% in Either Group Discontinuation rates due to renal events were identical in both arms (0.3%) DeJesusE, et al, Lancet 2012; 379: 2429-38

  31. TDF/FTC/EVG/COBI vs. EFV or ATV/r: Lipid changes P =0.006 P =0.44 P =0.001 P= 0.001 P <0.001 Conclusion: While some lipid fractions better with Quad than EFV or ATV/r, overall differences were modest and unlikely to be of clinical significance. Sax P, et al, Lancet 2012: 379::2439-48; DeJesusE, et al, Lancet 2012; 379: 2429-38

  32. EVG/COBI/TDF/FTC vs. EFV or ATV/r: Creatinine Changes Conclusion: Cobicistat is associated with reduced active secretion of creatinine in the renal tubules leading to initial rises in creatinine levels. Sax P, et al, Lancet 2012: 379::2439-48; DeJesusE, et al, Lancet 2012; 379: 2429-38

  33. A5202: Study Design Arm TDF/FTC QD TDF/FTC QD EFV EFV A QD QD ABC/3TC Placebo QD HIV-1 RNA ≥1000 c/mL Any CD4+ count > 16 years of age ABC/3TCQD ABC/3TC QD EFV EFV B QD QD TDF/FTC Placebo QD TDF/FTC Placebo QD ART ART - - naïve naïve 1857 enrolled N=1858 Randomized 1:1:1:1 Randomized 1:1:1:1 TDF/FTC QD TDF/FTCQD ATV/r ATV/r C QD QD ABC/3TC Placebo QD ABC/3TC Placebo QD Stratified by screening HIV-1 RNA (< or ≥ 100,000 c/mL) Enrolled 2005-2007 Followed through Sept 2009, 96 wks after last pt enrolled ABC/3TCQD ABC/3TC QD ATV/r ATV/r D QD QD TDF/FTC Placebo QD TDF/FTC Placebo QD

  34. A5202: Time to Virologic Failure in Patients with HIV RNA >100,000 c/mL Probability of No Virologic Failure TDF-FTC (26 events) ABC-3TC (57 events) P<0.001, log-rank testHazard ratio, 2.33 (95% CI, 1.46-3.72) Sax PE, et al. NEJM 2009;361:2230-2240.

  35. ABC/3TC vs. TDF/FTCLow Viral Load Stratum Sax PE, et al. JID 2011: 204:1191-1201.

  36. HEAT: Virologic Failure by Baseline HIV-1 RNA (A5202 Efficacy Endpoint) 100% 15% 22% 4% 80% ~37% 19% ~59% 18% 50% Proportion of Subjects with VF Percent without Virologic Failure 18% 40% 63% 41% 20% 0% ABC/3TC TDF/FTC 100,000 - <250,000 c/mL ≥500,000 c/mL n= 188 205 155 140 250,000 - <500,000 c/mL <100,000 c/mL Pappa K, et al. 17th IAC, Mexico City, 2008. Abst. THAB0304.Young B, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-1233.

  37. D:A:D Study: NRTIs and Risk of MI 1.9 1.5 1.2 1 0.8 0.6 Relative Risk of MI (95% CI) ** Recent Exposure*: yes/no Cumulative Exposure: per year ZDV ddI ddC d4T 3TC ABC TDF #PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157 #MI: 523 331 148 405 554 221 139 Adjusting for eGFR does not change ABC MI finding: Adjusted RR 1.89; 95% CI (1.46 – 2.44; P=0.0001) * Recent use=current or within the last 6 months. **Not shown (low number of patients currently on ddC) Lundgren J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 44LB. Sabin C, et al. Lancet 2008;371:1417-26.

  38. Concerns regarding NRTIs • Many studies have not seen relationship between ABC and CV events • TDF-associated with greater decline in bone mineral density • TDF-associated with variable decline in renal function

  39. DHHS Guidelines for Adolescents/Adults: What to Start DHHS Guidelines. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf . Revision March 27, 2012.

  40. ART: What to StartIAS–USA Recommendations, 2012 Thompson MA, et al. JAMA. 2012;308(4):387-402

  41. Your Patient • 43 year old man found to be HIV infected • HIV VL 56,000 c/ml • CD4 count 340 cells/ul • Seropositive for HBV

  42. Initial Evaluation • Physical exam: normal; no hepatosplenomegaly • Initial laboratory studies • ALT 1.7 x ULN, bilirubin normal • Platelet count: 150,000 • HCV Abnegative • HBV DNA 6.1 x 105IU/mL • HBsAg+ / HBeAg+

  43. FDA Approved Therapies Available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ Accessed 02/18/10. CLDF HBV Advisory Board

  44. TDF: Virologic Suppression at Year 6 • 80% of 585 patients entering the open-label phase remained on study at year 6; 73% of enrolled patients remained on study • HBeAg loss/seroconversion rates of 50% and 37%, respectively, through 6 years • 11% of HBeAg+ patients had confirmed HBsAg loss (8% with seroconversion) • No resistance to TDF was detected through 6 years Marcellin P, et al. AASLD 2012; Boston. #374.

  45. HBsAg Loss Occurred in 33% of HBeAg+ Pts Treated With 5 Years of ETV HBsAg Loss in HBeAg-positive Patients • HCC developed at yearly rate of 2.5% despite good viral suppression Conclusions: • Long-term ETV monotherapy efficiently suppressed HBV replication in naïve HBV patients • High rates of HBsAg loss can also be seen with this therapy 33% Months Lampertico P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 366.

More Related