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Antiretrovirals in the Management of HIV Infection: Case-Based, Panel Discussion

Antiretrovirals in the Management of HIV Infection: Case-Based, Panel Discussion. Eric S. Daar , MD Professor of Medicine David Geffen School of Medicine at University of California Los Angeles. From ES Daar , MD, at Los Angeles, Ca: April 22, 2013, IAS-USA. . When to Start: Case 1.

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Antiretrovirals in the Management of HIV Infection: Case-Based, Panel Discussion

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  1. Antiretrovirals in the Management of HIV Infection: Case-Based, Panel Discussion Eric S. Daar, MDProfessor of MedicineDavid Geffen School of Medicineat University of California Los Angeles From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

  2. When to Start: 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 Adapted from Mike Saag

  3. When to Start: Case 1b • 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

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

  5. 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higher than “normal” HIV + Untreated (n=82) HIV + ART (n=65) HIV – (n=132) Hunt et al JID 2003, PLoS ONE 2011 and unpublished

  6. 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) 740 500 400 <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 CD 4 Count Moore RD, Keruly JC. Clin Infect Dis 2007;44:441-446. From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

  7. Reasons to Start Early: The Biology Association of Inflammation and Disease Better Tolerated/Easier to Take Medications Randomized Controlled Trial Data Cohort Data Irreversible Damage Public Health

  8. Most New Infections Transmitted by Persons Who Do Not Know Their Status account for… ~25% Unaware of Infection ~54% New Infections ~42% Aware of Infection ~46% of New Infections Source: G. Marks et al. AIDS 2006 From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

  9. 1763 HIV discordant couples (HIV+ partner CD4 350-550) 886 immediate HAART 874 delayed HAART (CD4 250) 1 transmission* & 3 cases of extrapulmonary TB *96% reduction in HIV transmission to HIV-negative partner median follow-up 2 years HPTN 052 All receiving HIV prevention services 27 transmissions* & 17 cases of extrapulmonary TB

  10. So ….what is the harm? • Destruction of lymphoid tissue • Inflammation • Increased cardiovascular events • Increased incidence of certain malignancies • Increased ‘aging’ • Accelerated cognitive decline

  11. When to Start Treatment *Unless elite controller (HIV RNA <50 copies/mL) or has stable CD4 cell count and low-level viremia in absence of therapy. The IAS-USA guidelines also recommend initiating antiretroviral therapy in HIV-infected patients with active hepatitis C virus infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection. DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 2013; Thompson MA, et al. JAMA. 2012;308:387-402.

  12. When to Start: Case 2 • 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

  13. When to Start ARV with Complications • ARVs within 0-2 weeks of diagnosis • Infections for which there is no specific treatment (e.g. dementia, cryptosporidium, microsporidium, PML) (AIII) • Other OIs, e.g. PCP (AI) • Consider deferring therapy for crypto meningitis • Tuberculosis • Within 2 weeks for CD4 <50 cells/uL (AI) • Within 2-4 weeks for severe symptoms with CD4 50-200 (BI) and >200 cells/uL (BIII) • Within 8-12 weeks for mild symptoms and 50-500 cells/uL (AI) and >500 cells/uL (BIII) • Meningitis 2 months (AI) in RLS, perhaps earlier in other settings (CIII) DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 2013; Thompson MA, et al. JAMA. 2012;308:387-402.

  14. A 49 year old asymptomatic man presents to your clinic after recently being diagnosed with HIV • History of HTN with CrCl ~42 mL/min • HBsAb+, HCV antibody negative • CD4 cells repeatedly 700-420 cells/uL • Plasma HIV RNA 30-50,000 copies/mL • Not anxious to start antiretrovirals but willing if you think it is necessary

  15. 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

  16. 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 74 74 74 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

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

  18. STARTMRK: RAL vs. EFV ITT, NC=F 86 81 76 42 71 100 82 79 80 69 67 61 74 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 281 278 279 280 281 281 274 280 281 281 274 279 Efavirenz740 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.

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

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

  21. 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

  22. 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.

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

  24. Study 236-103: ATV/r vs. TDF/FTC/COBI/EVG HIV-1 RNA < 50 c/mL 100 90 80 70 74 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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.

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

  31. HEAT: Virologic Failure by Baseline HIV-1 RNA (A5202 Efficacy Endpoint) 100% 15% 22% 4% 80% ~37% 19% ~59% 18% 74% 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.

  32. Concerns regarding NRTIs • Conflicting results regarding relationship between ABC and CV events • TDF-associated with greater decline in bone mineral density • TDF-associated with variable decline in renal function

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

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

  35. A 45 year old African American woman presents to your clinic having been diagnosed with HIV and severe thrush/onychomycosis • Clinically stable on fluconazole • History mild depression, diabetes, HTN and dyslipidemia on ACE, metformin, atorvastatin • Laboratories • HBsAg and HCV antibody negative • AST/ALT- 42/82 IU/mL, CrCl~70 mL/min (relatively stable), HgbA1C=7.1%, UA- 3+ proteinuria • CD4= 78 cells/uL, HIV-RNA= 219,000 copies/mL • HIV genotype- WT • Ready to start antiretrovirals if recommended with no specific concerns regarding various adverse events but would prefer simple regimen

  36. Patient starts TDF/FTC/EFV, TMP/SMX and continues other meds. At 2 months CD4 190 cells/uL, HIV RNA 220 copies/mL, but patient has increasing depression and persistent neurologic symptoms thought to be associated with EFV. CrCl is repeatedly ~70 mL/min. She is seeing psych and on antidepressants. • A 45 year old African American woman • H/O depression, DM, HTN, dyslipidemia, CKD • CrCl- 70 mL/min with proteinuria • CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL

  37. Switch TDF/FTC + EFV to RPV (N=49) RPV mean Ctroughin ECHO/THRIVE Mills A, et al. 51st ICAAC; Chicago, IL; September 17-20, 2011. Abst. H2-794c.

  38. Patient switched to TDF/FTC + ATV/r and continued other meds. After 4 months neurologic symptoms resolved, CD4 250 cells/uL, HIV RNA <40 copies/mL but patient CrCl has gradually declined (now off TMP/SMX) to 40-45 mL/min with no change in other labs or UA (glucosuria and proteinuria). • A 45 year old African American woman • H/O depression, DM, HTN, dyslipidemia, CKD • CrCl- 40-45 mL/min with proteinuria (HLA-B5701-negative) • CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL

  39. 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 ddIddC d4T 3TC ABC TDF #PYFU: 138,109 74,407 29,676 95,320 153,009 53,300 39,157 #MI: 533 331 148 405 554 221 139 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.

  40. Unadjusted HR of AMI for each PY of exposure to each one of the categories Adjusted for estimated GFR prior to regimen onset (by MDRD method) VA Case Registry: Use of ABC or TDF in Last Regimen and Risk of MI 2.2 2.0 1.8 1.6 1.4 Hazard ratio 1.2 1.0 0.8 0.6 0.4 0.2 ABC TDF Both ABC and TDF NRTI in Last Regimen During Observation Period Bedimo R, et al. ClinInf Dis. 2011;53:84-91.

  41. Cumulative Exposure to ARVs and Risk of CKD Tenofovir Cockcroft-Gault (n=225) MDRD (n=274) CKD-EPI (n=258) INSIGHT def (n=129) Indinavir Censoring ATV Censoring TDF Censoring boosted PI Atazanavir Lopinavir/r 0.9 1.4 Mocroft A, et al. AIDS. 2010; 53:1667-78

  42. Week 48 A5202: ABC/3TC vs. TDF/FTCMedian Change in Creatinine Clearance Week 96 p-values: ABC/3TC vs. TDF/FTC Wk 48, p=0.83 Wk 96, p=0.14 Wk 48, p<0.001 Wk 96, p<0.001 Change in Calculated Creatinine Clearance, (mL/min) TDF/FTC ABC/3TC TDF/FTC ABC/3TC ATV/r EFV 191 173 217 191 186 157 200 178 N= >25% decr(%): 3 2 7 6 2 3 1 3 Daar ES, et al. Ann Intern Med 2011; 154:445-456.

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