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

Antiretroviral Therapy: A Case-Based Panel Discussion (Part II). Eric S. Daar , MD Michael S. Saag , MD. From MS Saag , MD and ES Daar , MD at San Francisco, CA: March 29,2013, IAS-USA. . Switch for Toxicity. Eric S. Daar , MD Professor of Medicine David Geffen School of Medicine at UCLA.

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

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

  2. Switch for Toxicity Eric S. Daar, MDProfessor of MedicineDavid Geffen School of Medicineat UCLA

  3. 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- 75/82 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

  4. 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 ~50-41 mL/min. She is seeing psych and on antidepressants. • A 45 year old African American woman • H/O depression, DM, HTN, dyslipidemia, CKD • CrCl- 70mL/min with proteinuria • CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL

  5. 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.

  6. 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

  7. 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 95,320 141,009 41,300 39,157 #MI: 413 331 148 405 554 221 139 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.

  8. 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 obs. period Bedimo R, et al. 2011 Jul 1;41(1):84-91.

  9. Cumulative Exposure to ARVs and Risk of CKD Tenofovir Cockcroft-Gault (n=225) MDRD (n=277) 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; 41:1667-78

  10. Week 48 A4102: 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.

  11. Patient switched to ABC + 3TC + DRV/r with good tolerance, sustained viral suppression and improvement in CrCl to consistently between 50 and 41 mL/min. • A 45 year old African American woman • H/O depression, DM, HTN, dyslipidemia, CKD • CrCl- 50-41mL/min with proteinuria (HLA-B5701-negative) • CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL

  12. When to Use New ARV Drugs? Michael S. Saag, MDProfessor of MedicineDirector, Center for AIDS ResearchUniversity of Alabama at Birmingham From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.

  13. Assume dolutegravir is now available or approved by FDA

  14. Case 1 • 34 yo woman diagnosed with HIV 4 weeks ago • Initial Lab values • CD4 82 cells/uL • VL 76,000 c/mL • No other significant medical condition • Genotype reveals wild type virus

  15. GS-7340: US-120-0104: TFV Levels TDF 300 mg GS-7340 40 mg 1000 GS-7340 25 mg GS-7340 8 mg 100 AUC Cmax TDF 300 mg TFV plasma concentration (ng/ml) 79% 89% 10 86% 94% 96% 98% 1 0 6 12 18 41 Time (hr) Ruane CROI 2012 #103

  16. GS-7340: US-120-0104 Primary Efficacy Endpoint Ruane CROI 2012 #103

  17. GS-7340: Intracellular (PBMC) TFV-DP 100 >20X 50 Intracellular TFV-DP (µM*h) ~7X ~1X X 0 TDF GS-7340 GS-7340 GS-7340 8 mg 25 mg 40 mg 300 mg Ruane CROI 2012 #103 From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.

  18. Tenofovir and COBI Interact with Distinct Renal Transport Pathways Slide 18 of 41 Anion Transport Pathway Cation Transport Pathway OAT1 ATP OCT2 MRP4 MATE1 H+ OAT3 Tenofovir Creatinine COBI Blood (Basolateral) Blood (Basolateral) Urine (Apical) Urine (Apical) Active Tubular Secretion Active Tubular Secretion Ray A, et al. Antimicro Agents Chemo 2006;3297-3304 Lepist E, et al. ICAAC 2011; Chicago. #A1-1741 The active tubular secretion of tenofovir and the effect of COBI on creatinine are mediated by distinct transport pathways in renal proximal tubules From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.

  19. Cobicistat Cobicistat ATV + Cobi plus TFV/FTC vs ATV + Ritonavir plus TFV/FTC : Study Design Study 114 From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. Gallant IAS 2012

  20. Gallant IAS 2012

  21. Gallant IAS 2012

  22. Gallant IAS 2012

  23. From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. Gallant IAS 2012

  24. Gallant IAS 2012

  25. QUAD vs TFV/FTC/EFV vs ATV plus TFV/FTC: DTG 50mg plus ABC/3TC FDC QD+ EFZ/TDF/FTC Placebo EFZ/TDF/FTC QD + DTG plus ABC/3TC FDC Placebo

  26. EFZ/TDF/FTC: 81% EFZ/TDF/FTC QD • DTG 50mg +ABC/3TC QD was statistically superior to EFZ/TDF/FTC at Week 48 (primary endpoint) • Subjects receiving DTG +ABC/3TC achieved virologic suppression faster than EFZ/TDF/FTC, median time to HIV-1 RNA <50c/mL of 28 days (DTG +ABC/3TC) vs 84 days (EFZ/TDF/FTC), P<0.0001 From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.

  27. Difference in Proportion (95% CI)(DTG - EFZ/TDF/FTC) EFZ/TDF/FTC QD (N=419)

  28. EFZ/TDF/FTC208 cells/mm3 EFZ/TDF/FTC QD From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.

  29. EFZ/TDF/FTC QD(N=419)

  30. EFZ/TDF/FTC QD(N=419) (%) *EFZ/TDF/FTC: Most commonly reported events were CNS, gastrointestinal and rash **DTG+ABC/3TC: 1 drug hypersensitivity^ EFZ/TDF/FTC: 4 psychiatric, 2 drug hypersensitivity, 1 cerebral vascular accident, 1 renal failure ¥ Deaths: n=1 primary cause of death judged unrelated to study drug but complicated by renal failure judged possibly related to EFZ/TDF/FTC, n=1 not related to EFZ/TDF/FTC (pneumonia).

  31. EFZ/TDF/FTC QD EFZ/TDF/FTC QD

  32. Treatment as Prevention Eric S. Daar, MDProfessor of MedicineDavid Geffen School of Medicineat UCLA From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.

  33. A 36 year AA male was recently diagnosed with asymptomatic HIV infection • CD4 720 cells/uL, VL 21,000 copies/mL • No other medical problems or medications • Insists that he does not want to start ARVs • Patient presents with girlfriend who is repeatedly HIV antibody negative • Regular condom use, but not 100% • Key questions for you • How to minimize risk of HIV transmission? • Can they safely have a biologic child in the future?

  34. HPTN 041: Immediate vs Delayed ART in Serodiscordant Couples • Primary efficacy endpoint: virologically linked HIV transmission • Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death • Couples received intensive counseling on risk reduction and use of condoms Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3 (n = 886 couples) HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm3 (N = 1763 couples) Delayed ARTInitiate ART at CD4+ cell count ≤ 250 cells/mm3* (n = 877 couples) *Based on 2 consecutive values ≤ 250 cells/mm3. Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print]

  35. HPTN 041: Linked HIV Transmission Events n=27; incidence rate 1.7 per 100 p-y (95% CI 1.1, 2.5) n=1; incidence rate 0.1 per 100 p-y (95% CI 0.0, 0.4) Cohen M, et al. NEJM July 18, 2011.

  36. Efficacy Rates of Prevention Trials Effect Size, Percent (95% CI) Study ART for prevention; HPTN 041, Africa, Asia, Americas 96 (73-99) PrEP for discordant couples;Partners PrEP, Uganda, Kenya 73 (49-85) PrEP for heterosexual men and women; TDF2, Botswana 63 (21-84) Medical male circumcision; Orange Farm, Rakai, Kisumu 54 (38-66) PrEP for MSMs; iPrEX, Americas, Thailand, South Africa 44 (15-63) Sexually transmitted diseases treatment; Mwanza, Tanzania 42 (21-58) Microbicide;CAPRISA 004, South Africa 39 (6-41) HIV vaccine;RV144, Thailand 31 (1-51) PrEP for women; FEM-PrEP, Kenya, SA, Tanzania 0 (-69-41) Efficacy (Percent) 0 20 40 41 80 100 Adapted from: Abdool Karim SS and Karim QA. Lancet 2011; 378(9809):e23-5 and Celum C and Baeten JM. Curr Opinion Infect Dis 2012; 25:51-57

  37. Slide 37 of 41 • Indication (added to MSM recommendations): • Women and men at very high risk for acquiring HIV from heterosexual sex • One of several options to protect negative partner during attempts to conceive MMWR , Aug 2012; 61: 586-589.

  38. Slide 38 of 41 • Before PrEP • Exclude HIV (and acute if symptoms or exposure last month) • Exclude pregnancy • Confirm at ongoing, very high risk for acquiring HIV • If partner positive, assist with linkage to care • Confirm CrCl≥41 mL/min • Screen for HBsAg, STIs • Prescribe TDF/FTC for 90 days, renew after f/u testing • Risk reduction counseling/condoms • R/O pregnancy in women • HIV antibody, q2-3 months • STI testing q6 months or for symptoms • At 3 months then q6 months check creatinine MMWR , Aug 2012; 61: 586-589.

  39. After much discussion partner decides to not use PrEP while partner is on ARVs • Patient’s viral load is now undetectable and they are more adherent with condoms • They now want to discuss options for safe conception • After detailed discussion the following is noted • They do not want to consider sperm donor • Sperm washing with or without ICSI is not available or affordable for the couple

  40. Slide 40 of 41 • Indication (added to MSM recommendations): • Women and men at very high risk for acquiring HIV from heterosexual sex • One of several options to protect negative partner during attempts to conceive MMWR , Aug 2012; 61: 586-589.

  41. August 1, 2012

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