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HIV Update Ardis Moe, M.D. amoe@mednet.ucla UCLA CARE clinic/NEVHC Van Nuys 21 June 2014

HIV Update Ardis Moe, M.D. amoe@mednet.ucla.edu UCLA CARE clinic/NEVHC Van Nuys 21 June 2014. I do not have any financial arrangements or affiliations with commercial sponsors which have direct interest in the subject matter. Goals:. Discuss PREP and PEP options DHHS treatment options

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HIV Update Ardis Moe, M.D. amoe@mednet.ucla UCLA CARE clinic/NEVHC Van Nuys 21 June 2014

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  1. HIV UpdateArdis Moe, M.D.amoe@mednet.ucla.eduUCLA CARE clinic/NEVHC Van Nuys 21 June 2014

  2. I do not have any financial arrangements or affiliations with commercial sponsors which have direct interest in the subject matter

  3. Goals: • Discuss PREP and PEP options • DHHS treatment options • New HIV meds

  4. PREP and PEP update

  5. Audience Response Questions • 1)I have prescribed PREP for at least one patient • 2)I have never prescribed PREP

  6. PREP • Truvada (tenofovir/emtricitabine) 1 pill a day • FDA approved to prevent HIV infections in MSM/transgender women • Needs baseline HIV, hep B testing and testing every 3 months while on truvada • $8 a pill. Risk of kidney, bone damage.

  7. ART Prophylaxis for HIV Infection in Injection Drug Users in Bangkok, Thailand • Randomized, double-blind, placebo-controlled, phase 3 clinical trial of tenofovir vs placebo to prevent HIV • DOT option based on investigator discretion • N = 2413 • Median age, 31 yrs • 80% men • < 10% injected daily; 18% shared needles Choopanya K, et al. 2013;381:2083-2090.

  8. PrEP for IDUs: Results Kaplan-Meier Estimates of Time to HIV Infection in Modified ITT Population 10 TenofovirPlacebo 8 Incident infections: TDF: 17 Placebo: 33 48.9% reduction (95% CI: 9.6-72.2; P = .01) 6 Cumulative Probability of HIV Infection (%) 4 2 0 0 12 48 84 36 72 24 60 Mos Since Randomization Pts at Risk, nTenofovirPlacebo 12041207 10071029 933948 857844 736722 521500 241234 Choopanya K, et al. Lancet. 2013;381:2083-2090.

  9. Update to Interim Guidance for PrEP for Prevention of HIV Infection: PrEP for IDUs • Recommendations • Consider for those at “very high risk”: • Sharing of equipment • Injecting daily • Using cocaine or crystal meth • Critical to exclude HIV first • Use TDF/FTC (truvada --not tenofovir) MMWR. 2013;62:463-465.

  10. US PrEP Demonstration Project: Implementation of PrEP (2012-2014) • STD clinics in San Francisco, Miami, Washington, DC (N = 831) • Offered up to 48 wks of open-label TDF/FTC • Accepted PrEP: 60.4% • Adherence rate higher than in previously reported studies • 77% had TDF-DP levels consistent with taking > 4 doses/wk Tenofovir-DP Levels (Wk 4) 60 Miami (n = 157) Washington, DC (n = 100) San Francisco (n = 300) 52 50 43 43 40 40 35 30 Samples (%) 27 18 20 14 11 10 5 4 4 2 2 0 0 250-550 > 550-950 > 950 BLD < 250 Doses/Wk: < 2 < 2 2 4 > 4 Tenofovir-DP (fmol/punch)* *Measure of flux density. Cohen SE, et al. CROI 2014. Abstract 954.

  11. PREP. • Any alternatives to taking pills?

  12. PrEP Proof-of-Concept: Long-Acting Integrase Inhibitor in Nanosuspension for Injection • Macaque model of SHIV transmission • Study 1 (vaginal transmission)[1] • Low-dose SHIV (50 TCID50) twice a wk • GSK744 LA (50 mg/kg) 3 injections at Wks 0, 4, 8 • 6 of 6 pigtail macaques (lunar menstrual cycles) protected against SHIV infection • Study 2 (rectal transmission)[2,3] • Wkly SHIV (50 TCID50) until systemic infection detected • One GSK744 LA (50 mg/kg) injection at Wk 0 Vaginal SHIV Exposure 100 80 P = .0005 60 Aviremic (%) 40 GSK744 LA (n = 6) Placebo (n = 6) 20 0 0 2 4 6 8 10 12 14 16 30 Wk Rectal SHIV Exposure 100 80 GSK744 LA (n = 12) Placebo (n = 4) 60 Aviremic (%) 40 20 P < .0001 0 0 2 4 6 8 10 12 14 16 18 20 22 24 1. Radzlo J, et al. CROI 2014. Abstract 40LB. 2. Andrews CD, et al. CROI 2014. Abstract 39. 3. Andrews CD, et al. Science. 2014;343:1151-1154. Wk

  13. Treatment as Prevention • PARTNER study • 1st study to show that treatment of MSM also prevents transmission to HIV neg partner • 40% MSM couples in this study • Average 2 years of observation

  14. PARTNER: Risk of HIV Transmission With Condomless Sex on Suppressive ART Risk Behaviors, % • Observational study of rate of HIV transmission in heterosexual and MSM serodiscordant couples (N = 767 couples) • HIV+ partner on suppressive ART • Condoms not used • Analyses: Risk-behavior questionnaire every 6 mos, HIV-1 RNA (HIV+), HIV test (HIV) • Endpoint: Phylogenetically linked transmissions • No linked transmissions recorded in any couple during study period 80 100 0 20 40 60 HT♀ Vaginal sex with ejaculation HT♂ Vaginal sex Receptive anal sex Receptive anal sex with ejaculation MSM Only insertive anal sex Rate of Within-Couple Transmission Events Per 100 CYFU, % (95% CI) 4 0 1 2 3 Vaginal sex with ejaculation (CYFU = 192) HT♀ HT♂ Vaginal sex (CYFU = 272) Receptive anal sex with ejaculation (CYFU = 93) Receptive anal sex without ejaculation (CYFU = 157) MSM Insertive anal sex (CYFU = 262) Rodger A, et al. CROI 2014. Abstract 153LB. Reproduced with permission. Estimatedrate 95% CI

  15. Study will continue for 3 more years

  16. Management of Occupational Exposure to HIV and Recommendations for PEP • First choice: TDF/FTC + raltegravir (isentress and truvada)x 28 days[1] • ID consult recommended for complex cases (eg, source patient on isentress and truvada) • Follow-up shortened to 4 mos if 4th-generation Ag/Ab combination test used • Baseline HIV testing, 6 weeks, 3 months, 6 months. 1. Kuhar DT, et al. Inf Cont Hosp Epi. 2013. 2. NYS Dept Health. HIV prophylaxis following occupational exposure. October 2012.

  17. For pregnant HCW: Lopinavir/ritonavir + zidovudine/lamivudine (Kaletra+Combivir) still first choice for PEP

  18. Initial Therapy – Established Drugs

  19. Dolutegravir Plus Abacavir-Lamivudine (Tivicay+Epzicom) vs Atripla • DTG superior to EFV at Wk 48[1] and Wk 96[2] • Treatment-related study d/c: 3% in DTG vs 11% in EFV arm at Wk 96; comparable rates of virologic failure (6% in each arm at Wk 96) • No resistance in DTG arm through Wk 9 DTG + ABC/3TC EFV/TDF/FTC 100 DTG: 80% 80 60 EFV: 72% Proportion of Patients (%) Wk 96 adjusted difference in response (95% CI): +8.0% (+2.3% to +13.8%); P = .006 40 CD4 ∆ from BL 20 0 0 4 8 12 16 24 32 40 48 60 72 84 96 Wk 1. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 2. Walmsley S, et al. CROI 2014. Abstract 543.

  20. DHHS May 2014: What to Start *Only for pts who are HLA-B*5701 negative. Only for those with CD4+ cell counts > 200 cells/mm3. DHHS guidelines. May 2014.

  21. Ok, so what cocktail works best for what sort of patient? • Plan A, B,C, D system—Dr. Moe’s quick and dirty plan of action

  22. Plan A: A pill a day for Type A Personalities

  23. Plan A drugs • Complera (only for those with <100,000 viral load and no GERD) • Atripla (risk of depression,vivid dreams, panic attacks) • Stribild (risk of diarrhea) • Tivcay/epzicom (risk of diarrhea; needs HLAB5701 blood test to be negative before starting) • All with low barriers to resistance; need for near perfect adherence

  24. Mollan K, et al. IDWeek 2013. Abstract 40032. Increased Risk of Suicidality Associated With EFV 5% .05 EfavirenzEfavirenz-free .04 HR (95% CI) 2.28 (1.27-4.10), P = .006 .03 Probability 47 events/5817 PY* (8.08/1000 PY) .02 .01 15 events/4099 PY* (3.66/1000 PY) 0 192 96 48 144 72 24 168 120 0 As-treated HR 2.16 (1.16-4.00) Wks to Suicidality *Person-years, sum of at-risk follow-up.

  25. Plan B: Boosted protease inhibitors for batty buddies on the brink:

  26. Plan B: poor adherence risk factors • Mentally ill • Meth/cocaine/alcoholic • In and out of jail • Homeless • Chaotic home life • Or: on the brink: CD4 count <200, AIDS OI or cancer

  27. Plan B drugs • Reytataz/norvir/truvada • Prezista/norvir/truvada

  28. Plan C: Curses I forgot the contraception

  29. Plan C • Combivir and Kaletra • Still has the most extensive and best data on safety in pregnancy. • Reyataz, norvir, truvada • Complera • Truvada and isentress are also options • AVOID Sustiva (efavirenz, atripla) : neural tube defects on one study in France

  30. Plan D: Darn I stuck myself or Drug-Drug interactions

  31. Plan D • Isentress and truvada • Fewest drug interactions (warfarin, dilantin) • Need to double dose of isentress when taken with rifampin • Preferred PEP med for needlestick injuries

  32. Novel Strategies for Treatment

  33. HIV Cure: The Score So Far • Still without HIV relapse • 1 patient (“Berlin”) post–stem cell transplant from CCR5 delta 32 negative donor • 1 baby (“Mississippi”) treated at birth[1] • No consistently detectable virus in reservoir (important: still on ART) • Another baby treated at birth (“Long Beach”)[1] 1. Persaud D, et al. CROI 2014. Abstract 75LB. 2. Hatano H, et al. CROI 2014. Abstract 397LB. 3. Heinrich TH, et al. CROI 2014. Abstract 144LB.

  34. What if my Plan B patient (or patient on Atripla) wants to switch to Stribild?

  35. STRATEGY Trials: Switch to EVG/COBI/TDF/FTC in Suppressed Pts • Randomized, open-label switch studies in pts virologically suppressed on an NNRTI- or boosted PI–based regimen (both with TDF/FTC) for ≥ 6 mos • Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 Switch to EVG/COBI/TDF/FTC QD (n = 291) STRATEGY-NNRTI[1] (N = 434) Remain on NNRTI + TDF/FTC (n = 143) HIV-1 RNA < 50 c/mL,  2 previous regimens, no resistance to FTC or TDF and CrCl ≥ 70 mL/min Switch to EVG/COBI/TDF/FTC QD (n = 293) STRATEGY-PI[2]* (N = 433) Remain on Boosted PI + TDF/FTC (n = 140) *Pts with previous VF ineligible. 1. Pozniak A, et al. CROI 2014. Abstract 553LB. 2. Arribas J, et al. CROI 2014. Abstract 551LB.

  36. STRATEGY-NNRTI: Change to EVG/COBI Noninferior to Stable NNRTIs at Wk 48 Δ +5.3%(95% CI: -0.5 to +12) • Regimens: EFV, 78%; NVP, 17%; RPV, 4%; ETR, < 1%; 74% on EFV/TDF/FTC; 91% on first regimen • Results similar across all baseline virologic and demographic subgroups • 3 pts with VF in EVG/COBI arm and 1 in NNRTI arm • No pts with resistance in either arm • 5 in the switch arm and 1 in the NNRTI arm discontinued due to AE 100 93 88 EVG/COBI/TDF/FTC (n = 290) 80 Stable NNRTIs (n = 143) 60 Patients (%) 40 20 11 6 1 3 < 1 1 n = 271 126 16 16 0 Virologic Success* Virologic Nonresponse No Data *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm. Discontinued for AE, death, or missing data. Pozniak A, et al. CROI 2014. Abstract 553LB. Reproduced with permission.

  37. STRATEGY-PI: Change to EVG/COBI Better Than Maintaining bPIs at Wk 48 Δ +6.7%(95% CI: 0.4-13.7) • Regimens: ATV, 40%; DRV, 40%; LPV, 17%; FPV, 3%; SQV, < 1%; 79% on first regimen • Results similar across all baseline virologic and demographic subgroups • 2 pts with VF in each arm but no pts with resistance in either arm • 5 in the switch arm and 2 in the bPI arm discontinued due to AE • Lipids in switch pts •  TGs vs all bPIs •  TC, TG, HDL-C vs LPV/RTV •  HDL-C vs DRV/RTV 100 94 EVG/COBI/TDF/FTC (n = 290) 87 80 Stable bPIs (n = 139) 60 Patients (%) 40 20 12 6 1 2 < 1 2 n = 272 121 16 16 0 Virologic Success* Virologic Nonresponse No Data *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm. Discontinued for AE, death, or missing data. Arribas J, et al. CROI 2014. Abstract 551LB.

  38. Audience Response: Which is TRUE • 1)there have been 10 cases of cure of HIV so far • 2)the best drug cocktail for pregnant women is atripla • 3)the best drug cocktail for a homeless, mentally ill man is atripla • 4)if my patient has an undetectable viral load and is on reyataz/norvir/truvada and wants to switch to stribild, this is safe to do.

  39. Investigational Drugs

  40. TAF:Son of viread

  41. 48-Wk Results of TAF vs Tenofovir DF in ART-Naive Pts • TAF (GS-7340), investigational prodrug of tenofovir with lower TFV plasma concentrations, increased delivery to hepatocytes, lymphoid cells • Randomized, placebo-controlled, phase II trial of TAF vs TDF, each coformulated with FTC/EVG/COBI, in ART-naive patients Wk 24 Wk 48 Gut TFV TDF TAF Plasma TDF/TFV TAF Lymphoid Cells TAF/FTC/EVG/COBI(n = 112) ART-naive patients, CD4+ cell count > 50 cells/mm3, eGFR ≥ 70 mL/min(N = 170) TFV TAF Cathepsin A TDF/FTC/EVG/COBI(n = 58) TFV-MP TFV-DP Zolopa A, et al. CROI 2013. Abstract 99LB. Sax P, et al. ICAAC 2013. Abstract H-1464d. Reproduced with permission.

  42. TAF/FTC/EVG/COBI Noninferior to TDF/FTC/EVG/COBI Through Wk 48 Δ 1.0% (95% CI: -12.1 to +10.0; P = .84) • Noninferiority at Wk 24 primary endpoint analysis[1] • 89.7% vs 87.5 % with HIV-1 RNA < 50 c/mL, respectively • 6 pts (3 per arm) eligible for resistance analysis at Wk 48[2] • No pts with resistance in TAF arm • 1 pt with NRTI and INSTI resistance in TDF arm (M184V, E92Q) 100 88.4 87.9 TAF/FTC/EVG/COBI TDF/FTC/EVG/COBI 80 60 Patients (%) 40 20 10.3 6.3 5.4 1.7 99 51 6 6 1 7 n = 0 Virologic Success* Virologic Nonresponse No Data *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm. Discontinued for AE, death, or missing data. 1. Zolopa A, et al. CROI 2013. Abstract 99LB. 2. Sax P, et al. ICAAC 2013. Abstract H-1464d.

  43. TAF vs TDF Phase II Study: Change in Estimated GFR Over Time 20 TAF/FTC/EVG/COBI TDF/FTC/EVG/COBI 10 0 Median (Q1, Q3) Change From Baseline eGFR Cockroft-Gault (mL/min) -5.5 -10 P = .041 -10.0 -20 36 48 0 24 12 Time (Wks) TAF/FTC/EVG/COBI also had significantly less effect on markers of renal tubular toxicity (retinol binding protein, B2 microglobulin) than TDF/FTC/EVG/COBI Sax P, et al. ICAAC 2013. Abstract H-1464d.

  44. TAF vs TDF Phase II cont’d: Percent Change in Spine and Hip BMD (DEXA) HIP SPINE TDF/FTC/EVG/COBI TAF/FTC/EVG/COBI 2 2 -1.00 -0.62 0 0 P < .001 Median (Q1, Q3) Change in BMD -2 -2 P < .001 -2.39 -4 -4 -3.37 -6 -6 0 12 24 36 48 0 12 24 36 48 Time (Wks) Time (Wks) No decrease in hip BMD in 32% TAF/FTC/EVG/COBI pts vs 7% TDF/FTC/EVG/COBI pts (P < .001) Wk 48 Median Value of Bone Biomarkers as % of Baseline: TAF/FTC/EVG/COBI vs TDF/FTC/EVG/COBI Procollagen Type 1 N-terminal propeptide (P1NP): 109% vs 169% (P < .001) C-terminal telopeptide (CTx): 119% vs 178% (P < .001) Sax P, et al. ICAAC 2013. Abstract H-1464d.

  45. Drugs With Novel Mechanisms for Pan-Resistant HIV in Phase II or Later • BMS-663068 (attachment inhibitor) • … that’s it! It is therefore critical that patients with highly resistant virus preserve virologic suppression through excellent adherence! Discontinuation notice for vircoTYPE, November 2013 Lalezari J, et al. CROI 2014. Abstract 86.

  46. AI438011: BMS-663068 Monotherapy: Mean Change in HIV-1 RNA From BL* 400 mg BID(n = 7) 800 mg BID(n = 5) 600 mg QD(n = 10) 1200 mgQD (n = 10) 0.5 0 -0.5 -0.69 Mean Change in HIV-1 RNAFrom Baseline (Log10 C/mL) -1 -1.22 -1.37 -1.5 -1.47 -2 4 2 0 8 6 Day *Error bars represented standard error of the mean. Lalezari J, et al. CROI 2014. Abstract 86.

  47. In next few months expect… • Coformulated cobisistat with prezista, reyataz. • New one pill regimen: tivicay/epzicom • Son of viread: TAF

  48. Summary • Truvada works for IDU as well as MSM and transgender women. • Injectable once monthly PREP meds in future • Ok to switch to stribild if HIV viral load undetectable on boosted PI or atripla • Plan A,B,C,D cocktails • Truvada and isentress first choice for PEP • Son of viread coming

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