Disclosures. Goals/Format. Patient 1 12/8/18. Antiretroviral Therapy Management. Harry Lampiris: None. Gabriel Chamie: None.

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1 Disclosures Antiretroviral Therapy Management Panel Discussion & Debate Medical Management of AIDS & Hepatitis December 6, 2018 Harry Lampiris, MD, 1 Gabriel Chamie, MD, MPH 2 Susa Coffey, MD, 2 and Vivek Jain, MD, MAS 2 1 SFVAHCS, Infectious Disease Section, UCSF 2 Division of HIV, Infectious Diseases & Global Medicine, SF General Hospital, UCSF Harry Lampiris: None Gabriel Chamie: None Susa Coffey: None Vivek Jain: None Goals/Format Explore three cases highlighting modern topics in ART management Elicit audience opinions Patient 1 Expert panel reflections

2 Patient 1 32 yo HIV+ cisgender woman, recently diagnosed with HIV and referred for ART. She has no significant medical history and is on no medications. She wants to have children in the near-ish future. She would like to start ART, and prefers to take one pill per day. Audience Preliminary Vote Would you start bictegravir/taf/ftc (Biktarvy) in this patient? (A) Yes (B) No Case 1 Yes Case 1: Susa Yes, okay to initiate BIC/TAF/FTC ART should be started today -- our first priority is control of her HIV BIC/TAF/FTC is potent and tolerable, appropriate for RAPID ART start Noninferior to DTG + TAF/FTC; recommended in DHHS GL for 1 st line ART Data in women: naïve (limited) and switch studies Okay to offer BIC/TAF/FTC She is not pregnant now, and not desiring pregnancy immediately Can use contraception for the near term; could consider changing the regimen if/when she plans pregnancy Kityo, CROI 2018 Abs 500

3 What if? Case 1 Yes Safety of INSTIs in pregnancy: no evidence of a class effect BIC 25 pregnancies w/ BIC exposure, 18 prospectively reported + preconception or 1 st trimester exposure, no NTDs EVG/cobi 630 pregnancies, 155 prospectively reported and with preconception or 1 st trimester exposure. 2 reports of NTD, both retrospective reports. RAL Hundreds of pregnancies with 1 st trimester exposure, no e/o incr. risk of teratogenicity; the recommended INSTI in pregnancy (Perinatal GL) -Farrow T et al, Glasgow 2018, P030 -Perinatal GL -Antiretroviral Pregnancy Registry Case 1 Yes If not BIC, then what? (no perfect SPC options ) DTG/ABC/3TC need HLA B5701 result NNRTIs risk of transmitted resistance. Also: RPV/TFV/FTC need to know HIV VL, CD4 EFV/TDF/FTC really? AEs * DOR/TDF/FTC no data, no experience EVG/cobi/TFV/FTC: not recommended in pregnancy (Perinatal GL) * DRV/cobi/TAF/FTC DRV/cobi not recommended in pregnancy (Perinatal GL and package label) - low drug levels * (TAF: no data in pregnancy) * = problematic drug interactions with hormonal contraceptives If either of these is chosen now, must change in pregnancy Case 1 Yes Pt self efficacy she is capable of deciding what is best for her, after discussion of potential risks, benefits, and (significant) unknowns Case 1: Counterpoint: Gabe No, not comfortable initiating BIC/TAF/FTC DHHS: For those who are using effective contraception, a DTG-based regimen can be considered after weighing the risks and benefits of DTG use with the individual

4 Why to avoid BIC in this case 1. The main concern here is re: neural tube defects (NTD) /teratogenicity of future pregnancies for this 31 yo woman of child-bearing age with a desire to conceive in near future. Bictegravir is similar in chemical structure to Dolutegravir In Tsepamo study, the largest study to date of pregnancy outcomes among women on Dolutegravir, both pre-and post-conception, the risk of NTD was significantly increased compared with other ARVs Women on DTG at conception with NTD prevalence ~10x higher than all other scenarios Why to avoid BIC in this case 2. We do not have sufficient data on TAF in pregnancy TAF not approved in pregnant women 3. Not ideal to start a regimen and change shortly thereafter. We have other effective (though not SPC) options: DRV/r + Truvada or ATV + Truvada if she is not planning to use contraception and planning to conceive RPV/TDF/FTC once VL & GT back 4. Worth noting that major studies of Bictegravir in ART-naïve patients (GS-1489 & 1490) ~90% of participants were men 5. Why take the risk in this young woman who wishes to conceive at this point when there are other safer options? Zash, IAS, 2018 Final Audience Vote Would you start bictegravir/taf/ftc (Biktarvy) in this patient? (A) Yes (B) No Case 1 Consensus 1. Overall, Tsepamo data finding an association with DTG use and NTD represent a concerning, preliminary signal, and without further data on BIC (or TAF) in conception/pregnancy, cannot recommend use of bictegravir in this patient planning to conceive 2. However, important to discuss risks/benefits for well-informed, patient-centered decision-making. May proceed if patient understands and willing to accept the risk; also ok if on effective contraception 3. No evidence of increased risk of starting DTG during pregnancy, and INSTIs remain important tool for rapid viral suppression particularly women initiating ART late in pregnancy For more: Dr. Cohan, Reproductive Health, Friday 1:20PM

5 Patient 2 Patient 2 26 year old man with active substance use diagnosed with HIV. WT genotype at ART start. Prescribed TAF/FTC and DTG initially. Says pharmacy dispensed only TAF/FTC last month. He thought his provider must have discontinued DTG), and he has been off DTG for a few weeks. His VL is 2,500 and there is a new M184V on repeat GT. He really would like a single pill combination, and admits he struggles with daily adherence. Debate topic: Is BIC/TAF/FTC an acceptable regimen in this case? Audience Preliminary Vote Would you (A) Prescribe BIC/TAF/FTC (B) Prescribe DRV/c/TAF/FTC Case 2: Gabriel Chamie Yes, ok to use BIC/FTC/TAF in this patient

6 Case 2: Yes use BIC/FTC/TAF We now have prospective data supporting use of EVG/c/FTC/TAF in pts with M184v or M184I Open-label, single arm switch study to E/C/F/TAF in suppressed patients with historical GT with M184V/I, no INSTI or PI-resistance, no additional NRTI or PI mutations on sequencing of integrated DNA, no history of virologic failure, and on stable ART regimen -> VS at 24 wks Abstract TUAB0104-Table 1. No virological failures or emergent resistance PerezValero, IAS, 2018, Abstract TUAB0104 Case 2: Yes use BIC/FTC/TAF We also have retrospective observational data that switch to DTG and EVG/c single tablet regimens in pts with M184V maintains high levels viral suppression (VS) 51 patients with VS and prior genotyping switched to DTG/ABC/3TC or EVG/c/TDF/FTC 47 with RNA GT, and 4 with DNA GT only M184V most common (present in 88% of GTs) After median 13 months follow-up, only 1 case of VF (failed >2 years after switch, and had poor adherence) Pronier, IAS, 2017, Abstract MOPEB0320 Case 2: Yes use BIC/FTC/TAF Bictegravir Similar chemical structure to Dolutegravir In vitro has resistance profile similar to Dolutegravir, and also has a higher barrier to drug resistance than RAL or EVG/c Well-tolerated SPC may be optimal, if poor adherence in this patient is due to intolerance or trouble managing >1 pill Case 2: Counterpoint: Harry Lampiris No, I would not use Biktarvy in a patient with a history of virologic failure and an M184V mutation Chemical structure of bictegravir Markham, Drugs, 2018

7 Case 2: Counterpoint What are the potential choices for a simple regimen in a patient with prior M184V? The strongest data supports a boosted-pi based regimen, such as SYMTUZA An alternative potent regimen would be DOL + TAF/FTC but this is not an STR BIKTARVY (no reported experience), but might be willing to use at some point in the future TRIUMEQ ( or any ABC/3TC based regimen) not appealing because M184V makes abacavir less active, therefore neither NRTI protects INSTI What about GENVOYA? Study 1824: Suppressed Adults with M184V/I Switched to E/C/F/TAF Part 1 Part 2 Study Design Ongoing, multicenter, international, open label, single arm study in HIV-1-infected adults with HIV-1 RNA < 50 copies/ml receiving FTC/TDF or ABC/3TC + third agent NRTI-R: M184V/I only NRTI-R: M184V/I and up to 2 TAMs* N = 37 N = 50 enrolling *TAMs: M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E/N/R E/C/F/TAF QD 12 weeks 24 weeks E/C/F/TAF QD 12 weeks 24 weeks Primary Endpoint HIV-1 RNA < 50 copies/ml at Week 12 using PVR (pure virologic response) *Pure Virologic Response defined with no confirmed virologic failure before W12 or W24, absence of premature discontinuation with last VL 50 c/ml. DC prior to W12 or W24 for other than viral rebound are considered to have PVR. 1. Perez-Valero I, et al. IDRW 2017; 2. Perez-Valero I, et al. AIDS Amsterdam, NL. Amsterdam. Netherlands. Oral TUAB weeks 48 weeks Baseline Resistance (n=37) Efficacy and Safety Results through Week 24 Study 1824: Suppressed Adults with M184V/I Switched to E/C/F/TAF (Part 1 interim analysis) Historical Proviral DNA* M184V/I only n=18 M184V/I +NNRTI-R n=19 WT n=19 M184V/I only n=8 Historical genotype: All participants had M184V/I Approximately half of participants also had NNRTI-R HIV-1 *Genosure Archive Perez-Valero I, et al. AIDS Amsterdam, NL. Poster TUAB0104 M184V/I +NNRTI-R n=8 NNRTI-R only n=2 Study 1824: Suppressed Adults with M184V/I Switched to E/C/F/TAF (Part 1 interim analysis) Participants, % Efficacy Analysis by PVR* 100% W12 100% N=37/37 W24 HIV RNA < 50 copies/ml Switching to E/C/F/TAF may be an option for virologically suppressed participants with pre-existing M184V and/or M184I mutations *Pure virologic response defined with no confirmed virologic failure before W12 or W24, absence of premature discontinuation with last VL 50 c/ml. DC prior to W12 or W24 for other than viral rebound are considered to have PVR. **Muscle spams Perez-Valero I, et al. AIDS Amsterdam, NL. Poster TUAB0104 0% W12 0% W24 (37/37) (37/37) (0/37) (0/37) HIV RNA 50 copies/ml Study Drug-Related Adverse Events (AEs) E/C/F/TAF (n=37) n (%) Any Study Drug-Related AE 8 (22) Any Grade 3 or 4 Study Drug-Related AE 0 (0) AEs Leading to Premature Study Drug Discontinuation ** 1 (3)

8 Final Audience Vote Would you (A) Prescribe BIC/TAF/FTC Patient 3 (B) Prescribe DRV/c/TAF/FTC Patient 3 Patient 3 (con t) 67 yo man with AIDS, CD4 nadir 30, HIV positive since 1988 Active problems include osteoporosis, depression, insomnia, HBsAg positive with suppressed HBV DNA Currently has hyperlipidemia which is not well controlled with high dose rosuvastatin Has a long history of intermittent ARV adherence Is it possible to change his ARV regimen to better manage his hyperlipidemia? ARV history: D4T, 3TC, DDI, ABC, TDF, NVP, NLF, lopinavir/r, in the past, with intermittent viremia Current meds: DRV/c + TAF/FTC, rosuvastatin, omeprazole, Ca/VitD, trazodone, mirtazapine Recent labs: CD4 267, HIV RNA <40 detected, Cr 1.5, chol 250, TG 273, HDL 40, LDL 183, LFTs WNL Prior genotype: RT M41L, L74V, K103N, Y181C, M184V, T215F PI L10I, K20R, M36I, M46I, I54V, L63P, G73S, V82A, L90M

9 Audience Preliminary Vote Would you change this patient s regimen to bictegravir/taf/ftc + doravirine? A. Yes Case 3: Harry Yes, change to BIC/TAF/FTC + DOR B. No Case 3: Why to change to BIK + DOR Simple regimen for this patient which is PIsparing Lipid improvements with changing off DRV/c based regimens have been demonstrated in multiple studies DOR has been studied in switch studies in suppressed patients (DRIVE SHIFT) Doravirine has high genetic barrier, no food requirements, minimal DDIs, no HL, minimal neuropsychiatric side effects or rash Case 3: Counterpoint: Susa No, do not change to BIC/TAF/DOR

10 No, don t change to BIK + DOR This regimen is working well continue it to maintain virologic control (can simplify to D/c/F/TAF for SPC) 3 arguments: 1) Data and clinical experience do not support use of DOR or BIC No clinical data on BIC with resistant virus, some in vitro data No clinical data on DOR with resistant virus In vitro data DRIVE-SHIFT in stable suppressed pts, no resistance to components DOR: unclear barrier to resistance VF in naïve studies-> emergence of multiple NNRTI mutations 2 NNRTI mutations present (K103N, Y181C), and multip NRTIs muts (impaired NRTI backbone) In vitro data suggest modest incr in DOR IC50, but NOT studied in people! What if NNRTI mutations not seen on GT? No, don t change to BIC + DOR 2) Pt has long history of intermittent ARV adherence Consequence of VF here may be huge new RT + IN resistance 3) D/c of PI won t be enough to lower lipids LDL = 183 mg/dl on statin DRIVE-FORWARD - DOR vs DRV/r: mean diff in LDL = 14 mg/dl at wk 48, 19 for TC DRIVE-SHIFT: group changed DOR/TDF/FTC from rtv-boosted PI: mean decr LDL = 16.5 mg/dl at week 24, 26 for TC Switch to BIC from PI/b (DRV or ATV): mean decr LDL 2-7 at wk 48 Optimize control of lipids eg, add ezetimibe, PSK9 inhib. No, don t change to BIC + DOR Proposed change is too risky -- and w/o more data and additional compelling reason to change the ART, would not do Can reevaluate when we have more data on or clinical experience with BIC and DOR Final Audience Vote Would you change this patient s regimen to bictegravir/taf/ftc + doravirine? A. Yes B. No

11 Bonus Case 45y.o. man newly diagnosed with HIV: CD4=438, VL=81,000, and genotype=wild type. Initiates therapy with Triumeq. Within first 2 weeks, complains of headache. You counsel him to continue Triumeq while you monitor At approximately 8 weeks of therapy, the headache is persistent and he wishes to switch to another drug as it is affecting his work. What do you recommend switching to? Audience Vote (A) Symtuza (TAF/FTC/cobi/DRV) (B) Biktarvy (TAF/FTC/BIC) (C) Odefsey (TAF/FTC/RPV) (D) ABC/3TC + RAL Panelist Commentary (A) Symtuza (TAF/FTC/cobi/DRV) (B) Biktarvy (TAF/FTC/BIC) (C) Odefsey (TAF/FTC/RPV) (D) ABC/3TC + RAL Acknowledgements Monica Gandhi, MD Oliver Bacon, MD Annie Luetkemeyer, MD Thank you for participating!