Antiretroviral Therapy Management: Expert Panel Discussion George Beatty Susa Coffey Steve O Brien December 3, 2011 Moderated by Annie Luetkemeyer Case # 1 38 y.o. man, CD4 =350, VL=340K, new to your clinic Prior Atripla 1 year ago, had freak out after 2 doses and stopped ART. Irritable bowel syndrome with intermittent diarrhea- has undergone full GI workup Otherwise good health Case #1 (cont d) In relationship with HIV negative partner and wants to restart ART Genotype off meds: Wild type HLA B5701 negative His goals for ART: Once daily if possible No Efavirenz Prefers no ritonavir given IBS 1
What would you chose for him? 1) Rilpivirine/emtricitabine/tenofovir (Complera) 2) Raltegravir once daily/ Truvada 3) Try Atripla again- may tolerate better 4) QD darunavir/ritonavir/truvada with antimotility agent if needed 5) Raltegravir BID/emtricitabine/tenofovir CD4 550, VL 340K, Genotype wild type, prior bad experience with Atripla Questions for the panel How does this patient s high viral load affect your thinking about ART choices when restarting HIV treatment? QD MRK VL>100K n=152 TRV + BID RAL 84.2% n=152 TRV + QD RAL 74.3% VL<100K n=236 91.9% n=230 89.1% BID 88.9% QD 83.2% Difference -9.9% Difference -2.7% (-19.05 to -0.8%) (-8.3% to +2.7%) Overall QD Raltegravir less efficacious If High VL, QD RAL has even lower efficacy More FTC & RAL resistance in QD vs BID Ral Eron Lancet 2011 2
ACTG 5202 Baseline VL >100K: Abacavir inferior to Tenofovir Epzicom vs. Truvada : HR for VF = 2.3 (1.0-5.4, p<0.001) Epzicom vs. Truvada : free of VF @ 48w = 84% vs. 93% Sax NEJM 2011 % < 50 copies/ml 90 80 70 60 50 40 30 20 10 0 BL VL: 77 77 83 80 74 73 75 60 Overall <=100K >100K-500K >500K RPV EFV Nelson, EACS, European AIDS Conference, Belgrade Oct 12-15 2011 Treatment Failure in ECHO and THRIVE RPV Patients (%) EFV VF with resistance data, n 75 37 No NNRTI or NRTI RAMs, % 29 43 Resistant to RPV, % 41 Resistant to EFV, % 25 Resistant to NRTIs, % 48 15 Most frequent NNRTI RAM E138K K103N Most frequent NRTI RAM M184I M184V 10 8 6 4 2 0 9 6.7 4.8 2 Failure Tolerability RPV EFV Etravirine resistant Etravirine sensitive Rilpivirine, package insert. 3
Case #1, part 2 Now assume the patient has chronic renal failure from type 1 diabetes and hypertension with a stable creatinine of 3.0 (creatinine clearance 25) Amenable to BID dosing Takes no PPI/ H2 blocker What ART would you offer? 1) Raltegravir BID/ emtricitabine*/tenofovir * 2) Atazanavir/ritonavir/emtricitabine*/ tenofovir* 3) Atazanavir/ritonavir/abacavir/ lamivudine* 4) Darunavir/ritonavir/etravirine/lamivudine* 5) Darunavir/ritonavir/zidovudine*/lamivudine* * Renally Dosed CD4 550, VL 340K, Genotype wild type, Creatinine Clearance 25 Questions for the panel Would you use abacavir in this patient with a high viral load and risk factors for coronary disease? Would you ever use tenofovir in a patient with chronic renal failure? If you don t use NRTIs (beyond 3TC), what NRTI sparing regimens are you most comfortable with? 4
Academic Center Trials Mantel-Haenszel Risk Difference, % (95% CI) -0.53 0.31 1.16 MI Frequency (Events/Subjects) Abacavir No Abacavir 6/702 4/863 NIH (ACTG) Trials -0.45 0.03 0.51 12/1985 9/1610 Manufacturer Trials -0.43-0.11 0.21 6/2341 9/2367 All Trials -0.26 0.008 0.27 24/5028 22/4840-0.8-0.6-0.4-0.2 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Ding X, et al. CROI 2011. Abstract 808. NRTI- sparing regimens Regimen Comments Darunavir + Raltegravir 5262: may be suboptimal, especially if high HIV RNA RADAR: appeared equivalent Kaletra + Raltegravir Atazanavir (unboosted) + Raltegravir Atazanavir + Maraviroc PROGRESS: promising Stopped early due to hyperbilirubinemia Suboptimal (74% vs 83% RNA <50 at week 48) compared to MVC/Truvada Case #2 44 y.o. man, on first regimen of Atripla for several years with suppressed viral load Lost insurance 2 months ago and ran out of ART Reestablishing care in your clinic CD4 330, VL 44,000 Genotype at this time RT: K103N, M184V PI: no mutations Wants to restart ART, with same regimen if possible No other medications or comorbidities 5
What ART do you offer him? 1) Atripla 2) Rilpivirine/emtricitabine/tenofovir (Complera) 3) Darunavir(QD)/ritonavir/emtricitabine/ tenofovir 4) Raltegravir BID/emtricitabine/tenofovir 5) Darunavir(QD)/ ritonavir/ raltegravir/ emtricitabine/tenofovir Case #2: Panel Questions How many fully active ART agents does this patient need, given presence of M184V? 2 vs. 3? Can rilpivirine be used after an efavirenz failure? 6
PI + 1 Active NRTI? British Columbia HIV Drug Treatment Program Retrospective cohort of patients failing 1 st line regimen with M184V 41% received P1/r/3TC + 1 NRTI 21% as above + 1 active drug 38% PI/r/+ 2 NRTIs ( no 3TC/FTC) All three equally effective in HIV suppression HIV (74%) Suggests 2 ACTIVE agents (PI/r + 1 NRTI) sufficient Hull M et al. 49 th ICAAC San Francisco, abstract H-916, 2009. Case #3 44 y.o. man, CD4 nadir110 ART History: Regimen NVP/ ABC/TDF Atazanavir/r/ AZT/3TC/ tenofovir Unboosted fosamprenavir/ AZT/3TC/tenofovir Unboosted fosamprenavir/ FTC/tenofovir/raltegravir Outcome Virologic failure Genotype: K65R, Y115F, V179D, Y181C Virologically suppressed but GI intolerance of ritonavir Initial suppression then low level viremia HIV RNA suppressed x 2 years Case # 3 Genotype: RT: K65R, Y115F, V179D, Y181C Tenofovir resistance ( in absence of M184V) Abacavir, low level TDF resistance Etravirine resistance (Y181C>V179D), NVP, EFV Stopped ART due to lapse in insurance benefits x 4 months, restarted ART but failed to resuppress HIV RNA despite adherence Returns to clinic: CD4 190, VL 110K Resistance testing pending 7
What regimen to start while waiting for resistance testing? 1) Restart same regimen (unboosted fosamprenavir/raltegravir/ 3TC/tenofovir) 2) Darunavir/ritonavir/ 3TC/raltegravir 3) Darunavir/ritonavir/3TC/tenofovir 4) Darunavir/ritonavir/ 3TC/ etravirine/ 5) Raltegravir/etravirine/maraviroc/3TC 6) None, wouldn t feel comfortable starting any ART until resistance testing is available CD4 190, VL 110 K Genotype 6 yrs ago: K65R, Y115F, V179D, Y181C Questions for panel What integrase resistance testing would you order, if any? What is the likilihood of an integrase inhibitor retaining activity in this situation? What ART would you prescribe while waiting for resistance testing, if any? If M184V now present, does this change your approach to using tenofovir? Resistance testing Genotype/Phenotype unable to be run due to lab error 8
K65R Relatively uncommon mutation, seen after TDF, DDI, ABC, and occasionally D4T failures (subtype C) 2-4% of RT mutations Fitness cost to K65R M184V partially resensitizes Tenofovir activity Analysi of mutations in French and US isolates 57% of K65R seen with M184V Use of tenofovir: 64% with virologic suppression McColl Antiviral Ther 2008, Grant AAC 2010, Frankel AIDS 2007 What ART would you choose now? 1) Darunavir/ritonavir/ Truvada 2) Darunavir/ritonavir/ 3TC/Raltegravir 3) Darunavir/ritonavir/Raltegravir 4) Darunavir/ritonavir/3TC/ etravirine/ 5) Raltegravir/etravirine/maraviroc/3TC 6) None, wouldn t feel comfortable starting any ART until resistance testing is available Case #3 Darunavir/ritonavir BID + Raltegravir + 3TC started Patient with some GI distress from PI/r but able to tolerate VL suppressed on new regimen 9
Case #4 55 year old woman, current CD4 550, HIV RNA undetectable, on Atripla x 3 years as her first regimen Has been trouble by the intense dreams and AM fatigue wants to switch to another regimen Prefers QD, and no side effects, please! No other comorbidities Pretherapy: CD4 150, HIV 150,000, Genotype: wild type What would you offer her? 1) Rilpivirine/emtricitabine/tenofovir (Complera) 2) Raltegravir BID/emtricitabine/tenofovir 3) Darunavir/ritonavir QD + emtricitabine/ tenofovir 4) Raltegravir QD/ emtricitabine/tenofovir 5) Nevirapine XR/ emtricitabine/tenofovir CD4 550, VL undetectable Genotype pretreatment: wild type. Questions for the panel Does the baseline viral load affect your choice of ART in a suppressed patient switching for tolerability? Does a high baseline viral load steer you away from agents like rilpivirine? Is it safe to switch to nevirapine at a high CD4 cell count if the viral load is suppressed at the time of switch? 10
EFV to Rilpvirine switch study 49 patients switching from Atripla to Complera all remained suppressed at week 12 after switch No baseline HIV RNA data given Mills A. et al. H2-794c, Sept 17-20, 2011, Chicago, ICAAC Switching to NVP with high CD4 PreART CD4 Current CD4 OK to switch if low pre-art, high current ART and HIV RNA suppressed Probably best to switch to full dose NVP (200 BID) after EFV Wit CID 2008 ATHENA cohort Winston AIDS 2004, Laureillard HIV Med 2008 Case #4 followup Switched to rilpivirine/emtricitabine/tenofovir Fixed dose combination (Complera) VL remains suppressed 3 months later Dreams have improved but AM fatigue has not 11
THANK YOU! 12