2017 NSTC Annual Meeting Eric Daar April 18, 2017

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1 Antiretroviral Therapy Update for TB Clinicians Eric S. Daar, M.D. Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Grants Consultant Disclosures Gilead, Merck, ViiV ie, Bristol Myers Squibb, Gilead, Janssen, Merck, Teva, ViiV Objectives Describe data supporting preferred treatment options for HIV infection to inform treatment decisions for improved patient outcomes Summarize patient characteristics that influence the choice of treatment for HIV infection to inform treatment decisions for improved patient outcomes Outline key drug-drug interactions and management strategies for HIV/TB co-infected individuals to inform treatment decisions for improved patient outcomes CC: HPI: Fever, cough, night sweats 31 yr old Hispanic man with no past medical history presents to Emergency Department with 2 months of fever, cough, night sweats and 15 lb of weight loss PE: Thin male in NAD T o C, BP- 110/60, RR- 22, HR- 101, O 2 Sat- 92% Thrush, onychomycosis of toes; No adenopathy or HSM; Lungs- bilateral rhonchi Labs: Hbg gm/dl (MCV 91), WBC 3.2 (73% PMN, 15% Lymphs, 12% monos), Metabolic panel unremarkable with normal transaminases 2017 National TB Conference 1

2 Patient put in respiratory isolation CXR performed 4 th generation HIV Ab/Agrepeatedly reactive CD4-32 cells/ul (5%) HLAB*5701-neg GeneXpert MTB/RIF (x 2): positive without rifampin resistance Started Rifabutin, Isoniazid, Pyrazinamide, Ethambutol Plasma HIV RNA- Pending HIV resistance genotype- Pending When to Start Antiretrovirals? HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: cells/mm 3 (N = 1763 couples) Immediate ART Initiate ART at CD4+ cell count cells/mm 3 (n = 886 couples) Delayed ART Initiate ART at CD4+ cell count 250 cells/mm 3 * (n = 877 couples) *Based on 2 consecutive values 250 cells/mm 3. 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 Cohen MS, et al. IAS Abstract MOAX0102. Cohen MS, et al. N Engl J Med Jul 18. [Epub ahead of print] 2017 National TB Conference 2

3 HPTN 052: Final Results of HIV Prevention in Stable Heterosexual Couples Linked HIV transmission to HIVnegative partner (n=46) Overall 93% reduction in risk of transmission with early therapy Linked partner infections diagnosed after index partner started ART (n=8)* Recently initiated ART (n=4) Virologic failure (n=4) No HIV transmission among people who were suppressed Timing of the linked transmission events supports the model that HIV transmission is very unlikely in the setting of viral suppression Linked Partner Infections (number) Linked HIV Transmission Delayed ART 43 Early ART Overall *Phylogenetic methods compared HIV pol sequences from index partner pairs and controls. Linkage probability was further assessed by comparing the genetic distances between pol sequences (Bayesian analysis). Cohen M, et al. J Int AIDS Soc. 2015;18(suppl 4):15. Abstract MOAC0101LB. Eshleman SH, et al. J Int AIDS Soc. 2015;18(suppl 4):18. Abstract MOAC0106LB. START Study Outcomes: Composite Primary Endpoint and its Components Immediate ART (>500 cells/mm 3 ) superior to deferred ART (<350 cells/mm 3 Serious and non-serious AIDS events 68% of the primary endpoints with CD4 >500 cells/mm 3 Similar reductions in events across all subgroups No increase in AEs associated with immediate ART Number of Events Composite Endpoint 57% Reduction (P<0.001) Number of Serious Events 50 72% Reduction (P<0.001) 14 Deferred ART (n=2359) Immediate ART (n=2326) 47 39% Reduction (P=0.04) 29 AIDS- Non-AIDS Related Related Components (Serious Events) Lundgren J, et al. 8 th IAS Conference. Vancouver, Abstract MOSY0301. The INSIGHT START Study Group. N Engl J Med. 2015;July 20. [Epub ahead of print]. SMART and START Studies: Disease Risk Combined analysis of SMART and START studies (n=10,157) AIDS events (n=123) Serious non-aids events (n=244) AIDS CVD (n=103) Serious Cancer (n=117) non-aids events Death (n=118) AIDS and serious non-aids events (n=359) CVD Immune preservation through immediate and Cancer continuous ART significantly reduces the risk of AIDS and non-aids events Death Cancer risk reduction did not vary by type of cancer AIDS or serious non-aids event Hazard Ratio for Reducing Risk of Events Favors Immediate and Continuous ART Borges AH, et al. 24 th CROI. Seattle, Abstract National TB Conference 3

4 Similar findings in START 2 and TEMPRANO 3 1. Severe P et al. NEJM 2010; 363: ; 2. START NEJM 2015; 373: ; 3. TEMPRANO ANRS NEJM 2015; 373: When to Start ART AIDS or CD4 Count (cells/mm 3 ) HIV-Related Symptoms < >500 United States DHHS (2016) Yes Yes Yes Yes Yes IAS-USA (2016) Yes Yes Yes Yes Yes British HIV Association (2015) Yes Yes Yes Yes Yes European AIDS Clinical Society (2015) Yes Yes Yes Yes Yes WHO (2015) Yes Yes Yes Yes Yes DHHS. Revision Jan Günthard HF, et al. JAMA EACS. Revision October2015. BHIVA. Revision WHO. Revision September Projected Impact of ART on Survival of a 20-yo in a High Income Country Source: UNAIDS / Lohse et al / Hoog et al / May et al / Hogg et al 2017 National TB Conference 4

5 Issues to be aware of with ARVs in TB When to start ART Significant PK drug-drug interactions between anti-tb and ARV agents Additive toxicities associated with concomitant ARV and anti-tb drug use Development of TB-associated immune reconstitution inflammatory syndrome (IRIS) after ART DHHS Guidelines. July 2016 ACTG 5164: Immediate vs Deferred ARVs During Acute OI Zolopa AR, et al. PLoS ONE. 2009;4:e5575. Similar findings in SAPiT 2 and A Blanc F-X, et al and CAMELIA Study Group. NEJM 2011; 365: ; 2. Abdool Karim SS, et al and SAPiT NEJM 2011; 365: ; 3. Havlir D et al, and A5221 NEJM 2011; 365: National TB Conference 5

6 When to Start with AIDS-defining Events Initiate within 2 weeks in virtually all cases Best support in setting of PCP, cryptosporidium, microsporidium, PML Cryptococcal meningitis possibly after 2 week TB Within 2 weeks if CD4< 50 cells/ul Within 8 weeks if CD4> 50 cells/ul Possibly after 2 weeks for TB meningitis DHHS Guidelines. July 2016 Reported in up to 40% of patients starting ART after TB is diagnosed Predictors of IRIS include a lower baseline CD4 (e.g. <50 cells/ul), higher on-art CD4 counts and severity of TB Most IRIS occurs within 3 months of starting ART and presenting with a variety of symptoms, e.g. fever, respiratory distress, lymphadenitis, sepsis syndrome Mild IRIS can be managed with NSAID, more severe may require corticosteroids In setting of IRIS neither ARVs or TB therapy should be stopped DHHS Guidelines. July 2016 Tuberculosis IRIS What Antiretrovirals to Start? 2017 National TB Conference 6

7 ACTG 5257: Open-Label ATV + RTV vs RAL vs DRV + RTV in First-line ART Stratified by HIV-1 RNA < or 100,000 copies/ml, participation in metabolic substudy, CV risk Wk 96 after last pt enrolled ATV + RTV mg QD + TDF/FTC (n = 605) ART-naive pts with HIV-1 RNA 1000 copies/ml (N = 1809) RAL 400 mg BID + TDF/FTC (n = 603) DRV + RTV 800/100 mg QD + TDF/FTC (n = 601) Primary endpoints Virologic failure: time to HIV-1 RNA > 1000 copies/ml (at Wk 16 or before Wk 24) or > 200 copies/ml (at or after Wk 24) Tolerability failure: time to discontinuation of randomized component for toxicity Composite endpoint: the earlier occurrence of either VF or TF in a given participant Switch of regimens allowed for tolerability Lennox JL, et al. Ann Intern Med. 2014;161: ACTG 5257: Primary Endpoint Analyses at Wk 96 Virologic Failure Regimens equivalent in time to VF Tolerability Failure Significantly greater incidence of treatment failure with ATV + RTV vs RAL or DRV + RTV In part due to high frequency of hyperbilirubinemia* Composite Endpoint Considering both efficacy and tolerability, RAL superior to either boosted PI DRV + RTV superior to ATV + RTV Favors RAL ATV + RTV vs RAL ATV + RTV vs RAL 3.4% (-0.7 to 7.4) 12.7% ( ) DRV + RTV vs RAL DRV + RTV vs RAL 5.6% ( ) 3.6% ( ) Favors DRV + RTV ATV + RTV vs DRV + RTV ATV + RTV vs DRV + RTV -2.2% (-6.7 to 2.3) 9.2% ( ) Difference in 96-Wk Cumulative Incidence (97.5% CI) *Pts were allowed to switch regimens and remain on study. Lennox JL, et al. Ann Intern Med. 2014;161: Favors RAL ATV + RTV vs RAL 14.9% ( ) Favors RAL DRV + RTV vs RAL 7.5% ( ) Favors DRV + RTV ATV + RTV vs DRV + RTV 7.5% ( ) Cobicistat + Atazanavir or Darunavir with NRTIs HIV RNA <50 Copies/mL ATV 300 mg + Cobi 150mg vs. RTV 100 mg + TDF/FTC HIV RNA <50 Copies/mL DRV 800 mg + Cobi 150mg + 2 NRTIs (n=313) Gallant JE, et al. J Infect Dis. 2013;208: Tashima K, et al. AIDS Res Ther. 2014;11: National TB Conference 7

8 Low Virologic Failure and Treatment-Emergent Resistance With Boosted PIs Trial Name F/u, Wks CASTLE [1] 96 ACTG 5202 [2] 96 Study 103 [3] 144 ARTEMIS [4] 96 FLAMINGO [5] 96 ACTG 5257 [6] 96 Treatment Arm Virologic Failure, Treatment-Emergent n (%) Primary Mutations, n ATV/RTV + TDF/FTC (n = 440) 28 (6) 1 (PI), 7 (NRTI) LPV/RTV + TDF/FTC (n = 443) 29 (7) 10 (NRTI) ATV/RTV + NRTIs (n = 928) 140 (15) 1 (PI), 16 (NRTI) EFV + NRTIs (n = 929) 129 (14) 68 (NNRTI), 36 (NRTI) ATV/RTV + TDF/FTC (n = 355) NR (7) 2 (NRTI) EVG/COBI/TDF/FTC (n = 353) NR (8) 8 (INSTI), 8 (NRTI) DRV/RTV + TDF/FTC (n = 343) NR (12) 2 (NRTI) LPV/RTV + TDF/FTC (n = 346) NR (17) 5 (NRTI) DRV/RTV + 2 NRTI (n = 242) 4 (2) 0 DTG + 2 NRTI (n = 242) 2 (< 1) 0 ATV/RTV + TDF/FTC (n = 605) 95 (16) 1 (INSTI), 8 (NRTI) DRV/RTV + TDF/FTC (n = 601) 115 (19) 11 (INSTI), 3 (NRTI) RAL + TDF/FTC (n = 603) 85 (14) 1 (INSTI), 7 (NRTI) 1. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53: Daar ES, et al. Ann Intern Med. 2011;154: Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e Mills A, et al. AIDS. 2009;23: Molina JM, et al. Glasgow HIV Abstract O Lennox JL, et al. Ann Intern Med. 2014;161: Patients (%) HIV RNA <50 Copies/mL EVG/COBI/FTC/TDF Difference (%): 2.7 (-2.1, 7.5) 90% 87% 48 (n=353/355) Week ATV/r + FTC/TDF Difference (%): 1.1 (-4.5, 6.7) 83% 82% 96 (n=353/355) DeJesus E, et al. Lancet. 2012;379: Rockstroh J, et al. JAIDS. 2013;62: Study 103: ATV/r + FTC/TDF vs. EVG/COBI/FTC/TDF Treatment-emergent adverse events (%) Diarrhea Nausea Upper respiratory infection Headache Fatigue Ocular icterus Grade 3/4 creatine kinase abnormality (%) Median change in egfr (ml/min) (C-G) Mean change in lipids (mg/dl) Total cholesterol LDL-C HDL-C Triglycerides EVG/COBI/ FTC/TDF (n=353) ATV/r + FTC/TDF (n=355) National TB Conference 8

9 Elvitegravir-Based Regimens in Treatment-Naïve Patients: HIV RNA <50 Copies/mL (Week 48) Week 48 HIV RNA <50 Copies/mL (%) Study 102 Elvitegravir/cobicistat/FTC/TDF (n=348) 88 Efavirenz + FTC/TDF (n=352) 84 Favors Comparator 3.6% Favors Elvitegravir Study 103 Elvitegravir/cobicistat/FTC/TDF (n=353) Atazanavir + RTV + FTC/TDF (n=355) % Adjusted Treatment Difference (%) Sax PE, et al. Lancet. 2012;379: DeJesus E, et al. Lancet. 2012;379: Dolutegravir + NRTIs in Treatment- Naive Patients HIV-1 RNA < 50 c/ml by Snapshot Analysis: 95% CI for Treatment Difference SINGLE [1] Favors Favors EFV/TDF/FTC DTG + ABC/3TC FLAMINGO [2] Favors Favors DRV/RTV DTG SPRING-2 [3,4] Favors Favors RAL DTG ARIA [5] Favors Favors ATV+TDF/FTC DTG/ABC/3TC Wk % 2.5% 12.3% 7.1% 0.9% 13.2% 2.5% -2.2% 7.1% 10.5% 3.1% 17.8% Wk % 2.3% 13.8% 12.4% 4.7% 20.2% 4.5% -1.1% 10% Wk % 2% 14.6% -5% 0 15% -12% 0 25% -12% 0 12% -5% 0 20% No resistance selected for in any DTG-containing regimen 1. Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;[Epub ahead of print]. 2. Molina JM, et al. Glasgow HIV Abstract O Raffi F, et al. Lancet. 2013;381: Raffi F, et al. Lancet Infect Dis. 2013;13: Orrell C, et al. IAS Tenofovir Alafenamide (TAF) 90% Lower TFV Levels in Plasma Minimizes Renal and Bone Effects While Maintaining High Potency for Suppressing HIV GI Tract PLASMA HIV TARGET CELL TVF TFV TDF 300 mg TAF 25 mg TFV HIV TFV Lee W, et al. Antimicrob Agents Chemother. 2005;49: ; Birkus G, et al. Antimicrob Agents Chemother. 2007;51: ; Babusis D, et al. Mol Pharmacol. 2013;10: Ruane P, et al. JAIDS. 2013;63: Sax P, et al. JAIDS. 2014;2014;67: Sax P, et al. Lancet. 2015;385: National TB Conference 9

10 GS 104/111: Efficacy Pts (%) Virologic Outcome 90 EVG/COBI/FTC/TAF (n = 866) EVG/COBI/FTC/TDF (n = 867) Treatment Difference (95% CI) Favors TDF Favors TAF 2.0% -0.7% 4.7% EVG/COBI/FTC/TAF 20 n = Virologic Success Virologic No Data Failure -12% 0 +12% Discontinued for AE, death, or missing data. FTC/RPV/TAF EVG/COBI/FTC/TAF was noninferior to EVG/COBI/FTC/TDF at Wk 48 in each study: 93% vs 92% (Study 104); 92% vs 89% (Study 111) Race not significant predictor of virologic efficacy in multivariate analysis Declines in egfr and in hip and spine BMD significantly less in TAF arm FTC/TAF 1. Sax PE, et al. Lancet. 2015;385: Wohl D, et al. ID Week Abstract Studies 104 and 111: Change in egfr (Cockcroft-Gault) With TAF or TDF TAF versus TDF Significantly smaller decreases in egfr (Cockcroft-Gault) (P<0.001) Significantly less proteinuria, albuminuria, and tubular proteinuria (P<0.001) No cases of tubulopathy/fanconi syndrome in either arm Discontinuations due to renal adverse events E/C/F/TAF: 0 (0%) E/C/F/TDF: 4 (0.5%) Mean Change (ml/min) Mean Change in egfr E/C/F/TAF (n=866) E/C/F/TDF (n=867) -6.6 P< Treatment Week Sax PE, et al. Lancet. 2015;385: E/C/F: elvitegravir/cobicistat/emtricitabine. TAF: tenofovir alafenamide; TDF: tenofovir DF. Studies 104 and 111: Spine and Hip BMD With TAF or TDF 2 1 Spine BMD E/C/F/TAF (n=845) E/C/F/TDF (n=850) 2 1 Hip BMD E/C/F/TAF (n=836) E/C/F/TDF (n=848) Mean Change (%) P<0.001 Mean Change (%) P< Treatment Week E/C/F: elvitegravir/cobicistat/emtricitabine. TAF: tenofovir alafenamide; TDF: tenofovir DF Treatment Week Sax PE, et al. Lancet. 2015;385: National TB Conference 10

11 GS1089: Switch from F/TDF to F/TAF Gallant JE, et al. Lancet HIV 2016: e Efficacy at Week 48 (Snapshot) Virologic Outcome Treatment Difference (95% CI) F/TDF F/TAF HIV-1 RNA <50 c/ml, % % 0 +10% Non-success No difference by age, sex, race and baseline VL or CD4 cell count Gallant JE, et al. Lancet HIV 2016: e Changes in egfr Median (Q1, Q3) change egfr * (ml/min) 8.4 ml/min 2.8 ml/min p <0.001 * egfr calculated with Cockcroft-Gault equation Gallant JE, et al. Lancet HIV 2016: e National TB Conference 11

12 Change in Bone Mineral Density through Week 48 Spine Hip Mean % change (95% CI) p < p <0.001 F/TAF, n F/TDF, n Weeks Weeks % BMD increase at Week 48 F/TAF 30% 17% p<0.001 F/TDF 14% 9% p=0.003 Gallant JE, et al. Lancet HIV 2016: e DHHS, IAS-USA, EACS Guidelines: Recommended Regimens for First-line ART Class DHHS [1] IAS-USA [2] EACS [3] INSTI DTG/ABC/3TC DTG + TDF (TAF)/FTC EVG/COBI/TDF/FTC EVG/COBI/TAF/FTC RAL + TDF (TAF)/FTC DTG + ABC/3TC DTG + TAF/FTC EVG/COBI/TAF/FTC RAL + TAF/FTC DTG/ABC/3TC DTG + TDF/FTC EVG/COBI/TDF/FTC RAL + TDF/FTC Boosted PI DRV + RTV + TDF (TAF)/FTC DRV + RTV + TDF/FTC NNRTI RPV/TDF/FTC Recommendations may differ based on baseline viral load, CD4+ count, CrCl, egfr, HLA-B*5701 status, HBsAg status, and osteoporosis status 1. DHHS Guidelines. July Günthard HF, et al. JAMA EACS Guidelines. October Choosing Integrase Inhibitors Agent Advantages Disadvantages Raltegravir Longest experience Fewer drug interactions than EVG, DTG Twice-daily dosing (for now) No coformulation Elvitegravir Dolutegravir Single-tablet regimen Once-daily dosing Available with TAF The only non-tdf containing single-tablet regimen Once-daily dosing Higher barrier to resistance Few drug interactions Active against some RAL- and EVG-resistant virus Requires COBI boosting COBI drug interactions similar to RTV Coformulated with ABC/3TC only Increases metformin levels 2017 National TB Conference 12

13 Individualizing First-line Therapy: Specific Circumstances Pre-ART characteristics CD4, RNA, HLA-B*5701, transmitted resistance (known or unknown) ART characteristics Pill count, dosing frequency, drug-drug, drug-food interactions Concomitant conditions CKD, psych, cardiovascular risk, risk for pregnancy, pregnancy Co-infections HCV, HBV, TB Adherence concerns DHHS. July Individualizing First-line Therapy: Specific Circumstances Pre-ART characteristics CD4, RNA, HLA-B*5701, transmitted resistance (known or unknown) ART characteristics Pill count, dosing frequency, drug-drug, drug-food interactions Concomitant conditions CKD, psych, cardiovascular risk, risk for pregnancy, pregnancy Co-infections HCV, HBV, TB Adherence concerns DHHS. Revision July Patients Who Must Be Treated Before HIV Drug Resistance Results Become Available Consideration(s) Avoid NNRTI-based regimens Rationale Transmitted mutations conferring NNRTI resistance are more likely than mutations associated with PI or INSTI resistance Recommended ART regimens: Darunavir/r + FTC/TAF or FTC/TDF Dolutegravir + FTC/TAF or FTC/TDF Resistance to darunavir/r and dolutegravir emerges slowly Transmitted resistance to darunavir is rare Transmitted resistance to dolutegravir has not been reported to date DHHS. Revision July 14, National TB Conference 13

14 Drug-Drug Interactions Antimycobacterial ARV Recommendations Rifampin (RIF) All PIs (boosted) Efavirenz (EFV) Nevirapine Etravirine Rilpivirine Maraviroc (MVC) Raltegravir (RAL) Elvitegravir Dolutegravir (DTG) Tenofovir alafenamide EFV 600 mg/d (800 mg/d if >60 kg- controversial) (controversial/no lead in dose) MVC 300 mg bid with inh (600 mg bid without inh) RAL 800 mg bid DTG 50 mg bid (do not use if INSTI mutations) Bedaquiline All PIs (boosted) Efavirenz Nevirapine Use with caution/monitor QTc and liver No dose adjustment DHHS. HIV OI GL April 2017 ( Drug-Drug Interactions Antimycobacterial ARV Recommendations Rifabutin (RFB) All PIs (boosted) Efavirenz Nevirapine Etravirine (ETR) Rilpiviriine (RPV) Maraviroc (MVC) Raltegravir Elvitegravir (COBI) Dolutegravir Tenofovir alafenamide RFB 150 qd or 300 mg tiw (consider drug levels) RFB mg/d (or 600 mg tiw) No dose adjustment ETR 300 mg/d if no inh (do not use with inh) RPV 50 mg/d MVC 150 mg bid with inh (300 mg bid without inh) No dose adjustment No dose adjustment DHHS. HIV OI GL April 2017 ( Thank You!! 2017 National TB Conference 14