Antiretroviral Therapy in Joel Gallant, MD, MPH Johns Hopkins University School of Medicine

Transcription

1 Antiretroviral Therapy in 2013 Joel Gallant, MD, MPH Johns Hopkins University School of Medicine

2 When to Start

3 When to Start: DHHS Guidelines, February 2013 ART recommended for all HIV+ individuals to reduce risk of disease progression. Strength and evidence for recommendation vary by pretreatment CD4 count: CD4 350 CD CD4 >500 AI AII BIII ART recommended for HIV-infected individuals for prevention of HIV transmission. Strength and evidence for recommendation vary by transmission risk: Perinatal transmission Heterosexual transmission All other risk groups AI AI AIII US DHHS Guidelines, February 2013.

4 When to Start: IAS-USA Guidelines, July 2012 ART recommended and should be offered regardless of CD4 count. Strength of recommendation varies based on CD4 count: CD4 500 CD4 >500 Pregnancy Clinical Condition and/or CD4 Count HIV-associated nephropathy HBV coinfection HCV coinfection Age >60 Acute phase of primary infection Recommendations AIa BIII AIa AIIa AIIa CIII BIIa BIII US Thompson DHHS Guidelines, MA, et al. January JAMA ;308:

5 Why abandon CD4 thresholds? Observational data showing improved survival and/or lack of harm Association between copy-year viremia and morbidity and mortality Presumed benefit of reducing inflammation and immune activation Minimal incremental difference between treating everyone vs. treating a CD4 of 500 Prevention

6 Association of CD4 nadir with clinical outcomes Low CD4 nadir associated with Increased rates of HIV-associated neurocognitive disorders [1] Arterial stiffness contributing to CV risk [2] Coronary heart disease [3] Decreased bone density [4] Increased risk of fracture [5] Malignancies [6,7] 1. Ellis R, et al. AIDS. 2011;25: Ho JE, Scherzer R, Hecht FM, et al. AIDS [Epub ahead of print] and CROI Klein D, et al. CROI Abstract Grant P, et al. CROI Abstract Young B, et al. Clin Infect Dis Apr 15;52(8): Abraham A, et al. CROI Abstract Worm S, et al. CROI Abstract 130

7 N=2027, 6579 p-y F/U Copy-year viremia predicted all-cause mortality independent of cross-sectional VL, CD4 count Cumulative HIV replication causes harm independent of its effect on degree of immunodeficiency. Clin Infect Dis 2011;53:927

8 SMART: Inflammatory Markers Strongly Associated with Mortality and CVD Events Biomarker All-Cause Mortality (N=85) Fatal or Non-fatal CVD (N=136) OR P-value OR P-value hs-crp IL < Amyloid A Amyloid P D-dimer 13.3 < F Kuller L et al. PLoS Med, 2008

9 NA-ACCORD: Early vs. Deferred ART Risk of Death With Deferral of ART a CD4 Count Relative Risk (95% CI) P Value ( ) <0.001 > ( ) <0.001 Study controlled for factors that could affect decision to defer ART Adjustment for sex, age, and CD4 counts at baseline VL response similar in early vs. deferred arms Results similar when IDUs excluded Limitations: observational study with potential for unmeasured confounding a Without inclusion of VL data. Kitahata MM, et al. N Engl J Med. 2009;360:

10 When to Start ART: HIV-CAUSAL Collaboration 20,971 HIV+, ART-naive persons with baseline CD4 < 500 in European HIV clinics and U.S. V.A. Initiation at CD4 of 500 increased AIDS-free survival but not mortality Study did not evaluate non-aids morbidity Cain LE, et al. Ann Intern Med 2011;154:563-55

11 Late HAART Era Patients Still Have 10 Year Shorter Life Expectancy than Uninfected Controls 1 Survival from Age 25 Years N= 3,990 Probability of Survival Early HAART ( ) Pre-HAART ( ) Age, years Population controls Late HAART ( ) Adapted from Lohse N, et al. Ann Intern Med 2007;146:87 95 (See Also: ART-CC, Lancet, 2008; Lewden, JAIDS, 2007)

12 The difference is explained by comorbidities, substance abuse, and risk factors for mortality Probability of survival Age (years) Group 0 Group 1 Group 2 Group 3 Group 4 Lohse et al., Ann Intern Med January 16, :I-39

13 Current CD4 count and mortality in virologic responders to ART SMART and ESPRIT: N=3280 Non-IDU virologic responders to ART CD4 >500: death rate same as general population CD : death rate higher than general population AQUITAINE cohort 2 : Mortality same as that of general population in patients with CD4 >500 after 6 th year of ART Rodger A, et al. Abstract th CROI, Seattle Seattle. 2. Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72-7.

14 ATHENA: Suboptimal CD4 Gains Common Among Patients who Initiate ART Late 1000 Baseline CD4 Count CD4 Cell Count (cells/mm 3 ) >500 (n=389) (n=694) (n=1,513) (n=1,773) <50 (n=930) ~50% of those with CD4 nadir <200 fail to reach 500 after 7 years VL suppression Week Gras L, et al. JAIDS. 2007;45:

15 CASCADE: Time from HIV seroconversion to CD4 thresholds 18,495 European pts with well-estimated dates of seroconversion Predicted time from seroconversion to CD4 thresholds before ART Almost half would require treatment within 1 year of infection with threshold of 500 Conclusions: Early testing needed to identify large number of pts requiring treatment Lodi S, et al. Clin Infect Dis 2011;53: Immediate ART represents ~2% (vs. CD4 500) or ~9% (vs. CD4 350) more time on ART for a patient Dx d at age 25 and living to

16 When to Start EACS Guidelines, July 2012 Condition CD4 Count >500 Asymptomatic HIV C D Symptomatic HIV, including TB R R Primary HIV infection C C Pregnancy (before 3 rd trimester) R R HIV-related conditions (other than CDC stage B/C) HIV-associated kidney disease HIV-associated neurocognitive impairment Hodgkin s lymphoma HPV-associated cancers Other non-aids-defining cancers requiring therapy Autoimmune disease, otherwise unexplained CVD or high risk for CVD Chronic viral hepatitis HBV requiring therapy HBV not requiring therapy HCV for which therapy being considered or given HCV for which therapy not feasible US DHHS Guidelines, January R R R R C C C R C/R R R R R R R C C C R D D C

17 Benefits of ART to reduce health risk on the basis of CD4 count Henry K, et al. Ann Intern Med 2011;154:563-5

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20 HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV-infected, sexually active serodiscordant couples; CD4 count of infected partner: (N = 1763 couples) Immediate ART Initiate ART at CD (n = 886 couples) Delayed ART Initiate ART at CD4 250* (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 DSMB recommended release of results as soon as possible following 4/28/11 review; follow-up continues but all HIV+ partners offered ART after release of results. Cohen MS, et al. IAS Abstract MOAX0102. Cohen MS, et al. N Engl J Med 2011

21 HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P <.0001) Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 Delayed Arm: 27 P <.001 Immediate Arm: 1 Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to suppression of VL Cohen MS, et al. IAS Abstract MOAX0102. Cohen MS, et al. N Engl J Med 2011

22 Efficacy of HIV Prevention Strategies From Randomized Clinical Trials Abdool Karim SS, et al. Lancet 2011; Jul 17.

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24 San Francisco: Predicted HIV Prevalence and Reduction in New HIV Infections Among MSM, by Specific Test & Treat Strategy Predicted HIV Prevalence by ART Strategy Reduction in New HIV Infections, % Tx <500 Tx All Test & Tx All %* 59% 76% %* 55% 81% 10 0 Tx CD4 <350 Tx CD4 <500 Tx All Test + Tx All *Implementing current DHHS Guidelines treating pts with CD4 <500 predicted to result in 1,554 less HIV infections in 5 yrs and 4,940 less over 20 yrs Year Charlebois, CROI 2010; 996.

25 28% of HIV-infected individuals in U.S. have undetectable viral loads 28% CDC MMWR, December 2, 2011 / 60(47); )

26 Urgency of ART Predicted nonadherence Reluctance to start High CD4 Low viral load Slow CD4 decline Low CD4 High VL Rapid CD4 decline Opportunistic diseases Pregnancy HIVAN HBV coinfection Risk of transmission High-risk behavior Willingness to start

27 Frequent CD4 Count Monitoring Not Necessary for Patients With CD4 > 300 Retrospective review of VA lab database of > 25,000 paired VL and CD4 counts from 1821 unique pts ( ) Virologically suppressed pts with CD4 > 300 extremely unlikely to have CD4 count dip < 200 Eligible pts had sequences : consecutive VL/CD4 pairs with VL < 200 CD4 count > 200 %CD4 >14 Analysis of pts with sequences (n = 846) who experienced CD4 dips < 200 during periods of virologic suppression (n = 61) Gale H, et al. AIDS Abstract WEPDB0101. Probability of Maintaining CD4 >200 During Viral Suppression DHHS Guidelines: 0.80 < 390 days between CD4 counts In clinically stable patients with suppressed 0.70 viral load, CD4 count can be monitored every 6 12 months Probability Viral Suppression, Yrs

28 The Initial Regimen

29 DHHS Guidelines, Febuary 2013: What to Start Preferred Regimens NNRTI based Boosted PI based INSTI based Alternative Regimens NNRTI based Boosted PI based INSTI based EFV/TDF/FTC ATV/r + TDF/FTC DRV/r + TDF/FTC RAL + TDF/FTC EFV + ABC/3TC RPV/TDF/FTC or RPV + ABC/3TC (VL <100,000) ATV/r + ABC/3TC DRV/r + ABC/3TC FPV/r + (ABC/3TC or TDF/FTC) LPV/r + (ABC/3TC or TDF/FTC) RAL + ABC/3TC EVG/COBI/FTC/TDF(eGFR >70) DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. February 2013

30 IAS-USA Guidelines, July 2012: What to Start Recommended Regimens NNRTI based EFV/TDF/FTC or EFV + ABC/3TC* Boosted PI based ATV/r + (TDF/FTC or ABC/3TC* ) DRV/r + TDF/FTC INSTI based Alternative Regimens RAL + TDF/FTC NNRTI based NVP + (TDF/FTC or ABC/3TC* ) RPV/TDF/FTC or RPV + ABC/3TC* Boosted PI based INSTI based DRV/r + ABC/3TC LPV/r + (TDF/FTC or ABC/3TC* ) RAL + ABC/3TC* EVG/COBI/TDF/FTC *HLA-B*5701 screening recommended before ABC administration to reduce risk of HSR.. Consider avoiding use of ABC or LPV/r for pts with or at high risk of CV disease. ZDV/3TC is alternative NRTI component of NNRTI-, PI/r-, and RAL-based regimens, but toxicity profile of ZDV reduces its utility. Thompson MA, et al. JAMA 2012;308:

31 BHIVA Guidelines, 2012: What to Start Preferred Alternative NRTI backbone TDF/FTC ABC/3TC 3 rd agent ATV/r DRV/r EFV RAL LPV/r FPV/r NVP RPV

32 EACS Guidelines, 2012: What to Start Preferred regimens (A+B) A B NNRTI EFV RPV ABC/3TC TDF/FTC PI/r NVP ATV/r DRV/r LPV/r TDF/FTC ABC/3TC TDF/FTC INSTI RAL TDF/FTC Alternative regimen components PI/r NRTI CCR5 inhibitor SQV/r FPV/r TDF + 3TC ZDV/3TC ddi + 3TC or ddi + FTC MVC

33 NNRTIs

34 ECHO/THRIVE: Viral Load <50, 96 Week ITT-TLOVR Data RPV Cohen C, et al. J Acquir Immune Defic Syndr. 2012

35 ECHO/THRIVE: RPV vs EFV: 96 Week Results by Baseline VL Responders RPV -5.2 (-12, 1.5) EFV Non responders Discontinued due to other reasons Discontinued due to AE/death VF eff 100K >100K RPV: More virologic failures and NNRTI/NRTI resistance; cross-resistance with ETR (138K mutation) EFV: More adverse effects (rash, CNS side effects), greater increase in lipids Cohen C, et al. J Acquir Immune Defic Syndr. 2012

36 STaR: RPV/TDF/FTC vs. EFV/TDF/FTC Week 48FDA Snapshot Analysis ITT Population RPV/FTC/TDF non-inferior to EFV/FTC/TDF 95% CI for Difference Proportion of Subjects, % 338/ 394 RPV/FTC/TDF EFV/FTC/TDF 320/ /394 22/392 24/394 50/392 Favors EFV/FTC/TDF Favors RPV/FTC/TDF p= % 0 12% (VL<50 c/ml) CD4 change: RPV/FTC/TDF +200 vs EFV/FTC/TDF +191 (p=0.34) Cohen C, et al. 11th Int l Conf on Drug Therapy in HIV Infection, Glasgow, 2012

37 STaR: RPV/TDF/FTC vs. EFV/TDF/F Virologic Suppression by Baseline Viral Load 2% 1% 8% 0% 19% 4% 231/ / / 98 96/ / 36 20/ 25 Baseline VL c/ml * * * Post hoc analyses; analyses for non-inferiority only pre-specified for 100,000 c/ml and >100,000 c/ml Cohen C, et al. 11th Int l Conf on Drug Therapy in HIV Infection, Glasgow, 2012

38 Switching From TDF/FTC/EFV to TDF/FTC/RPV in Suppressed Pts Single-arm study of 50 pts virologically suppressed on TDF/FTC/EFV as first regimen for 3 mos No known resistance mutations to study meds Desiring to switch to TDF/FTC/RPV for intolerance of regimen 100% Percent with VL <50 at 12 weeks VL <50 Mills A, et al. ICAAC Abstract H2-794c.

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40 SPIRIT: Switch to RPV/TDF/FTC From Boosted-PI Regimens in Suppressed Pts Switch to RPV/TDF/FTC noninferior to maintaining boosted-pi regimen at Wk % vs 89.9% with VL < 50 Noninferior regardless of pretreatment VL stratum 17/17 with baseline K103N maintained suppression after switch Sig. reductions in TC, LDL, TG, HDL, TC:HDL ratio (P <.001) and in 10-yr Framingham score (P =.001) at Wk 24 with switch Pts With VL < 50 c/ml (%) % (-1.6 to 9.1) 93.7 n = VL< 50 at Wk 24 RPV/TDF/FTC 89.9 Overall 5.9% (-1.4 to 12.9) / 160 Boosted PI / % (-4.8 to 11.3) / / 52 < 100K 100K Baseline VL (When Naive)* *Excludes 23 RPV and 14 boosted PI pts lacking baseline VL while ARV naive. Palella F, et al. AIDS Abstract TUAB0104.

41 Integrase Inhibitors

42 STARTMRK: Final 5-Yr Phase III Results of Efavirenz vs Raltegravir in Naive Pts Pts With VL < 50 c/ml (%) Double-blind phase III trial of EFV vs RAL, with TDF/FTC, in ART-naïve pts Wk 240 = +9.5 (95% CI, ) Noninferiority P < Wks RAL EFV 61 RAL noninferior at Wk 48 1 o endpoint RAL superior to EFV at wks by VL < 50 (ITT, NC = F analysis) CD4 gain: +374 (RAL) vs +312 (EFV) Consistent virologic and immunologic effects by subgroup (e.g., baseline CD4/VL, age, sex, race, etc.) Low levels of resistance among patients with VF and VL > 400 in both arms RAL, n = 7; EFV, n = 12 Fewer drug-related AEs in RAL arm Pts, n Smaller increases in TC, HDL-C, LDL- C, and TG levels with RAL vs EFV Rockstroh JK, et al. J Acquir Immune Defic Syndr 2013

43 GS 102: EVG/COBI/TDF/FTC vs. TDF/FTC/EFV: VL <50 Quad (n=348) EFV/TDF/FTC (n=352) 95% CI for Difference Percentage of subjects (%) Favors EFV/TDF/FTC Favors Quad W48 3.6% -1.6% 8.8% 2.7% W96-2.9% 8.3% -12% 0 12% Virologic Success Virologic Nonsuppression No data at W48 (or 96) Zolopa A, et al. J Acquir Immune Defic Syndr 2013.

44 GS 102: Changes in serum creatinine Change in Cr (mg/dl), Median [IQR] Discontinuation due to renal A/Es Quad 1.4% 2.0% 0.4 EFV/TDF/FTC 0% 0% STB ATR BL Week STB (n=) ATR (n=) (mmol/l) Zolopa A, et al. J Acquir Immune Defic Syndr 2013.

45 GS 102: Drug Resistance Through Week 96 Quad (n=348) EFV/TDF/FTC (n=352) BL-Week 48 BL-Week 96 BL-Week 48 BL-Week 96 Subjects Analyzed for Resistance*, n (%) 14 (4%) 17 (5%) 17 (5%) 23 (7%) Subjects with Resistance to ARV Regimen, n (%) 8 (2%) 10 (3%) 8 (2%) 10 (3%) Any Primary INSTI-R, n Any Primary NNRTI-R, n Any Primary NRTI-R, n * Subjects who experienced either suboptimal virologic response (VL 50 c/ml and <1 log 10 below baseline at Week 8 and confirmed at the subsequent visit), virologic rebound (two consecutive visits with VL either 400 c/ml after achieving VL <50, or >1 log 10 increase from nadir), or had VL 400 c/ml at Week 48, Week 96, or their last visit (at or after Week 8). Zolopa A, et al. J Acquir Immune Defic Syndr 2013.

46 GS 103: EVG/COBI/TDF/FTC vs. TDF/FTC + ATV/r: VL <50 EVG/COBI/FTC/TDF (n=353) ATV/r + FTC/TDF (n=355) 95% CI for Difference Percentage of subjects (%) Favors ATV/r + FTC/TDF Favors EVG/COBI/FTC/TDF 2.7 W W % 0 12% Virologic Success Virologic Non suppression No data at W48 (or 96) Figure 1: Efficacy (Snapshot Analysis) through Week 48 (Primary) and Week 96 (Secondary) Rockstroh JK, et al. J Acquir Immune Defic Syndr 2013.

47 GS 103: Changes in Serum Creatinine Change from Baseline in Serum Creatinine (mg/dl) BL Week QUAD (n=): ATV/r +FTC/TDF (n=): Median change W48: 0.12 mg/dl vs mg/dl (Quad vs. ATV/r + FTC/TDF group, p<0.001) DeJesus E, et al. Lancet 2012;379:

48 GS 103: Drug resistance through week 48 Quad (n=353) ATV/r + FTC/TDF (n=355) Subjects Analyzed for Resistance a, n (%) 12 (3) 8 (2) Subjects with Resistance to ARV Regimen, n (%) 5 (1) 0 Any Primary Integrase-R, n 4 - E92Q 1 - T66I 1 - Q148R 2 - N155H 2 - Any Primary PI-R, n - 0 Any Primary NRTI-R, n 4 0 M184V/I 4 K65R 1 DeJesus E, et al. Lancet 2012;379:

49 GS 102: Common Neuropsychiatric AEs Quad (n=348) EFV/TDF/FTC (n=352) Abnormal Dreams Dizziness Patients with AE (%) Weeks Incidence (bar) and Prevalence (line) Weeks Zolopa A, et al. J Acquir Immune Defic Syndr 2013.

50 SPRING-2: Dolutegravir Noninferior to Raltegravir at 48 Wks Pts With VL < 50 c/ml (%) DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) CD4 gain of +230 from BL in both arms No significant differences by baseline VL or NRTI backbone Per protocol response: 90% (DTG) vs 88% (RAL) by snapshot analysis 1.6% (95% CI: -2.7% to 5.9%) 88% 85% 2.5% (95% CI: -2.2% to 7.1%) 0 BL Raffi F, et al. IAC Abstract THLBB04. Wk

51 SPRING-2: Safety and Resistance Less confirmed virologic failure at or after Wk 24 with DTG vs RAL (5% vs 7%) Patients DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) Subjects with virologic failure, n Resistance, n/n INSTI resistance mutations NRTI resistance mutations 0/8 0/12 1/18 4/19 DTG had favorable safety profile, comparable to RAL Few AEs necessitating discontinuation (2% in each arm) Greater increase in creatinine with DTG vs RAL ( vs mg/dl) DTG increases serum creatinine by inhibiting renal creatinine secretion but does not affect actual GFR [2] No premature discontinuation for renal events 1. Raffi F, et al. IAC Abstract THLBB Koteff J, et al. ICAAC Abstract A

52 SINGLE: Dolutegravir + ABC/3TC vs. EFV/TDF/FTC DTG+ABC/3TC: 88% Proportion (%) with <50 c/ml WK 48 difference in response (95% CI): +7.4% (+2.5% to +12.3%); p=0.003 EFV/TDF/FTC: 81% DTG 50 mg + ABC/3TC QD EFV/TDF/FTC QD BL Week DTG +ABC/3TC QD superior to EFV/TDF/FTC at Wk 48 (1 o endpoint) Subjects receiving DTG +ABC/3TC achieved faster suppression than EFV/TDF/FTC, med. time to FL <50 c/ml of 28 vs 84 days, P< Walmsley S, et al. 52 nd ICAAC Sept Abstract H-556b.

53 SINGLE: DTG + ABC/3TC vs. EFV/TDF/FTC: Disposition Outcome (snapshot) at Week 48 DTG 50 mg +ABC/3TC n=411 n (%) EFV/TDF/FTC (N=419) n (%) Virologic success 364 (88) 338 (81) Virologic nonresponse 21 (5) 26 (6) Data in window not <50 c/ml 6 (1) 5 (1) Discontinued for lack of efficacy 7(2) 9 (2) Discontinued for other reason while not <50 c/ml 8 (2) 12 (3) No virologic data at Week (7) 55 (13) Discontinued because of AE or death* 9 (2) 40 (10) Discontinued for other reasons 20 (5) 14 (3) Missing data during window but on study 0 1 (<1) *Deaths: n=2, both on EFV/TDF/FTC: n=1 primary cause of death (sepsis) judged unrelated to study drug but complicated by renal failure judged possibly related to EFV/TDF/FTC; n=1 not related to EFV/TDF/FTC (pneumonia). Walmsley S, et al. 52 nd ICAAC Sept Abstract H-556b.

54 SINGLE: DTG + ABC/3TC vs. EFV/TDF/FTC: Resistance DTG 50mg +ABC/3TC (N=414) EFV/TDF/FTC (N=419) Subjects with PDVF 18 (4%) 17 (4%) PDVF genotypic population 11 9 PDVF Genotypic (RT Results at Baseline and PDVF) 9 9 NRTI tmt-emergent major mutations 0 1(K65R) NNRTI tmt-emergent major mutations 0 4 (K101E, K103N, G190A)* PDVF Genotypic (IN Results at Baseline and PDVF) 7 7 INI-r tmt-emergent major substitution 0** 0 * n=1 with K101E, n=1 with K103N, n=1 with G190A and n=1 with K103N+G190A **E157Q/P polymorphism detected with no significant change in IN phenotypic susceptibility Walmsley S, et al. 52 nd ICAAC Sept Abstract H-556b.

55 PIs

56 GS 114: Cobicistat-Boosted vs RTV- Boosted ATV in ART-Naïve Patients Patients (%) n = VL < 50 at Wk 48 (Snapshot Analysis) -2.2% ATV/COBI ATV/r (-7.4 to 3.0) P = NS P = NS P = NS Overall 179/ 212 CD4 count gain: +213 with ATV/COBI vs +219 with ATV/r Among 24 pts with suboptimal virologic response and genotype: no primary PI or TDF resistance; M184V/I in 2 pts in COBI arm, 0 in RTV arm Gallant J, et al. J Infect Dis / 205 Baseline VL 100K 114/ / 143 Baseline VL > 100K 156/ / 183 Baseline CD P = NS / / 165 Baseline CD4+ > 350

57 ATV/COBI vs ATV/r: Changes in Serum Creatinine and egfr COBI serum creatinine and egfr by inhibiting renal creatinine secretion [1] COBI does not affect actual GFR [2] Change in Serum Creatinine, Median (IQR) ATV/COBI ATV/r 0-10 Change in egfr, Median (IQR) mg/dl BL Wk 6 pts in COBI arm and 5 in RTV arm D/C d therapy due to renal abnormalities [3] Higher proportion with hyperbilirubinemia with COBI but discontinuations similar by arm 5 of 6 in COBI arm vs 2 of 5 in RTV arm with proximal tubulopathy discontinued therapy ml/min ATV/COBI ATV/r BL Wk 1. Lepist EI, et al. ICAAC Abstract A German P, et al. J Acquir Immune Defic Syndr. 2012;[Epub ahead of print]. 3. Gallant J, et al. J Infect Dis 2013.

58 PI News Coming soon? DRV/COBI and ATV/COBI coformulations Coming later? DRV/COBI/FTC/TDF ( D/C/F/TAF ) coformulation Awaiting results: ACTG ARENT: DRV/r vs. ATV/r vs. RAL comparison

59 HIV Entry Inhibitors CD4 Binding Coreceptor Binding Virus-Cell Fusion BMS Ibalizumab CD4 gp41 gp120 V3 loop CCR5 antagonists Enfuvirtide Cell Membrane CCR5/CXCR4 (R5/X4)

60 New Entry Inhibitors Cenicriviroc (TBR-652): CCR5 antagonist with anti-ccr2 properties (anti-inflammatory) BMS : CD4 attachment inhibitor Ibalizumab (TNX-355): Anti-CD4 monoclonal antibody; once weekly IV dosing

61 NRTIs

62 ACTG 5202: Time to Virologic Failure by Baseline Viral Load and CD4 Count ABC/3TC TDF/FTC Probability of Remaining free of Virologic Failure CD4<50, RNA 100K (n=98, 35 VF) CD4<50, RNA<100K (n=78, 23 VF) CD4 50 to <200, RNA 100K (n=80, 19 VF) CD4 50 to <200, RNA<100K (n=153, 10 VF) CD4 200 to <350, RNA 100K (n=39, 6 VF) CD4 200 to <350, RNA<100K (n=273, 28 VF) CD4 350, RNA 100K (n=23, 5 VF) CD4 350, RNA<100K (n=184, 29 VF) Probability of Remaining free of Virologic Failure CD4<50, RNA 100K (n=80, 6 VF) CD4<50, RNA<100K (n=83, 17 VF) CD4 50 to <200, RNA 100K (n=70, 9 VF) CD4 50 to <200, RNA<100K (n=158, 19 VF) CD4 200 to <350, RNA 100K (n=55, 8 VF) CD4 200 to <350, RNA<100K (n=289, 29 VF) CD4 350, RNA 100K (n=20, 2 VF) CD4 350, RNA<100K (n=173, 24 VF) Weeks from Randomization Weeks from Randomization Grant P, et al. CROI Abstract 535.

63 Abacavir and MI Risk: Recent published studies Reference Study Design Increased risk? Choi, AIDS 2011, VA Observational Yes Bedimo, CID 2011, VA Observational No Durand, J AIDS 2011, Montreal Observational Yes Ribaudo, CID 2011, ACTG Cohort from RCTs No Cruciani, AIDS 2011 Met-analysis No How difficult it is to find a consensus can be exemplifiedby the fact that even identical data sources (Veterans Health Administration) analyzed by different investigators can lead to conflicting results Georg Behrens, AIDS 2011; Paul Sax

64 Abacavir and MI Risk Conflicting data from observational and prospective studies Proposed pathogenic models: Inflammation Increased platelet reactivity/adhesion Impaired flow-mediated dilatation Atherogenic lipid profile Guidelines: use with caution in patients with high CV risk DHHS Guidelines, October 14, 2011

65 VA Study: TDF and risk of kidney disease 10,841 HIV+ pts at VA Time to first occurrence of 1) proteinuria 2) rapid decline in kidney function and 3) CKD (egfr rate < 60 ) Each year of exposure to TDF associated with: 34% increased risk of proteinuria (p < ) 11% increased risk of rapid decline (p = ) 33% increased risk of CKD (p < ). Pre-existing renal risk factors did not appear to worsen the effects of tenofovir. Scherzer R, et al. AIDS 2012 [Epub ahead of print]

66 Cumulative Use of TDF and/or Boosted PIs And Risk of Osteoporotic Fractures Retrospective analysis of 56,660 HIV+ male Veterans enrolled from Osteoporotic fractures assessed from ICD-9 codes Cumulative use of TDF and/or PI/r associated with higher risk in ART era, after controlling for risk factors Highest risk with concomitant use Cumulative use of LPV/r also associated with higher fracture risk PI association limited to LPV/r Cumulative use of ABC, thymidine analogs, NNRTIs not associated with higher risk Bedimo R, et al. AIDS [epub ahead of print]. HR for Fracture, HAART Era Limitations TDF Univariate analysis Controlled for effects of CKD, age, race, smoking, DM, BMI, and HCV. Controlled for covariates in Model 1 plus concomitant exposure to ARVs. Retrospective cohort study BMD data not available PI/r Fractures not verified to be osteoporotic

67 Switch to TDF increases bone turnover and reduces bone mineral density Subjects on AZT/3TC (n=54) randomized to continue or switch to TDF/FTC Continue AZT/3TC BMD Med. (IQR) Within group p-value Femoral neck 1.36 (-3.26, 1.63) Lumbar spine (-2.35, 1.85) Randomization group Switch to TDF/FTC Med. (IQR) (-3.04, 0.22) (03.28, -0.40) Within group p-value Between group p-value Markers of bone formation and bone resorption also increased in TDF/FTC group Cotter A, et al. Abstract 125LB, CROI 2012

68 Switching from TDF to RAL improves BMD Bloch, 2012

69 NRTI-sparing regimens Study Regimen Efficacy/ Resistance Lipids Renal Bone Bilirubin A LPV/r + EFV Neutral Elevated Neutral Neutral - PROGRESS 4 LPV/r + RAL Neutral Elevated Neutral - - CCTG589 5 LPV/r + RAL Neutral SPARTAN 6 ATV + RAL More Resistance Neutral - - Elevated MVC Manufacturer 7 ATV/r + MVC Neutral Elevated MONET 8 DRV/r Not Non-Inferior Elevated A DRV/r + RAL Inferior TBD TBD TBD TBD 1. Riddler S, et al. New Engl J Med 2008;358: Huang J, et al. WAIDS Vienna. WEAB Goicoechea M, J et al. WAIDS Vienna. WEAB Reynes J, et al. WAIDS 2010; Vienna. MOAB Goicoechea M, J et al. WAIDS Vienna. THPE Kozal MJ, et al. WAIDS 2010; Vienna. THLBB Portsmouth S, et al. WAIDS 2010; Vienna. THLBB Rieger A, et al. WAIDS 2010; Vienna. THLBB Taiwo B, et al. CROI 2011; Boston. Poster 551

70 ACTG 5262: DRV/r + RAL 1.0 Time to Virologic Failure (VF) 1.0 Time to VF by Baseline HIV-1 RNA Probability of not having a VF Time (weeks) n with VF: n at risk: Taiwo B, et al. AIDS 2011,;25: Probability of not having a VF % failure by week 48 HIV-1 RNA 100,000 copies/ml HIV-1 RNA > 100,000 copies/ml Log Rank Test p= Time (weeks) VL 100,000 n with VF: n at risk: VL > 100,000 n with VF: n at risk:

71 Boosted PI Monotherapy: Systematic Review Overall efficacy of PI/r monotherapy inferior to that of standard HAART Bierman WFW, et al. AIDS 2009, 23:

72 MONET: DRV/r monotherapy after suppression on DRV/r-based HAART DRV/r monotherapy noninferior to DRV/r-based HAART at Wk 48 1 pt with virologic failure in each arm developed primary PI and/or multiclass mutations Drug Resistance, n DRV/r (n = 127) DRV/r + 2 NRTIs (n = 129) Pts with 1 genotype No primary PI, DRV, or NRTI mutations M184V 1 0 Primary PI mutations 1 1 DRV RAMs 0 1 HIV-1 RNA < 50 c/ml at Wk 48 (%) DRV/r (n = 127) DRV/r+ 2 NRTIs (n = 129) * Overall (ITT) *Noninferiority definition: lower limit < 12%; lower limit 95% CI: -1.0% to -9.9% Adverse events similar between groups Arribas JR, et al. IAS Abstract TUAB106LB.

73 Tenofovir alafenamide fumarate (TAF): Tenofovir pro-drug with greater antiviral activity than TDF Dosing Placebo (n = 7) TDF 300 mg (n = 6) TAF 8 mg (n = 9) TAF 25 mg (n = 8) TAF 40 mg (n = 8) Day Higher intracellular tenofovir diphosphate levels and lower circulating plasma tenofovir levels with TAF vs TDF Ruane PJ, et al. CROI Abstract 103.

74 GS-US : E/C/F/TDF vs. E/C/F/TAF Phase 2 Study Design Randomized, placebo-controlled, double-blind study Treatment Arm 1 (n=100) E/C/F/TAF QD ART-naive subjects (n=150) Randomized 2:1 Stratification by VL >/ 100,000 E/C/F/TDF Placebo QD Treatment Arm 2 (n=50) E/C/F/TDF QD E/C/F/TAF Placebo QD Week 48 Primary endpoint --Proportion with VL < 50 at Week 24 (Snapshot) Zolopa, et al., CROI 2013;# 99LB

75 GS-US : Virologic Response (M=F, ITT), week E/C/F/TDF 89.7% % Subjects with VL <50 (M=F, ITT) E/C/F/TAF 87.5% E/C/F/TAF (n=112) E/C/F/TDF (n=58) Time (Weeks) Mean change from baseline CD4 count: E/C/F/TAF, +163 STB, +177 (p = 0.76) Zolopa, et al., CROI 2013; Paper # 99LB

76 GS-US : Median Change in Serum Creatinine through Week E/C/F/TAF STB Median (Q1, Q3) change from baseline Serum Creatinine (mg/dl) p = Time (Weeks) Change in serum creatinine at Week 24 E/C/F/TAF: 0.07 mg/dl E/C/F/TDF: 0.12 mg/dl (p=0.02) Zolopa, et al., CROI 2013; Paper # 99LB

77 GS-US : Percent Change in Bone Mineral Density (DEXA) at Week 24 SPINE HIP Mean % change in BMD p = Mean % change in BMD p < Time (Weeks) Time (Weeks) Proportion of subjects with no decrease in BMD Spine: E/C/F/TAF, 38%; E/C/F/TDF, 12% Hip: E/C/F/TAF, 41%; E/C/F/TDF: 23% Zolopa, et al., CROI 2013; Paper # 99LB

78 Single tablet regimens PROS CONS TDF/FTC/EFV PK forgiving of missed doses CNS side effects TDF/FTC/RPV TDF/FTC/ EVG/COBI Better tolerated than EFV Good switch data Non-inferior to TDF/FTC/ EFV Better tolerated than EFV Teratogenicity Resistance with interruption Rash More lipid effects than others Recommended only if VL <100,000 Less forgiving of non-adherence More resistance with failure, including ETR cross-resistance Food requirement No PPI, caution with H2 blockers COBI drug interactions COBI effect on egfr

79 Single tablet regimens PROS CONS TDF/FTC/EFV PK forgiving of missed doses CNS side effects TDF/FTC/RPV TDF/FTC/ EVG/COBI ABC/3TC/DTG Better tolerated than EFV Good switch data Non-inferior to TDF/FTC/ EFV Better tolerated than EFV Only non-tdf-based STR Superior to TDF/FTC/EFV (better tolerability) Teratogenicity Resistance with interruption Rash More lipid effects than others Recommended only if VL <100,000 Less forgiving of non-adherence More resistance with failure, including ETR cross-resistance Food requirement No PPI, caution with H2 blockers COBI drug interactions COBI effect on egfr Possible increased risk of MI with ABC

80 Why prescribe more than one tablet in 2013? Boosted PI + 2 NRTIs: Patients with unreliable adherence Transmitted resistance Pregnancy RAL + 2 NRTIs: Few drug interactions. Ideal for patients needing HCV therapy ABC/3TC + 3 rd agent: Kidney disease Osteoporosis/osteopenia

81 Choice of ART: Special populations and scenarios Pregnancy or likelihood of pregnancy Avoid EFV (1 st trimester) No data on newer agents (RPV, EVG/COBI) NRTIs: AZT/3TC, TDF/FTC PIs: LPV/r, ATV/r HCV coinfection RAL: can be used with telaprevir, boceprevir ATV: can be used with telaprevir EFV: requires higher dose telaprevir HBV coinfection TDF/FTC-based regimen if possible

82 Choice of ART: Special populations and scenarios Chronic kidney disease Avoid TDF (and ATV, LPV/r?) Pre-existing osteoporosis/osteopenia Avoid TDF Need for urgent ART without resistance data (primary HIV, acute OI) Boosted PI-based regimen Transmitted resistance Depends on mutations PI-based regimen preferred for NRTI resistance

83 ART: New formulations 3 single-tablet regimens now available 3 more in development: DTG/ABC/3TC EVG/COBI/FTC/TAF ( E/C/F/TAF ) DRV/COBI/FTC/TAF ( D/C/F/TAF ) Other possible coformulations: ATV/COBI DRV/COBI EVG/COBI TAF/FTC

84 Treatment-Experienced Patients

85 Elvitegravir Comparable to Raltegravir in ART- Experienced Patients at Wk 96 Patients, % VL< 50 c/ml (ITT, TLOVR) Virologic Response W48 W96 W48 W96 W48 W96 Virologic Failure EVG (n = 351) RAL (n = 351) Others CD4 gain: +205 (EVG) vs +198 (RAL) at Wk 96 Similar rates of treatmentemergent integrase resistance in each arm (7%) Similar rates of AEs overall More diarrhea with EVG vs RAL (13% vs 8%) More liver-related AEs with RAL (1.7% vs 0.8%) Elion R, et al. International AIDS Conference Abstract TUAB105.

86 SECOND-LINE: Treatment options after failure of NNRTI + 2 NRTIs 541 patients failing initial therapy randomized to: LPV/r NRTIs selected by genotype LPV/r + RAL LPV/r + NRTs (N=271) LPVr + RAL (N=270) VL < (81%) 223 (83%) 0.59 VL < (70%) 192 (71%) 0.56 CD4 increase P Boyd M, et al. CROI Abstract 180 LB

87 EARNEST trial: 2 nd line therapy Randomized 1:1:1 144 wks follow up 1º 96 Good clinical disease control : Alive + no new WHO 4 event + CD4 > VL<10K Failing 2NRTI / NNRTI (WHO stage 4 or CD4 <250 with VL >50; or VL >10K) (N = 1200) PI/r + RAL PI/r + 22NRTI* PI/r (monotherapy)** superiority noninferiority *2NRTI standardized to TDF/FTC if patients on 1 st line AZT or d4t based-regimen; **PI/r monotherapy preceded by initial 3 month induction with RAL

88 ACTG OPTIONS: Are NRTIs necessary in treatment-experienced patients? 360 pts failing ART w/ NRTI, NNRTI, and PI resistance or experience Regimen chosen based on review of ART history, resistance, and tropism PSS >2 required Randomized to omit or include NRTIs Omit NRTIs N=179 Regimen failure through wk (30%) 48 (26%) VL <50 at wk 48 64% 68% Severe signs/sx or lab abnormality 67 (38%) 65 (35%) Include NRTIs N=181 NRTIs not necessary if >2 active drugs included in regimen Tashima K, et al. CROI Abstract 153LB

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