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First and foremost choosing and using first line antiretroviral therapy.2013

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  • ARV, antiretroviral; EFV, efavirenz.
  • Transcript

    • 1. First and Foremost: Choosing and Using First-line Antiretroviral Therapy This program is supported by an educational grant from
    • 2. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
    • 3. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Program Director Daniel R. Kuritzkes, MD Chief, Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts
    • 4. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Faculty Judith S. Currier, MD, MSc Paul E. Sax, MD Eric S. Daar, MD Kimberly Y. Smith, MD, MPH Professor of Medicine Chief, Division of Infectious Diseases David Geffen School of Medicine University of California, Los Angeles Los Angeles, California Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California Clinical Director HIV Program and Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts Associate Professor of Medicine Division of Infectious Diseases Rush University Medical Center Chicago, Illinois
    • 5. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Disclosures Daniel R. Kuritzkes, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Celera, Gilead Sciences, GlaxoSmithKline, InnoVirVax, Merck, and Tobira; fees for non-CME services from Gilead Sciences and ViiV; and funds for research support from Gilead Sciences and Merck. Judith S. Currier, MD, MSc, has disclosed that she has received consulting fees from Serono and ViiV and has received funds for research support from Merck. Eric S. Daar, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV and funds for research support from Bristol-Myers Squibb, Gilead Sciences, Merck, and ViiV. Paul E. Sax, MD, has disclosed that he has received consulting fees from BristolMyers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, and Merck. Grants to Harvard Medical School have been received from Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline on his behalf. Kimberly Y. Smith, MD, MPH, has disclosed that she has received consulting fees from AbbVie, Bristol-Myers Squibb, GlaxoSmithKline/ViiV, Janssen, and Merck.
    • 6. Initial Therapy: US Guidelines and Recent Clinical Trials
    • 7. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv DHHS 2013 Guidelines: What to Start Preferred Regimens Alternative Regimens  EFV/TDF/FTC  EFV + ABC/3TC*  RPV/TDF/FTC or RPV + ABC/3TC* Boosted PI  ATV/RTV + TDF/FTC  DRV/RTV + TDF/FTC     INSTI  RAL + TDF/FTC  RAL + ABC/3TC*  EVG/COBI/TDF/FTC‡ NNRTI ATV/RTV + ABC/3TC* DRV/RTV + ABC/3TC* FPV/RTV + (TDF/FTC or ABC/3TC*) LPV/RTV + (TDF/FTC or ABC/3TC*) *In HLA-B*5701–negative patients with baseline HIV-1 RNA < 100,000 copies/mL.  RPV is not recommended in patients with baseline HIV-1 RNA > 100,000 copies/mL. ‡ EVG/COBI/TDF/FTC should not be started in patients with an estimated CrCl < 70 mL/min. DHHS Guidelines. February 2013.
    • 8. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv IAS-USA 2012 Guidelines: What to Start Recommended Regimens NNRTI  EFV/TDF/FTC or  EFV + ABC/3TC*  ATV/RTV + (TDF/FTC or Boosted PI ABC/3TC*)  DRV/RTV + TDF/FTC INSTI  RAL + TDF/FTC Alternative Regimens  NVP + (TDF/FTC or ABC/3TC*)  RPV/TDF/FTC or RPV + ABC/3TC*  DRV/RTV + ABC/3TC  LPV/RTV + (TDF/FTC or ABC/3TC*)  RAL + ABC/3TC*  EVG/COBI/TDF/FTC *In HLA-B*5701–negative patients with baseline HIV-1 RNA < 100,000 copies/mL. † Avoiding the use of ABC or LPV/RTV might be considered for patients with or at high risk of cardiovascular disease. Thompson MA, et al. JAMA. 2012;308:387-402.
    • 9. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Initial Therapy Options: Important Differences Between DHHS and IAS-USA IAS-USA[1] DHHS[2] ABC/3TC (with EFV or ATV/RTV) “Recommended” (provided BL HIV-1 RNA < 100k copies/mL) “Alternative” NVP (with ABC/3TC or TDF/FTC) “Alternative” “Other” 1. Thompson MA, et al. JAMA. 2012;308:387-402. 2. DHHS Guidelines. February 2013.
    • 10. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Guidelines for Initial Therapy: Time for a Change?  In 2009, DHHS listed 4 regimens as “preferred”; no changes since Current Preferred Regimens  Since then, several new agents have been approved: RPV, EVG/COBI, DTG ATV/RTV  What do the clinical trials of these agents show? NRTIs Third Agent EFV TDF/FTC + DRV/RTV RAL
    • 11. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv ECHO/THRIVE: Rilpivirine Noninferior to Efavirenz Through Wk 96  More virologic failures with RPV vs EFV: 14% vs 8% HIV-1 RNA < 50 c/mL at Wk 96 (ITT-TLOVR) 100 78 80 78 60 – Development of NRTI mutations more common with RPV vs EFV 40 20 0 – Difference due to more failures between Wks 0-48; failures comparable between arms from Wks 48-96 n= 686 682 RPV EFV Pooled Data Cohen CJ, et al. AIDS. 2013;27:939-950. – E138K mutation with RPV → cross-resistance with ETR  Discontinuation for AEs more common with EFV vs RPV: 9% vs 4%
    • 12. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv ECHO/THRIVE Post Hoc Analysis: Wk 96 Efficacy by Baseline VL and CD4+ Count Rilpivirine HIV-1 RNA < 50 copies/mL (%) 100 84 80 80 71 Efavirenz 76 100 73 80 69 65 60 60 40 85 79 56 40 20 71 75 81 79 20 0 n = 368 329 249 270 ≤ 100k 69 83 > 100k > 500k ≤ 500k By Baseline HIV-1 RNA (copies/mL) Cohen CJ, et al. AIDS. 2013;27:939-950. 0 n = 34 36 < 50 194 175 313 307 144 164 50 200 ≥ 350 < 200 < 350 By Baseline CD4+ Count (cells/mm3)
    • 13. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Open-Label STaR Trial: RPV/TDF/FTC Noninferior to EFV/TDF/FTC at Wk 48  RPV/TDF/FTC noninferior to EFV/TDF/FTC in overall population and in pts with baseline HIV-1 RNA > 100,000 c/mL – RPV/TDF/FTC superior to EFV/TDF/FTC in pts with baseline HIV-1 RNA ≤ 100,000 c/mL RPV/TDF/FTC (n = 394) Δ: 4.1% (95% CI: -1.1 to 9.2) 100 86 80 82 Δ : 7.2% (95% CI: 1.1-13.4) 89 Δ : -1.8% (95% CI: -11.1 to 7.5) EFV/TDF/FTC (n = 392) Post Hoc Analysis 82 80 82 83 82 204/ 250 107/ 134 116/ 142 81/ 98 96/ 117 72 80 60 40 20 n/N = 0 338/ 394 320/ 392 All Pts 231/ 260 VL ≤ 100k Cohen C, et al. Glasgow 2012. Abstract O425. VL > 100k VL > 100k 500k 26/ 36 20/ 25 VL > 500k
    • 14. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Summary of Results From Phase III Studies of RPV vs EFV  More virologic failures, especially with HIV-1 RNA > 100k[1,2] – Difference reduced in open-label study, suggesting importance of adherence, food effect[2] – DHHS: RPV is not recommended in patients with pretreatment HIV-1 RNA > 100,000 copies/mL; higher rate of virologic failures reported in patients with pre-ART CD4+ count < 200 cells/mm 3 who were treated with RPV + 2 NRTIs[3]  RPV resistance mutation (E138K) causes cross-resistance with ETR[1,2]  Fewer drug discontinuations with RPV than EFV[1,2] – Fewer rash, CNS events; better lipids[1,2] 1. Cohen CJ, et al. AIDS. 2013;27:939-950. 2. Cohen C, et al. Glasgow 2012. Abstract O425. 3. DHHS Guidelines. February 2013.
    • 15. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Elvitegravir/Cobicistat/TDF/FTC Noninferior to Efavirenz/TDF/FTC Through Wk 144 EVG/COBI/TDF/FTC (n = 348) Δ: 3.6% (95% CI: -1.6 to 8.8) 100 80 60 40 20 0 EFV/TDF/FTC (n = 352) Δ: 4.9% (95% CI: -1.3 to 11.1) Δ: 2.7% (95% CI: -2.9 to 8.3) 88 84 84 82 80 75  Results consistent across subgroups: BL HIV-1 RNA, CD4+ count, age, sex, race  Resistance at VF detected in 8 pts per arm through Wk 48, plus 2 additional pts per arm through Wk 96—rates similar btwn arms; no additional pts on EVG/COBI developed resistance after Wk 96 – In those on EVG/COBI, 9/10 pts had primary integrase and 10/10 had NRTI resistance mutations – In those on EFV, 10/10 had NNRTI and 3/10 had NRTI resistance mutations Wk 48 Wk 96 Wk 144 Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. Sax PE, et al. Lancet. 2012;379:2439-2448. Wohl D, et al. ICAAC 2013. Abstract H-672a.
    • 16. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv EVG/COBI/TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 96 EVG/COBI/TDF/FTC (n = 353) HIV-1 RNA < 50 c/mL (%) 100 80 ATV/RTV + TDF/FTC (n = 355) Δ: 2.7% Δ: 1.1% (95% CI: -2.1 to 7.5) (95% CI: -4.5 to 6.7) 90 87 83 82 60 40  Results consistent across subgroups: BL HIV-1 RNA, CD4+ count, adherence, age, sex, race  In EVG/COBI arm, resistance at VF detected in 5 pts through Wk 48, plus 1 additional pt through Wk 96 vs 0 pts in ATV/RTV arm – 5/6 had primary integrase and 5/6 had NRTI resistance mutations 20 0 Wk 48 Wk 96 Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. De Jesus E, et al. Lancet. 2012;379:2429-2438.
    • 17. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Summary of Results From Tx-Naive Phase III Studies of EVG/COBI/TDF/FTC  Virologic outcomes noninferior to EFV/TDF/FTC and ATV/RTV + TDF/FTC – Activity sustained in high VL stratum  2% failed with resistance, usually to both NRTIs and EVG  Adverse events – vs EFV: fewer CNS, rash events; better lipids; more nausea – vs ATV/RTV: less jaundice  Small, rapid increase in serum creatinine related to inhibition of tubular secretion of creatinine  5 pts (0.7% of total) developed tubulopathy, likely from TDF
    • 18. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv SPRING-2: Dolutegravir QD Noninferior to Raltegravir BID Through Wk 96 DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) NRTIs: investigator chosen ABC/3TC (40%) or TDF/FTC 60%) HIV-1 RNA < 50 c/mL (%) 100 88 85 80 81 76 60  DTG noninferior to RAL at Wk 48[1] and Wk 96[2] – Response similar with either NRTI pair and across VL strata  Adverse events and discontinuation rates similar  No resistance at VF with DTG vs 1 subject with integrase resistance and 4 with NRTI resistance in RAL group 40 20 0 Wk 48 Wk 96 Raffi F, et al. Lancet. 2013;381:735-743. Raffi F, et al. IAS 2013. Abstract TULBPE17.
    • 19. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv HIV-1 RNA < 50 c/mL at Wk 48 (%) SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC at Wk 48 100 Difference 7.4% (95% CI: +2.5 to +12.3; P = .003) 88 81 80 60  4% on each arm with protocoldefined VF  Among pts with VF in EFV arm, 1 pt with NRTI and 4 with NNRTI resistance vs 0 pts with resistance in DTG arm 40 20 0  DTG superior to EFV at Wk 48 primary efficacy endpoint DTG 50 mg + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) Walmsley S, et al. ICAAC 2012. Abstract H-556b.  Treatment-related study discontinuation in 10% on EFV vs 2% on DTG  CNS events and rash more common with EFV
    • 20. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv HIV-1 RNA < 50 c/mL at Wk 48 (%) FLAMINGO: DTG + NRTIs Superior to DRV/RTV + NRTIs at Wk 48 100 Difference 7.1% (95% CI: +0.9 to +13.2; P = .025) 90 83 80  VF: 2 pts (1%) on each arm 60  No treatment-emergent resistance in either arm 40  Treatment-related study discontinuation in 1% of DTG pts and 4% of DRV/RTV pts 20 0  DTG superior to DRV/RTV (both with TDF/FTC or ABC/3TC) at Wk 48 primary efficacy endpoint DTG 50 mg QD + NRTIs (n = 242) DRV/RTV 800/100 mg QD + NRTIs (n = 242) Feinberg J, et al. ICAAC 2013. Abstract H1464a.  More diarrhea with DRV/RTV; more headache with DTG
    • 21. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Summary of Results From Tx-Naive Phase III Studies of DTG  DTG + NRTIs noninferior to RAL + NRTIs; superior to DRV/RTV + NRTIs; DTG + ABC/3TC superior to EFV/TDF/FTC – More drug discontinuations in EFV and DRV/RTV arms  No DTG resistance mutations as yet detected with virologic failure  DTG well tolerated with low rates of study drug discontinuation – Fewer CNS and rash events compared with EFV – Less diarrhea than DRV/RTV  Small rapid increase in serum creatinine related to inhibition of tubular secretion of creatinine – No drug-related renal events
    • 22. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Dolutegravir Approval—August 2013  Dolutegravir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children aged 12 yrs and older and weighing at least 40 kg – Dolutegravir 50 mg QD in treatment-naive or INSTI-naive treatment-experienced patients – Dolutegravir 50 mg BID in INSTI-experienced patients or when administered with certain UGT1A/CYP3A inducers  Not yet included in guidelines Dolutegravir [package insert].
    • 23. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Potential Benefits of New Treatment Options for HIV Rilpivirine  Smallest single-tablet regimen  Fewer CNS and rash events vs EFV  Better lipids than EFV  Superior to EFV if HIV-1 RNA < 100k Elvitegravir/Cobicistat Dolutegravir  Single-tablet regimen  Maintains comparable virologic activity to EFV, ATV across low and high HIV-1 RNA  Fewer CNS and rash events vs EFV  Better lipids than EFV, comparable to ATV/RTV  Less jaundice than ATV/RTV  Superior to EFV/TDF/FTC and DRV/RTV  Maintains at least comparable virologic activity to EFV, RAL, DRV/RTV across low and high HIV-1 RNA  Fewer CNS and rash events vs EFV  Better lipids than EFV  No resistance detected with virologic failure  Fewer drug–drug interactions than boosted PIs, EVG/COBI
    • 24. Making the Match
    • 25. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv 2013 Recommendations for ART Initiation  ART is recommended for all HIV-infected ART-naive pts to reduce risk of disease progression and transmission – Strength of recommendation varies by CD4+ cell count and risk group (perinatal, heterosexual, other) – Pts should be ready to commit to ART and understand benefits and risks of therapy and importance of adherence; individual pts may elect to defer ART  Selection of a regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing frequency, drug–drug interaction potential, resistance testing results, and comorbid conditions DHHS Guidelines. February 2013.
    • 26. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Considerations When Selecting First-line Antiretroviral Therapy Patient/Viral Factors  Baseline CD4+ cell count/ HIV-1 RNA level Age Sex Occupation (eg, work schedule)  Comorbid conditions (eg, CV risk, renal abnormalities) Plans for pregnancy Access to care Concurrent medications Adherence to other medications Genetics (eg, HLA-B*5701) Viral tropism Antiretroviral Drug Factors Efficacy  Baseline drug resistance Tolerability  Long-term toxicity/metabolic effects Drug–drug interactions Dosing frequency Pill burden Pharmacokinetics Cost
    • 27. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Which Patient for EFV? Considerations in Favor Considerations Against  Coformulation; 1 pill QD[1]  High risk of resistance at virologic failure[3]  Effective across HIV-1 RNA, CD4+ strata[2]  CNS effects[1]  Most experience of all NNRTIs  Potential for teratogenesis in early pregnancy[4]  Most experience of all preferred drugs  Drug–drug interactions with other drugs metabolized by CYP system[1]  Increases in lipids[5] 1. TDF/FTC/EFV [package insert]. 2. Ribaudo HJ, et al. J Infect Dis. 2008;197:1006-1010. 3. Gallant J, et al. N Engl J Med. 2006;354:251-260. 4. DHHS Perinatal Guidelines. July 2012. 5. Daar E, et al. Ann Intern Med. 2011;154:445-456.
    • 28. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv DHHS Guidelines: Using EFV in Pts Who Are (or Are Likely to Become) Pregnant  ARV regimens that do not include EFV should be strongly considered in women who – Are planning to become pregnant or – Are sexually active and not using effective contraception  Avoid initiation of EFV or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother throughout the pregnancy  EFV may be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided there is virologic suppression on the regimen DHHS Perinatal Guidelines. July 2012.
    • 29. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Which Patient for Boosted PIs? Considerations in Favor Considerations Against  Effective across HIV-1 RNA, CD4+ strata[1,2]  No coformulations with NRTIs  Few CNS adverse events[1,2]  Little/no emergence of resistance at VF[1,2]  Preferred agents in pregnancy (ATV/RTV, LPV/RTV)[3]  Low risk for new resistance to develop in those with transmitted resistance  Variable lipid effects[1,2]  Concerns about renal function (greatest concern when ATV/RTV combined with TDF)[1,4]  Drug–drug interactions with other drugs metabolized by CYP system[5,6]  Hyperbilirubinemia with ATV[1,5] 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Ortiz R, et al. AIDS. 2008;22:1389-1397. 3. DHHS Perinatal Guidelines. July 2012. 4. Mocroft A, et al. AIDS. 2010;24:1667-1678. 5. Atazanavir [package insert]. 6. Darunavir [package insert].
    • 30. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv DHHS Guidelines on ART for Patients With Early Infection  Patients with early infection should be offered ART – “Early” HIV infection now refers to acute (after infection, prior to seroconversion) and recent (< 6 mos) infections – Choice of regimen should be among those recommended for patients with chronic disease – ART can be initiated before drug resistance test results are available; if so, a boosted PI + 2 NRTIs should be chosen DHHS Guidelines. February 2013.
    • 31. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Which Patient for RAL? Considerations in Favor Considerations Against  Effective across HIV-1 RNA, CD4+ strata[1]  No coformulations with NRTIs  Few adverse events[1]  Twice-daily dosing[2,4]  Few drug–drug interactions[2]  High risk of resistance at VF[3]  Limited effects on lipids[3]  Most experience of all INSTIs 1. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85. 2. Raltegravir [package insert]. 3. Lennox J, et al. Lancet. 2009;374:796-806. 4. Eron JJ Jr, et al. Lancet Infect Dis. 2011;11:907-915.
    • 32. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Which Patient for TDF/FTC? Considerations in Favor Considerations Against  Effective across HIV-1 RNA, CD4+ strata[1] Associated with decreases in renal function[4]  Not shown to be associated with MI in D:A:D[2] Associated with greater decreases in BMD[5]  Coformulations with EFV, EVG, RPV  Active against HBV[3] 1. Sax P, et al. N Engl J Med. 2009;361:2230-2240. 2. Worm S, et al. J Infect Dis. 2010; 201:318-330. 3. DHHS Guidelines. February 2013. 4. Gallant J, et al. AIDS. 2008;22:2155-2163. 5. McComsey G, et al. J Infect Dis. 2011;203:1791-1801.
    • 33. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Which Patient for ABC/3TC? Considerations in Favor Considerations Against No specific association with decreases in renal function  No current coformulations Less decrease in BMD than with TDF[1]  Less effective at HIV-1 RNA > 100,000 with EFV and ATV/RTV[2]  Associated with acute MI in some studies[3-5]  Requirement for HLA-B*5701 test before use[6]  Not optimal as lone NRTI pair in HBV-coinfected pts 1. McComsey G, et al. J Infect Dis. 2011;203:1791-1801. 2. Sax P, et al. N Engl J Med. 2009;361:2230-2240. 3. Worm S, et al. J Infect Dis. 2010; 201:318-330. 4. Martin A, et al. Clin Infect Dis. 2009;49:1591-1601. 5. Durand M, et al. J Acquir Immune Defic Syndr. 2011;57:245-253. 6. ABC/3TC [package insert].
    • 34. What About the Newer Drugs?
    • 35. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Which Patient for RPV? Considerations in Favor Considerations Against Coformulated/1 pill daily Superior vs EFV at lower VL[1] Fewer CNS adverse events than EFV[2]  Less effective at high BL VL[2] (not recommended at high VL and low CD4+)[3]  Food requirement[4]  Restricted use with PPIs or H2 blockers[4]  High risk of resistance and cross-resistance with other NNRTIs at VF[2] 1. Cohen C, et al. Glasgow 2012. Abstract O425. 2. Cohen C, et al. AIDS. 2013;27:939-950. 3. DHHS Guidelines. February 2013. 4. TDF/FTC/RPV [package insert].
    • 36. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Which Patient for TDF/FTC/EVG/COBI? Considerations in Favor Considerations Against  Coformulated/1 pill dally  Includes pharmacologic booster  Once-daily INSTI regimen  Noninferior to EFV and ATV/RTV across HIV-1 RNA, CD4+ strata[1,2]  Fewer CNS AEs than EFV[1]  High risk of resistance at VF[14]  Cross resistance with RAL[5]  Drug–drug interactions[6]  Concerns about monitoring renal function with COBI[6] 1. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 3. Sax PE, et al. Lancet. 2012;379:2439-2448. 4. DeJesus E, et al. Lancet. 2012;379:24292438. 5. DeJesus E, et al. IAS 2007. Abstract TUPEB032. 6. TDF/FTC/EVG/COBI [package insert].
    • 37. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Which Patient for DTG? Considerations in Favor Considerations Against  Once-daily INSTI without boosting  Not yet available as coformulation  Superior efficacy vs EFV and DRV/RTV[1,2]  Concerns about monitoring renal function[4]  Potentially less resistance at VF[1,3]  No guideline recommendation at this time  Effective at high VL with both ABC/3TC and TDF/FTC[3]  Well tolerated[1-3]  Few drug–drug interactions[4] 1. Walmsley S, et al. ICAAC 2012. Abstract H-556b. 2. Feinberg J, et al. ICAAC 2013. Abstract H1464a. 3. Raffi F, et al. Lancet. 2013;381:735-743. 4. Dolutegravir [package insert].
    • 38. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Individualizing First-line Therapy: Specific Circumstances Circumstance Agents No genotype  Use boosted PI High HIV-1 RNA  Caution with ABC, RPV Renal disease  Caution with TDF, ATV/RTV; monitoring complicated with COBI and DTG Dyslipidemia  RAL, DTG, RPV most lipid neutral CV risk factors  Possible association with ABC, ddI, LPV/RTV  No data for DRV/RTV, INSTIs, MVC Pregnancy  Preferred: ZDV/3TC + NVP, LPV/RTV, or ATV/RTV  EFV can be used after first 5-6 wks Chronic HBV infection  Preferred TDF + 3TC or FTC  Alternative is entecavir Decreased BMD  Caution with TDF Concerns about CNS effects  Caution with EFV for at least first mo
    • 39. Managing Patients Receiving First-line Therapy
    • 40. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv What’s New in the Guidelines With Laboratory Tests  Repeat HIV serology at entry into care if diagnosis not confirmed  Obtain HCV serology at entry into care and when clinically indicated  A genotypic viral tropism test is now available, but the phenotypic test is preferred  At VF of an INSTI-based regimen, an integrase genotypic resistance assay should be obtained DHHS Adult Guidelines. February 2013.
    • 41. Adverse Events
    • 42. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Low Discontinuation for AEs in Clinical Trials With Preferred and Newer Agents Agent EFV (ACTG 5202)[1] Discontinuation Rate for AEs by Wk 48 in Major Clinical Trials, % 9 (TDF/FTC arm) ATV/RTV (CASTLE)[2] 2 DRV/RTV (ARTEMIS)[3] 3 RAL (STARTMRK)[4] 3 RPV (ECHO)[5] 2 EVG/COBI (GS102)[6] 4 DTG (SINGLE)[7] 2 1. Daar E, et al. Ann Intern Med. 2011;154:445-456. 2. Molina JM, et al. Lancet. 2008;372:646-655. 3. Ortiz R, et al. AIDS. 2008;22:1389-1397. 4. Lennox J, et al. Lancet. 2009;374:796-806. 5. Molina JM, et al. Lancet. 2011;378:238-246. 6. Sax P, et al. Lancet. 2012;379:2439-2448. 7. Walmsley S, et al. ICAAC 2012. Abstract H-556b.
    • 43. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Most Common Adverse Events Expected With Newer Drugs Most Common AEs RPV[1]  Depressive disorders  Headache  Insomnia  Rash TDF/FTC/EVG/COBI[2]  Nausea  Diarrhea  Abnormal dreams DTG[3]  Insomnia  Headache 1. Rilpivirine [package insert]. 2. TDF/FTC/EVG/COBI [package insert]. 3. Dolutegravir [package insert].
    • 44. Drug–Drug Interactions
    • 45. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Drug–Drug Interactions With First-line ART and Lipid-Lowering Therapy Antiretroviral Contraindicated Titrate Dose RPV[1] EVG/COBI/TDF/ FTC[1] No Dose Adjustment Atorvastatin Lovastatin Simvastatin Atorvastatin Rosuvastatin ATV/RTV[1] Lovastatin Simvastatin Atorvastatin Rosuvastatin Pitavastatin DRV/RTV[1] Lovastatin Simvastatin Atorvastatin Pravastatin Rosuvastatin Pitavastatin DTG[2] EFV[1] Atorvastatin Simvastatin Pravastatin Rosuvastatin RAL[1] 1. DHHS Adult Guidelines. February 2013. 2. Dolutegravir [package insert].
    • 46. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Drug–Drug Interactions With OCPs Antiretroviral Effect on OCP Dosing Recommendation Ethinyl estradiol AUC ↑ 14% Norethindrone: no significant change No dose adjustment Ethinyl estradiol AUC ↓ 25% Norgestimate ↑ No clinically relevant interaction Weigh the risks and benefits of norgestimate ↑ and consider alternative contraceptive ATV/RTV[1,2] Ethinyl estradiol AUC ↓ Norgestimate ↑ OCP should contain ≥ 35 mcg ethinyl estradiol DRV/RTV[1,2] Ethinyl estradiol AUC ↓ 44% Norethindrone AUC ↓ 14% No effect on ethinyl estradiol Active metabolites of norgestimate ↓ Additional methods of contraception recommended RPV[1,2] EVG/COBI TDF/FTC[1,3] DTG[4] EFV[1,2] RAL[1,2] No clinically relevant interaction No dose adjustment A reliable method of barrier contraception must be used in addition to hormonal contraceptives No dose adjustment 1. DHHS Adult Guidelines. February 2013. 2. DHHS Perinatal Guidelines. July 2012. 3. TDF/FTC/EVG/COBI [package insert]. 4. Dolutegravir [package insert].
    • 47. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Drug–Drug Interactions With BOC and TVR Antiretroviral Interactions With Boceprevir Interactions With Telaprevir No clinically relevant interactions No clinically relevant interactions No data No clinically relevant interactions No clinically relevant interactions No clinically relevant interactions ATV/RTV[5] Coadministration not recommended Coadministration not recommended DRV/RTV[5] Coadministration not recommended Coadministration not recommended EFV[5] Coadministration not recommended Increase TVR dose to 1125 mg q8h RAL[5] No clinically relevant interactions No clinically relevant interactions RPV[1,2] EVG/COBI TDF/FTC[3] DTG[4] 1. Rhee E, et al. CROI 2013. Abstract 537. 2. Rilpivirine [package insert]. 3. Custodio J, et al. ICAAC 2013. Abstract A-1576. 4. Dolutegravir [package insert]. 5. DHHS Adult Guidelines. February 2013.
    • 48. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Drug–Drug Interactions With AcidReducing Medications and Newer ARVs ARV Antacids H2-Receptor Antagonists Proton Pump Inhibitors Give antacids at least 2 hrs before or at least 4 hrs after RPV Give H2-receptor antagonists at least 12 hrs before or at least 4 hrs after RPV Contraindicated EVG/COBI TDF/FTC[1] Separate EVG/COBI/ FTC/TDF and antacid administration by > 2 hrs No clinically relevant interactions No clinically relevant interactions DTG[2] DTG should be given 2 hrs before or 6 hrs after taking medications containing polyvalent cations RPV[1] 1. DHHS Adult Guidelines. February 2013. 2. Dolutegravir [package insert]. No clinically relevant interactions
    • 49. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Drug–Drug Interactions Between RTVBoosted PIs and Steroid Preparations  Steroid preparations should be given with caution with boosted PIs, regardless of administration route  Coadministration can result in adrenal insufficiency, including Cushing’s syndrome; coadministration is not advised unless potential benefits outweigh the risks DHHS Adult Guidelines. February 2013.
    • 50. Managing ART in Pts Who Become Pregnant on Therapy
    • 51. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Changes in Perinatal Guidelines—2012  The Panel recommends that EFV be continued in pregnant women receiving EFV-based ART who present for antenatal care in the first trimester, provided the regimen is resulting in virologic suppression (CIII)  Pregnant women receiving and tolerating NVP-containing regimens who are virologically suppressed should continue the regimen, regardless of CD4+ cell count (AIII) DHHS Perinatal Guidelines. July 2012.
    • 52. Lipids
    • 53. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Lipid Comparisons in Clinical Trials ARV Comparisons RPV[1] vs EFV at Wk 48 Smaller changes in TC, HDL-C, LDL-C, TG (all P < .0001) COBI[2] vs RTV at Wk 48 when combined with ATV Similar changes in lipids in all fractions EVG/COBI TDF/FTC[3-5] vs EFV at Wk 48 Smaller changes in TC (P < .001), HDL-C, LDL-C (both P = .001) Similar changes in TG between arms vs ATV/RTV at Wk 48 Similar changes in TC, HDL-C, LDL-C Smaller change in TG (P = .006) DTG[6] vs RAL at Wk 48 Similar small changes in lipids in all fractions vs EFV at Wk 48 Smaller changes in TC, HDL-C, LDL-C 1. Cohen C, et al. AIDS. 2013;27:939-950. 2. Gallant J, et al. J Infect Dis. 2013;208:32-39. 3. Sax P, et al. Lancet. 2012;379:2439-2448. 4. DeJesus E, et al. Lancet. 2012;379: 2429-2438. 5. Sax P, et al. CROI 2012. Abstract 101. 6. Dolutegravir [package insert].
    • 54. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Lipid and Efficacy Data in Recent Switch Studies  SPIRIT: Switch boosted PI to RPV vs remain on boosted PI – BL to Wk 48: improvement in mean fasting TC, LDL-C, TG, and TC:HDL-C ratio – Switching noninferior to continuing boosted PI regimen at Wk 24 – Noninferiority maintained at Wk 48 but 5 additional cases of VF between Wks 24 and 48 Fisher M, et al. Glasgow 2012. Abstract P285.
    • 55. Renal
    • 56. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Change From BL in Serum Creatinine (mg/dL; IQR) EVG/COBI/TDF/FTC vs EFV or ATV/RTV: Creatinine Changes  0.35 0.30 EVG/COBI/TDF/FTC EFV/TDF/FTC 0.28 0.24 0.25 EVG/COBI/TDF/FTC ATV/RTV + TDF/FTC 0.20 0.20 0.16 0.15 0.12 0.10 0.08 0.05 0 0.04 -0.05 0 -0.10 -0.04 BL 2 4 8 12 16 24 Wks 32 40 48 BL 2 4 8 12 16 24 Wks 32 40 48 Cobicistat is associated with reduced active secretion of creatinine in the renal tubules leading to initial rises in creatinine levels Sax P, et al. Lancet. 2012;379:2439-2448. DeJesus E, et al. Lancet. 2012;379:2429-2438.
    • 57. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv SPRING-2: Changes in Serum Creatinine and Creatinine Clearance DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) 0.28 0.22 0.17 +0.14 0.11 +0.05 0.06 10 0 10 -20 0 -30 0.06 2 4 8 12 16 24 Wk 32 40 48 Baseline (mg/mL): DTG 0.85 vs RAL 0.85  Change in CrCl, Mean (± SD)[2] Mean Change From Baseline (mL/min) Mean Change From Baseline of Creatinine (mg/dL) Change in Serum Creatinine, Mean (± SD)[1] BL 4 12 24 Wk 48 Baseline (mL/min): DTG 125 vs RAL 128 DTG increases serum creatinine by the benign inhibition of the organic cation transporter 2, which is responsible for tubular secretion of creatinine[3] 1. Raffi F, et al. Lancet. 2013;381:735-743. 2 Raffi F, et al. AIDS 2012. Abstract THLBB04. 3. Koteff J, et al. Br J Clin Pharmacol. 2013;75:990-996.
    • 58. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Special Considerations for Monitoring Renal Function  Some drugs have an effect on creatinine including cimetidine, cobicistat, trimethoprim, RPV, and DTG – Expected minor increases in creatinine and decreases in estimated CrCl during treatment with these agents do not reflect changes in actual CrCl  Baseline CrCl < 70: do not use EVG/COBI/TDF/FTC – Stop if estimated CrCl < 50 (cannot adjust dose)  Pts at risk of renal disease: monitor urine protein, glucose, serum phosphorus, and CrCl – Confirmed rise in serum creatinine of > 0.4 mg/dL is considered significant
    • 59. First and Foremost: Choosing and Using First-line Antiretroviral Therapy clinicaloptions.com/hiv Summary  Several excellent options for first-line ART – Safety and tolerability continues to improve – Important differences in drug–drug interactions  Individualize selection and monitoring and plan for longterm success