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Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials: Baseline Survey Located at the front of your syllabus CME Evaluation with Post-activity Survey Located at the back of your syllabus. Disclosures.

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  1. Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials: • Baseline Survey • Located at the front of your syllabus • CME Evaluation with Post-activity Survey • Located at the back of your syllabus

  2. Disclosures • The relevant financial relationships reported by facultythat they or their spouse/partner have with commercial interests are located on page 5 of your syllabus • The relevant financial relationships reported by the steering committee that they or their spouse/partner have with commercial interests are provided on page 5 of your syllabus • The relevant financial relationships reported by the non-faculty content contributorsand/or reviewers that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus

  3. Off-label Discussion Disclosure This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

  4. Learning Objectives • Integrate recent clinical trial data into updated HIV management guidelines to provide the most individualized treatment for HIV-1-infected patients • Develop a patient-centered approach to individualizing treatment for HIV by minimizing short- and long-term treatment-related complications • Incorporate considerations about a patient’s risks for adverse events, non-adherence, and comorbid conditions when individualizing HIV treatments

  5. Polling QuestionBaseline Survey • Please take out the Baseline Survey from your packet • Fill out the demographic information at the top of the form; then, throughout the program, as Baseline Survey questions are asked, please take a moment to select your answer to the corresponding question on this form • Your answers are important and will help us shape and improve future CME activities: • Degree:___ MD/DO ___ Nursing Professional ___ PharmD • ___ Other:_____________________________ • Specialty: ___ Internist ___ Infectious Disease Specialist ___ PCP • ___ Other: _____________________________

  6. Polling QuestionBaseline Survey Please rate your confidence in your ability to individualize antiretroviral therapy for patients newly diagnosed with HIV-1 • Not at all confident • Slightly confident • Confident • Very confident • Expert

  7. Polling QuestionBaseline Survey How often do you consider a patient’s cardiovascular comorbidities when selecting an initial antiretroviral therapy for HIV-1? • Never • Rarely • Sometimes • Most of the time • Always

  8. Polling QuestionBaseline Survey In a recent trial by HPTN 052, early initiation of ART was associated with which of the following outcomes compared to deferred initiation of therapy? • Decrease in mortality • Decreases in risk for transmission of HIV and development of AIDS-related conditions • Decrease in transmission of HIV, but no difference in AIDS-related conditions or mortality • Decreases in mortality, risk for transmission of HIV, and development of AIDS-related conditions

  9. Case • 58-year-old manwith a new HIV diagnosis. • Tested as part of an evaluation for prolonged viral syndrome, now recovered; previous negative test 8 months earlier. • PMHx: • Hypertension • Diabetes • Non-alcoholic steatohepatitis • Stage III kidney disease (eGFR 30-59) • Esophageal reflux

  10. Case • Medications: amlodipine, lisinopril, glipizide, metformin, simvastatin, pantoprazole. • Social history: Works as a medical interpreter at a local hospital; MSM, in a long-term relationship (partner also newly diagnosed HIV+); 2-3 drinks/week; no cigarettes or other drugs. • PE: BMI = 31; liver edge 2 cm below costal margin; 1+ bilateral edema.

  11. Case Labs • Glucose = 185; HgbA1c = 7.9 • Creatinine = 1.6 (eGFR = 50, calculated creatinine clearance 61) • ALT = 85, AST = 90; HBSAb positive, HCV antibody and RNA negative • Total cholesterol 230 (non-fasting) • U/A 1+ protein • HLA-B*5701: Negative • CD4 cell count = 780 (34%) • HIV RNA = 45,000 • Genotype: No resistance

  12. Polling QuestionBaseline Survey Would you treat? • Yes, as soon as possible • Yes, as soon as he is ready • Would focus on correcting metabolic issues first • Only if he has partners outside of relationship • Other

  13. Polling QuestionBaseline Survey According to DHHS guidelines, all of the following antiretroviral regimens recommended for initial therapy might be appropriate for patient, EXCEPT: • Dolutegravir/ABC/3TC • Efavirenz/TDF/FTC • Elvitegravir/cobicistat/TDF/FTC • Raltegravir + TDF/FTC

  14. DHHS. Available at: www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 1, 2014. IAS-USA. GunthardHF et al. JAMA. 2014;312:410-425. EACS. Available at: www.europeanaidsclinicalsociety.org. Version 7.0 October 2013. BHIVA. Available at: www.bhiva.org. WHO. Available at: www.who.int/publications/guidelines/hiv_aids/en/index.html. When to Start HIV TherapyGuidelines Compared

  15. Earlier ART Associated with Decreased Mortality and Disease Progression Observational Studies KitahataMM et al. N EnglJ Med. 2009;360):1815-1826. When To Start Consortium; Sterne JA et al. Lancet.2009;373:1352-1363. HIV-CAUSAL Collaboration. Ann Intern Med. 2011;154:509-515.Writing Committee for the CASCADE Collaboration. Arch Intern Med. 2011;171:1560-1569.Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. PLoSMed. 2012;9:e1001194. .

  16. Prevention of HIV-1 Infection with Early Antiretroviral Therapy • Randomized study of early vs delayed ART in 1763 serodiscordant couples • Study stopped early by DSMB • Linked HIV transmission to HIV-negative partner • Early therapy (n=1) – 0.1 per 100 person-years • Delayed therapy (n=27) – 7 per 100 person-years • Early ART led to a 96% reduction of sexual transmission of HIV in serodiscordant couples Linked HIV Transmission 0.2 HR: 0.04 (95% CI 0.01-0.27) (P<0.001) 0.15 Delayed ART Cumulative Probability 0.1 0.05 Early ART 0 0 1 2 3 4 5 Years Cohen MS et al. N Engl J Med. 2011;365:493-505.

  17. HPTN 052Early Treatment Delays AIDS Events Time to First AIDS-Defining Disease P=0.03 Grinsztejn B et al. Lancet Infect Dis. 2014;14:281-290.

  18. HIV Viremia Is Hazardous to Your Health • Cumulative uncontrolled viral replication associated with all-cause mortality • 2027 patients contributing 6579 person-years of follow-up in a longitudinal cohort of patients initiating ART from 2000-2008 • Hazard ratio for mortality was 1.44 (1.07-1.94) per log10 copy y/mL • Stronger predictor of mortality than CD4 cell count 1.00 .95 .90 Viremia copy-years (log 10) .85 Proportion surviving <5 5-7 >7 .80 Months from antiretroviral therapy initiation .75 0 6 12 18 24 30 36 42 48 54 60 MugaveroMJ et al. Clin Infect Dis. 2011;53:927-935.

  19. Treatment May be Deferred for Some • Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence • Patients may choose to postpone ART • Providers may elect to defer ART, based on an individual patient’s clinical or psychosocial factors Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Revised August, 2014.

  20. Special Cases – HIV Treatment Generally Indicated • Pregnancy • Acute infection • Cardiovascular disease • Malignancies • HIV-associated nephropathy (HIVAN) • HBV/HCV co-infection • Neurologic complications • Serodiscordant relationships Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Revised August, 2014.

  21. Historical Trends in CD4 Thresholds for When to Start Antiretroviral Therapy MK 035 and ACTG 320 demonstrate virologic suppression and improved clinical outcomes: "Hit Hard and Early" Era and “HAART” ACTG 019and other NRTI monotherapy studies in asymptomatic individuals HPTN 052 Integrase inhibitors & 2nd-generation PIs/NNRTIs; single-tablet regimens (2 NRTIs) SMART study 1st generation PIs & NNRTIs BW 002: ZDV reduces deaths in patients with AIDS Treatment reduces immune activation, non-AIDS events, & HIV transmission Disappointing results form Concorde, VA, & Delta Trials Lypodystrophy & other ARV-associated metabolic side effects described Low potency and high toxicity Still greater potency, decreased toxicity. Higher potency, higher toxicity Adapted from Vittoria M.

  22. DHHS 2014 Guidelines:What to Start *In HLA-B*5701–negative patients RPV is not recommended in patients with baseline HIV-1 RNA >100,000 copies/mL or CD4 <200 ‡EVG/COBI/TDF/FTC should not be started in patients with an estimated CrCl<70 mL/min. • Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Revised August, 2014.

  23. IAS-USA 2014 Guidelines:What to Start * ABC has been associated with increased CV risk, although data are conflicting; use with caution in patients with high CV risk. Should only be used in HLA-B*5701-negative patients. † Rilpivirine-based therapy is not recommended in patients with baseline HIV-1. € The combination of abacavir and lamivudine was less efficacious with baseline HIV-1 RNA level above 100,000 copies/mL than the combination of tenofovir and emtricitabine when combined with efavirenz or ritonavir-boosted atazanavir. GunthardHFet al JAMA. 2014;312:410-425.

  24. NNRTI-based Regimens Long the Default First Choice, But Time for Reconsideration? Strengths Weaknesses High risk of resistance at virologic failure3 Transmitted NNRTI resistance more common than other drug classes TDF/FTC/EFV CNS/rash/hepatic effects1 Concern for teratogenesis in first trimester4 Dyslipidemia (LDL, Triglycerides)5 Drug-drug interactions (including methadone)1 TDF/FTC/RPV More virologic failure with HIV RNA >100K or CD4 <2007 Must be taken with meal PPIs contra-inidicated • One pill, once per day • (TDF/FTC/EFV) Atripla and TDF/FTC/RPV (Complera) • TDF/FTC/EFV • Effective across CD4/VL strata2 • Until recently, had never lost a head-to-head with another regimen6 • Longest clinical experience • Least expensive of recommended regimens • TDF/FTC/RPV • Smallest pill size among single tablet regimens • Favorable metabolic profile • TDF/FTC/EFV [package insert] • RibaudoHJet al. J Infect Dis. 2008;197:1006-1010. • Gallant JE et al. N Engl J Med. 2006;354:251-260. • Recommendations for Use of Antiretroviral Drugs in PregnantHIV-1-Infected Women for Maternal Health and Interventions toReduce Perinatal HIV Transmission in the United States. www.aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/143/introduction. Updated March 2014. • 5 Daar E et al. Ann Intern Med. 2011;154:445-456. • Walmsley S et al. N Engl J Med. 2013;369:1807-1818. • Molina JM et al. Lancet. 2011:378:238-246.

  25. MollanKR et al. Ann Intern Med. 2014;161:1-10. Increased Risk of Suicidality Associated with EFV 5% HR (95% CI) 2.28 (1.27 to 4.10), P=0.006 47 events/5817 PY* (8.08/ 1000 PY) 15 events/4099 PY* (3.66/1000 PY) As-treated HR 2.16 (1.16-4.00) *Person Years = sum of at-risk follow-up

  26. If you couldn’t (or didn’t want to) use an NNRTI-based regimen, which would you choose?Differentiating Between Non-NNRTI Regimens

  27. Polling QuestionBaseline Survey In ACTG study A5257, which compared raltegravir to darunavir/ritonavir and atazanavir/ritonavir, each with tenofovir/emtricitabine in treatment-naïve subjects, which of the following outcomes was reported? • Similar incidence of tolerability failure between all 3 groups • Greater virologic efficacy with atazanavir/ritonavir compared to raltegravir • Similar cumulative incidence of virologic or tolerability failure between all 3 groups • A higher rate of discontinuations due to toxicity with atazanavir/ritonavir compared to raltegravir

  28. Polling QuestionBaseline Survey In addition to virologic outcomes, which of the following effects on cardiovascular risk was identified in the A5257 study: • Greater decreases in HDL-C with raltegravir compared to the protease inhibitors • No differences between groups in incidence of metabolic syndrome or lipid profile • Greater increases in triglycerides and LDL-C with the protease inhibitors compared to raltegravir • Greater incidence of new-onset metabolic syndrome with raltegravir compared to the protease inhibitors

  29. ACTG A5257 Study Design* HIV-infected patients, ≥18 yr, with no previous ART, VL ≥ 1000 c/mL at US Sites, n=1809 Randomized 1:1:1 to Open Label Therapy Stratified by screening HIV-1 RNA level (≥ vs < 100,000 c/mL) cardiovascular risk *With the exception of RTV, all ART drugs were provided by the study Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85. ATV 300mg QD + RTV100 mgQD + FTC/TDF 200/300 mg QD n=605 RAL 400 mg BID + FTC/TDF200/300mgQD n=603 DRV 800mgQD+RTV 100mgQD + FTC/TDF 200/300 mg QD n=601 Study Conclusion 96 weeks after final participant enrolled Follow-up continued for 96 weeks after randomization of last subject (range 2-4 years) regardless of status on randomized ART

  30. Cumulative Incidence of Virologic Failure 1.00 Difference in 96 wkcumulative incidence (97.5% CI) ATV/r RAL DRV/r ATV/r vs RAL 0.75 3.4% (-0.7%, 7.4%) DRV/r vs RAL 5.6% (1.3%, 9.9%) Cumulative incidence 0.50 ATV/r vs DRV/r -20 -10 0 10 20 -2.2% (-6.7%, 2.3%) 0.25 0.00 0 64 24 48 96 144 112 80 128 Weeks since study entry Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.

  31. Cumulative Incidence of Tolerability Failure 1.00 Difference in 96 wkcumulative incidence (97.5% CI) Favors RAL ATV/r RAL DRV/r ATV/r vsRAL 0.75 13% (9.4%, 16%) DRV/r vs RAL Favors DRV/r 3.6% (1.4%, 5.8%) Cumulative incidence 0.50 ATV/r vs DRV/r -20 -10 0 10 20 9.2% (5.5%, 13%) 0.25 0.00 0 64 24 48 96 144 112 80 128 Weeks since study entry • Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.

  32. Cumulative Incidence of Virologic or Tolerability Failure 1.00 Difference in 96 wkcumulative incidence (97.5% CI) Favors RAL ATV/r RAL DRV/r ATV/r vs RAL 0.75 15% (10%, 20%) Favors RAL DRV/r vs RAL 7.5% (3.2%, 12%) Favors DRV/r Cumulative incidence 0.50 ATV/r vs DRV/r -20 -10 0 10 20 7.5% (2.3%, 13%) 0.25 0.00 0 64 24 48 96 144 112 80 128 Weeks since study entry *Consistent results seen with TLOVR at a 200 copies/ml threshold • Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.

  33. Proportion VL ≤50 copies/mL ITT, regardless of ART change ITT, off-ART=failure (SNAPSHOT) ATV/r ATV/r RAL RAL DRV/r DRV/r 1.0 1.0 0.8 1.6 1.6 Prop of subjects w/HIV-1 RNA <=50 copies/mL Prop of subjects w/HIV-1 RNA <=50 copies/mL 0.4 0.4 0.2 0.2 Number of subjects contributing data Number of subjects contributing data 0.0 0.0 515 526 518 605 603 601 ATV/r RAL DRV/r ATV/r RAL DRV/r 605 603 601 605 603 601 394 410 387 471 483 468 605 603 601 563 566 564 553 555 542 605 603 601 24 24 0 0 48 48 64 64 80 80 96 96 120 120 144 144 Study Week Study Week *Consistent results seen with TLOVR at a 200 copies/ml threshold Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.

  34. Change in CD4 Count from Baseline ATV/RTV Median (Q1-Q3) Mean (95% CI) 1000 ATV/r RAL DRV/r 400 750 500 300 250 200 CD4 count change from baseline (cells/mm3) 0 • ATV/r: 284(269,300) • RAL: 288(272, 304) • DRV/r: 256(240, 271) CD4 count change from baseline (cells/mm3) -250 100 400 Number of subjects contributing data 0 300 395 418 394 605 603 601 175 179 173 564 565 559 ATV/r RAL DRV/r 523 541 525 200 48 0 66 144 192 100 Study Week 24 48 96 114 24 48 96 114 24 48 96 114 Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.

  35. Analysis of CIMT Progression Carotid Bifurcation CIMT CCA CIMT DRV DRV ATV ATV RAL RAL 100 100 75 75 ATV/r vs DRV/r P=0.013 ATV/r vs RAL P=0.15 DRV/r vs RAL P=0.31 ATV/r vs DRV/r P=0.007 ATV/r vs RAL P=0.30 DRV/r vs RAL P=0.11 50 50 25 25 0 0 -25 -25 48 96 144 0 Study week 48 96 144 0 Study week CIMT: Carotid intima media thickness Stein JW et al. Presented at: ACC 2014, Abstract 147.

  36. Take Home Messages from A5257/A5260s • Virologic suppression: RAL = DRV/r = ATV/r • Tolerability: RAL=DRV/r > ATV/r • ATV/r discontinuations most commonly caused by cosmetic jaundice/hyperbilirubinemia • Combined endpoints: RAL > DRV/r > ATV/r • Slightly better virologic outcomes and absence of GI side effects • Lipids and bone mineral density loss favored RAL over both PIs • Increased fasting TC, non-HDL-C and LDL-C with ATV/r and DRV/r, while they decreased or remained unchanged with RAL. • CIMT progression most favorable with ATV/r • Mechanism unclear • OfotokumI et al. Presented at: ACTG5257 Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014; Boston, MA. • Brown T et al. Presented at: 2014 Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014; Boston, MA. Abstract 779LB.

  37. SINGLE: ABC/3TC + DTG vs TDF/FTC/EFV for Treatment-naïve Patients ABC/3TC FDC PO QD + DTG 50 mg PO QD TDF/FTC/EFV STR PLACEBO PO QHS n=422 HIV-infected treatment naïve men and women VL >1000 c/mL n=844 ABC/3TC FDC PLACEBO PO QD + DTG PLACEBO PO QD TDF/FTC/EFV STR PO QHS n=422 Primary Proportion <50 c/mL at 48 weeks Secondary Time to virologic suppression Change in CD4 Safety Resistance at virologic failure WalmsleyS et al. N Engl J Med. 2013;369:1807-1818.

  38. SINGLE DTG + ABC/3TC Superior to EFV/TDF/FTC at Week 48 Difference 7.4%(95% CI: +2.5 to +12.3; P=0.003) 100 • DTG superior to EFV at week 48 primary efficacy endpoint • 4% on each arm with protocol-defined 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 • Treatment-related study discontinuation in 10% on EFV vs 2% on DTG • CNS events and rash more common with EFV 88 81 80 60 HIV-1 RNA < 50 c/mL at Wk 48 (%) 40 20 0 EFV/TDF/FTC QD (n = 419) DTG 50 mg + ABC/3TC QD (n = 414) WalmsleyS et al. N Engl J Med. 2013;369:1807-1818.

  39. SPRING-2: 2 NRTIs + DTG vs 2 NRTIs + RAL for Treatment-naïve Patients 2NRTIs + DTG 50 mg PO QD RAL PLACEBO PO BID n=411 HIV-infected treatment naïve men and women VL >1000 c/mL n=822 2NRTIs + RAL 400 mg PO BID DTG PLACEBO QD n=411 Primary Proportion <50 c/mL at 48 weeks Secondary Time to virologic suppression Change in CD4 Safety Resistance at virologic failure Stratified by baseline VL > or ≤100,000 c/mL and NRTI backbone RaffiF et al. Lancet. 2013;381:735-743. Raffi F et al. Lancet Inf Disease. 2013;13:927-935.

  40. SPRING-2: Dolutegravir QDNon-inferior to Raltegravir BID Through Week 96 • DTG non-inferior to RAL through 96 weeks • 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 DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) NRTIs: investigator chosen ABC/3TC (40%) or TDF/FTC 60%) 100 88 85 81 80 76 60 HIV-1 RNA <50 c/mL (%) 40 20 0 Wk 96 Wk 48 RaffiF et al. Lancet. 2013;381:735-743. Raffi F et al. Lancet Inf Disease. 2013;13:927-935.

  41. FLAMINGO: DTG vs DTV/r for Treatment-naïve Patients 2NRTIs + DTG 50 mg PO QD n=243 HIV-infected treatment naïve men and women VL >1000 c/mL n=488 2NRTIs + RTV 100 mg PO QD + DRV 800 mg PO QD n=245 Stratified by baseline VL > or ≤100,000 c/mL and NRTI backbone Primary Proportion <50 c/mL at 48 weeks Secondary Time to virologic suppression Change in CD4 Safety Resistance at virologic failure Patient Reported Outcomes Clotet B et al. Lancet.2014;383:2222-2231.

  42. FLAMINGO: DTG + NRTIs Superior to DRV/RTV + NRTIs at Week 48 Difference 7.1%(95% CI: +0.9 to +13.2; P = 0.025) • DTG superior to DRV/RTV (both with TDF/FTC or ABC/3TC) at week 48 primary efficacy endpoint • VF: 2 pts (1%) on each arm • No treatment-emergent resistance in either arm • Treatment-related study discontinuation in 1% of DTG pts and 4% of DRV/RTV patients • More diarrhea with DRV/RTV; more headache with DTG 100 90 83 80 60 HIV-1 RNA <50 c/mL at Wk 48 (%) 40 20 0 DRV/RTV 800/100 mg QD + NRTIs (n = 242) DTG 50 mg QD + NRTIs (n = 242) NRTIs: investigator chosen ABC/3TC (33%) or TDF/FTC 67%) Clotet B et al. Lancet. 2014;383:2222-2231.

  43. Several Drugs Inhibit Tubular Secretion of Creatinine, Raising Serum Creatinine Levels Proximal Tubule ATP Pgp ATP-Binding Cassette ATP BCRP ATP MRP2 OCT2 MATE1 Creatinine H+ Cobicistat Ritonavir Cimetidine Trimethoprim MATE2-K SoluteCarrier Dolutegravir OCTN1 OCTN2 No apparent effect on actual GFR Blood (Basolateral) Urine (Apical) Active Tubular Secretion Lepist et al. Presented at: 51st ICAAC, Sep 17-20, 2011, Chicago, IL.

  44. Phase III Studies of TDF/FTC/COB/EVG vs NNRTI • Non-inferior to Efavirenz/TDF/FTC Through Wk 144 • Consistent across subgroups • Resistance at VF detected in 10 pts per arm • In EVG/COB, 9/10 pts had primary integrase and 10/10 had NRTI resistance mutations • In EFV, 10/10 had NNRTI and 3/10 had NRTI resistance mutations • Renal safety • 13/701 discontinuation (1.9%), including 4 due to proximal renal tubulopathy in EVG/COB • No discontinuation in EFV vs PI/r • Non-inferior to ATV/RTV + TDF/FTC Through Wk144 • Consistent across subgroups • In EVG/COB, resistance at VF detected in 6 pts through Wk 96 vs 0 pts in ATV/RTV arm • 5/6 had primary integrase and 5/6 had NRTI resistance mutations • Renal safety • 13/701 discontinuation (1.9%), including 4 due to proximal renal tubulopathy in EVG/COB • 8/355 discontinuation (2.3%), including 3 due to proximal renal tubulopathy in ATV/RTV RockstrohJ et al. J Acquir Immune DeficSyndr. 201363:77-85. De Jesus E et al. Lancet. 2012; 30:2429-2438. Cohen C et al. IAC 2014; Melbourne, Australia. Poster WEPE063. ZolopaA et al. J Acquir Immune DeficSyndr. 2013;63:96-100. Sax PE et al. Lancet. 2012;379:2439-2448. Wohl D et al. ICAAC 2013. Abstract H-672a.

  45. Summary of Results from Tx-Naïve Phase III Studies of EVG/COB/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 cobicistat’s inhibition of tubular secretion of creatinine from inhibition of MATE-1 transporter

  46. Important NRTI-sparing or NRTI-limiting Studies *Only fully powered NRTI-limiting study to date demonstrating comparable efficacy and tolerability to standard-of-care regimens. RiddlerSA et al. N Engl J Med. 2008;358:2095-106. ReynesJ1 et al. HIV Clin Trials. 2011;12:255-267.Taiwo B1, et al. AIDS. 2011;25:2113-2122. KozalMJ et al. HIV Clin Trials. 2012;13:119-130. BedimoRJ et al. PLoS One. 2014;9:e106221. Raffi F et al. Lancet. 2014. [Epub ahead of print]. Cahn P et al. Lancet Infect Dis. 2014;14:572-580.Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.

  47. First-line Therapy: Special Situations Sax PE. Key Principles and Recommended Regimens for First-line Antiretroviral Therapy. In “InPractice HIV” Eron JJ, Jr., MD; Kuritzkes DR; Squires, KE Editors; http://www.inpractice.com/Textbooks/HIV.aspx; Revised 9/8/14.

  48. First-line Therapy: Special Situations Sax PE. Key Principles and Recommended Regimens for First-line Antiretroviral Therapy. In “InPractice HIV” Eron JJ, Jr., MD; Kuritzkes DR; Squires, KE Editors; http://www.inpractice.com/Textbooks/HIV.aspx; Revised 9/8/14.

  49. First-line Therapy: Special Situations Sax PE. Key Principles and Recommended Regimens for First-line Antiretroviral Therapy. In “InPractice HIV” Eron JJ, Jr., MD; Kuritzkes DR; Squires, KE Editors; http://www.inpractice.com/Textbooks/HIV.aspx; Revised 9/8/14.

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