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New Drugs and New Strategies from the 2014 CROI

New Drugs and New Strategies from the 2014 CROI. Jeffrey Lennox, MD Co-PI, Emory HIV/AIDS Clinical Trials Unit. Learning Objectives. After attending this presentation, learners will be able to:. Describe the antiviral properties of 4 new medications in clinical trials

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New Drugs and New Strategies from the 2014 CROI

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  1. New Drugs and New Strategies from the 2014 CROI Jeffrey Lennox, MD Co-PI, Emory HIV/AIDS Clinical Trials Unit

  2. Learning Objectives After attending this presentation, learners will be able to: Describe the antiviral properties of 4 new medications in clinical trials Recall the differential benefits of certain of the DHHS-preferred initial therapies Discuss possible approaches for patients with CNS symptoms on long-term EFV

  3. Disclosure Dr. Lennox has received grants awarded to Emory University from Gilead Sciences, Inc and ViiVHealthcare, and has served as a scientific consultant to Merck INC and to BMS. (Updated 03/28/13)

  4. AI438011- A study of an HIV-1 attachment inhibitor • Randomized, partially blinded study of BMS663068 an oral attachment inhibiter. BMS663068 is converted to the active drug, 626529, in the GI tract. • 626529 binds to HIV gp120, blocking binding to the CD4 receptor. HIV-1 binding and fusion is therefore inhibited. • In vitro 626529 is active against HIV-1 except subtype AE and group O. • In a small proof of concept study BMS663068 led to reductions in viral load. A dose ranging study was therefore done Lallezari WED AM

  5. AI438011 Study • ARV experienced: 29% R 3TC, 28% R EFV, 13% TAMS. All required to be sensitive to RAL, TDF, ATVr • 50 patients/arm were given TDF/FTC plus 4 different doses of 663068 or ATV/r 300/100. 10 patients /arm had 7 days of monotherapy

  6. Results The company is planning further trials, likely with a QD regimen

  7. GSK1265744- The LATTE study • GSK is developing an IM long acting integrase inhibitor and an IM long acting NNRTI that can be used in combination. The current study tested the oral version of the integrase as a proof of concept • GSK1265744 is similar to dolutegravir, has a t1/2 orally of 40 hours, and a t1/2 IM of 40 days • In naïve patients the LATTE study included 3 doses of GSK744 (10mg, 30mg, 60mg) daily plus 2NRTI, vs EFV + 2NRTI • After 24 weeks those on GSK744 with HIV-1RNA <50 c/mL had the 2NRTI replaced with Rilpivirine 25mg QD in a maintenance phase Margolis WED AM

  8. LATTE Baseline Characteristics

  9. The company is starting a trial of monthly IM GSK744 LA + RPV LA for maintenance of virologic suppression in treated patients

  10. MK1439- Doravirine • Doravirine is a NNRTI active in vitro against K103N, Y181C, G190A, E138K • In a POC study 40 ARV naïve pts/arm were given 1 of 4 dosesof MK1439 vs EFV, all QD in combination with TDF/FTC The 100mg dose is moving forward into the next phase of development Morales-Ramirez WED AM

  11. New Strategies and Other Findings from CROI A case-based discussion

  12. Case 1 • A 26-year-old male is newly diagnosed with HIV-1 infection. His CD4 cell count is 350 cells/mm³, HIV-1 RNA is 121,000 c/mL, CrCl=110 mg/min, Genotype reveals a K103N mutation. Which of the following DHHS-referred regimens in combination with TDF/FTC would you recommend? • Atazanavir/r • Raltegravir • Darunavir/r • Elvitegravir/c • Dolutegravir

  13. Case 1, Question 1 Which of the following DHHS-referred regimens in combination with TDF/FTC would you recommend? • Atazanavir/r • Raltegravir • Darunavir/r • Elvitegravir/c • Dolutegravir

  14. Case 1, Question 2 For which regimen will < 5% of patients develop virologic failure and ARV resistance by 48-96 weeks? • Atazanavir/r • Raltegravir • Darunavir/r • Elvitegravir/c • Dolutegravir • All will be < 5% • a,c,e

  15. A5257 Study Design* HIV-infected patients, ≥18 yr, with no previous ART, VL ≥ 1000 c/mL at US Sites Randomized 1:1:1 to Open Label Therapy Stratified by screening HIV-1 RNA level (≥ vs < 100,000 c/mL), A5260s metabolic substudy participation, cardiovascular risk *With the exception of RTV, all ART drugs were provided by the study ATV 300mg QD + RTV 100mgQD + FTC/TDF 200/300 mg QD RAL 400 mg BID + FTC/TDF200/300mgQD DRV 800mgQD+RTV 100mgQD + FTC/TDF 200/300 mg QD 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

  16. Endpoints • Primary Endpoints* • Time to HIV-1 RNA >1000 c/mL wk 16to before wk 24, or >200 c/mL at or after wk 24 (VF) • Time to discontinuation of randomized component for toxicity (TF) • Pre-planned Composite Endpoint • The earlier occurrence of either VF or TF in a given participant • Equivalence = 97.5% CI on the pairwise difference in 96-week cumulative incidence entirely within ±10% * Time measured from date of study entry/randomization

  17. Participants Enrolled 1814 Participants Excluded 1 acute illness, 1 prior ART and 3 prior ART + resistance Participants Eligible 1809 RAL 603 (4 never started ART) DRV/r 601 (4 never started ART) ATV/r 605 (5 never started ART) 546 (91%) Completed 96 Weeks 560 (93%) Completed 96 Weeks 556 (92%) Completed 96 Weeks

  18. Baseline Characteristics

  19. Cumulative Incidence of Virologic Failure Difference in 96 wkcumulative incidence (97.5% CI) ATV/r vs RAL 3.4% (-0.7%, 7.4%) DRV/r vs RAL 5.6% (1.3%, 9.9%) ATV/r vs DRV/r -2.2% (-6.7%, 2.3%) -20 -10 0 10 20

  20. Cumulative Incidence of Tolerability Failure Difference in 96 wkcumulative incidence (97.5% CI) ATV/r vsRAL Favors RAL 13% (9.4%, 16%) DRV/r vs RAL 3.6% (1.4%, 5.8%) Favors DRV/r ATV/r vs DRV/r 9.2% (5.5%, 13%) -20 -10 0 10 20

  21. Cumulative Incidence of Virologic or Tolerability Failure Difference in 96 wkcumulative incidence (97.5% CI) ATV/r vs RAL Favors RAL 15% (10%, 20%) Favors RAL DRV/r vs RAL 7.5% (3.2%, 12%) Favors DRV/r ATV/r vs DRV/r 7.5% (2.3%, 13%) -20 -10 0 10 20 *Consistent results seen with TLOVR at a 200 copies/ml threshold

  22. Proportion VL ≤50 copies/mL ITT, regardless of ART change ITT, off-ART=failure (SNAPSHOT)

  23. Tolerability FailureToxicity Associated Discontinuation of randomized ART * *Participants allowed to switch therapy for intolerable toxicity

  24. A Closer Look at ATV/r Hyperbilirubinemia

  25. Resistance to Study Agents 1809 Participants 1 Baseline Missing 56 VF Failed to Amplify 295 Virologic Failures RAL ATV/r DRV/r 75/94 VF Available 65/85 VF Available 99/115 VF Available 9Any Resistance (1.5% of ATV/r) 18Any Resistance (3% of RAL) 4Any Resistance (<1% of DRV/r) 7 isolated M184V 1 isolated integrase mutation 7 integrase + M184V 3 integrase + M184V + K65R 3 isolated M184V 1 integrase mutation 5 isolated M184V 1 integrase mutation 2 T69D/T215AIT 1 K70N + M184V *Stanford University Genotypic Resistance Interpretation Algorithm V 6.3.1

  26. Conclusions • ATV/r, RAL, and DRV/r were equivalent for virologic efficacy • ATV/r was less well tolerated than DRV/r or RAL • Largely due to cosmetic hyperbilirubinemia • RAL was superior to both PI/r regimens for combined tolerability and virologic efficacy • DRV/r was superior to ATV/r • VF with resistance was rare • More frequently observed with RAL • Analyses are ongoing to evaluate: • Cardiovascular, metabolic, skeletal, fat, inflammatory biomarkers, behavior, adherence, and key subgroup differences

  27. Case 2, Question 1 A 29-year-old male is newly diagnosed with HIV-1 infection. His HIV RNA is 30,000. His CD4 cell count is 350 cells/mm³, he is HLAB5701-, and he has a CrCl of 30 mL/min. Nephrology gives a working diagnosis of HIVAN. Which of the following would you recommend? • TDF/FTC + II • ABC/3TC + PI/r • ABC/3TC + II • II + PI/r • Another Combination

  28. Week 96 results of the Single Study-Dolutegravir vs Efavirenz • 833 patient, placebo-controlled study of ABC/3TC+DOL vs TDF/FTC/EFV

  29. Single Study-virologic failure and resistance • 6 (1.4%) patients in the EFV-based arm developed a major NNRTI resistance mutation, vs 0 patients with INI resistance in the dolutegravir arm.

  30. Case 2b, cousin to case 2 A patient has been on long-term TDF/FTC + PI/r. He now has developed renal insufficiency, with a CrCL of 25 mL/min. His HIV RNA is >50 c/mL, and HLAB5701+. What would you prescribe? • II + PI/r • II + PI/r + 3TC • MVC + PI/r + 3TC • PI monotherapy • Another Combination

  31. PI Monotherapy Maintenance Revisited-PIVOT Study • 587 patients with HIV-1 RNA <50 c/ml randomized to continue triple therapy or to begin PI monotherapy (80% DRV/r, 14% LPV/r, 6% other PI)

  32. PIVOT Study- Results • Viral rebound more common in mono arm, but responded to reintroduction of NRTIs • Primary endpoint of loss of future drug options was not different between arms Paton #550 LB

  33. Case 3 A patient with long-term suppression of HIV-1 on a first line regimen since 2003 has persistently elevated LDL cholesterol and triglycerides despite diet, exercise and a statin. He wants to change his medication to ELV/c/TDF/FTC. What would you recommend? • Do not switch, the lipids will not improve and there is a risk of undetected 3TC resistance • Switch, lipids may improve and there is little risk of virologic failure • Switch to another regimen that does not contain either cobicistat or ritonavir

  34. Stribild “Strategy” Studies • Randomized, open label comparison studies. Patients on NNRTI or PI/r 1st or 2nd line regimens with HIV RNA < 50c/mL, and no history of virologic failure or drug resistance • Randomized 2:1 to switch to ELV/c/TDF/FTC or remain on current regimen • Primary endpoint HIV-1 RNA <50 c/mL at week 48, with a 12% non-inferiority margin LB Posters 551 & 553

  35. Strategy Studies- Results * p=0.01 overall, p=0.32 for DRV/r, p=0.001 for LPV/r LB Posters 551 & 553

  36. Case 4 A patient with long-term suppression of HIV-1 on EFV/TDF/FTC reports mild depression and forgetfulness. The patient’s partner questions whether it is due to EFV. What would you recommend? • Probably not related to EFV, do not change therapy • May be related to EFV but treatment switch data is unconvincing, do not change therapy • Possibly related to EFV, change to Rilpivirine or INI • Possibly related to EFV, change to Maraviroc for better CNS penetration and to decrease CNS trafficking

  37. Changing EFV to MVC in patients with neurocognitive impairment • 12 patients on TDF/FTC/EFV with documented neurocognitive impairment, changed to ABC/3TC+MVC Small sample size limits study, trends interesting Poster 427

  38. Improvement of Depression and Anxiety after Discontinuation of Efavirenz • 23 patients on long-term EFV who had symptoms of depression, anxiety or physical symptoms • Neuropsych testing done before, and at 2 weeks and 3 months after switch of EFV to Rilpivirine For those 17 patients switching due to neuropsychiatric symptoms, the improvement in depression and anxiety was statistically significant (p=0.036) Poster 476

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