Boosted Protease Inhibitors. Current and Future Role in HIV Therapy.2014
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Boosted Protease Inhibitors. Current and Future Role in HIV Therapy.2014
- 1. Boosted Protease Inhibitors: Current and Future Role in HIV Therapy This activity is supported by an independent educational grant from Janssen Therapeutics
- 2. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy 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 Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Faculty and Disclosure Information Sally Hodder, MD Professor of Medicine Rutgers, New Jersey Medical School Newark, New Jersey Sally Hodder, MD, has disclosed that she has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck; has received funds for research support from Bristol-Myers Squibb, Gilead Sciences, Janssen, and ViiV; and her spouse has ownership interest in Merck.
- 4. Boosted Protease Inhibitors: Current and Future Role in HIV Therapy
- 6. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy 60,000 AIDS-Related Mortality and Advent of PIs Introduction of PI-containing triple ART 80,000 70,000 50,000 40,000 30,000 20,000 10,000 0 Deaths(n) Yr of Death 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 CDC.gov. Epidemiology of HIV infection.
- 7. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Milestones in the Evolution of the PI Class PAST PRESENT (Not-too-distant) FUTURE Many pills per day Multiple doses necessary Improved tolerability Some boosted 1 pill per day (+ RTV & NRTIs) Boosting gold standard Manageable toxicity More coformulations Single-tablet regimens High toxicity Once-daily dosing Coformulation Some treatment-limiting toxicity SQV RTV IDV APV NFV FPV/RTV LPV/RTV ATV ATV/RTV DRV/RTV ATV/COBI DRV/COBI DRV/COBI/TAF/FTC SQV/RTV IDV/RTV
- 8. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Ritonavir-Boosted PIs PIs traditionally coupled with RTV (100-400 mg QD) as a pharmacologic booster RTV inhibits CYP3A4 in the liver, increasing PI exposure and half-life[1] Boosting allows less frequent PI administration and lower daily dose RTV associated with diarrhea and nausea, increased lipids, many drug–drug interactions[2] MeanPlasmaConcentration (SD) atSteadyState(ng/mL)[3] Hrs 0 4 8 12 16 20 24 ATV 400 mg QD ATV/RTV 300/100 mg QD 0 10 100 1000 10,000 Median wild-type EC90 = 14 ng/mL 1. Merry C, et al. AIDS 1997;11:F29-F33. 2. Ritonavir [package insert]. 3. Atazanavir [package insert]. Pharmacologic Boosting of ATV by RTV
- 9. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Key Drug–Drug Interactions With RTV Exposures Increase With RTV Maraviroc Antiarrythmics Anticancer agents Anticonvulsants (some) Antidepressants (some) Beta-blockers Calcium channel blockers Colchicine Digoxin Erectile dysfunction drugs Glucocorticoids Methamphetamine Rifabutin Sedatives/hypnotics Statins (some) Exposures Decrease With RTV Anticonvulsants (some) Antidepressants (some) Bupropion Ethinyl estradiol Methadone Theophylline Rifampin Ritonavir [package insert].
- 10. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Cobicistat: A New Boosting Agent Small molecule with no HIV activity Similar ↑ from BL in fasting TC and TGs compared with RTV when boosting same agent[1] Inhibitor of and metabolized by CYP3A4; many drug–drug interactions[2,3] Modest, rapid increase in serum Cr due to inhibition of tubular secretion[3] – Not associated with any change in actual GFR – Other drugs (including certain ARVs) have similar effect[4,5] 1. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 2. DHHS Guidelines. May 2014. 3. TDF/FTC/EVG/COBI [package insert]. 4. Rilpivirine [package insert]. 5. Dolutegravir [package insert].
- 11. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy 8000 DRV/COBI FDC Bioequivalent to DRV + RTV and to DRV + COBI PK analyses in healthy subjects DRV Concentration When DRV and COBI Administered as Single Agents or as Coformulation[2] DRV Concentration When Administered as DRV + RTV or as DRV/COBI Coformulation[1] 1. Kakuda TN, et al. Clin Pharmacol. 2012. Abstract O_20. 2. Kakuda TN, et al. IAS 2013. Abstract MOPE029. Hrs PlasmaConcentrationofDRV (ng/mL;Mean±SD) Hrs DRV/RTV 800/100 mg QD as single agents (n = 32) DRV/COBI 800/150 mg QD as FDC (n = 33) DRV/COBI 800/150 mg QD as FDC (n = 33) Single agents; fed (n = 38) FDC; fed (n = 40) Single agents; fasted (n = 72) FDC; fasted (n = 74) 6000 4000 2000 0 240 6 12 18 8000 6000 4000 2000 0 0 4 8 12 16 20 24
- 12. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Key Drug–Drug Interactions With COBI Exposure Increased With COBI Antacids Antiarrythmics Benzodiazepines Beta-blockers Calcium channel blockers Erectile dysfunction drugs Inhaled/injectable corticosteroids OCPs (norgestimate) Statins Increase COBI Exposure Azole antifungals Clarithromycin Decrease COBI Exposure Rifabutin Carbamazepine Phenytoin DHHS Adult Guidelines. May 2014. No interaction between COBI and methadone
- 13. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Creatinine Changes With Cobicistat and Ritonavir Interpretation of changes in renal function may be problematic when using coformulations of COBI and TDF[1] Coformulated drugs containing COBI should not be initiated in patients with estimated CrCl < 70 mL/minor used with other nephrotoxic drugs[2,3] 1. Gallant J, et al. J Infect Dis. 2013;208:32-39. 2. TDF/FTC/EVG/COBI [package insert]. 3. DHHS Guidelines. May 2014. ChangeinCreatinine Level,Medianmg/dL(IQR) Wks 0 -0.1 0.1 0.2 0.4 0.3 -0.2 BL 12 24 36 48 COBI RTV
- 14. Boosted PIs in Treatment-Naive Patients, Including Acute HIV Infection
- 15. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Zolopa AR, et al. PLoS One. 2009;4:e5575. ACTG 5164: Immediate vs Deferred ART for Acute OI Total PCP Bacterial Infection Other Ol Fungal Crypto Mycobacterial > 1 Ol CD4+ < 50 CD4+ ≥ 50 0 0.25 0.5 20.08.02.51.0 54 28 11 42 12 8 8 30 39 15 282 181 41 194 52 41 18 148 196 86 # Events # Total Log OR of Death/AIDS Progression Favors Early ART Favors Deferred ART
- 16. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Transmitted HIV Drug Resistance in MSM in 11 Jurisdictions, 2008-2011 Genotypic analysis of pol sequences of samples from 10,894 newly diagnosed MSM pts in CDC National HIV-1 Surveillance System Bañez Ocfemia MC, et al. CROI 2014. Abstract 579. All cases with sequences Cases classified as recent infections (n = 3083) Cases classified as long-standing infections (n = 7810) 0 4 Transmitted Drug Resistance Mutations 1 or more 20 8 12 16 NNRTI NRTI PI 17.4 9.0 6.6 4.6 18.8 10.9 6.5 4.7 8.3 6.7 4.5 16.8
- 17. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy DHHS Guidelines: Boosted PIs in Recommended Regimens If initiating ART in a pt with acute/early HIV before resistance test results are available, use a boosted PI plus NRTIs due to slow emergence of PI resistance and uncommon transmitted resistance DHHS Guidelines. May 2014. For All Pts, Regardless of BL VL or CD4+ Count Only for Pts With Pre-ART VL < 100,000 c/mL NNRTI EFV/TDF/FTC EFV + ABC/3TC* RPV/TDF/FTC Boosted PI ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC ATV/RTV + ABC/3TC* INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + ABC/3TC* DTG + TDF/FTC *Only for pts who are HLA-B*5701 negative. Only for those with CD4+ cell counts > 200 cells/mm3 .
- 18. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Key Considerations in Choosing RTV-Boosted PIs in First-line ART Advantages Disadvantages Potent activity; low rates of transmitted PI resistance CD4+ cell count increase generally greater than with EFV Resistance to PI rare at virologic failure Low risk of NRTI resistance with boosted PI failure Options (including PIs) retained for future use Metabolic complications due to some PIs and/or low-dose RTV GI intolerance due to some PIs and/or low-dose RTV Potential drug–drug interactions (CYP450) LPV/RTV currently* only coformulated PI (others in advanced development) Current boosted PI regimens are more pills (3) than some other options No single-tablet regimen using current preferred PIs currently* available *Current as of July 2014
- 19. Key Clinical Data on Atazanavir/Ritonavir and Darunavir/Ritonavir in Treatment-Naive Patients
- 20. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Atazanavir/Ritonavir Comparative Studies in Treatment-Naive Pts Randomized, noninferiority phase III studies Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 ART-naive pts VL ≥ 5000 c/mL (N = 883) ATV/RTV + TDF/FTC (n = 440) LPV/RTV BID* + TDF/FTC (n = 443) *SGC until Wk 48. ART-naive pts VL ≥ 1000 c/mL (N = 1857) ATV/RTV + ABC/3TC (n = 463) EFV + TDF/FTC (n = 464) CASTLE[1] (open label) ACTG 5202[2] (third agent, open label; NRTIs prematurely unblinded) ATV/RTV + TDF/FTC (n = 355) EVG/COBI/TDF/FTC (n = 353) ART-naive pts VL ≥ 5000 c/mL eGFR ≥ 70 mL/min (N = 708) GS-103[3] (placebo controlled) 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar E, et al. Ann Intern Med. 2011;154:445-456. 3. De Jesus E, et al. Lancet. 2012;379:2429-2438. ATV/RTV + TDF/FTC (n = 465) EFV + ABC/3TC (n = 465)
- 21. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy CASTLE: ATV/RTV vs LPV/RTV in Naive Pts Through 96 Wks ATV/RTV noninferior to LPV/RTV at Wk 48[1] ; superior at Wk 96[2] – Results consistent across BL HIV-1 RNA, CD4+ cell count, subgroups VF in 7% of each arm by Wk 96 – 1 pt in ATV/RTV arm with major PI mutation at Wk 96 vs 0 in LPV/RTV arm; NRTI resistance in 7 vs 10, respectively Treatment-related study d/c: 3% in each arm at Wk 96 Similar CD4+ cell count increase: +268 (ATV/RTV) vs +290 (LPV/RTV) at Wk 96 0 20 40 60 80 100 Wk 96 6874 Wk 48 76 78 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332. Δ 1.7% (-3.8 to 7.1) P = NS LPV/RTV = TDF/FTC (n = 443) ATV/RTV + TDF/FTC (n = 440) Δ 6.1% (0.3 to 12.0) P < .05 343/ 440 338/ 443 327/ 440 302/ 443n/N =
- 22. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy A5202: Efficacy With ATV/RTV vs EFV Similar time to VF with ATV/RTV vs EFV, whether with TDF/FTC or ABC/3TC Time to safety (P = .048) and tolerability (P < .001) endpoints shorter with EFV when paired with ABC/3TC but not when with TDF/FTC Similar CD4+ count increase with ATV/RTV vs EFV when paired with ABC/3TC (+250 vs +251) but greater when paired with TDF/FTC (+252 vs +221) Less resistance at VF with ATV/RTV vs EFV Daar ES, et al. Ann Intern Med. 2011;154:445-456. Sax PE, et al. J Infect Dis. 2011;204:1191-1201. EFV + TDF/FTC (57 events) ATV/RTV + TDF/FTC (57 events) EFV + ABC/3TC (72 events) ATV/RTV + ABC/3TC (83 events) *Interim analysis showed time to VF shorter with ABC/3TC in pts with BL VL > 100,000 c/mL 0 4 16 36 8460 108 156132 180 1.0 0.8 0.6 0 0.2 0.4 8 24 48 72 96 144 168120 Wks From Randomization CumulativeProbabilityofVF Resistance at Wk 96 Pts With Resistance, n EFV Arms ATV/RTV Arms NRTI 36 16 NNRTI 68 1 NRTI + NNRTI 36 0 PI resistance 0 1
- 23. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy EVG/COBI/TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 144 EVG/COBI arm noninferior to ATV/RTV arm at Wk 48 primary endpoint[1] and through Wk 144[2,3] – Results consistent across subgroups: BL HIV-1 RNA, CD4+ count, adherence, age, sex, race Treatment-related study d/c: 6% in EVG/COBI arm vs 9% in ATV/RTV arm at Wk 144 VF: 8% in EVG/COBI arm vs 7% in ATV/RTV arm at Wk 144 – 8 pts with resistance (NRTI + INSTI) in EVG/COBI arm vs 2 (PI only) in ATV/RTV arm at Wk 144 Similar CD4+ count increase at Wk 144: +280 (EVG/COBI) vs +293 (ATV/RTV) 1. DeJesus E, et al. Lancet. 2012;379:2429-2438. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. EVG/COBI/TDF/FTC (n = 353) ATV/RTV + TDF/FTC (n = 355) Δ 3.0% (-1.9 to 7.8) Δ 1.1% (-4.5 to 6.7) Wk 48 Wk 144 78 75 0 20 40 60 80 100 90 87 Δ 3.1% (-3.2 to 9.4) 83 82 Wk 96
- 24. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Lipid Changes From BL to Wk 48 This slide is an illustration only and not meant to be a cross-study comparison. 10 8 1111 56 8 23 P = .006 ATV/RTV EVG/COBI Study 103[3] EFV + TDF/FTC ATV/RTV + TDF/FTC P < .001 ACTG 5202[2] P < .0001 ATV/RTV LPV/RTV 17 38 11 17 27 32 14 58 P < .0001 CASTLE[1] TC LDL HDL TG MedianChange(mg/dL) 0 10 20 30 40 50 60 70 TC LDL HDL TG MedianChange(mg/dL) 0 10 20 30 40 50 60 70 TC LDL HDL TG MedianChange( 0 10 20 30 40 50 60 70 22 10 40 15 12 21 13 24 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar E, et al. Ann Intern Med. 2011;154:445-456.. 3. De Jesus E, et al. Lancet. 2012;379:2429-2438. 10 8 2 5 14 8 13 29 EFV + ABC/3TC ATV/RTV + ABC/3TC P < .001 P < .001 P < .001 P < .001 P = .002
- 25. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy ATV/RTV Adverse Events Summary ATV/RTV vs LPV/RTV[1,2] : – More rash ATV/RTV vs EFV[3] : – Decrease in CrCl (with TDF/FTC) vs increase with EFV; fewer CNS events – Substudy[4] : greater loss in spine (not hip) BMD All studies: – More jaundice and hyperbilirubinemia – Overall low rate (5% to 9%) of moderate to severe jaundice/scleral icterus in clinical studies of ATV/RTV[5] 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332. 3. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 4. McComsey G, et al. J Infect Dis. 2011;203:1791-1801. 5. Atazanavir [package insert].
- 26. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy ACTG 5202 Substudy: Loss of Bone With EFV vs ATV/RTV Initiation Change in Spine BMD Change in Hip BMD McComsey G, et al. J Infect Dis. 2011;203:1791-1801. 0 -5 -1 -2 -3 -4 1920 24 48 96 144 Visit Wk From Randomization EFV ATV/RTV 133 125 117 116 109 102 107 91 86 81 58 48 P = .035 EFV ATV/RTV 0 -5 -1 -2 -3 -4 1920 24 48 96 144 Visit Wk From Randomization EFV ATV/RTV 131 123 114 114 107 101 105 90 81 80 59 48 P = .61 ChangeFromBL(%) ChangeFromBL(%)
- 27. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy DRV/RTV Comparative Studies in Treatment-Naive Pts Randomized, noninferiority phase III studies Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 ART-naive pts VL ≥ 5000 c/mL (N = 689) DRV/RTV + TDF/FTC (n = 343) LPV/RTV QD or BID + TDF/FTC (n = 346) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. ARTEMIS[1,2] (open label) DTG + 2 NRTIs* (n = 242) DRV/RTV + 2 NRTIs* (n = 242)ART-naive pts VL ≥ 1000 c/mL (N = 484) FLAMINGO[3] (open label) 1. Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills A, et al. AIDS. 2009;23:1679-1688. 3. Clotet B, et al. Lancet. 2014;[Epub ahead of print]. No phase III clinical trial comparison with EFV
- 28. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy ARTEMIS: DRV/RTV vs LPV/RTV in Naive Pts Through 96 Weeks DRV/RTV noninferior to LPV/RTV at Wk 48; superior at Wk 96 – Efficacy results better in DRV/RTV arm among those with BL VL > 100K (P = . 023) c/mL and CD4+ < 200 (P = .009) VF in 1% of DRV/RTV arm vs 2% of LPV/RTV by Wk 96 – No major PI mutations in either arm at Wk 96; NRTI mutations in 2 pts in DRV/RTV arm vs 5 in LPV/RTV arm Treatment-related study d/c: 4% in DRV/RTV arm vs 9% in LPV/RTV arm at Wk 96 CD4+ count increase at Wk 96: +171 (DRV/RTV) vs +188 (LPV/RTV) Significantly smaller mean change in TC and TG at Wk 48 with DRV/RTV 0 20 40 60 80 100 71 7978 84 Wk 48[1] Wk 96[2] 1. Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills A, et al. AIDS. 2009;23:1679-1688. LPV/RTV + TDF/FTC (n = 346) DRV/RTV + TDF/FTC (n = 343) Δ 8.4% (1.9-14.8) P < .001 noninferiority P < .012 superiority Δ 5.6% (-0.1 to 11.0) P < .001 noninferiority
- 29. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Naive Patients at Wk 48 DTG superior to DRV/RTV at Wk 48 primary efficacy endpoint – Efficacy results better in DTG arm among pts with BL VL > 100K VF < 1% (n = 2) in each arm at Wk 48 – No pts with resistance in either arm at Wk 48 Treatment-related study d/c: 2% in DTG arm vs 4% in DRV/RTV arm Same CD4+ cell count increase at Wk 48: +210 cells/mm³ in each arm Mean increase in fasting LDL-C at Wk 48 significantly lower in DTG arm than DRV/RTV arm (P < .0001) HIV-1RNA<50c/mLatWk48(%) 90 83 Δ +7.1% (0.9-13.2; P = .025) Clotet B, et al. Lancet. 2014;[Epub ahead of print]. DTG 50 mg QD + NRTIs DRV/RTV 800/100 mg QD + NRTIs 217/ 242 200/ 242 0 20 40 60 80 100
- 30. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy DRV/RTV Adverse Events Summary DRV/RTV vs LPV/RTV[1] – At Wk 96, significantly more diarrhea with LPV/RTV; more rash in DRV/RTV arm (3% vs 1%, not significant) DRV/RTV vs DTG[2] – More diarrhea with DRV/RTV; more headache with DTG – Small, rapid increase in serum creatinine in first 4 wks of treatment with DTG related to inhibition of tubular secretion of creatinine by DTG 1. Mills A, et al. AIDS. 2009;23:1679-1688. 2. Clotet B, et al. Lancet. 2014;[Epub ahead of print].
- 31. Key Drug–Drug Interactions With ATV/RTV and DRV/RTV
- 32. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Drug–Drug Interactions With First-line Boosted PIs and Lipid-Lowering Therapy Antiretroviral Contraindicated Titrate Dose No Dose Adjustment ATV/RTV Lovastatin Simvastatin Atorvastatin Rosuvastatin Pitavastatin DRV/RTV Lovastatin Simvastatin Atorvastatin Pravastatin Rosuvastatin Pitavastatin DHHS Adult Guidelines. May 2014.
- 33. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy First-line Boosted PI Drug–Drug Interactions With OCPs Antiretroviral Effect on OCP Dosing Recommendation ATV/RTV[1,2] Ethinyl estradiol AUC ↓ 19% Norgestimate AUC ↑ 85% OCP should contain ≥ 35 mcg ethinyl estradiol DRV/RTV[1,2] Ethinyl estradiol AUC ↓ 44% Norethindrone AUC ↓ 14% Additional methods of contraception recommended 1. DHHS Adult Guidelines. May 2014. 2. DHHS Perinatal Guidelines. March 2014.
- 34. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy First-line Boosted PI Drug–Drug Interactions With Acid-Reducing Agents ARV Antacids H2-Receptor Antagonists Proton Pump Inhibitors ATV/RTV Give ATV ≥ 2 hrs before or 1 hr after antacids or buffered medications Give ATV/RTV simultaneously with and/or ≥ 10 hrs after the H2-receptor antagonist If using TDF and H2-receptor antagonist in ART-experienced pts, use ATV/RTV 400/100 mg Use dose equivalent of famotidine ≤ 40 mg BID in ART- naive pts or ≤ 20 mg BID in ART-experienced pts PPIs should be administered at least 12 hrs before ATV/RTV PPIs not recommended in PI-experienced pts Use dose equivalent of omeprazole ≤ 20 mg daily in PI-naive pts DRV/RTV No clinically relevant interactions No clinically relevant interactions No clinically relevant interactions DHHS Adult Guidelines. May 2014.
- 35. ACTG 5257: Comparison of ATV/RTV vs RAL vs DRV/RTV in First-line Therapy
- 36. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy ACTG 5257: Open-Label ATV/RTV vs RAL vs DRV/RTV in First-line ART Primary endpoints – VF: time to HIV-1 RNA > 1000 c/mL (at Wk 16 or before Wk 24) or > 200 c/mL (at or after Wk 24) – TF: time to discontinuation of randomized component for toxicity Composite endpoint: the earlier occurrence of either VF or TF in a given participant Switch of regimens allowed for tolerability Landovitz R, et al. CROI 2014. Abstract 85. ART-naive patients with HIV-1 RNA ≥ 1000 c/mL (N = 1809) ATV/RTV 300/100 mg QD + TDF/FTC (n = 605) RAL 400 mg BID + TDF/FTC (n = 603) Stratified by HIV-1 RNA < or ≥ 100,000 c/mL, participation in metabolic substudy, CV risk DRV/RTV 800/100 mg QD + TDF/FTC (n = 601) Wk 96 after last patient enrolled
- 37. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy ACTG 5257: Primary Endpoint Analyses at Wk 96 Regimens equivalent in time to VF Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission. Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV – In part due to high proportion of pts with hyperbilirubinemia Considering both efficacy and tolerability, RAL superior to either boosted PI DRV/RTV superior to ATV/RTV Virologic Failure Tolerability Failure Composite Endpoint Difference in 96-Wk Cumulative Incidence (97.5% CI) 0-10 10 20 ATV/RTV vs RAL 3.4% (-0.7 to 7.4) DRV/RTV vs RAL 5.6% (1.3-9.9) ATV/RTV vs DRV/RTV -2.2% (-6.7 to 2.3) ATV/RTV vs DRV/RTV 9.2% (5.5-13.0) 0-10 10 20 ATV/RTV vs RAL 13% (9.4-16.0) DRV/RTV vs RAL 3.6% (1.4-5.8) Favors RAL Favors DRV/RTV 0-10 10 20 ATV/RTV vs RAL 15% (10-20) DRV/RTV vs RAL 7.5% (3.2-12.0) ATV/RTV vs DRV/RTV 7.5% (2.3-13.0) Favors RAL Favors DRV/RTV Favors RAL
- 38. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy 89% ACTG 5257: Virologic Efficacy In ITT analysis with ART changes allowed (per protocol), regimens similar in virologic efficacy at Wk 96 and through Wk 144 In ITT analysis when change = failure (Snapshot), RAL superior to both boosted PIs at Wk 96 and DRV/RTV superior to ATV/RTV at Wks 96 and 144 Mean change in CD4+ count across arms – ATV/RTV (+284); RAL (+288) DRV/RTV (+256) cells/mm3 1.0 ProportionWithHIV-1RNA≤50c/mL 0.8 0.6 0.4 0.2 0 ITT, Regardless of ART Change 0 24 48 64 80 96 120 144 1.0 0.8 0.6 0.4 0.2 0 ITT, NC = Failure (Snapshot) RAL DRV/RTV ATV/RTV Study Wk 0 24 48 64 80 96 120 144 88% 94% 63% 73% 80% RAL DRV/RTV ATV/RTV Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.
- 39. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy ACTG 5257: Resistance VF with drug resistance occurred more often in patients initially assigned to RAL[1] – 3% randomized to RAL had ≥ 1 resistance mutation and 1.8% had INSTI mutations – 1.5% randomized to ATV/RTV and < 1% randomized to DRV/RTV developed resistance – No major PI mutations observed 1. Landovitz R, et al. CROI 2014. Abstract 85.
- 40. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy ACTG 5257: Mean Change From BL in Fasting Lipids 30 20 10 0 0 24 48 96 144 15 10 5 0 -5 0 24 48 96 144 0 24 48 96 144 0 24 48 96 144 10.0 7.5 5.0 2.5 0 40 20 0 -20 Study Wk Change(mg/dL) Fasting TC Study Wk Fasting LDL-C Study Wk Fasting TG Study Wk Fasting HDL-C ATV/RTV RAL DRV/RTV Ofotokun I, et al. CROI 2014. Abstract 746. Change(mg/dL) Change(mg/dL) Change(mg/dL)
- 41. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy ACTG 5257: Loss of BMD With First-line Boosted PI vs RAL All arms associated with significant loss of BMD through Wk 96 (P < .001) At hip and spine, similar loss of BMD in the PI arms – Significantly greater loss in the combined PI arms than in the RAL arm ATV/RTV RAL DRV/RTV Combined PI arms -5 -4 0 -3 -2 -1 -3.9 -3.4 -3.7 -2.4 -1.8 -4.0 -3.8 -3.6 P = .36 Total Hip Total Spine P = .005 P = .42 P < .001 Brown T, et al. CROI 2014. Abstract 779LB. Reproduced with permission.
- 42. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy PI Resistance Rare at VF in First-line Studies of Boosted PIs Study n PI Wk Genotypes Major PI Mutations CASTLE[1] 440 443 ATV/RTV LPV/RTV 96 26 26 1 0 ACTG 5202[2] 463 465 ATV/RTV 96 83 57 1 0 Study 103[3] 355 ATV/RTV 144 NR 0 ARTEMIS[4] 343 346 DRV/RTV LPV/RTV 96 31 46 0 0 FLAMINGO[5] 242 DRV/RTV 48 NR 0 ACTG 5257[6] 605 601 ATV/RTV DRV/RTV 96 75 99 0 0 1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. 4. Mills A, et al. AIDS. 2009;23:1679-1688. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print]. 6. Landovitz R, et al. CROI 2014. Abstract 85. Among 4303 pts in these trials, only 2 pts developed major PI mutations at initial VF
- 43. Special Considerations: Boosted PIs in Pregnancy and First Failure
- 44. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Antiretroviral Agents and Pregnancy Guideline Categorization NRTI NNRTI PI Entry Inhibitor INSTI Fusion Inhibitor Preferred ABC/3TC* TDF/FTC or 3TC ZDV/3TC‡ EFV§ LPV/RTV¶ ATV/RTV Alternative NVP‖ DRV/RTV SQV/RTV** RAL Insufficient data RPV FPV/RTV MVC DTG EVG/COBI Not recommended‡‡ ABC/3TC/ZDV d4T ddl ETR IDV/RTV NFV RTV TPV T20 DHHS Perinatal Guidelines. March 2014. *Should not be used in pts who are HLA-B*5701 positive. TDF combinations should be used with caution in pts with renal insufficiency. ‡ Most experience for use in pregnancy but potential for hematologic toxicity. § After first 8 wks of pregnancy. Preferred when potential for drug–drug interactions with PI a problem. ¶ Once-daily administration not recommended for pregnant pts. ‖ Use with caution in pts with CD4+ counts > 250 cells/mm3 due to potential for liver toxicity; use with caution with ABC since both associated with potential for HSR. **Baseline EKG recommended; contraindicated in pts with preexisting cardiac condition. Limited data on use in pregnancy, but may be considered when drug–drug interactions with PI regimens are a concern. ‡‡ Because of toxicity, lower rates of virologic suppression or lack of data in naive pts.
- 45. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Antiretroviral Pregnancy Registry: Birth Defects With First Trimester Exposure Enrolls ~ 1300 women exposed to ART each yr (80% US) 18,488 live births with follow-up data through July 2013 – 7790 with first trimester exposure Overall birth defect prevalence comparable to CDC population– based surveillance data: 2.9 per 100 live births vs 2.7 Commonly used PIs not associated with increased birth defect rate Antiretroviral Pregnancy Registry. Interim Report. December 2013.
- 46. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy PI-Based ART and Preterm Delivery Mma Bana (study of HAART for PMTCT, N = 530) – PI-based HAART (ZDV/3TC + LPV/RTV) associated with 2-fold higher rate of preterm delivery than triple-NRTI HAART, but no increase in infant morbidity or mortality through 6 mos of life[1] Retrospective US analysis – Among 161 HIV-infected women in US with singleton pregnancies (n = 53 on PI-based ART, 84 on non–PI-based ART, 6 on no ART), no association between PI and premature birth or low birth weight[2] 1. Powis K, et al. J Infect Dis. 2011;204 :506-514. 2. Dola CP, et al. J Perinat Med. 2011;40:51-55.
- 47. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy ACTG 5202: Efficacy and Tolerability by Sex With EFV and ATV/RTV Of 1857 pts, 322 were women Women on ATV/RTV arm had a higher risk of VF with either NRTI backbone ATV/RTV and EFV did not differ significantly by sex in safety and tolerability measures Women on ABC/3TC had a significantly higher (32%) safety risk compared with men With TDF/FTC, the safety risk was 20% larger for women compared with men (not statistically significant) Self-reported adherence similar between sexes Smith K, et al. Clin Infect Dis. 2014;58:555-563. VF(all) VF (univariate) ATV/RTV EFV VF (multivariate) ATV/RTV EFV Grade 3/4 Safety (all) Grade 3/4 Safety (univariate) ATV/RTV EFV Tolerability (all) Tolerability (univariate) ATV/RTV EFV 1.05 (0.70-1.58) 1.70 (1.01-2.87) 0.63 (0.33-1.20) 1.72 (0.99-2.99) 0.51 (0.25-1.02) 1.32 (1.03-1.70) 1.44 (0.98-2.10) 1.20 (0.86-1.68) 0.86 (0.64-1.16) 0.85 (0.52-1.37) 0.82 (0.57-1.19) .017 .006 .035 .49 .31 .92 Women vs Men P Value Men at Higher Risk Women at Higher Risk 0.17 1.00 6.00 HR (95% CI) With ABC/3TC VF (all) VF (univariate) ATV/RTV EFV VF (multivariate) ATV/RTV EFV Grade 3/4 Safety (all) Grade 3/4 Safety (univariate) ATV/RTV EFV Tolerability (all) Tolerability (univariate) ATV/RTV EFV 1.74 (1.13-2.69) 2.69 (1.54-4.70) 1.00 (0.49-2.05) 2.36 (1.30-4.26) 0.88 (0.42-1.84) 1.20 (0.88-1.62) 1.38 (0.91-2.08) 1.03 (0.66-1.61) 1.11 (0.81-1.52) 1.17 (0.75-1.83) 1.07 (0.68-1.67) .028 .034 .26 .35 .51 .78 P Value Men at Higher Risk Women at Higher Risk 0.17 1.00 6.00 HR (95% CI) TDF/FTC
- 48. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy SECOND-Line: Boosted PI ART After First-line VF on an NNRTI-Based Regimen Randomized, multinational, open-label noninferiority phase IIIb/IV trial Primary endpoint: HIV-1 RNA < 200 copies/mL at Wk 48 LPV/RTV + RAL (n = 270) LPV/RTV + 2-3 NRTIs* (n = 271) HIV-infected pts with VF on first-line regimen of NNRTI + 2 NRTIs (N = 541) Δ -1.8% (-4.7 to 8.3) HIV-1RNA<200c/mLatWk48(%) 83 81 223 219 0 20 40 60 80 100 n = *77% received 2 NRTIs; 23% received 3 NRTIs. Most common NRTIs: TDF, 81%; FTC/3TC, 87%; ZDV, 45% Wk 48 Wk 96 Boyd MA, et al. Lancet. 2013;381:2091-2099.
- 49. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy In Pts With Isolated M184V, (3TC or FTC) + NRTI + bPI Sufficient for Suppression Retrospective analysis of pts with M184V mutation in British Columbia HIV Drug Treatment Program, 2000-2006 Pts categorized by regimen after identification of M184V – 3TC or FTC + NRTI + bPI (n = 48) – 3TC or FTC + NRTI + bPI + another ART agent (n = 25) – 3TC/FTC-sparing: 2 NRTIs + bPI ± another ART agent (n = 44) Neither failed regimen nor subsequent regimen associated with time to HIV-1 RNA suppression Factor Associated With Virologic Suppression HR (95% CI) IDU history 0.37 (0.24-0.59) Regimen failed at M184V detection NNRTI based Reference bPI based 0.77 (0.42-1.41) Other 1.37 (0.83-2.26) Subsequent regimen (3TC or FTC) + NRTI + bPI Reference (3TC or FTC) + NRTI + bPI + additional active agent(s) 1.09 (0.60-1.96) (3TC or FTC)-sparing: 2 NRTIs + bPI ± additional agents 0.61 (0.37-1.03) ≥ 95% adherence 6 mos after study start, % 2.40 (1.31-4.43) Hull M, et al. ICAAC 2009. Abstract H-916.
- 50. Summary and Future Directions: Potential for New Coformulations
- 51. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy ATV/COBI + TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 48 Randomized, double-blind, phase III trial in ART-naive patients – Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 Gallant JE, et al. J Infect Dis. 2013;208:32-39. ART-naive pts, HIV-1 RNA ≥ 5000 c/mL, eGFR ≥ 70 mL/min (N = 692) TDF/FTC + ATV/COBI (n = 344) TDF/FTC + ATV/RTV (n = 348) Wk 48Wk 24 ATV/COBI ATV/RTV Δ -2.2% (-7.4 to 3.0) Virologic Success* Virologic Failure Patients(%) 85 87 293 304 0 20 40 60 80 100 5.8 4.0 9.0 8.6 6 20 14 No Data n = 31 30 *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data. Coformulation of ATV and COBI being considered for approval by FDA
- 52. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Ongoing Studies of COBI-Boosted DRV Plus 2 NRTIs Phase IIIb study in tx-naive tx-exp’d pts with no DRV RAMs[1] – Primary endpoint: grade 3 or grade 4 AEs by Wk 24 – Secondary endpoints: HIV-1 RNA at Wk 24 and Wk 48 Randomized, double-blind phase II trial[2] – Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24 Pts with HIV-1 RNA ≥ 500; naive or on stable ART for 12 wks and sensitive to 2 NRTIs with no DRV RAMS (N = 300) DRV + COBI + 2 NRTIs Wk 48 1. ClinicalTrials.gov. NCT01440569. 2. ClinicalTrials.gov. NCT01565850. ART-naive pts, HIV-1 RNA ≥ 5000 c/mL, eGFR ≥ 70 mL/min (N = 150) DRV/COBI/TAF/FTC QD (n = 75) DRV/COBI + TDF/FTC (n = 75) Wk 48Wk 24 Wk 24 Coformulation of DRV and COBI being considered for approval by FDA
- 53. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Boosted Atazanavir: Advantages and Disadvantages Advantages Disadvantages Efficacy comparable to EFV at Wk 96[1] Favorable lipid profile[2,3] Low risk of resistance at failure[1-3] Pill burden similar to DRV/RTV— lowest among boosted PIs Can be given unboosted Once-daily dose requires only RTV 100 mg/day Currently being studied as coformulated boosted PI with cobicistat[4] Higher rates of treatment failure than DRV/RTV and RAL in ACTG 5257 due to tolerability[5] Associated with increase in unconjugated bilirubin and scleral icterus in 4% to 9% of patients[6] Absorption impaired with acid- reducing agents[6] Food requirement for dosing[6] No plans for single-tablet regimen 1. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 2. Molina JM, et al. Lancet. 2008;372:646-655. 3. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332. 4. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 5. Landovitz R, et al. CROI 2014. Abstract 85. 6. Atazanavir [package insert].
- 54. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Boosted Darunavir: Advantages and Disadvantages Advantages Disadvantages Favorable lipid profile[1,2] Low risk of resistance at failure[1,2] Pill burden similar to ATV/RTV—lowest among boosted PIs Lower risk of treatment failure than ATV/RTV in ACTG 5257[3] Once-daily dose requires only RTV 100 mg/day[5] Currently being studied as coformulated boosted PI with cobicistat and single-tablet regimen Rash in ~ 6% of patients; use with caution in patients with sulfa allergy[4] Inferior to DTG in Flamingo study[5] Cannot be given unboosted 1 Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills AM, et al. AIDS. 2009;23:1679-1688. 3. Landovitz R, et al. CROI 2014. Abstract 85. 4. Darunavir [package insert]. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print].
- 55. clinicaloptions.com/hiv Boosted Protease Inhibitors: Current and Future Role in HIV Therapy Conclusions Boosted PIs appropriate for many ART-naive and treatment- experienced patients Long history of clinical experience with this class Low prevalence of transmitted resistance High levels of virologic suppression in first-line therapy No major PI resistance at initial VF in many clinical trials Newer preferred PIs have improved metabolic profile Ritonavir and cobicistat associated with many drug–drug interactions Newer booster, cobicistat, may offer new opportunities for coformulation with a concomitant decrease in pill burden
- 56. Go Online for More Educational Content on Boosted Protease Inhibitors! Interactive Virtual Presentation featuring streaming narration of these slides and case studies illustrating the use of boosted protease inhibitors across the treatment spectrum by expert faculty Sally Hodder, MD clinicaloptions.com/boostedPI
Editor's Notes
- My name is Dr. Sally Hodder. Welcome to this program on “Boosted Protease Inhibitors: Current and Future Role in Therapy”
- You are invited to use these slides for personal study or in your own noncommercial presentations.
- I’m Director of the adult HIV program at Rutgers, New Jersey Medical School and my disclosures are shown on this slide.
- Let’s move into the presentation
- ART, antiretroviral therapy. With the introduction of protease inhibitor–containing triple multiagent therapy in the mid-1990s, the AIDS-related mortality rate plummeted, as shown on this slide. Since that time, protease inhibitors have remained an important class of antiretroviral agents in the armamentarium to treat HIV infection.
- APV, amprenavir; ATV, atazanavir; COBI, cobicistat; DRV, darunavir; FPV, fosamprenavir; FTC, emtricitabine; IDV, indinavir; LPV, lopinavir; NFV, nelfinavir; RTV, ritonavir; SQV, saqunavir; TAF, tenofovir alafenamide fumarate. However, from the mid-1990s, the protease inhibitor class has undergone evolution with increasing tolerability, decreased toxicity, and more convenient dosing. Though currently there are no single-tablet fixed-dose combinations containing protease inhibitors, efforts are ongoing to bring coformulated regimens to patients. As shown on the current slide, development is addressing coformulation of atazanavir and darunavir with the booster agent cobicistat. Furthermore, there exists the possibility of a coformulated regimen with darunavir, cobicistat, TAF—which is a new tenofovir agent—and emtricitabine.
- ATV, atazanavir; QD, once daily; RTV, ritonavir. Protease inhibitors have traditionally been coupled with ritonavir as a pharmacologic booster. Ritonavir inhibits the CYP3A4 enzyme in the liver, increasing protease inhibitor exposure and half-life—as shown on the panel on your right. Boosting allows less frequent protease inhibitor administration and lower daily dose. Ritonavir is associated with diarrhea and nausea, increased lipids, and many drug–drug interactions.
- RTV, ritonavir. Shown on this slide are the many drug–drug interactions that exist with ritonavir. To cite two specific examples, when given with ritonavir exposure to glucocorticoids, including inhaled glucocorticoids, may result in increased glucocorticoid exposure and the potential for resulting morbidity. In contrast, shown in the column at the right of the slide are drugs demonstrating decreased exposure when given with ritonavir. For example, rifampin is a commonly used agent in multidrug regimens to treat tuberculosis; however, ritonavir-boosted protease inhibitor regimens greatly decrease rifampin levels and therefore may not be given with rifampin.
- ARV, antiretroviral; BL, baseline; Cr, creatinine; GFR, glomular filtration rate; RTV, ritonavir; TC, total cholesterol; TG, triglyceride. Recently, a new boosting agent, cobicistat, has become available. Cobicistat is a small molecule with no HIV activity. It exhibits similar increases from baseline in fasting total cholesterol and triglycerides compared with ritonavir, and it’s an inhibitor of and is metabolized by CYP3A4 with consequently many drug–drug interactions, as is the case with ritonavir. Modest, rapid increases in serum creatinine have been observed and are due to inhibition of tubular secretion of creatinine. It should be noted that these increases in creatinine are not associated with any changes in actual glomerular fil filtration rate. Other drugs such as trimethoprim and antiretroviral agents such as dolutegravir have been observed to have a similar effect.
- COBI, cobicistat; DRV, darunavir; FDC, fixed-dose combination; PK, pharmacokinetic; QD, once daily; RTV, ritonavir; SD, standard deviation. Shown in this slide are studies conducted in healthy subjects demonstrating bioequivalence of ritonavir and cobicistat boosting. As you can see on the panel at the left of the slide, 2 slightly different fixed-dose combinations of darunavir and cobicistat, shown in orange and green, resulted in very similar concentrations of darunavir compared with ritonavir boosting shown in blue. The panel on the right of the slide demonstrates similar darunavir concentrations, whether darunavir and cobicistat are administered as single agents or as coformulations. Noteworthy is that consistently lower darunavir concentrations are observed when cobicistat and darunavir are administered in the fasting state.
- COBI, cobicistat; OCP, oral contraceptives. Key drug–drug interactions with cobicistat are demonstrated in this slide. Noteworthy is that cobicistat does not decrease methadone concentrations, in contrast to ritonavir which does decrease methadone concentrations.
- BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; IQR, interquartile ranges; RTV, ritonavir; TDF, tenofovir. Shown on this slide is the increase in serum creatinine level that is observed with cobicistat administration. This increase in creatinine reflects cobicistat-mediated inhibition of tubular creatinine excretion rather than any decrease in the glomerular filtration rate. Interpretation of renal function changes may be difficult when using coformulations of cobicistat with tenofovir; however, increases in creatinine mediated by cobicistat occurs soon after initiation of cobicistat and usually plateau within several weeks. Coformulated drugs containing cobicistat should not be initiated in patients with estimated creatinine clearances of less than 70 mL/min or used with other nephrotoxic drugs.
- ART, antiretroviral therapy; OI, opportunistic infection; OR, odds ratio; PCP, Pneumocystis carinii pneumonia. Shown in this slide of data from the ACTG study 5164 is the impact of immediate vs deferred antiretroviral therapy in patients who have acute opportunistic infections. Prior to presentation of this study, it was common to delay antiretroviral therapy until the patient had recovered from their opportunistic infection; however, as shown in this slide, initiation of antiretroviral therapy within 14 days of starting treatment for the acute opportunistic infection, when compared with antiretroviral therapy that was initiated after OI treatment, there were fewer deaths or AIDS progression. And, therefore, with the advent of the results of this study, it’s now considered best to get the patient who presents with an opportunistic infection—and particularly, as you can see there, pneumocystis pneumonia—on antiretroviral therapy as soon as possible.
- CDC, Centers for Disease Control and Prevention; MSM, men who have sex with men. As the next slide shows, transmitted drug resistance is not uncommon.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; COBI, cobicistat; DRV, darunavir; DHHS, US Department of Health and Human Services; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load. Shown on this slide are current recommendations from the Department of Health and Human Services, of which boosted atazanavir and boosted darunavir are a part. Noteworthy is that a previous study—ACTG 5202—demonstrated an increased risk of virologic failure amongst treatment-naive individuals with baseline viral loads greater than 100,000 copies who were initiated on boosted atazanavir or efavirenz in combination with abacavir and lamivudine. Therefore those regimens are not ideal choices in the setting of high baseline viral loads.
- ART, antiretroviral therapy; EFV, efavirenz; GI, gastrointestinal; LPV, lopinavir; RTV, ritonavir. Key considerations in choosing ritonavir-boosted protease inhibitors in first-line therapy include the advantages that the agents have potent activity with low rates of transmitted protease inhibitor resistance, as we saw in the previous slides; the CD4 count increases are generally greater than with efavirenz; resistance to protease inhibitors are rare at virologic failure; and there’s also low risk of nucleoside reverse transcriptase inhibitor resistance with boosted protease inhibitor failure as well. Options, including protease inhibitors, are therefore retained for future use. However, there are disadvantages for protease inhibitors which include metabolic complications due to some protease inhibitors and/or the low-dose ritonavir that’s used for boosting; GI intolerance which can be observed, again, due to either the protease inhibitor or the ritonavir boosting; the drug–drug interactions that we previously discussed; lopinavir/ritonavir is the only coformulated protease inhibitor to date—though as seen in a previous slide others are in the pipeline; currently boosted protease inhibitor regimens are more pills than other options; and today there is no single-tablet regimen using preferred protease inhibitors available, though again coformulations are in development.
- In the next section of this presentation, we’ll review results of trials assessing boosted atazanavir and boosted darunavir in treatment-naive patients.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BID, twice daily; COBI, cobicistat; DTG, dolutegravir; eGFR, estimated glomerular filtration rate; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; LPV, lopinavir; QD, once daily; RAL, raltegravir; RTV, ritonavir; SGC, soft gel capsule; TDF, tenofovir; VL, viral load. This slide demonstrates 3 pivotal studies comparing regimens containing boosted atazanavir vs boosted lopinavir in the case of the CASTLE study, boosted atazanavir vs efavirenz in the case of ACTG study 5202, and boosted atazanavir vs elvitegravir in Study 103. Please paste from 3-4
- ATV, atazanavir; BL, baseline; FTC, emtricitabine; LPV, lopinavir; NS, not significant; RTV, ritonavir; TDF, tenofovir; VF, virologic failure. In the CASTLE study, ritonavir-boosted atazanavir was found to be noninferior to ritonavir-boosted lopinavir at Week 48; however, at Week 96 ritonavir-boosted atazanavir was superior to ritonavir-boosted lopinavir. These results were consistent across a number of subgroups of patients, including patients with high baseline HIV RNA levels, CD4 counts, and other subgroups. Virologic failure was 7% in each of the arms by Week 96. One patient in the boosted atazanavir arm had a major PI mutation at Week 96; however, no patients in the ritonavir-boosted lopinavir arm developed resistance. NRTI resistance emerged in 7 patients in the boosted atazanavir arm vs 10 patients in the boosted lopinavir arm. Treatment-related study discontinuations were 3% in each arm, and there were similar CD4 cell increases in the boosted atazanavir compared with boosted lopinavir arm at Week 96.
- 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; BL, baseline; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir; VF, virologic failure. In the ACTG study 5202, there was similar time to virologic failure with ritonavir-boosted atazanavir vs efavirenz, whether tenofovir/emtricitabine or abacavir/lamivudine were used. Time to safety and tolerability endpoints were shorter with efavirenz when paired with abacavir and lamivudine, but not when paired with tenofovir and emtricitabine. Similar CD4 count increases with ritonavir-boosted atazanavir compared with efavirenz were seen when paired with abacavir and lamivudine, but CD4 counts were greater when paired with tenofovir/emtricitabine. As shown in the box at the lower left-hand corner of the slide, there was less resistance at virologic failure with ritonavir-boosted atazanavir vs efavirenz.
- ATV, atazanavir; BL, baseline; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. Study 103 a single-tablet formulation of elvitegravir/cobicistat/tenofovir and emtricitabine were compared with ritonavir-boosted atazanavir plus tenofovir/emtricitabine. The elvitegravir arm was found noninferior to the boosted atazanavir arm at Week 48 and through Week 144. Results were consistent across subgroups that included different baseline viral loads, CD4 counts, adherence, age, race, and sex. Treatment-related discontinuations were 6% in the elvitegravir arm vs 9% in the boosted atazanavir arm at Week 144. Virologic failure was similar in the arms: 8% in the elvitegravir arm vs 7% in the boosted atazanavir arm. And 8 patients developed resistance in the elvitegravir arm compared with 2 in the boosted atazanavir arm. Similar CD4 counts were observed at Week 144, as shown in the slide.
- BL, baseline; ATV, atazanavir; COBI, cobicistat; DRV, darunavir; EVG, elvitegravir; HDL, high density lipoprotein; FPV, fosamprenavir; LDL, low density lipoprotein; LPV, lopinavir; RTV, ritonavir; SGC, soft-gel capsule; SQV, saquinavir; TC, total cholesterol; TG, triglycerides. Shown on this slide are the composite lipid results from all 3 of the studies that we just discussed. In the CASTLE study, ritonavir-boosted lopinavir was associated with a significantly greater increase in total cholesterol and triglycerides compared with boosted atazanavir. In study ACTG 5202 shown at the bottom of the slide, efavirenz was consistently associated with greater increases in total cholesterol, LDL, and HDL compared with ritonavir-boosted atazanavir, regardless of the nucleoside backbone. And finally at the top right corner in Study 103, statistically significant differences in lipid parameters were only seen for triglycerides; the boosted atazanavir was associated with greater increases in triglycerides than the elvitegravir arm.
- ATV, atazanavir; BMD, bone mineral density; CNS, central nervous system; CrCl, creatinine clearance; EFV, efavirenz; FTC, emtricitabine; LPV, lopinavir; RTV, ritonavir; TDF, tenofovir. To summarize adverse events that were observed in the boosted atazanavir studies, more rash was seen with boosted atazanavir. Decreases in creatinine clearance were observed in boosted atazanavir when combined with tenofovir/emtricitabine, and this is compared with some increases in creatinine clearance which were observed with the efavirenz arms. As might be expected, boosted atazanavir was associated with fewer CNS events compared with efavirenz. Across studies, there was more jaundice and hyperbilirubinemia with the atazanavir boosted with ritonavir due to the known inhibition of UDP glucuronosyltransferase by atazanavir. It should be noted that the hyperbilirubinemia is not associated with hepatotoxicity and is reversible on discontinuation of the drug. Now going back to the lower point in the second bullet, there was greater loss in spine bone mineral density with atazanavir vs efavirenz, and this is shown in the next slide.
- ATV, atazanavir; BL, baseline; BMD, bone mineral density; EFV, efavirenz; RTV, ritonavir. It’s been previously observed that antiretroviral therapy initiation is usually associated with a decrease in bone mineral density over the first year or so which then plateaus. As this slide shows, there are significantly less bone mineral density decrease at the spine with efavirenz vs atazanavir; however, if you look at the panel to the right of the slide, you see there are no significant differences of bone mineral density changes at the hip.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BID, twice daily; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; LPV, lopinavir; QD, once daily; RAL, raltegravir; TDF, tenofovir; VL, viral load. Moving on to a discussion of boosted darunavir treatment in naive patients, we will discuss 2 studies shown on this slide: the ARTEMIS study which compared boosted darunavir with tenofovir/emtricitabine with that of boosted lopinavir, again with tenofovir and emtricitabine, and the FLAMINGO study which compared boosted darunavir with 2 nucleoside reverse transcriptase inhibitor agents to dolutegravir with 2 nuke agents.
- BID, twice daily; BL, baseline; DRV, darunavir; FTC, emtricitabine; LPV, lopinavir; QD, once daily; RTV, ritonavir; TC, total cholesterol; TDF, tenofovir; TG, triglycerides; VF, virologic failure; VL, viral load. First discussing the ARTEMIS study, boosted darunavir was noninferior to boosted lopinavir at Week 48. However, at Week 96, boosted darunavir was found to be superior to ritonavir-boosted lopinavir. And you can see there in the bar graph at Week 96 significantly more individuals—79%—with the boosted darunavir were had suppressed viral load compared with 71% of the ritonavir-boosted lopinavir. Efficacy results were better in the ritonavir-boosted darunavir arm among those with baseline viral loads that were high—greater than 100,000—and those with low CD4 counts—less than 200. Virologic failure was 1% in the boosted darunavir arm and 2% in the boosted lopinavir arm by Week 96. There were no major protease inhibitor mutations in either arm at Week 96. Nucleoside reverse transcriptase inhibitor mutations were observed in 2 patients in the boosted darunavir arm compared with 5 patients in the ritonavir-boosted lopinavir arm. Treatment-related study discontinuations were 4% in the darunavir arm and about twice that, 9%, in the ritonavir-boosted lopinavir arm. CD4 counts at Week 96 were similar, as shown in this slide. There was a significantly smaller mean change in total cholesterol and triglycerides at Week 48 in the boosted darunavir vs the boosted lopinavir arm.
- BL, baseline; DRV, darunavir; DTG, dolutegravir; LDL-C, low density lipoprotein cholesterol; QD, once daily; RTV, ritonavir; VF, virologic failure; VL, viral load. Moving to the FLAMINGO study which compared dolutegravir to ritonavir-boosted darunavir, each with 2 nucleoside agents, dolutegravir was found to be superior to ritonavir-boosted darunavir at Week 48, which was the primary efficacy endpoint. Interestingly, efficacy results were better in the dolutegravir arm among those patients with high baseline viral loads above 100,000. Virologic failure was very low in each arm, less than 1%, and there were no patients with emergent resistance. Treatment-related study discontinuations were 2% in the dolutegravir arm vs 4% in the boosted darunavir arm, and the CD4 cell increases were identical, 210 cells in each arm. Mean increases in fasting LDL at Week 48 were significantly lower in the dolutegravir arm vs boosted darunavir.
- DRV, darunavir; DTG, dolutegravir; LPV, lopinavir; RTV, ritonavir. To summarize the adverse events that were seen with the boosted darunavir studies, at Week 96 there was significantly more diarrhea in the ritonavir-boosted lopinavir arm , but there was more rash in the ritonavir-boosted darunavir arms, though this difference was not statistically significant. Moving to the FLAMINGO study, there was more diarrhea in the ritonavir-boosted darunavir arm vs dolutegravir, but participants in the dolutegravir arm had more headache. There was a small, rapid increase in serum creatinine in the first 4 weeks of treatment with dolutegravir which was related to inhibition of tubular secretion of creatinine by the dolutegravir and again was not related to any decrease in the glomerular filtration rate. From 3-12
- ATV, atazanavir; DRV, darunavir; RTV, ritonavir. Now as we mentioned earlier, there are a number of drug–drug interactions that one must consider when using boosted protease inhibitors, and this section of the presentation just reviews some of the most important interactions that you should be aware of.
- ATV, atazanavir; DRV, darunavir; RTV, ritonavir. One of the major interactions is with statins, particularly lovastatin and simvastatin, the levels are greatly increased, and both of those statins are contraindicated with either boosted atazanavir or boosted darunavir. Atorvastatin and rosuvastatin have been demonstrated to have increased levels in the setting of boosted protease inhibitors but can be used provided one starts at a low dose and then titrates the dose. There is no dose adjustment, however, that is needed for pitavastatin with either darunavir or atazanavir.
- ATV, atazanavir; AUC, area under the concentration curve; DRV, darunavir; OCP, oral contraceptive; RTV, ritonavir. Moving to another important drug–drug interaction, protease inhibitors do impact oral contraceptive agents. And as shown in this slide, the levels decrease to the levels of ethinyl estradiol decrease someone, though, interestingly, ritonavir-boosted atazanavir may be associated with increased levels of norgestimate, while ritonavir-boosted darunavir is associated with slightly decreased levels of norethindrone. Noteworthy is that boosted atazanavir can be used with oral contraceptives, but the oral contraceptive should contained at least 35 mcg of ethinyl estradiol. However, in the case of ritonavir-boosted darunavir, additional methods of contraception are recommended.
- ART, antiretroviral therapy; ATV, atazanavir; BID, twice daily; DRV, darunavir; PPI, proton pump inhibitor; RTV, ritonavir; TDF, tenofovir. And, finally, interactions with acid-reducing agents are important for ritonavir-boosted atazanavir, as summarized in this slide. Atazanavir must be given at least 2 hours before or 1 hour after antacids or buffered medications. In the case of H2 receptor antagonists, the atazanavir and ritonavir may be given simultaneously or may be given at least 10 hours after the H2 antagonist. If using tenofovir and an H2 receptor antagonist in antiretroviral-experienced patients, it is recommended that the dose of atazanavir be 400 mg with 100 mg of ritonavir boosting. And, finally, the dose equivalent of famotidine should be less than or equal to 40 mg twice daily in antiretroviral-naive patients but 20 mg or less twice daily in treatment-experienced patients. And, finally, relevant to proton pump inhibitors with atazanavir, the dose equivalent should not exceed 20 mg of omeprazole. Frequently 40 mg is used, and if 40 mg is the proton pump inhibitor dose, it should not be given to either treatment-naive or experienced patients. Now, if the 20 mg dose is used, it may be given in treatment-naive patients but should not be used at all with treatment-experienced patients. And if proton pump inhibitors are used in treatment-naive patients, they should be administered at least 12 hours before boosted atazanavir. As shown at the bottom of the slide, there are no really clinically relevant interactions of either H2 receptor antagonists or proton pump inhibitors with boosted darunavir.
- ATV, atazanavir; DRV, darunavir; RAL, raltegravir; RTV, ritonavir. Recently, there has been a presentation of a trial that compared several of the recommended agents in the DHHS guidelines—ACTG 5257—which compared boosted atazanavir to raltegravir to ritonavir-boosted darunavir in treatment-naive patients.
- ART, antiretroviral therapy; ATV, atazanavir; BID, twice daily; CV, cardiovascular; DRV, darunavir; FTC, emtricitabine; QD, once daily; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir; TF, tolerability failure; VF, virologic failure. On this slide you see the study design. Eligible patients had to have an HIV-1 RNA greater than or equal to 1000 copies, though participants were stratified by HIV-1 RNA, as shown in the slide. Primary endpoints included virologic failure which was time to a viral load greater than 1000 copies at Week 16 or before Week 24, or greater than 200 copies at or after Week 24. And there was tolerability failure: time to discontinuation of randomized component for toxicity. There was a composite endpoint, which was the earlier occurrence of either virologic or tolerability failure in a given participant. And switch of regimens was allowed for tolerability.
- ATV, atazanavir; DRV, darunavir; RAL, raltegravir; RTV, ritonavir; VF, virologic failure. This slide shows the various endpoints that were just defined. To your left you see virologic failure, and regimens that were compared were equivalent in time to virologic failure. In the middle panel, tolerability failure is shown, and there was a significantly greater incidence of treatment failure with ritonavir-boosted atazanavir compared with either raltegravir or ritonavir-boosted darunavir regimens. And this, in part, was due to the high proportion of patients on boosted atazanavir who experienced hyperbilirubinemia. The panel to the right shows the composite endpoint, and when considering both efficacy and tolerability, raltegravir was superior to either of the boosted protease inhibitor regimens. Comparing the 2 PI regimens, ritonavir-boosted darunavir was superior to the ritonavir-boosted atazanavir arm, as shown.
- ART, antiretroviral therapy; ATV, atazanavir; DRV, darunavir; ITT, intent to treat; NC, noncompleter; RAL, raltegravir; RTV, ritonavir. Now if we just look at virologic efficacy in the intent-to-treat analysis where antiretroviral changes were allowed, the regimens were similar in virologic efficacy at 96 weeks through 144 weeks, as shown in the top diagram. In the intent-to-treat analysis when change equaled failure, or the SNAPSHOT analysis, raltegravir was superior to both boosted protease inhibitors at Week 96, and ritonavir-boosted darunavir was superior to boosted atazanavir at both Weeks 96 and 144. Mean change in CD4 count across arms is shown; it was 284 in the boosted atazanavir arm, 288 in the raltegravir arm, and 256 in the ritonavir-boosted darunavir arm.
- DRV, darunavir; RAL, raltegravir; RTV, ritonavir; VF, virologic failure. Virologic failure with drug resistance occurred more often in patients initially assigned to raltegravir; 3% of those randomized to raltegravir had greater than or equal to 1 resistance mutation and 1.8% had integrase inhibitor mutations; 1.5% randomized to boosted atazanavir and less than 1% randomized to boosted darunavir developed resistance; and no major protease inhibitor mutations were observed.
- ATV, atazanavir; BL, baseline; DRV, darunavir; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; RAL, raltegravir; RTV, ritonavir; TC, total cholesterol; TG, triglycerides. The next slide shows the mean change from baseline in fasting lipids, and as you can see in fasting total cholesterol—the upper left-hand panel—and fasting triglycerides, both the boosted protease inhibitors had larger increases than the raltegravir. Looking at LDL, the same pattern was seen; however, if you look at the panel in the lower right-hand side of the slide, fasting HDLs were similar among the arms.
- ATV, atazanavir; BMD, bone mineral density; DRV, darunavir; RAL, raltegravir; RTV, ritonavir. As we discussed earlier in this presentation, antiretroviral therapy has been observed to be associated with significant loss of bone mineral density, and that was seen again in this study. However, at hip and spine, there were similar losses of bone mineral density in the protease inhibitor arms, and this was significantly greater than that observed with the raltegravir arms, which is shown in the panel on the right—raltegravir is shown in orange.
- ATV, atazanavir; DRV, darunavir; LPV, lopinavir; NR, not reported; RTV, ritonavir; VF, virologic failure. This is a composite table taken from a number of studies. And if you go over to the column Major PI Mutations to your right, you see that emergent mutations are very, very rare.
- As many HIV-infected women are desiring children, it is critically important to choose appropriate antiretroviral therapy for women who are or who desire pregnancy.
- 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; COBI, cobicistat; d4T, stavudine; ddl, didanosine; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EKG, electrocardiogram; ETR, etravirine; EVG, elvitegravir; FTC, emtricitabine; HSR, hypersensitivity reaction; IDV, indinavir; MCV, Maraviroc; NPV, nevirapine; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir; TPV, tipranavir; ZDV, zidovudine. This slide demonstrates current DHHS guidelines for antiretroviral agents in pregnancy. Ritonavir -boosted lopinavir and boosted atazanavir are classified as preferred. As you can see, darunavir is considered an alternative agent. And though raltegravir is recommended as an alternative agent when drug–drug interactions are present, data in pregnancy are limited, as is the case with the other integrase inhibitors and rilpivirine. As efavirenz has been associated with neural tube defects in animal studies and there have been several reports of neurologic congenital malformations in babies born of mothers taking efavirenz during pregnancy, efavirenz is not recommended during the first 8 weeks of pregnancy.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; CDC, Centers for Disease Control and Prevention; d4T, stavudine; ddl, didanosine; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; IDV, indinavir; LPV, lopinavir; NFV, nelfinavir; NVP, nevirapine; RPV, rilpivirine; RTV, ritonavir. The Antiretroviral Pregnancy Registry is critical to assessing experience with use of antiretroviral agents in pregnancy. Pregnant women must be enrolled before the end of the pregnancy, and roughly 1300 women exposed to antiretroviral therapy are enrolled each year; most of those are from the US. Through July 2013, there have been 18,488 live births with follow-up data. More than 7700 have been associated with first trimester exposure. Importantly, overall birth defect prevalence is comparable to that of the CDC population, as shown. And as shown in the middle part of the table to the right of the slide, commonly used protease inhibitors have not been associated with increased birth defect rates, though, as you see, there is relatively limited experience particularly with darunavir.
- 3TC, lamivudine; ART, antiretroviral therapy; LPV, lopinavir; PMTCT, prevention of mother to child transmission; RTV, ritonavir; ZDV, zidovudine. You should be aware that protease inhibitors have been associated with preterm delivery, though the data are conflicting. In the Mma Bana study—which was a study done in Africa that looked at ritonavir-boosted lopinavir plus zidovudine/lamivudine—a 2-fold higher rate of preterm delivery was observed when compared with triple NRTI treatment, but there was no increase in that study in infant morbidity or mortality through 6 months of life. In a separate study done in the US which was a retrospective analysis of a relatively small number of cases, 161 HIV-infected women with single pregnancies were assessed, and no association was found between protease inhibitor use and premature birth or low birth weight.
- 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir; VF, virologic failure. Historically, women have comprised a minority of patients in antiretroviral studies, raising questions as to whether there are differences in either efficacy or tolerability in women compared with men. In the study shown on this slide—ACT study 5202—17% of trial participants were women. Interestingly, women on the boosted atazanavir arm had a higher risk of virologic failure with either of the NRTI backbones—either the tenofovir/emtricitabine or abacavir/lamivudine backbones. Boosted atazanavir and efavirenz did not differ significantly by sex in safety and tolerability. Women on abacavir and lamivudine had a significantly higher safety risk compared with men. And with tenofovir/emtricitabine, the safety risk was 20% larger for women compared with men, though this was not statistically significant. Importantly, self-reported adherence was similar between sexes.
- 3TC, lamivudine; FTC, emtricitabine; LPV, lopinavir; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir; VF, virologic failure; ZDV, zidovudine. Looking at studies of second-line boosted protease inhibitor therapy after first-line failure on an nonnucleoside agent, you can see in this study individuals were randomized to either ritonavir-boosted lopinavir plus raltegravir, and ritonavir-boosted lopinavir plus 2 or 3 NRTIs. Most (three quarters) received 2 NRTIs. The efficacy results, less than 200 copies, were relatively comparable and were noninferior.
- 3TC, lamivudine; ART, antiretroviral therapy; bPI, boosted PI; FTC, emtricitabine; IDU, injection drug use. In this slide, a retrospective analysis of patients with M184V mutation was conducted in British Columbia in their HIV Drug Treatment Program, and patients were categorized by regimen after identification of emergent M184V resistance, as shown. Neither failed regimen nor subsequent regimen was associated with time to HIV RNA suppression, suggesting that treatment with boosted protease inhibitor plus a nucleoside agent plus either emtricitabine or lamivudine was an acceptable choice.
- In the next section of this presentation, we’ll discuss an alternative to ritonavir boosting, and that is cobicistat. And with the advent of cobicistat, there is the potential for new coformulations.
- AE, adverse event; ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. This study shows that cobicistat-boosted atazanavir vs ritonavir-boosted atazanavir, both with tenofovir and emtricitabine, resulted in similar rates of virologic success. As you can see in the panel on the right, virologic failure was similar in both regimens.
- AE, adverse event; COBI, cobicistat; DRV, darunavir; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; FTC, emtricitabine; QD, once daily; RAM, resistant-associated mutations; TAF, tenofovir alafenamide; TDF, tenofovir. There are several ongoing studies of cobicistat-boosted darunavir plus 2 NRTIs. To the left of the slide, there’s a phase IIIb study in treatment-naive and treatment-experienced patients who do not have any antecedent darunavir resistance, and the study design is shown. On the right of the panel, there is a randomized double-blind phase II study that compares darunavir/cobicistat/TAF—the new agent that is tenofovir like—and emtricitabine (and you should know that that’s a fixed-dose combination) compared with cobicistat-boosted darunavir plus tenofovir and emtricitabine. And we’re looking forward to these data when they come out hopefully in the not-too-distant future.
- DRV, darunavir; EFV, efavirenz; RAL, raltegravir; RTV, ritonavir. Just to review some of the advantages and disadvantages which are summarized on this slide for boosted atazanavir: There is comparable efficacy to efavirenz, there’s a favorable lipid profile, a low risk of resistance at failure, pill burdens that are similar to boosted darunavir and are really lowest among the entire boosted protease inhibitor class. Noteworthy is that atazanavir may be given unboosted at a dose of 400 mg. It should be noted, however, that that should not be given in the setting of tenofovir, and the once-daily dose requires only 100 mg daily of ritonavir. Currently being studied are as coformulated boosted PI is atazanavir and cobicistat. The disadvantages are highlighted on the right side of this table and include higher rates of treatment failure than boosted darunavir and raltegravir in ACTG 5257 largely due to tolerability—the hyperbilirubinemia that we discussed. Boosted atazanavir is associated with an increase in unconjugated bilirubin and scleral icterus, ranging from 4% to 9% of patients. Absorption is impaired with acid-reducing agents, and food is required for dosing. To date, there are no plans for a single-tablet regimen incorporating atazanavir.
- ATV, atazanavir; DTG, dolutegravir; RTV, ritonavir. The next slide summarizes the advantages and disadvantages of boosted darunavir. Advantages include a favorable lipid profile, a low risk of emergent resistance, a pill burden that is low amongst the boosted PI class, a lower risk of treatment failure than boosted atazanavir in ACTG 5257, again largely due to tolerability issues. Once-daily dosing requires only 100 mg of ritonavir, and as we stated several times, it’s currently being studied as a coformulated boosted PI with cobicistat and also as a single-tablet regimen. Disadvantages include rash in approximately 6% of patients, and darunavir should be used with caution in those individuals who have a history of sulfa allergy. Boosted darunavir was inferior to dolutegravir in the recently presented FLAMINGO study, and darunavir may not be given without boosting.
- ART, antiretroviral therapy; VF, virologic failure. So in conclusion, boosted protease inhibitors are appropriate for many antiretroviral-naive and treatment-experienced patients. They have a long history of clinical experience, a low prevalence of transmitted resistance, and protease inhibitors have high levels of virologic suppression in first-line therapy. There are no major PI resistance at initial virologic failures in many clinical trials, and newer preferred protease inhibitors have improved metabolic profiles. Ritonavir and cobicistat are associated with many drug interactions with the booster agents ritonavir and cobicistat. And, finally, the new booster, cobicistat, may offer new opportunities for coformulation with a concomitant decrease in pill burden.