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Tratamiento de VIH/SIDA análisis de fármacos e inicio del mismo

Tratamiento de VIH/SIDA análisis de fármacos e inicio del mismo

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  • DHHS, US Department of Health and Human Services.
  • ART, antiretroviral therapy; COBI, cobicistat; CrCl, creatinine clearance; EVG, elvitegravir; FTC, emtricitabine; DHHS, US Department of Health and Human Services; RPV, rilpivirine; TDF, tenofovir.
  • ART, antiretroviral therapy; COBI, cobicistat; DHHS, US Department of Health and Human Services; EFV, efavirenz; INSTI, integrase strand transfer inhibitor; RTV, ritonavir.
  • 3TC, lamivudine; ART, antiretroviral therapy; ELISA, enzyme-linked immuno sorbent assay; LPV, lopinavir; NVP, nevirapine; PCR, polymerase chain reaction; RTV, ritonivir; ZDV, zidovudine. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/48LB.aspx .
  • 3TC, lamivudine; ART, antiretroviral therapy; LPV, lopinavir; NVP, nevirapine; PBMC, peripheral blood mononuclear cell; RTV, ritonavir; VL, viral load; ZDV, zidovudine. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/48LB.aspx .
  • ART, antiretroviral therapy; ELISA, enzyme-linked immuno sorbent assay; PBMC, peripheral blood mononuclear cell; WB, Western blot. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/47.aspx .
  • AE, adverse events; ART, antiretroviral therapy; PBMC, peripheral blood mononuclear cell; QD, once daily. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/50LB.aspx .
  • PrEP, pre-exposure prophylaxis.
  • FTC, emtricitabine; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate; TFV, tenofovir.
  • CI, confidence interval; DSMB, data and safety monitoring board; FTC, emtricitabine; HR, hazard ratio; mITT, modified intent to treat; PrEP, pre-exposure prophylaxis; PY, patient-years; TDF, tenofovir disoproixil fumarate; TFV, tenofovir. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/26LB.aspx .
  • FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; TFV, tenofovir. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/26LB.aspx .
  • FTC, emtricitabine; IM, intramuscular; PrEP, pre-exposure prophylaxis; SHIV, simian human immunodeficiency virus; TDF, tenofovir disoproxil fumarate.
  • ART, antiretroviral therapy; BID, twice daily; DRV, darunavir; OBR, optimized background regimen; QD, once daily. For more detailed information about this study go: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/179LB.aspx .
  • AE, adverse event; BL, baseline; CI, confidence interval; DTG, dolutegravir; IC50, inhibitory concentration of 50%; OBR, optimized background regimen; RAL, raltegravir; VF, virologic failure. For more detailed information about this study go: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/179LB.aspx .
  • 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; TDF, tenofovir. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/554.aspx .
  • 3TC, lamivudine; ABC, abacavir; CI, confidence interval; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; TDF, tenofovir. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/554.aspx .
  • BID, twice daily; LPV, lopinavir; RAL, raltegravir; RTV, ritonavir; QD, once daily; VF, virologic failure. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/180LB.aspx .
  • LPV, lopinavir; mITT, modified intent to treat; RAL, raltegravir; RTV, ritonavir. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/180LB.aspx .
  • ART, antiretroviral therapy; DRV, darunavir; ENF, enfuvirtide; ETR, etravirine; MVC, maraviroc; RAL, raltegravir; RTV, ritonavir; TPV, tipranavir; VF, virologic failure. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/153LB.aspx .
  • 3TC, lamivudine; ART, antiretroviral therapy; DRV, darunavir; ENF, enfuvirtide; ETR, etravirine; MVC, maraviroc; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir; TPV, tipranavir; VF, virologic failure; ZDV, zidovudine. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/153LB.aspx.
  • ART, antiretroviral therapy; CI, confidence interval. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/153LB.aspx.
  • ART, antiretroviral; COBI, cobicistat; DP, diphosphate; EVG, elvitegravir; FTC, emtricitabine; MP, monophosphate; TDF, tenofovir disoproxil fumarate; TFV, tenofovir. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/99LB.aspx.
  • COBI, cobicistat; DP, diphosphate; EVG, elvitegravir; FTC, emtricitabine; ITT, M = F, intent to treat, missing equals failure; PBMC, peripheral blood mononuclear cell; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/99LB.aspx.
  • BMD, bone mineral density; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; TAF, tenofovir alafenamide; TDF, tenofovir. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/99LB.aspx.
  • AE, adverse event; ART, antiretroviral therapy; CNS, central nervous system; QD, once daily. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/100.aspx.
  • ART, antiretroviral therapy; BL, baseline; CVC, cenicriviroc; EFV, efavirenz; FTC, emtricitabine; QD, once daily; TDF, tenofovir. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/106LB.aspx.
  • CVC, cenicriviroc; DC, discontinued; EFV, efavirenz; FDA, US Food and Drug Administration; FTC, emtricitabine; ITT, intent to treat; TDF, tenofovir. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/106LB.aspx.
  • ART, antiretroviral therapy; CI, confidence interval; HR, hazard ratio; LTFU, lost to follow-up; WHO, World Health Organization.
  • ART, antiretroviral therapy; CDC, Centers for Disease Control and Prevention; DRV, darunavir; GT, genotype; INSTI, integrase strand transfer inhibitor; IAS, International Antiviral Society. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/615.aspx.
  • AOR, adjusted odds ratio; APR, Antiretroviral Pregnancy Registry; ART, antiretroviral therapy; CI, confidence interval; EFV, efavirenz; PMTCT, prevention of mother-to-child transmission; ZDV, zidovudine Pachygyria is a congenital malformation of the cerebral hemisphere. It results in unusually thick convolutions of the cerebral cortex. Typically, children have developmental delay and seizures, the onset and severity depending on the severity of the cortical malformation. Infantile spasms are common in affected children, as is intractable epilepsy. For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/81.aspx.
  • Transcript

    • 1. March 3-6, 2013 Atlanta, Georgia Highlights of Atlanta 2013: ART as Treatment and Prevention CCO Independent Conference Coverage of the 2013 Conference on Retroviruses and Opportunistic Infections* *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from
    • 2. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 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 Clinical Impact of New Data From Atlanta 2013 Faculty Joel E. Gallant, MD, MPH Professor of Medicine and Epidemiology Associate Director, Johns Hopkins AIDS Service Division of Infectious Diseases Johns Hopkins University School of Medicine Baltimore, Maryland Kathleen E. Squires, MD Professor of Medicine Director, Division of Infectious Diseases Jefferson Medical College Thomas Jefferson University Philadelphia, Pennsylvania Andrew R. Zolopa, MD Associate Professor of Medicine Director, Stanford Positive Care Program Principal Investigator, Stanford AIDS Clinical Trials Unit Stanford University School of Medicine Stanford, California
    • 4. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Disclosures Joel E. Gallant, MD, MPH, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Takara Bio and funds for research support from Gilead Sciences. Kathleen E. Squires, MD, has disclosed that she has received funds for research support from Biocryst, Gilead Sciences, Merck, and Vertex; has served on advisory boards for Abbott, Gilead Sciences, Janssen, Merck, Tobira, and ViiV; has received consulting fees from Tobira; and has served on a data and safety monitoring board for Pfizer. Andrew R. Zolopa, MD, has disclosed that he has received funds for research support from Gilead Sciences, Pfizer, and Vertex and consulting fees from Bristol-Myers Squibb, Gilead Sciences, and Janssen.
    • 5. DHHS Guideline Update
    • 6. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 2013 Update: DHHS Guidelines on ART for HIV-Infected Adults and Adolescents  ART is recommended for all HIV-infected, ART-naive pts to reduce risk of disease progression and transmission – Strength of recommendation varies by CD4+ cell count and risk group (perinatal, heterosexual, other) – Pts should be ready to commit to ART and understand benefits and risks of therapy and importance of adherence; individual pts may elect to defer ART  Regarding alternative regimens for ART-naive patients – RPV-based regimens recommended alternatives only for patients with baseline HIV-1 RNA ≤ 100,000 copies/mL – Fixed-dose EVG/COBI/TDF/FTC recommended for patients with CrCl > 70 mL/min – 3-NRTI regimens no longer recommended DHHS Guidelines. February 2013.
    • 7. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 2013 Update: DHHS Guidelines on ART for HIV-Infected Adults and Adolescents  Pts failing INSTI-based regimens should undergo genotypic assay for INSTI resistance to determine future utility of class  Genotypic tropism assay now available as potential alternative test prior to initiating CCR5 antagonist regimens  Patients with early infection should be offered ART – “Early” HIV infection now refers to acute (after infection, prior to seroconversion) and recent (< 6 mos) infections  EFV may be continued in pregnant women with virologic suppression  New data on roles/mechanisms of RTV and COBI as pharmacokinetic enhancers DHHS Guidelines. February 2013.
    • 8. Cure Research
    • 9. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Very Early Triple-Drug ART Elicits “Functional Cure” in HIV-Infected Child  Infant born to untreated HIV-infected mother at 35 wks’ gestation via spontaneous vaginal delivery[1] – Maternal HIV infection identified during labor via ELISA and Western blot – Infant HIV infection confirmed via HIV-1 DNA PCR, HIV-1 RNA analysis of 2 separate samples at 30 and 31 hrs of age[2] – ZDV/3TC + NVP (at therapeutic dose) initiated at 31 hrs of age, continued for 7 days – ZDV/3TC + LPV/RTV continued from 7 days to 18 mos of age – HIV-1 RNA undetectable by Day 30 – Mother removed patient from care at 18 mos of age 1. Persaud D, et al. CROI 2013. Abstract 48LB. 2. DHHS Pediatric Guidelines. 2012.
    • 10. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 “Functional Cure” Child: Standard HIV-1 Assays Undetectable to Age 26 Mos  Assessments at Mos 24 and 26 – Western blot negative – No HIV-specific CD8+ or CD4+ T-cell responses – Standard HIV-1 RNA and HIV-1 DNA undetectable – By ultrasensitive assays – Mo 24: HIV-1 RNA 1 c/mL; HIV-1 DNA < 2.7 c/million PBMCs – Mo 26: HIV-1 DNA 4 c/million PBMCs  Clinical trials of exposed infants treated with ART recommended Persaud D, et al. CROI 2013. Abstract 48LB.  ART regimens: ZDV/3TC + NVP (31 hours – 7 days)  ZDV/3TC + LPV/RTV (7 days – 18 months)  Plasma VL on ART displayed typical biphasic decay from baseline VL 19,812 c/mL – VL undetectable by < 30d of age – VL remained undetectable though > 80d of age
    • 11. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Early Treatment of Pts With Acute HIV Infection Restricts Seeding of Reservoirs  RV254/SEARCH 010: ongoing, prospective, open-label study of subjects seeking voluntary HIV testing (n = 75 with Fiebig stage I-III acute infection)  Before ART, HIV reservoir seeding limited – Integrated HIV-1 DNA undetectable in PBMCs (92%) and sigmoid colon (88%) of most Fiebig I pts – Lower infection frequencies of central memory CD4+ T cells vs other memory cells  After ART, decline in HIV reservoir size – Integrated HIV-1 DNA undetectable in PBMCs in 90% of pts at 1 yr – Reservoir primarily in transitional and effector memory CD4+ T cells  Suggests very early ART may prevent seeding of reservoirs Fiebig Stages Fiebig I: RNA+, p24 neg, 3rd-gen ELISA neg̶ – Would not be detected by 4th-gen ELISA Fiebig II: RNA+, p24+, 3rd-gen ELISA neg Fiebig III: 3rd-gen ELISA+, WB neg Ananworanich J, et al. CROI 2013. Abstract 47.
    • 12. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Vorinostat Activates HIV Transcription in Latently Infected CD4+ T Cells  Vorinostat investigated as possible strategy to eliminate latent HIV infection in pts on stable ART – Histone deacetylase inhibitor approved for cutaneous T-cell lymphoma – Single dose ↑ HIV-1 RNA expression in resting memory CD4+ cells of HIV-infected patients – Activation may result in elimination of latently infected T cells  Current study is a single-arm trial of vorinostat 400 mg QD for 14 days (N = 20) in pts on stable ART, CD4+ count > 500 cells/mm3  18/20 pts had significant increase in cell-associated unspliced HIV-1 RNA on ≥ 2 occasions while on drug – Mean 2.65-fold increase  All AEs mild (grade 1/2) – Most common: diarrhea, lethargy, thrombocytopenia, dysgeusia  No significant changes in HIV-1 DNA in PBMCs or rectal tissue – Suggests vorinostat alone not likely to eliminate latent infected cells Elliott EJ, et al. CROI 2013. Abstract 50LB.
    • 13. PrEP
    • 14. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 PrEP Trials to Date Trial Population/Setting Intervention Reduction in HIV Infection Rate, % CAPRISA[1] (N = 899) High-risk women in South Africa  Coitally applied vaginal TFV gel 39 iPrEX[2] (N = 2499) MSM, transgender women, 11 sites in US, South America, Africa, Thailand  Daily oral TDF/FTC 44 Partners PrEP[3] (N = 4747) Serodiscordant couples in Africa  Daily oral TDF  Daily oral TDF/FTC  Women: 71; men: 63  Women: 66; men: 84 TDF2[4] (N = 1219) Heterosexual males and females in Botswana  Daily oral TDF/FTC 62* FEM-PrEP[5] (N = 2120) High-risk women in Africa  Daily oral TDF/FTC  Equal numbers of infections in active and control arms  Study stopped for lack of efficacy 1. Abdool Karim Q, et al. Science. 2010;329:1168-1174. 2. Grant RM, et al. N Engl J Med. 2010;363: 2587-2599. 3. Baeten JM, et al. N Engl J Med. 2012;367:399-410. 4. Thigpen MC, et al. N Engl J Med. 2012;367:423-434. 5. Van Damme L, et al. N Engl J Med. 2012;367:411-422. *Underpowered to detect differences between sexes
    • 15. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 VOICE: Oral TDF, Oral TDF/FTC, Vaginal TFV Gel as PrEP in African Women  Phase IIB placebo-controlled trial of > 5000 women in South Africa, Uganda, and Zimbabwe of daily oral TDF, daily oral TDF/FTC, daily vaginal TFV 1% gel as PrEP – DSMB stopped daily oral TDF arm in September 2011 and daily vaginal gel arm in November 2011, both for lack of efficacy; daily oral TDF/FTC arm continued – 334 infections seen across 5 arms; 22 infected at enrollment Primary Efficacy Results (mITT) TDF* (n = 1007) Oral Placebo* TDF/FTC (n = 1003) Oral Placebo TFV Gel (n = 1007) Gel Placebo Infections, n 52 35 61 60 61 70 Infections/100 PY 6.3 4.2 4.7 4.6 5.9 6.8 Protective Efficacy vs Placebo HR (95% CI) 1.49 (0.97-2.30) 1.04 (0.7-1.5) 0.85 (0.6-1.2) P value .07 > .2 > .2 *Censored when sites took women off TDF and TDF placebo. Total n = 1009. Marrazzo J, et al. CROI 2013. Abstract 26LB.
    • 16. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 VOICE: Lack of Detectable TFV in Plasma; High Rate of Infection in Younger Women  Despite high self-reported adherence, < 40% of women had detectable plasma TFV at first study visit  TFV detected in mean of ≤ 30% of samples in each arm – ≥ 50% of women in each arm had no TFV detected in any sample  TFV detection less likely if unmarried, younger than 25 yrs, partner younger than 28 yrs – Highest rates of HIV acquisition in unmarried, younger than 25 yrs Marrazzo J, et al. CROI 2013. Abstract 26LB. Graphic used with permission. PtsWithDetectableTFV*(%) 100 80 60 40 20 1 2 3 4 5 6 TDF/FTC TDF TFV 1% gel TDF/FTC TDF TFV 1% 0 123 119 156 111 80 107 117 56 82 95 28 52 61 16 30 Quarterly Visits Plasma TFV Detection in Random Cohort Sample *Level of TFV detection: ≥ 0.3 ng/mL. Pts at Risk, n 135 147 166
    • 17. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Additional Data on PrEP  GSK1265744, dolutegravir analogue packaged in nanoparticles (GSK744LAP), permitting monthly or quarterly dosing in humans by IM injection – 8/8 macaques injected with GSK744LAP and rectally challenged with SHIV protected from infection; 8/8 controls became infected (P < .0001)[1]  Intravaginal rings containing TDF protected against SHIV infection in 6/6 macaques; 11/12 controls became infected (P < .0004)[2]  Among iPrEX participants stopping PrEP before entry into open-label extension (iPrEX OLE), incidence of HIV similar among participants originally on TDF/FTC PrEP and those originally on placebo (P = .43)[3] – Similarities indicate that although high-risk behaviors continued, there was lack of compensatory increase in high-risk behavior after PrEP discontinued – HIV incidence after stopping PrEP remained high 1. Andrews C, et al. CROI 2013. Abstract 24LB. 2. Smith J, et al. CROI 2013. Abstract 25LB. 3. Grant R, et al. CROI 2013. Abstract 27.
    • 18. Antiretroviral Therapy Trials: Current Agents
    • 19. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 SAILING: Dolutegravir vs Raltegravir in ART-Exp’d, Integrase Inhibitor–Naive Pts  Phase III randomized, double-blind, double-dummy, noninferiority study Pozniak A, et al. CROI 2013. Abstract 179LB. Treatment-experienced, integrase inhibitor–naive patients with HIV-1 RNA > 400 copies/mL and ≥ 2 class resistance (N = 715) Dolutegravir 50 mg QD + OBR (n = 354) Raltegravir 400 mg BID + OBR (n = 361) Stratified by number of fully active background agents, use of DRV, screening HIV-1 RNA ≤ vs > 50,000 copies/mL Wk 24 interim analysis Wk 48
    • 20. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 SAILING: Higher Rate of Virologic Suppression With DTG vs RAL at 24 Wks  Lower incidence of integrase resistance at VF with DTG – R263K at VF in 2 DTG pts; first report of treatment-emergent resistance on DTG – < 2-fold change in IC50 for both DTG and RAL – Y143, Q148, and/or N155 at VF in 9 RAL pts; consistent with previous studies – High-level resistance to RAL  Both regimens well tolerated with similar AE profiles Pozniak A, et al. CROI 2013. Abstract 179LB. Graphic used with permission. HIV-1RNA<50copies/mL(%) 100 80 60 40 20 0 BL 4 8 12 16 24 Wk Wk 24 adjusted difference in response: +9.7 in favor of DTG (95% CI: 3.4% to 15.9%; P = .003) 79% 70% Dolutegravir + OBR Raltegravir + OBR
    • 21. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Dolutegravir Efficacy in Phase III Studies in ART-Naive Pts: Subgroup Analyses  Retrospective analysis of phase III trials in treatment-naive pts[1] – SPRING-2[2] : DTG noninferior to RAL at Wk 48, each combined with investigator-selected NRTIs (TDF/FTC or ABC/3TC) – SINGLE[3] : DTG + ABC/3TC superior to TDF/FTC/EFV at Wk 48  In both trials, activity of DTG-based regimens similar in subgroup analyses by HIV risk factor, baseline HIV-1 RNA, CD4+ cell count, sex, age, race  In SINGLE, higher rates of HIV-1 RNA < 50 copies/mL with DTG-based therapy across patient subgroups  In both trials, no apparent subgroup differences in AEs or discontinuations 1. Brinson C, et al. CROI 2013. Abstract 554. 2. Raffi F, et al. Lancet. 2013;381:735-743. 3. Walmsley S, et al. ICAAC 2012. Abstract H-556b.
    • 22. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Subgroup Analyses of SPRING-2 and SINGLE: Virologic Suppression at Wk 48 Brinson C, et al. CROI 2013. Abstract 554. Graphic used with permission. ≤ 100,000 c/mL > 100,000 c/mL < 350 cells/mm3 ≥ 350 cells/mm3 Female Male < 50 yrs ≥ 50 yrs White Black SPRING-2 0% 50% 100% DTG RAL 30%20%10%0%-20% -10% Difference (DTG-RAL) and 95% CI In favor of RAL In favor of DTG ≤ 100,000 c/mL > 100,000 c/mL < 350 cells/mm3 ≥ 350 cells/mm3 Female Male < 50 yrs ≥ 50 yrs White Black SINGLE 0% 50% 100% DTG + ABC/3TC TDF/FTC/EFV 30%20%10%0%-20% -10% Difference (DTG-EFV) and 95% CI In favor of DTGIn favor of EFV
    • 23. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 SECOND-LINE: LPV/RTV + RAL vs LPV/RTV + NRTIs After First-line VF  Randomized, open-label, international, multicenter trial Humphries A, et al. CROI 2013. Abstract 180LB. Lopinavir/Ritonavir 400/100 mg BID + Raltegravir 400 mg BID (n = 270) Lopinavir/Ritonavir 400/100 mg BID + 2-3 NRTIs QD or BID (n = 271) HIV-infected pts with virologic failure on first-line regimen of 2 NRTIs + NNRTI (N = 541) Stratified by clinical site, baseline HIV-1 RNA (≤ or > 100,000 copies/mL) Wk 48 primary endpoint
    • 24. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 SECOND-LINE: Noninferiority of LPV/RTV + RAL vs LPV/RTV + NRTIs  Pooled pt data from ACTG A5142, A5202, A5208 of those failing first- line boosted PI regimens found 131/200 (66%) remained on same regimen[2] – Various regimen changes: n = 69 – HIV-1 RNA < 400 c/mL at Wk 24 similar between pts who maintained same regimen and those who switched – Pts with highest resuppression rates were those with higher CD4+ counts at regimen change and those who had ever responded to first regimen – Suggests better adherence 0 20 40 80 100 Wk LPV/RTV + RAL LPV/RTV + 2-3 NRTIs 60 0 12 24 36 48 HIV-1RNA<200c/mL(%)  Similar high levels of virologic suppression with each strategy in primary mITT analysis[1] 82.6 80.8 P = .59 1. Humphries A, et al. CROI 2013. Abstract 180LB. Graphic used with permission. 2. Zheng Y, et al. CROI 2013. Abstract 558.
    • 25. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 OPTIONS: NRTIs vs No NRTIs in Regimens for Highly ART-Experienced Pts  Randomized, noninferiority, multicenter trial (ACTG A5241) – Primary endpoint: regimen failure (VF or divergence from NRTI assignment, whichever occurred first) NRTI-Omitting Individualized Optimized Regimen* (n = 179) NRTI-Including Individualized Optimized Regimen* (n = 181) Treatment-experienced pts failing on PI-based regimen with NRTI, NNRTI experience and/or resistance (N = 360) Stratified by choice of MVC-containing regimen and previous enfuvirtide or integrase inhibitor experience *20 potential 3- to 4-drug combinations including DRV/RTV, ENF, ETR, MVC, RAL, TPV/RTV. Individualized selection of regimens with PSS > 2. Tashima K, et al. CROI 2013. Abstract 153LB. Yr 1 Primary Endpoint Yr 2 Secondary Endpoint
    • 26. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 OPTIONS: Pt-Specific Regimen Selected Then Randomized to ± NRTI Tashima K, et al. CROI 2013. Abstract 153LB. Graphic used with permission. Chosen Regimen and NRTI Combinations Add NRTIs TDF + FTC (3TC) ZDV + TDF + FTC (3TC) Other Regimen RAL + DRV/RTV + ETR RAL + DRV/RTV + MVC RAL + DRV/RTV + ETR + MVC RAL + ETR + MVC RAL + DRV/RTV + ETR + ENF Other Randomization Omit NRTIs 6% 12% 82% 6% 56% 7% 8% 14% 9% Add NRTIs
    • 27. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 OPTIONS: Omitting NRTIs Noninferior to Adding NRTIs to Optimized Regimen  Similar virologic suppression (HIV-1 RNA < 50 c/mL) in each arm (~ 65%)  Similar CD4+ cell count increases in each arm (90-106 cells/mm3 )  No significant difference in any safety outcome when globally evaluating symptoms and laboratory abnormalities – However, mortality significantly higher in NRTI-added arm (P < .001) – 6 deaths in NRTI arm, 2 possibly due to ART drug Tashima KT, et al. CROI 2013. Abstract 153LB. Graphic used with permission. Primary Efficacy Outcome Comparisons Outcome, n (%) Regimen failure Virologic failure Stop NRTI assignment Omit NRTIs (n = 179) 53 (30) 44 (25) 19 (8) Add NRTIs (n = 181) 48 (26) 45 (25) 10 (6) -30 -15 0 15 30 % Difference (Omit - Add) at 1 Yr (95% CI) Omitting NRTIs Not Inferior Inferior 3.2 (-6.1 to 12.5) -0.4 (-9.4 to 8.7) 3.6 (-1.7 to 9.0)
    • 28. Antiretroviral Therapy Trials: Investigational Agents
    • 29. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Tenofovir Alafenamide (TAF) vs Tenofovir DF in ART-Naive Pts  TAF (GS-7340), investigational prodrug of tenofovir with lower plasma concentrations, increased delivery to hepatocytes, lymphoid cells  Randomized, placebo- controlled phase II trial of TAF vs TDF, each coformulated with FTC/EVG/COBI, in ART-naive patients Zolopa A, et al. CROI 2013. Abstract 99LB. Graphic used with permission. HIV-infected, ART-naive patients (N = 170) TAF/FTC/EVG/COBI (n = 112) TDF/FTC/EVG/COBI (n = 58) Wk 48Wk 24Gut TFV TDF TAF Plasma TDF/TFV TAF Lymphoid Cells TAF TFV TFV-MP TFV-DP Cathepsin A
    • 30. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 TAF Noninferior to TDF at Wk 24 Primary Endpoint Zolopa A, et al. CROI 2013. Abstract 99LB. Graphic used with permission. TDF/FTC/EVG/COBI TAF/FTC/EVG/COBI 2 4 8 12 16 24 20 40 60 80 100 HIV-1RNA<50c/mL(%) Wks 0 ITT, M = F Analysis 89.7% 87.5% With TAF: PBMC TFV-DP exposure 5.3 x higher than TDF Plasma TFV exposure 91% lower
    • 31. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Change in BMD and Serum Creatinine With TAF vs TDF  Smaller change in BMD over 24 wks with TAF vs TDF  Median serum creatinine ↑: TAF 0.07 mg/dL vs TDF 0.12 mg/dL Zolopa A, et al. CROI 2013. Abstract 99LB. Graphic used with permission. 2 0 -2 Spine Mean%ChangeinBMD 0 12 24 Wks -0.8 -2.5 P = .002 2 0 -2 Hip 0 12 24 Wks -0.3 -2.0 P < .001 TAF/FTC/EVG/COBI (n = 112) TDF/DTC/EVG/COBI (n = 58)
    • 32. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Short-term Efficacy and Tolerability of MK-1439, Investigational QD NNRTI  MK-1439, investigational NNRTI, dosed QD, active against K103N, Y181C, G190A variants  Randomized phase Ib study in ART-naive pts (N = 18; 6 per arm) – 7-day monotherapy  Similar activity with MK-1439 25 mg vs 200 mg dose  All AEs mild to moderate – No rash/CNS events  Pharmacokinetics comparable to HIV-negative pts Anderson M, et al. CROI 2013. Abstract 100. Copyright © 2013 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. All Rights Reserved. ChangeinHIV-1RNA(log10) 0.3 0.0 -0.3 -0.6 -0.9 -1.2 -1.5 -1.8 1 2pre 3pre 4pre 5pre 6pre 7pre 724hr Dayshr From First Dose Placebo QD MK-1439 25 mg QD MK-1439 200 mg QD -1.26 -1.37
    • 33. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Cenicriviroc: Investigational QD Oral CCR5/CCR2 Receptor Antagonist  Randomized, double-blind, double-dummy, dose-finding phase IIb trial Gathe J, et al. CROI 2013. Abstract 106LB. ART-naive pts with CCR5-tropic HIV-1, no NRTI or NNRTI resistance (N = 143) CVC 100 mg + TDF/FTC (n = 59) CVC 200 mg + TDF/FTC (n = 56) EFV 600 mg + TDF/FTC (n = 28) Wk 48 final analysisStratified by BL HIV-1 RNA < 100,000 or ≥ 100,000 copies/mL Wk 24 primary analysis Complex dosing: 4 pills with breakfast (4 CVC or 4 CVC placebo or 2 of each); 1 pill on empty stomach at bedtime (EFV or EFV placebo); 1 pill taken anytime (open-label TDF/FTC)
    • 34. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Virologic Non- Response, % DC Other Than AE, % DC Due to AE, % 12 10 0 14 11 2 4 7 18 24-Wk Efficacy and Safety of Cenicriviroc + TDF/FTC vs EFV/TDF/FTC  CVC generally well tolerated with no safety signals  sCD14 decreased with CVC and increased with EFV Gathe J, et al. CROI 2013. Abstract 106LB. Graphic used with permission.. HIV-1RNA<50c/mL(%) Wks ITT (FDA Snapshot Analysis) CVC 100 CVC 200 EFV 100 80 60 40 20 0 BL 4 8 12 16 24201 2 76 73 71 0 2 0 3 2 4 11 4 5 25 17 12 37 28 16 44 33 18 42 40 19 45 41 20 CVC 100 CVC 200 EFV Pts at Risk, n
    • 35. Additional Data on Epidemiology and Antiretroviral Trends
    • 36. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 ART Initiation Associated With Better Retention in Care in Zambia  National ART program at 18 primary care sites in urban Zambia – ART started when CD4+ cell count < 200 cells/mm³ or WHO stage IV or WHO stage III and CD4+ cell count < 350 cells/mm3 – “Immediate” initiation defined as within 180 days of eligibility; lost to follow-up (LTFU) as ≥ 60 days late  ART started by 75% of 6419 eligible pts with CD4+ 175-225 cells/mm³ and WHO Stage I-II disease  Proportion lost to follow-up greater in those who delayed ART vs those who started ART immediately, P < .001  Pts who started therapy 4x more likely to be retained in care Factors Associated with LTFU Adjusted Hazard Ratio (95% CI) Did not start ART 4.13 (3.69-4.62) Age 25 yrs or younger 1.85 (1.65-2.07) CD4+ 175-199 1.16 (1.05-1.29 WHO Stage II 0.82 (0.74-0.90) Li M, et al. CROI 2013. Abstract 93.
    • 37. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 Trends in Genotypic Drug Resistance  Among 1484 ART-naive pts in HOPS cohort, GT testing rate increased from 20.8% in 1999-2002 to 62.8% in 2009-2011[1] – > 1/3 still not tested in most recent period  No statistically significant increase in transmitted resistance from 1999-2011 – Increased frequency of resistance in black, Hispanic, pts with CD4+ > 500 cells/mm3  17.5% of pts had any major IAS-USA mutation in 2009-2011 (similar to CDC analysis)[2] – Rates of class resistance: NRTI 10.8%; NNRTI 6.6%; PI 1.8%  Separate study showed major INSTI mutations in 1/5 of pts tested since availability of INSTI GT assay[3]  Additional study showed low rates of DRV resistance among all isolates tested that declined over time[4] 1. Buchacz K, et al. CROI 2013. Abstract 615. 2. Kim D, et al. CROI 2013. Abstract 149. 3. Hurt CB, et al. CROI 2013. Abstract 591. 4. Lathouwers E, et al. CROI 2013. Abstract 590.
    • 38. clinicaloptions.com/hiv Clinical Impact of New Data From Atlanta 2013 ART and Birth Defects in ANRS French Perinatal Cohort  French national prospective multicenter cohort studying PMTCT strategies in HIV-positive women[1] – N = 17,000 (~ 70% of HIV-positive women in France) – 13,124 live births exposed to ART in utero  In EFV first trimester-exposed infants, ↑ risk for neurologic (but not neural tube) defects but not for overall birth defects  In ZDV first-trimester-exposed infants, ↑ risk for both overall birth defects and heart defects  Findings inconsistent with meta- analysis of studies of EFV use[2] in pregnancy and data from the US Antiretroviral Pregnancy Registry[3] – Both indicate no ↑ risk of birth defect with EFV; APR shows no ↑ risk with ZDV Defects With First Trimester Exposure, AOR (95% CI) EFV (n = 372) ZDV (n = 3267) Overall birth defects 1.3 (0.9-1.9) P = .31 1.4 (1.1-1.8) P = .002 Specific organ system defects 3.2 (1.1-9.1) P = .03 2.5 (1.6-4.2) P = .001 1. Siubide J, et al. CROI 2013. Abstract 81. 2. Ford N, et al. AIDS. 2011;25:2301-2304. 3. Antiretroviral Pregnancy Registry. December 2012.
    • 39. Go Online for More CCO Coverage of CROI 2013! Capsule Summaries of key studies Additional downloadable slideset on Coinfection and Comorbidities Coming soon! CME-certified slidesets with expert faculty commentary on all key studies clinicaloptions.com/atlanta2013

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