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HIV Medicine Update: Where are we in 2014

Calvin Cohen MD CRI New England Harvard Vanguard Medical Assoc Boston MA. HIV Medicine Update: Where are we in 2014. Disclosures Grants/Research Support: Gilead, Viiv , Merck, Janssen, BMS Consultant: Gilead, Viiv , Merck, Janssen, BMS, Splicos Speakers’ Bureau: none

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HIV Medicine Update: Where are we in 2014

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  1. Calvin Cohen MD CRI New England Harvard Vanguard Medical Assoc Boston MA HIV Medicine Update:Where are we in 2014

  2. Disclosures • Grants/Research Support: Gilead, Viiv, Merck, Janssen, BMS • Consultant: Gilead, Viiv, Merck, Janssen, BMS, Splicos • Speakers’ Bureau: none • Stock Shareholder: none • Other Support: Expert Testimony - Gilead

  3. Rates of Diagnosis of HIV Infection Among Adults and Adolescents, 2011 United States and 6 Dependent Areas 9.5 N = 50,007 Total Rate = 19.1 5.2 3.0 2.6 VT 2.3 7.2 2.6 8.0 5.7 30.1 9.6 3.8 3.4 19.2 17.7 14.3 5.0 5.1 4.3 12.6 20.0 9.5 9.6 6.6 16.2 11.2 6.2 9.4 20.8 13.3 17.3 8.6 10.7 10.0 24.5 22.0 31.4 20.9 25.3 Rates per 100,000 population 36.6 4.6 < 10.0 33.2 10.0 – 19.9 20.0 – 29.9 6.8 American Samoa Guam Northern Mariana Islands Puerto Rico Republic of Palau U.S. Virgin Islands 0.0 0.0 5.3 28.6 0.0 39.5 ≥ 30.0 Note. Data include persons with a diagnosis of HIV infectionregardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays, but not for incomplete reporting.

  4. Preventing HIV TransmissionSafer Sex: the HOT Study • Cohort study of MSM • N = 439 • Six month observation period • Oral sex: No HIV infections observed despite lack of condom use (94%) • Conclusions: • Rate of transmission via oral sex is lowest • Not zero: <0.8% * HIV incidence determined in repeat testers ** RAI = receptive anal intercourse Adapted from Page-Shafer K, et al. XIV Intl AIDS Conference, Barcelona 2002, #4872; Balls et al. We PpC2072, Bangkok 2004

  5. HIV Prevention – What Else Can we do? • Treatment as Prevention • PrEP

  6. When to Start ART:Global Consensus and Diversity The IAS-USA guidelines also recommend initiating ART in HIV-infected patients with active HCV infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection. DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013; Thompson MA, et al. JAMA. 2012;308:387-402; EACS. Available at: http://www.europeanaidsclinicalsociety.org. Version 7.0 October 2013; BHIVA. Available at: www.bhiva.org; WHO. Available at: http://www.who.int/publications/guidelines/hiv_aids/en/index.html.

  7. HPTN 052: HIV Prevention in“Stable” Heterosexual Couples • DSMB halts trial • Median follow-up: 1.7 years • HIV RNA <400 copies/mL • Early ART: 90% • Delayed ART: 93% • Linked HIV transmissions to HIV-negative partner • Early therapy (n=1) • 0.1 per 100 person-years • Delayed therapy (n=27) • 1.7 per 100 person-years Linked HIV Transmission HR: 0.04 (95% CI 0.01-0.27) (P<0.001) Delayed ART Cumulative Probability 96% Early ART 0 1 2 3 4 5 Years Cohen MS, et al. N Engl J Med. 2011;365:493-505.

  8. PARTNER Study: HIV Transmission Risk Through Condomless Sex - Serodiscordant Couples • HIV transmission rate • None – despite condomless sexual activity with a partner on suppressive ART • Uncertainty over the upper limit of risk remains • Particularly with receptive anal sex with ejaculation • Duration of prior ART without transmission may have selected for lowest risk discordant couples Rate of Couple Transmission (per 100 Couple-Years Follow-Up) • Heterosexual (Male) • Vaginal sex with ejaculation • (192 CYFU) • Heterosexual (Female) • Vaginal sex (272 CYFU) • MSM • Receptive anal sex: • With ejaculation (93 CYFU) • Without ejaculation (157 CYFU) • Insertive anal sex (262 CYFU) 0 1 2 3 4 Rate (95% CI) Rodger A, et al. 21st CROI. Boston, 2014. Abstract 153LB.

  9. Continuum of HIV Care in United States 80% 77% 66% 89% 77% Of all with HIV infection, 850,000 individuals do not have suppressed HIV RNA (72%) MMWR (60), 2011.

  10. Until there is a Vaccine… • Treating HIV Negative Persons:Pre-Exposure Prophylaxis (PrEP)

  11. CDC Advocates PrEP

  12. iPrex Open Label Extension:HIV Incidence and Drug Concentrations Off PrEP On PrEP Grant R, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. TUAC0105LB; Grant R, et al, Lancet ID, published online July 22, 2014.

  13. iPrex: Drug Concentrations over Time First Evidence of HIV Infection TFV-DP: Control Case Control Case Grant R, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. TUAC0105LB; Grant R, et al, Lancet ID, published online July 22, 2014.

  14. iPrex: Correlates of TDF Drug Concentration Alcohol and Substance Use and Drug Concentrations in Dried Blood Spots Grant R, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. TUAC0105LB; Grant R, et al, Lancet ID, published online July 22, 2014.

  15. Ipergay: Effectiveness of “On-Demand” PrEP Randomized placebo-controlled trial • Regimen – Two doses 2-24 hours before sex, one dose for two days after • Counseling, testing for STI, condoms, vaccination, Post Exp Prophylaxis • Primary endpoint : HIV infection • Power - Incidence of HIV-infection: 3% PY, 50% efficacy, 64 events • N ~ 2000 pts Full prevention services + TDF/FTC before and after sex (n=950) • High risk MSM • Condomless anal sex with >2 partners within 6 months • eGFR >60 mL/mn Full prevention services + placebo before and after sex (n=950) www.ipergay.fr Fonsart J, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. LBPE28.

  16. Ipergay:Detection of TFV in Plasma % of Participants with TFV Detected in Plasma (548 samples from 113 Participants) 40 33 23 8 46 44 Overall detection: - 86% TDF/FTC - 4% placebo 2 2 2 3 3 (56) (57) (51) (56) (49) (52) (42) (44) (37) (40) (22) (26) (8) (8) Fonsart J, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. LBPE28.

  17. PrEP: Are Long Acting Agents the Answer? GSK1265744: Macaque Model with SHIV 50 mg/kg GSK744 LAP IM (n=8) • Based on very long parenteral (IM or IV) half life – protective effect of 744 will be assessed with q1-3 month dosing Week Rectal challenges (50 TCID50 SHIV162P3) Results GSK 744 P<0.0001 Andrews C, et al. 20th CROI; Atlanta, GA; March 3-6, 2013. Abst. 24LB.

  18. iPrex: Rates of Non-Condom Receptive Anal Intercourse (ncRAI) PrEP Started Later Immediate PrEP* No PrEP˄ *P = 0.006 ˄P = 0.03 Grant R, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. TUAC0105LB; Grant R, et al, Lancet ID, published online July 22, 2014.

  19. Antiretroviral Trials – Where are we?

  20. DHHS Guidelines: Preferred Regimens – Early 2013 INSTI: Integrase strand transfer inhibitors. 1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2Lamivudine may substitute for emtricitabine or visa versa. 3Tenofovir DF should be used with caution in patients with renal insufficiency. 4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day. 5Patients with creatinine clearance >70 mL/min. 6Patientswho are HLA-B*5701 negative. DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013. DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf. Update October 30,2013.

  21. DHHS Guidelines: Preferred Regimens – Oct 30 2013 INSTI: Integrase strand transfer inhibitors. 1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2Lamivudine may substitute for emtricitabine or visa versa. 3Tenofovir DF should be used with caution in patients with renal insufficiency. 4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day. 5Patients with creatinine clearance >70 mL/min. 6Patientswho are HLA-B*5701 negative. DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013. DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf. Update October 30,2013.

  22. DHHS Guidelines May 2014: Ten Recommended Regimens IAS-USA 2014 Guidelines concur on all ten Recommended Regimens DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf. Update May 2014

  23. How Do We Choose from Among these Ten Options? Drug Characteristics: • BID vs. QD (or less?) • Efficacy at any pre-treatment viral load and CD4 count • Food requirements • Number of pills per day (range 1-3) • Potential drug-drug interactions • Years of experience • Barrier to resistance if viremic

  24. How Do We Choose from Among these Ten Options? Patient Characteristics: • Pre-treatment virus resistance • Predicted Medication Adherence • Risk of Adverse Events • The rate of - and type of - adverse events • Type of evidence demonstrating the adverse event • Other medical comorbidities • CV, diabetes, renal, bone, psychological, and others • Financial Concerns • Patient copays, formulary restrictions, generics • Other?

  25. Criteria that Are Not Considered when selecting a Regimen • Age • Beyond specific co-morbidity concerns • Gender • Race • Weight / BMI

  26. D:A:D Study:Update on MI Risk and AbacavirUse • Prospective cohort (2000-2013) • N= >49,000 patients 11 cohorts in Europe, Australia, US • Abacaviruse was associated with a 98% increase in rate of MI • No difference pre vs. post-2008 • Results stable after stratifying by Framingham risk group, and other factors (eg, renal function, dyslipidemia, hypertension) • Current findings argue against channeling bias Adjusted Relative MI Rate and Current Abacavir Use Post 3/2008 Pre 3/2008 Overall 5 4 3 2 1 0.7 1.98 1.97 1.97 Reference No Abacavir PY: person-years. Sabin CA, et al. 21st CROI. Boston, 2014. Abstract 747LB.

  27. STaRAdverse Events Leading to Discontinuationof EFV/FTC/FTC through Weeks 48 & 96 Cohen C, et al. EACS Brussels 2013, LBPE7/17

  28. Mollan K, et al. IDWeek 2013. San Francisco, CA. #670. Efavirenz and Time to SuicidalityPrimary Analysis Hazard ratio (95% CI) 2.28 (1.27 to 4.10), p=0.006 EFV: 47 events/5817 PY* (8.08/1000 PY) No EFV: 15 events/4099 PY* (3.66/1000 PY) As-treated HR 2.16 (1.16-4.00) *Person Years, sum of at-risk follow-up

  29. ACTG 5257: Study Design • PrimaryEndpoints* • Time to HIV-1 RNA >1000 c/mL wk 16 to before wk 24, or >200 c/mL at or after wk 24 (VF) • Time to discontinuation of randomized component for toxicity (TF) • Pre-planned Composite Endpoint • The earlier occurrence of either VF or TF in a given participant HIV-infected patients, ≥18 yr, with no previous ART, VL ≥ 1,000 c/mL at U.S. Sites (N=1,809) Randomized 1:1:1 to Open Label Therapy Stratified by screening HIV-1 RNA level (≥ vs. <100,000 c/mL), A5260s metabolic substudy participation, cardiovascular risk ATV 300 mg QD + RTV 100 mg QD + FTC/TDF QD (N=605) RAL 400 mg BID + FTC/TDF QD (N=603) DRV 800 mg QD + RTV 100 mg QD + FTC/TDF QD (N=601) Landovitz L, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 85.

  30. ACTG 5257: Toxicity Associated Discontinuation Landovitz L, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 85.

  31. ACTG A5257 Study:Outcomes All patients received emtricitabine/tenofovir DF. Landovitz RJ, et al. 21st CROI. Boston, 2014. Abstract 85.

  32. DHHS Guidelines: Preferred Regimens Which Integrase Inhibitor? INSTI: Integrase strand transfer inhibitors. 1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2Lamivudine may substitute for emtricitabine or visa versa. 3Tenofovir DF should be used with caution in patients with renal insufficiency. 4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day. 5Patients with creatinine clearance >70 mL/min. 6Patientswho are HLA-B*5701 negative. DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013. DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf. Update October 30,2013.

  33. DHHS Guidelines May 2014: Ten Recommended Regimens Alternatives to TDF/FTC or ABC/3TC? IAS-USA 2014 Guidelines concur on all ten Recommended Regimens DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf. Update May 2014

  34. Cahn P et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. LBPS7/6. GARDEL Study: Study Design Stratified by ScreeningHIV RNA(≤ or > 100,000 copies/mL) Week 48Primary Endpoint ARV- naive patients ≥18 years HIV RNA >1,000 copies/mLNo IAS-USA defined NRTI or PI resistance at screening HB(s)Ag negative(N=426) Dual Therapy (DT): LPV/r 400/100 mg BID + 3TC 150 mg BID(n=217) Triple Therapy (TT): LPV/r 400/100 mg BID + 3TC or FTC and a third investigator-selected NRTI in fixed-dose combination (n=209)

  35. Cahn P et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. LBPS7/6. GARDEL Study:Primary Efficacy Outcome VL <50 copies/mL (ITTe) 88.3 83.7 P=0.171, difference +4.6% [Cl 95%: -2.2% to +11.8%] Percent Patients Week

  36. So – How do we Pick?

  37. Impacting AdherenceA Role for Simplification • Three types of Supportive Data: • Pt. preference • Small Randomized Trials • Large cohort analyses of adherence and outcomes

  38. Comparing Regimens: Copays and Numbers of Pills • Ordered by numbers of copays, then by pills per day • Alphabetically when identical in both

  39. Comparing Regimens: Copays and Numbers of Pills • Ordered by numbers of copays, then by pills per day • Alphabetically when identical in both

  40. Comparing Regimens: Copays and Numbers of Pills – End 2014? • Ordered by numbers of copays, then by pills per day • Alphabetically when identical in both

  41. Economics: Antiretroviral Drugs Available in U.S. as a Generic Formulation • Abacavir • Didanosine • Lamivudine • Nevirapine • Stavudine • Zidovudine • Zidovudine/lamivudine

  42. HOPS Cohort: Frequency of VL Monitoring and Risk of Treatment Failure For virological suppressed patients observed on stable cART ≥2 years, the association between frequency of VL monitoring in period 2 and VL non-suppression in period 3 • 1,607 patients starting ART • After virologic suppression, 1,002 with VL monitoring > 2x/year, remainder had it done less frequently • Multivariable models: No increased risk of treatment failure with less frequent VL monitoring • Cost savings estimated to be $116-348/person/year • Data support DHHS Guidelines to reduce frequency of VL monitoring in those with virologic suppression for >2 years Period 1 (1 Year) Period 2 (1 Year) Period 3 (1 Year) cd4 VL VL VL cd4 VL VL INDEX DATE: cART regimeninitiation Outcome (yes/no):VL >200 copies/mL Young B, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. WEPE045

  43. Hepatitis C – Profound Progress

  44. LDV/SOF: Phase 3 - HCV Mono Infection - ION-1, ION-2, ION-3 Week 0 Week 8 Week 12 Week 24 • ION-1: GT-1 HCV treatment-naïve,16% with cirrhosis; N = 865 • ION-2: GT-1 HCV treatment-experienced, 20% with cirrhosis; N = 440 • ION-3: GT-1 HCV treatment-naïve, without cirrhosis; N = 647 LDV/SOF + RBV LDV/SOF ION-12 ION-23 LDV/SOF + RBV LDV/SOF LDV/SOF + RBV ION-34 LDV/SOF Sulkowski M, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. LBPE15.

  45. Efficacy Summary (ITT) • 97% (1885/1952) overall SVR rate • 3% (67/1952) did not achieve SVR • 1.8% (36) relapsed • 1.2% (23) lost to follow-up • 0.3% (6) withdrew consent • 0.1% (2) virologic breakthrough (both due to non-adherence) LDV/SOF LDV/SOF+RBV 99 99 99 99 97 98 94 93 95 96 94 SVR12 (%) 211/214 211/217 212/217 215/217 202/215 201/216 206/216 102/109 107/111 108/109 110/111 12 Weeks 24 Weeks 8 Weeks 12 Weeks 12 Weeks 24 Weeks ION-1 GT-1 Treatment-naïve Including Cirrhotics ION-3 GT-1 Treatment-naïve Non-cirrhotic ION-2 GT-1 treatment-experienced Including Cirrhotics and PI Failures Sulkowski M, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. LBPE15. Error bars represent 95% confidence intervals.

  46. NIAID SYNERGY: Sofosbuvir/Ledipisvir FDC Alone or In Combination with GS-9451 or GS-9669 • Treatment naïve, genotype 1 infected patients • African American, 88% Virologic response: • SOF/LDV x 12 wks (n=20) • SVR12 100% • SOF/LDV/9669 x 6 wks (n=20) • SVR4 90%; Relapse, n=1 • SOF/LDV/9451 x 6 wks (n=20) • SVR4 100% • No discontinuation or SAE Kohli A, et al. 64th AASLD; Washington, DC; November 1-5, 2013. Abstract LB-8.

  47. Standard of Care for Treatment of Chronic HCV Infection? – by End 2014 www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM375285.pdf; www.fda.gov_downloads_AdvisoryCommittees_CommitteesMeetingMaterials_Drugs_AntiviralDrugsAdvisoryCommittee_UCM375113.pdf; Jacobson IM et al. 64th AASLD; Washington, DC; November 1-5, 2013; Abstract LB-3. (B)

  48. Stalemate? Or a Cure? “…may HIV flow from our bloodinto our history books…” - William Jefferson Clinton 10th Retrovirus Conf. Boston 2003

  49. Summary and Conclusion

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