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New Therapeutic Agents and Treatment Guidelines

New Therapeutic Agents and Treatment Guidelines. Bruce Polsky, MD Interim Chairman, Department of Medicine Chief, Division of Infectious Diseases St. Luke’s and Roosevelt Hospitals New York, New York. Guidelines for Initiating Antiretroviral Therapy in Asymptomatic Patients: 1998–2005.

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New Therapeutic Agents and Treatment Guidelines

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  1. New Therapeutic Agents and Treatment Guidelines Bruce Polsky, MD Interim Chairman, Department of MedicineChief, Division of Infectious DiseasesSt. Luke’s and Roosevelt HospitalsNew York, New York

  2. Guidelines for Initiating Antiretroviral Therapy in Asymptomatic Patients:1998–2005

  3. The Rationale for Earlier Therapy • Easier, more effective, and less toxic therapy

  4. 150 100 150 127 125 121 120 119 80 120 97 60 90 Median CD4 increase 40 60 20 30 0 0 1996 1997 1998 1999 2000 2001 2002 Treatment Responses in First Year of HAART: Improving Over Time • 4143 subjects from 5 clinic cohorts in Europe and Canada • Treatment-naïve; started HAART from 1996-2002 •  risk of virologic failure,  med CD4 count increase in later years • most “failure” now due to loss to follow-up or treatment discontinuation Median CD4 increase % with > 500 copies/mL % with VL >500 on ART 24.8 23.0 17.3 12.4 10 8.4 8 Lampe F, et al. 12th Conference on Retroviruses and Opportunistic Infections (CROI). February 22-25, 2005.Boston, MA.Abstract # 593.

  5. 120 90 60 30 0 1996-1997 1998-1999 2000-2001 2002-2003 2004-2005 Incidence of Second Virologic Failure Declining Over Time RR*=1.46 113.6 REF 70.7 Incidence per 100 PY RR*=0.82 41.5 RR*=0.51 RR*=0.54 17.9 15.1 *Adjusted for time from HAART initiation, sex, age, AIDS, CD4 count, VL at HAART initiation and switch, and type of HAART Deeks S, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI).February 3-6, 2008.Boston, MA.Abstract # 41.

  6. 600 3TC NRTI NNRTI PI Any 500 400 New cases of detected resistance (n) 300 200 100 0 1996 1998 2000 2002 2004 2006 2008 Decline in New Cases of Resistance British Columbia: 1996-2007 • Decline in new cases of resistance in province-wide data from BC Centre for Excellence in HIV/AIDS Drug Treatment Program • 21,300 resistance tests from 5216 subjects Year Lima VD, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008.Boston, MA. Abstract # 895.

  7. 1.00 0.75 0.50 0.25 0.00 0 12 24 36 48 60 72 84 96 108 Proportion Surviving FollowingAIDS Diagnosis: 1996–2003 2003 2002 2001 2000 1999 1998 1997 1996 Proportion Surviving Months AIDS Surveillance Report, 2004. http://www.cdc.gov/hiv/topics/surveillance/resources/slides/epidemiology/index.htm.

  8. The Rationale for Earlier Therapy • Easier, more potent, and less toxic therapy • Cohort studies showing benefit with earlier therapy

  9. 0.12 0.10 0.08 0.06 0.04 0.02 0.00 0 1 2 3 4 5 HAART and Survival Based on Initial CD4 Cell Count • Modeled data from ART Cohort Collaborative • 10,855 patients included • 934 progressed to AIDS or died • IDUs excluded from model Cumulative Probability of AIDS/Death According to CD4 Count at Initiation of HAART 101-200 cells/mm3 201-350 cells/mm3 351-500 cells/mm3 Probability of AIDS or death Years since initiation of HAART Sterne J, et al. 13th Conference on Retroviruses and Opportunistic Infections (CROI). February 5-8, 2006. Denver, CO.Abstract # 525.

  10. The Rationale for Earlier Therapy • Easier, more potent, and less toxic therapy • Cohort studies showing benefit with earlier therapy • Better response to therapy

  11. > 350 cells/mm3 201-350 cells/mm3 < 200 cells/mm3 900 800 700 600 500 400 300 200 100 0 0 1 2 3 4 5 6 Pre-HAART CD4 Predicts Progression to AIDS: Johns Hopkins Cohort • Johns Hopkins HIV Cohort • Patients with virologic suppression for up to 6 yrs (N=280) • Only patients with baseline CD4 >350 returned to near normal CD4 count levels • Rate of progression to AIDS or death significantly higher over time in patients with CD4 <200 and 201-350 vs >350 1.5%*† 12%* CD4 cells/mm³ 13%* *percent developing AIDS over 6 years of study †P<.05 compared with CD4+ <200. Moore RD, et al. 16thInternational AID Council (IAC). August 13-18, 2006. Toronto, Canada. Abstract # THPE0109. Year

  12. The Rationale for Earlier Therapy • Easier, more potent, and less toxic therapy • Cohort studies showing benefit with earlier therapy • Better response to therapy • Decreased transmission

  13. Viral Load Affects Probabilityof HIV Transmission 5.0 GUD No GUD 4.0 3.0 Probability of transmission/1000 coital acts 2.0 1.0 0 <1700 1700- 12500- 38500+ Log viral load (copies/mL) GUD=genital ulcer disease Gray R, et al. Lancet. 2001;357:1149-1153.

  14. The Rationale for Earlier Therapy • Easier, more potent, and less toxic therapy • Cohort studies showing benefit with earlier therapy • Better response to therapy • Decreased transmission • Prevent specific complications of HIV infection

  15. HIV-Associated Complications That Are Less CD4-Dependent • Neurocognitive impairment • Non-Hodgkin’s lymphoma • Neuropathy • HPV-associated dysplasia/cancer • Kaposi’s sarcoma

  16. The Rationale for Earlier Therapy • Easier, more potent, and less toxic therapy • Cohort studies showing benefit with earlier therapy • Better response to therapy • Decreased transmission • Prevent specific complications of HIV infection • Prevent non-opportunistic complications and death

  17. 100 10 1.0 0.1 <50 50-99 100-199 200-349 350-499 >500 D:A:D Study: CD4 Count Associated with Risk of Non-HIV Related Death • Cohort of >23,000 pts in Europe, Australia, USA • 1248 (5.3%) deaths 2000–2004 (1.6/100 person-years) • of these, 82% on ART RR of death according to immune function and specific cause Overall HIV Malignancy Liver Heart RR CD4 cells/mm3 Weber R, et al. 12th Conference on Retroviruses and Opportunistic Infections (CROI). February 22-25, 2005. Boston, MA.Abstract # 595.

  18. Risk of Death in Naïve Patients with CD4 Counts >350 • 24 cohorts and collaborations • Mortality in naïve patients w/ CD4 >350 higher than in matched general population controls • 487 deaths; 4.9/1000 patient-years • HIV-related deaths: 79 (16.2%) • non-HIV–related deaths: 235 (48.3%) • unknown cause of death: 173 (35.5%) • Despite high CD4 counts, ↑ CD4 still associated with ↓ risk of death • rate ratio: 0.95 per 100 cells higher (95% CI: 0.90-0.99; P=.0185) SMR=sex-standardized mortality ratio Lodwick R, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 141.

  19. When to Start Therapy:DHHS Guidelines 1/9/2008 • AIDS or symptomatic HIV disease • Asymptomatic: • CD4 <350 • Pregnancy • HIV-associated nephropathy • HBV coinfection when HB therapy required

  20. When to Start Therapy:DHHS Guidelines 1/9/2008 • CD4 >350 • Optimal time to start therapy unknown • Considerations: • Motivation and adherence • Viral load • Rate of CD4 decline • Risk of sexual transmission(eg, discordant couples) • Other comorbidities

  21. Caveats! • Data guiding the initiation of therapy come from observational studies • Patients who start therapy with advanced disease may do poorly for reasons unrelated to their CD4 counts • We may never have data from controlled clinical trials

  22. PROS Could provide the definitive answer about when to start therapy CONS Previous attempts to enroll such trials have failed Expensive Observational data already compelling Will the question or the chosen CD4 thresholds still be relevant by the time the results are available? The Pros and Cons of a Randomized Trial

  23. Caveats! • Data guiding the initiation of therapy come from observational studies • Patients who start therapy with advanced disease may do poorly for reasons unrelated to their CD4 counts • We may never have data from controlled clinical trials • Many patients present with advanced disease

  24. When is ART Started?CD4 Count at Initiation, 2003-2005 • 42 countries, 176 sites; N=33,008 • Since 2000, CD4 count at initiation in developed countries stable at ~150–200, increasing in Sub-Saharan Africa from 50 to 100 • In US, CD4 at initiation lower than in many other resource-rich nations Egger M, et al. 14thConference on Retroviruses and Opportunistic Infections (CROI). Feb 25-28, 2007. Los Angeles, CA. Abstract # 62.

  25. ACTG A5164: Improved Outcomes with Immediate ART During Acute Opportunistic Infections • Immediate vs deferred ART during acute OI • No difference in composite primary endpoint (virologic response, clinical progression, and death; P=.215) • Immediate treatment: • less clinical progression/death through Week 48 (P=.035) • shorter time to clinical progression or death (P=.023) • Safety and incidence of IRIS similar between groups • ~62% of patients presented with PCP; potential impact of steroids? Zolopa A, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA.Abstract # 142.

  26. Treat immediately Conditions for which ART is best or only therapy: Progressive multifocal leukoencephalopathy Dementia HIV-associated nephropathy Kaposis Sarcoma Cryptosporidiosis Microsporidiosis Conditions for which higher CD4 count improves prognosis Primary CNS lymphoma Non-Hodgkin's lymphoma Consider delaying treatment Potential for immune reconstitution inflammatory syndrome (IRIS) Tuberculosis M avium complex Cryptococcal meningitis Potential for overlapping drug toxicity or interactions Tuberculosis When to Start During Acute Opportunistic Infections

  27. The New Drugs

  28. DHHS Treatment Guidelines: 1/29/20082 NRTIs + Either NNRTI or PI www.aidsinfo.nih.gov

  29. Targets for Antiretroviral Therapy CCR5 Antagonists Fusion Inhibitors NRTIs, NNRTIs EntryInhibitors PIs Reverse Transcriptase Inhibitors Integrase Inhibitors Protease Inhibitors

  30. Antiretroviral Agents Approved in the US

  31. Antiretroviral Agents Approved in the US

  32. HIV-1 Entry Inhibitors CD4 Binding Coreceptor Binding Virus-Cell Fusion CCR5 antagonists Maraviroc Vicriviroc PRO140 Enfuvirtide TNX-355 gp41 gp120 V3 loop CD4 CCR5/CXCR4 (R5/X4) Cell Membrane CXCR4 antagonists

  33. T-Cell Surface • R5 Viruses • Utilize the CCR5 co-receptor • Also known as M-tropic or nonsyncytium inducing (NSI) • Transmitted variants • Prevalent in early disease Dual Viruses Can utilize either co-receptor • X4 Viruses • Utilize the CXCR4 coreceptor • Also known as T-tropic or syncytium inducing (SI) • Emerge in later disease • Associated with accelerated CD4 decline and disease progression CD4 CXCR4 CCR5 Berger EA, et al. Nature. 1998;391:240.

  34. 100 80 60 40 20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 MOTIVATE 1 and 2: Combined Virologic Efficacy at Week 48 PBO + OBT (n=209) MVC QD + OBT (n=414) MVC BID + OBT (n=426) 45.5%* Patients (%) 43.2%* 16.7% Time (wks) *P<.0001 vs placebo Hardy D et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA.Abstract # 792.

  35. Antiretroviral Agents Approved in the US

  36. Strand Transfer Inhibitors HIV Integrase Mechanism X

  37. 100 80 60 40 20 0 0 2 4 8 12 16 24 32 40 48 BENCHMRK-1: Patients with Viral Load <50 copies/mL at Week 48 65% 62% Patients (%) P<0.001 P<0.001 33% 31% Weeks RAL n = 232 231 231 230 229 232 229 230 231 PBOn = 118 118 118 118 117 118 118 118 118 Cooper DA , et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI).February 3-6, 2008.Boston, MA.Abstract # 788.

  38. 100 80 60 40 20 0 0 2 4 8 12 16 24 32 40 48 Raltegravir (RAL) vs Efavirenz (EFV) in ART-Naïve Patients • Pts randomized to TDF/3TC + EFV or RAL at 100, 200, 400 or 600 mg BID • mean VL 4.6–4.8 log c/mL • mean CD4 271–338 • Adverse events similar • more CNS AEs with EFV • lower TC, LCL, TG with RAL VL <50 c/mL (95% CI) [NC=F] Pts with VL <50 c/mL (%) Week RAL100 mg BID (n=39) RAL 200 mg BID (n=40) EFV 600 mg QD (n=38) RAL 400 mg BID (n=41) RAL 600 mg BID (n=40) Markowitz M, et al. 4thInternational AIDS Society (IAS) Conference. July 22 – 25, 2007. Sydney, Australia. Abstract #TUAB104.

  39. 80 60 40 20 0 0 2 4 8 12 16 20 24 32 40 48 DUET-1 and -2: VL <50 at Wk 48 • Mean CD4 change at Week 48 significantly greater in ETR arm: +98 vs +73 1,2 ITT-TLOVR 61% ETR (n=599) VL < 50 c/mL at Wk 48(% ± 95% CI) PBO (n=604) 40% P<.0001 Time (wks) • Haubrich R, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA.Abstract # 790. • Johnson M et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 791.

  40. 100 80 60 40 20 0 MOTIVATE 1 and 2: VL <50 at Wk 24 byNo. of Active Drugs in OBR PBO + OBR MVC QD + OBR MVC BID + OBR 61 58 55 53 52 Patients (%) 43 43 29 19 18 9 3 N = 51 56 44 130 134 59 64 132 121 35 104 88 No. of active drugs in OBR 0 1 2 ≥3 Nelson M, et al. 14thConference on Retroviruses and Opportunistic Infections (CROI). Feb 25-28, 2007. Los Angeles, CA. Abstract # 104aLB.Lalezari J, et al. 14thConference on Retroviruses and Opportunistic Infections (CROI). Feb 25-28, 2007. Los Angeles, CA.Abstract # 104bLB.

  41. 0 20 40 60 80 100 BENCHMRK-1 and -2: Undetectable VL at Week 48, Overall, and by Genotypic Sensitivity Score n RAL PBO 443 64 Overall 34 228 By GSS: 112 45 • 0 3 65 67 166 • 1 92 37 158 75 • ≥2 59 68 Patients (%) Cooper DA, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI).February 3-6, 2008.Boston, MA. Abstract # 788.

  42. 100 80 60 40 20 0 DUET-1 and -2: Viral Load <50 at Wk 48,by Active Agents in OBR ETR (n=599)Placebo (n=604) 76 61 60 VL < 50 c/mL at Wk 48 (%) 33 26 12/36 0/35 121/203 51/196 229/300 187/305 0 1 2 Number of active agents in OBR by PSS(DRV active if FC <40) • Haubrich R, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008.Boston, MA.Abstract # 790. • Johnson M, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008.Boston, MA. Abstract # 791. • Winters B, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008.Boston, MA. Abstract # 873.

  43. The goal of therapy is virologic suppression to <50 copies/mL in allpatients. DHHS & IAS-USA Guidelines The Goal of Therapy • US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/guidelines. Accessed May 7, 2007. • Hammer S, et al. JAMA. 2006;296:827-843.

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