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Two Decades of HAART Past, Present, and Future

Two Decades of HAART Past, Present, and Future. Overview. The Past Brief History of HAART The Present Considerations for Current Regimens Role of the CD4 and health Issues surrounding transmitted resistance The Future Prevention is key. Approved Antiretrovirals.

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Two Decades of HAART Past, Present, and Future

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  1. Two Decades of HAARTPast, Present, and Future

  2. Overview • The Past • Brief History of HAART • The Present • Considerations for Current Regimens • Role of the CD4 and health • Issues surrounding transmitted resistance • The Future • Prevention is key

  3. Approved Antiretrovirals Between ’87 and ’95, 5 antiretrovials were launched. Epivir Hivid Zerit Retrovir Videx ‘04 ‘05 ’93 ’87 ’88 ’89 ’90 ’91 ’92 ’94 ’95 ’96 ’97 ’98 ’99 ‘00 ’01 ‘02 ‘03 RTI NNRTI PI

  4. Fuzeon Approved Antiretrovirals Between ’87 and ’95, 4 antiretrovials were launched. Since ’95, 20 new products have been introduced. Combivir Truvada Viread Epivir Rescriptor Hivid Epzicom Ziagen Emtriva Viramune Sustiva Aptivus Trizivir Zerit Retrovir Videx ‘04 ‘05 ’93 ’87 ’88 ’89 ’90 ’91 ’92 ’94 ’95 ’96 ’97 ’98 ’99 ‘00 ’01 ‘02 ‘03 RTI Invirase Viracept Kaletra Reyataz NNRTI Fortovase Agenerase PI Norvir Lexiva Crixivan

  5. FDA-Approved Drugs for HIV Therapy: 2006 PIs NRTIs Amprenavir (APV) Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir/ritonavir (LPV/RTV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV hgc) Tipranavir (TPV) Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zalcitabine (ddC) Zidovudine (ZDV) 3TC/ABC 3TC/ABC/ZDV 3TC/ZDV FTC/TDF Fusion Inhibitors (FIs) Enfuvirtide (ENF) NNRTIs Multiple Class Delavirdine (DLV) Efavirenz (EFV) Nevirapine (NVP) Atripla (ATP) EFV/FTC/TDF

  6. Improving Outcomes With Evolving Antiretroviral Regimens 400 CD4+ RNA CD4+ RNA Monotherapy Monotherapy Dual-NRTI combinations 300 HAART 200 100 Change in HIV-1 RNA From Baseline (log10 copies/mL) Change in CD4+ Cell Count From Baseline (cells/mm3) 0 0 – 1 – 2 – 3 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 Years Acknowledgement: Cohen C. J.

  7. Improving Outcomes With Evolving Antiretroviral Regimens 400 CD4+ RNA CD4+ RNA Monotherapy Monotherapy Dual-NRTI combinations Dual-NRTI combinations 300 HAART 200 100 Change in HIV-1 RNA From Baseline (log10 copies/mL) Change in CD4+ Cell Count From Baseline (cells/mm3) 0 0 – 1 – 2 – 3 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 Years Acknowledgement: Cohen C. J.

  8. Improving Outcomes With Evolving Antiretroviral Regimens 400 CD4+ RNA CD4+ RNA Monotherapy Monotherapy Dual-NRTI combinations Dual-NRTI combinations 300 HAART HAART 200 100 Change in HIV-1 RNA From Baseline (log10 copies/mL) Change in CD4+ Cell Count From Baseline (cells/mm3) 0 0 – 1 – 2 – 3 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 Years Acknowledgement: Cohen C. J.

  9. The Art of HAART Dr. David HoMan of the Year, Dec 30, 1996 • Pioneering AIDS researcher Dr. David D. Ho, whose novel use of a "cocktail" of protease inhibitors and other antiviral drugs in the earliest stages of infection has shown remarkable promise in beating back the AIDS virus, is TIME Magazine's 1996 Man of the Year

  10. 0 -0.5 -1 -1.5 -2 -2.5 -3 Antiretroviral Activity:An Historical Perspective 1987: AZT Monotherapy 1994: Two-Drug Therapy 1997: HAART 0 0 -0.5 -0.5 -1 -1 -1.5 -1.5 HIV RNA change (log10 c/mL) -2 -2 -2.5 -2.5 -3 -3 24-week response 24-week response 24-week response Fischl, NEJM, 1987 Katzenstein, NEJM, 1996 Eron, NEJM, 1995;Hammer, NEJM, 1996 Gulick, NEJM, 1997; Cameron, Lancet, 1998

  11. SQV IDV RTV NFV APV Poor bioavailability Complex regimens High pill burden Unpredictable efficacy Hard to manage toxicity Signature resistance common Limitations of Early PIs

  12. Boosting PI Levels With RTV PI toxicity threshold boosted PI PI level required to overcome “resistant” virus Plasma Concentration PI PI level required to overcome WT virus Time Moyle G, et al. Drugs. 1996;51:701-712.

  13. SQV/RTV LPV/RTV ATV/RTV FPV/RTV Bioavailability improved by RTV boosting Less complex regimens Lower pill burden More predictable efficacy Negligible resistance in naive patients Greater activity against resistant virus Less toxicity? Advantages of Boosted PIs

  14. NNRTI-based Efavirenz* + (3TC or FTC) + (ABC or ddI or d4T) Nevirapine‡ + (3TC or FTC) + (ZDV or d4T or ddI or ABC or TDF) Triple NRTI** Abacavir + 3TC + ZDV (only when a preferred or an alternative NNRTI-or PI-based regimen cannot or should not be used) Recommended Regimens for HIV+Treatment-naïve Patients: DHHS May 2006 Preferred regimens Efavirenz* + (3TC or FTC) + (ZDV or TDF) Lopinavir/ritonavir + (3TC or FTC) + ZDV 400/100 mg (2 tablets) BID or 800/200 mg (4 tablets) QD Alternative regimens PI-based Atazanavir + (3TC or FTC) + (ZDV or d4Tor ABC or ddI) or (TDF + RTV 100 mg/d) Fosamprenavir + (3TC or FTC) + (ZDV or d4T or ABC or TDF or ddI) Fosamprenavir/RTV† + (3TC or FTC) + (ZDV or d4T or ABC or TDF or ddI) Indinavir/RTV† + (3TC or FTC) + (ZDV or d4T or ABC or TDF or ddI) Lopinavir/ritonavir + (3TC or FTC) + (d4T or ABC or TDF or ddI) Nelfinavir + (3TC or FTC) + (ZDV or d4T or ABC or TDF or ddI) Saquinavir§/RTV† + (3TC or FTC) + (ZDV or d4T or ABC or TDF or ddI) *Not recommended for use in 1st trimester, or in women with high pregnancy potential. †Low-dose: 100 to 400 mg/day as a pharmacologic booster. ‡Ritonavir 100 mg/day recommended when tenofovir DF is used with atazanavir. §Adult females and males with CD4 cell counts <250 and <400 cells/mm3, respectively.¶Soft-gel or hard-gel capsules, or tablets. May 2006 Available at: http://aidsinfo.nih.gov/guidelines

  15. An Issue of the Immune System The Role of CD4

  16. Overall HIV Malignancy Heart Liver 10 RR 1.0 <50 50–99 100–199 200–349 350–499 >500 CD4 Cells/mm3 0.1 Immunosuppression increases risk of non-HIV related death (D:A:D Study) RR of death according to immunofunction and specific cause 100 • Cohort study of >23,000 patients in Europe, Australia, and the USA • 1,248 (5.3%) deaths 2000–2004(1.6/100 person-years) • Of these, 82% on ART • Both HIV and non-HIV related mortality were associated with CD4+ cell count depletion, suggesting role for immunosuppression in causes of death typically considered not HIV-related* *Liver-related: Chronic viral hepatitis, liver failure (other); Malignancy-related: Malignancy, non-AIDS hepatitis; Heart-related: MI, other CVD, other heart disease Weber R, et al. 12th CROI, Boston 2005, #595

  17. Opportunistic Infections Mycobacterium avium complex (MAC) spleen - CD4 <50 Oral Thrush – CD4 <200 Kaposi’s Sarcoma – Any CD4

  18. So, it’s important to get that CD4 up! Mean change from baseline in CD4 count +529 cells/mm3 Study 720 Gulick RM. et al., HIV7, Glasgow, UK, Nov. 2004; #P28

  19. An Issue of Resistance Prevalence and Risk of Transmitted ARV Resistance

  20. Evolution of HIV Drug Resistance • Factors associated with development of resistance: • Generation of genetic variation in the virus • Selection of drug resistant variants during therapy • Extent of viral replication during therapy • Ease of acquiring a particular mutation • Effect of mutation on drug susceptibility and viral fitness • Resistant HIV strain can also be transmitted between individuals hivinsite.ucsf.edu

  21. Serosorting of sexual partners Early syphilis and male rectal gonorrhea1 • Serosorting implies that partners with similar HIV infection status seek each other as sexual partners to decrease HIV transmission risk • Serosorting does not occur when HIV infection status is unknown, and may lead to increases in unsafe sex • Widely reported in diverse populations (MSM, heterosexuals) and geographic areas (San Francisco, Atlanta, South America, Europe, Australia)1-9 • May be facilitated by internet communications in some areas4 • San Francisco: Stable to decreasing HIV incidence rates but increased incidence of syphilis and rectal gonorrhea among MSM1 HIV incidence1 1. Truong H-H, et al. XVI IAC, Toronto 2006, #MOAC0105; 2. Xia Q, et al. ibid, #MOPE0476; 3. Melo L, et al. ibid, #MOPE0493; 4. Berry M, et al. ibid, #TUPE0471; 5. Zablotska I, et al. ibid, #TUPE0760; 6. Cowan S, et al. ibid, #WEPDC03; 7. Elford J, et al. ibid, #WEPDC05; 8. Lama J, et al. ibid, #WEPE0298; 9. Kurtz S, et al. ibid, #THPE0475

  22. CDC survey: Drug-resistant HIV among newly diagnosed patients Bennett D, et al. 9th CROI, Seattle, 2002. Abstract 372. 12th CROI. Boston, 2005. Abstract 674.

  23. Drug resistance in 787 newly diagnosed ART-naïve subjects from 89 sites in 6 states (2003–2004) 16 14.5 14 12 10 8.4 7.1 Patients (%) 8 6 3.1 4 2.8 2 0 Any NRTI NNRTI PI >2 class classes US surveillance of HIV drug resistance Prevalence of resistance by drug class Bennett D, et al. 12th CROI, Boston 2005, #674

  24. N=55 recently infected adolescents 12-24 years old (mean age 19.7) Sample from 15 US cities Overall rate of resistance – (genotype 18%; phenotype 22%) NNRTI: 15%; 18% PI: 3.6%; 5.5% NRTI: 4%; 4% 81% of male risk was MSM Primary resistance in ARV-naïve adolescents Viani R, et al, 13th CROI, Denver 2006, #21

  25. Phoned 733,787 Responded 15,272 Eligible 2,676 Completed interview 1,976 100 80 Unprotected insertive anal sex Unprotected receptive anal sex 60 % HIV+ 40 20 0 Neither n=1388 (84%) 2 ED drug only n=266 (16%) 6 Meth only n=100 (5%) 5 Both n=139 (7%) 20 Use of ED drugs and crystal meth, and high-risk sexual behaviors • Random telephone survey conducted in San Francisco, June 2002 to January 2003 Median # sexual partners Spindler H, et al. XVI IAC, Toronto 2006, #MOPE0342

  26. Methamphetamine use and infection with resistant HIV • 214 recently infected, treatment-naïve MSM cohort in southern California • 15% of patients infected with drug-resistant HIV • ~50% resistance to NNRTIs • ~25% NNRTI + ≥ 1 other class resistance • ⅓ of men reported using methamphetamine with at least 1 of their last 3 sexual partners • MV regression analysis: pts who had drug-resistant virus were 5 times more likely to have used methamphetamine (odds ratio: 4.86; p=0.005) Drumright et al, XV IHDRW, Sitges, Spain, 2006, #99

  27. How long does transmitted resistance last?

  28. Reversions Primary HIV Infection Follow-up (Weeks) n=101 NNRTI (n=9) NRTI (n=3) PI (n=3) 1 of 10 9-145 None n=1 PI2 156 n=4 MDR3 None 36-260 n=24 MDR (n=1) NNRTI (n=1) None 26-156 Persistence of transmitted resistant virus • Reversion of MDR is rare even after 1 year Little SJ, et al. XII Resistance Workshop, Los Cabos 2003, #115; 2. Ravaux I, et al. 2nd IAS, Paris 2003, #822; 3. Brenner B, et al. J Virology 2002; 766:1753; 4. Chan K, et al. AIDS 2003; 17:1256

  29. An Ounce of Prevention

  30. Risk Factors for Seroconversion- Occupational *p<0.01 for all Cardo DM et al. NEJM 1997;337:1485-90

  31. Exposure Risks – Non-Occupational average, per episode, involving HIV-infected source patient

  32. Does Offering Non-occupational PEP Encourage High-Risk Behavior? • N = 401 participants receiving PEP following unprotected sexual or IDU exposure to HIV • 379 sexual exposures; 336 involved MSM • Most MSM reported decrease in risky behaviors on followup questioning • By 12 months of follow-up, 17% of MSM had received PEP for one or more repeat exposures Percentage of participants Change in Risky Behavior Martin J et al, 8th CROI, February 2001, Abstract 224.

  33. Tolerability of HIV PEP in Health Care Workers Incidence of Common Side Effects Percent of HCWs Wang SA. Infect Control Hosp Epidemiol 2000;231:780-5.

  34. When should PEP be started? • Efficacy of PEP thought to wane with time • At what point is PEP “no longer worth it”? benefits of PEP risks of PEP time exposure

  35. Timing of PEP: what’s the evidence? • Animal models and animal PEP studies: suggest substantially less effective beyond 24 - 36 hours1,2 • Case-control study: most subjects in each group received PEP within 4 hours3 • Analysis of PEP failures does not suggest a clear cut-off4 1. Tsai C-C et al. J Virol 1998;72:4265-73. 2. Shih CC et al. JID 1991. 3. Cardo DM et al. NEJM 1997;337:1485-90. 4. MMWR June 29, 2001:50(RR11);1-42.

  36. Timing of PEP: CDC Guidelines • “PEP should be initiated as soon as possible, preferably within hours rather than days of exposure.” • Interval after which there is no benefit for humans is not known • Obtain expert advice when interval has exceeded 24-36 hours MMWR 2005;54(No. RR-9).

  37. How Long Should PEP be Administered? • N = 24 macaques inoculated with SIV intravenously • PEP initiated 24 hours post-inoculation • PEP administered for 3, 10, or 28 days Tsai C-C et al. J Virol 1998;72:4265-73.

  38. Duration of PEP • In animal model, 28 days more effective than 10 days or 3 days of PEP1 • 4 weeks (28 days) used in case-control study2 and recommended by CDC guidelines3 1. Tsai C-C et al. J Virol 1998;72:4265-73. 2. Cardo DM et al. NEJM 1997;337:1485-90. 3. MMWR June 29, 2001:50(RR11);1-42.

  39. Which PEP regimen should be considered?

  40. PEP Regimens: Basic regimens • Two NRTIs • Simple dosing, fewer side effects • Preferred basic regimens: zidovudine (AZT) OR tenofovir (TDF) plus lamivudine (3TC) OR emtricitabine (FTC) • Alternative basic regimens: stavudine (d4T) OR didanosine (ddI) plus lamivudine (3TC) OR emtricitabine (FTC) MMWR 2005;54(No. RR-9).

  41. Expanded PEP Regimens • Basic regimen plus a third agent • Rationale: 3 drugs may be more effective than 2 drugs, though direct evidence is lacking • Consider for more serious exposures or if resistance in the source patient is suspected • Adherence more difficult • More potential for toxicity

  42. Expanded PEP Regimens • Preferred Expanded Regimen: • Basic regimen plus lopinavir/ritonavir (Kaletra) • Alternate Expanded Regimens: • Basic regimen plus one of the following: • Atazanavir* +/- ritonavir • Fosamprenavir +/- ritonavir • Indinavir +/- ritonavir • Saquinavir (hgc; Invirase) + ritonavir • Nelfinavir • Efavirenz MMWR 2005;54(RR-9) *Atazanavir requires ritonavir boosting if used with tenofovir

  43. Adverse Effects: Basic vs Expanded Regimens % of individuals Puro V et al. 9th CROI, February 2002, Abstract 478-M

  44. Other Antiretrovirals • ARVs to be considered only with expert consultation: • Enfuvirtide (Fuzeon; T-20) • ARVs not generally recommended for PEP: • Delavirdine • Zalcitabine • Abacavir • Nevirapine MMWR 2005;54(No. RR-9).

  45. Post-Exposure Prophylaxis: Core Principles • Evidence is limited • Balancing of risks vs benefits • Timing: the sooner the better, but interval beyond which there is no benefit is unclear

  46. Post-Exposure Prophylaxis: Core Principles • Optimal duration unclear, 28 days is recommended • Decision making can become very complex when drug resistance in the SP is suspected • Offering non-occupational PEP is indicated for risky exposures, and does not appear to increase unsafe sexual behavior for most recipients

  47. Summary Two decades of HIV have produced many advances But a few things haven’t changed • Current HAART does not eradicate HIV • Treatment will be life-long • Patients will never be 100% adherent • Behavioral changes are difficult to achieve • Transmitted resistance can occur as a result • Prevention is key!!

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