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Twenty Years of Antiretroviral Therapy: Lessons Learned and Unmet Needs Benjamin Young, MD PhD Rose Medical Center Division of General Internal Medicine.

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Presentation on theme: "Twenty Years of Antiretroviral Therapy: Lessons Learned and Unmet Needs Benjamin Young, MD PhD Rose Medical Center Division of General Internal Medicine."— Presentation transcript:

1 Twenty Years of Antiretroviral Therapy: Lessons Learned and Unmet Needs Benjamin Young, MD PhD Rose Medical Center Division of General Internal Medicine University of Colorado Denver and Health Sciences Center Denver, Colorado

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4 Overview Evolution in antiretroviral therapies Changing complexion of HIV epidemic New antiretrovirals Unmet needs

5 Denver, Colorado ~2.5 million pop. ~8700 HIV/AIDS Majority MSM Majority white 3000 deaths

6 Monarch pass, Colorado

7 Russia

8 26 years of the Epidemic  HIV/AIDS is one of the most formidable public health and scientific challenges ever confronted  In just two decades, remarkable advances have been made in the fight against AIDS, but the toll has been staggering 1985: –0 drugs –Little known about HIV mechanism of action –Little support for HIV patients who need access to treatment –16,000 U.S. AIDS cases reported; 20,000 globally 2007: –27 therapies; 4 drug classes, 2 classes in early access –Major advance in knowledge about viral lifecycle –Network of federal and local programs –Over one million people with HIV in U.S.; 38 million worldwide Note: U.S. HIV/AIDS statistics from CDC;global statistics from WHO (1985), UNAIDS (2005)

9 Let’s Go Back to 1995

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11 : Hope for the First Time  st PI (saquinavir) approved  1996  First reports of ritonavir extending life  Greeted with skepticism at CROI  RTV, IDV approved  NNRTI (nevirapine) approved by FDA  Mortality declines  “Highly Active Antiretroviral Therapy”  Transformed lives of PWAs - Health improves - Many return to work

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13 HOPS: Mortality and HAART Use Over Time Updated 2Q2004

14 HOPS: Opportunistic Infections (patients with CD4 < 100)

15 AIDS in Colorado: Survival by year of diagnosis *CDPHE 2006

16 Number of cases

17 Initial Problems with ART Tolerability High pill burden Diet restrictions Adherence Short term toxicity Neuropathy, Pancreatitis Long-term toxicity Lipodystrophy Cardiovascular disease

18 New Ideas  New strategies come and go  MegaHAART  Hydroxyurea/ddI  Intensification  New laboratory tests bring new insights, but more complicated decisions  Viral load  Resistance testing  New and investigational therapies offer hope - Sustained efficacy - Improved tolerability - Convenience, simplification

19 Dosing Daily pill burden IssuesRegimen 1998 ZDV/3TC/ efavirenz 5 pills, BID Gastrointestinal (GI) effects, anemia, neutropenia Central nervous system (CNS) toxicities Mitochondrial-related toxicities 1996 d4T/3TC/ indinavir 10 pills, TID Food restrictions, liquids frequently Poor tolerability Short- and long-term toxicities pills, BIDZDV/3TC/EFV Gastrointestinal (GI) effects, anemia, neutropenia Central nervous system (CNS) toxicities Mitochondrial-related toxicities Toward “Simpler” ART Regimens

20 Dosing Daily pill burden Issues pill QD Minimal to no side effects, good PK, and no food restrictions without compromising efficacy pills, QD Generally well tolerated; GI effects, CNS effects (EFV) TDF/ [FTC or 3TC] / EFV pills QD Minimal to no side effects, good PK, and no food restrictions without compromising efficacy Regimen FDC NRTI +EFV TDF/FTC/EFV

21 Antiretrovirals: 2007 Individualized treatment Host factors Genetics (pharmacogenomics) Side effect aversion Adherence Viral factors Genetics (resistance)

22 Antiretrovirals: 2007 Treatment permutations: 27 medications, 3 drug regimens 27 x 26 x 25= potential combinations How do we construct HAART regimens?

23 Antiretrovirals: 2007 Rise of evidence-based medicine Prospective clinical trials of defined regimens “Expert” opinion Treatment guidelines DHHS IAS-USA WHO

24 2006 IAS-USA Guidelines Recommended Components of Initial Antiretroviral Therapy* NRTIsNNRTIsPIs TDF/FTC † EFVLPV/RTV ZDV/3TC ‡ (NVP)ATV/RTV ABC/3TC ‡ FPV/RTV SQV/RTV *Therapy should consist of 2 NRTIs + either an NNRTI or PI. † Or 3TC. ‡ Or FTC. Hammer S, et al. JAMA. 2006;296:

25 Antiretrovirals: 2007 Many permutations of treatment combinations: IAS-USA: 6 NNRTI+12 PI Cautionary tales… Studies sometimes challenge conventional view: Early virologic failure of TDF/3TC/NVP qd (Daufin Study) 1 Increased risk of lipoatrophy of efavirenz (ACTG 5142) 2 1 Rey D et al., 14th CROI, 2007, 2 Haubrich R et al., 14th CROI, 2007

26 Trends in HIV Epidemiology Thinking Globally…

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31 The Global Pandemic 38 million dead 38 million dead By million infected By million infected By 2025, 83 million dead, 89 million infections By 2025, 83 million dead, 89 million infections Life expectancy in 9 African countries is already <40 years Life expectancy in 9 African countries is already <40 years

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34 AIDS in Russia

35 HIV/AIDS in Russia 30,000 cases in Saint Petersburg 800 on ART ~350 HIV+ pregnancies/year 35,000 cases in Moscow 2500 on ART ~400 HIV+pregnancies/year High frequency of HIV/TB coinfection Issues of IRIS, drug-drug interactions

36 HIV/AIDS in Russia 1.5 million cases (148 million population) ~3 times US case rate Fastest growing epidemic in world ~20-25% per year Injection drug use : heterosexual 30,000 cases in Saint Petersburg 800 on ART 35,000 cases in Moscow 2500 on ART

37 HIV in Russian Street Children Survey of street children of Saint Petersburg (age 15-19) 117/313 (34.9%) HIV infected Subgroups with >60% seroprevalence: Double orphans Homeless Previous STI Current injection or inhaled drug use Current needle sharing D Kissin, et.al., 14 th CROI 2007 #688

38 US policy issues Changing racial and geographic characteristics Delayed diagnosis Clinical outcomes Ineffective prevention strategies Many HIV+ don’t know status Role of routine HIV testing Access to care not guaranteed ADAP waitlists in 6 states ART pricing subject of state and federal investigation

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42 HIV Trends in Colorado *CDPHE 2004 HIV rates among Black men and women are greater than among Whites and Hispanics

43 Delay in HIV/AIDS diagnosis Many recently diagnosed HIV+ persons rapidly progress to AIDS Results in higher risk of complications Higher healthcare costs Higher disease burden 41.7% of Colorado HIV+ develop AIDS within 12 months of diagnosis* *CDPHE

44 Future trends in HIV therapies?

45 Future trends in HIV treatment Pharmacogenetics How will genetic screening affect HIV disease management? Viral factors Host factors New drug classes: How will new drugs change combination ART therapy? CCR5 Inhibitors HIV integrase inhibitors

46 Pharmacogenetics and HIV Viral factors Drug resistance Co-receptor tropism Host factors CCR5  32 and susceptibility to infection HLA B*5701 and abacavir HSR MDR1 and immunological response to HAART Cytochrome P450 and plasma drug levels UGT1A1*28 and hyperbilirubinemia

47 Viral genetics in treatments: resistance testing  HIV drug resistance testing recommended for management HIV-infected persons 1  Drug resistance testing associated with improved survival 2 1 DHHS Treatment Guidelines, October Palella et al., 14th CROI, 2007

48 / / / to 7/2005 Possible Abacavir-related symptoms, number of patients (including definitive ABC-HSR) Abacavir HSR, number of patients # 2 pts results not reviewed prior therapy $ 1 pt with informed choice/ incomplete haplotype Proportion of ABC-naïve patients discontinuing ABC within 6 weeks n=68n=131n=107n=60 # Before genetic screeningAfter genetic screening #$ *P<0.05 Host Genetics in HIV Treatment: Effect of HLAB*5701 Screening Rauch, et al. Clin Infect Dis 2006;43:

49 Pharmacogenomics: HLA pre-screening and abacavir HSR  Association between HLA B*5701 allele and risk of abacavir hypersensitivity reaction  Western Australia cohort 1 : –Decreased suspected abacavir HSR –Decreased abacavir all-cause discontinuations  Paris cohort 2 : –131 consecutive B*5701 negative patients started ABC –No cases of HSR –1 discontinuation 1 Rauch, et al., Clin Inf Disease Zucman, et al., JAIDS 2007

50 Unmet Needs of Current Antiretrovirals 1. Bennett D, et al. CROI Abstract 372-M. 2. Bennett D, et al. CROI Abstract Richman D, et al. AIDS. 2004,18:  Access to care –Cost –Distribution –Intellectual property  Drug Resistance –Transmitted drug resistance occurs in 5% to 15% of patients [1,2] –Multiclass resistance in large proportion of highly treatment–experienced patients [3]

51 Unmet Needs of Current Antiretrovirals  Toxicity/tolerability issues with current classes –Cardiovascular: dyslipidemia, insulin resistance –Lipodystrophy, lipoatrophy –Other: bone, hematologic, renal, CNS, reproductive  Drug-drug interactions –Rifamycins –Methadone

52 clinicaloptions.com/hiv Novel Antiretrovirals in Clinical Development TNX-355 CCR5 inhibitors CXCR4 inhibitors Maturation Inhibitors Bevirimat Raltegravir Elvitegravir Entry inhibitors Reverse transcriptase inhibitors Mature virus PIs Integrase inhibitors

53 clinicaloptions.com/hiv MOTIVATE: Maraviroc in Treatment- Experienced Patients With R5 Virus Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB. *Patients receiving PI (other than TPV) or DLV received 150 mg; all others received 300 mg. † OBR: 3-6 ARVs. Patients with R5 HIV-1; ≥ 5000 copies/mL; stable ART or no ART for ≥ 4 weeks; resistance to and/or ≥ 6 months of ≥ 1 antiretroviral from 3 classes or ≥ 2 PIs MOTIVATE 1 (N = 601) (Canada, US) MOTIVATE 2 (N = 475) (Europe, Australia, US) Placebo + OBR † Maraviroc 150 mg or 300 mg* once daily + OBR † Maraviroc 150 mg or 300 mg* twice daily + OBR † 2:2:1 randomization; stratified by ENF use and VL Planned interim analysis: Week 24: Week 48  Randomized, double-blind, placebo-controlled, parallel phase IIb/III studies  44% failed screening with X4 or dual/mixed virus detected  Primary endpoint: mean change in VL at Week 24  Baseline characteristics similar across treatment arms in the 2 studies

54 clinicaloptions.com/hiv Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB. MOTIVATE 1 and 2: VL < 400 copies/mL (ITT, NC = F) 61.3% 55.5% 23.1% P <.0001* 60.4% 54.7% 31.4% P <.0001* Placebo + OBR (n = 209)MVC QD + OBR (n = 414) MOTIVATE 1MOTIVATE 2 MVC BID + OBR (n = 426) *P values vs placebo at Week 24. Patients (%) Time (Weeks) Time (Weeks) Patients (%)

55 clinicaloptions.com/hiv MOTIVATE 1 and 2: Adverse Events and Resistance Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB.  Similar incidence of adverse events in maraviroc and placebo arms –Similar low incidence of hepatotoxicity in maraviroc and placebo arms –Lymphoma diagnosed in 3 patients in maraviroc arms and 2 patients in placebo arms  Resistance –Mutations seen in V3 loop among patients who failed on the maraviroc arms with R5 virus –No signature R5 mutations have been defined yet

56 clinicaloptions.com/hiv BENCHMRK-1 and -2: Raltegravir (MK- 0518) in Treatment-Experienced Pts Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB. Raltegravir 400 mg twice daily + OBR* BENCHMRK-1 (n = 232) BENCHMRK-2 (n = 230) Placebo + OBR* BENCHMRK-1 (n = 118) BENCHMRK-2 (n = 119) HIV infected; triple-class resistant; VL > 1000 copies/mL BENCHMRK-1 (N = 350) (Europe, Asia/Pacific, Peru) BENCHMRK-2 (N = 349) (North, South America) *Selected investigational antiretrovirals permitted in OBR. Primary endpoints: Week 16 Planned duration: Week 48  Randomized, double-blind, placebo-controlled, parallel phase III studies  Primary endpoints: VL, CD4+ cell counts, and adverse events at Week 16

57 clinicaloptions.com/hiv BENCHMRK-1 and -2: VL < 400 copies/mL (ITT, NC = F) Weeks Patients With VL < 400 copies/mL (%) P <.001 at Week 16 Weeks BENCHMRK-2 BENCHMRK-1 Raltegravir + OBRPlacebo + OBR 77% 41% 77% 43% n = n = Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB.

58 clinicaloptions.com/hiv Markowitz M, et al. IAC Abstract THLB0214. Raltegravir: Potent Activity of Integrase Inhibitor in Treatment-Naive Patients Raltegravir 600 mg BID (n = 40)* Raltegravir 400 mg BID (n = 41)* Efavirenz 600 mg QD (n = 41) Treatment-naive patients with no prior antiretroviral therapy > 6 days in total; VL ≥ 5000 copies/mL; CD4+ cell count ≥ 100 cells/mm 3 (N = 203)* Raltegravir 200 mg BID (n = 40)* Raltegravir 100 mg BID (n = 41)* *8 patients in each raltegravir arm previously treated with same dose of raltegravir monotherapy for 10 days. Week 48 Current analyses: Week 24 Each combined with TDF + 3TC

59 clinicaloptions.com/hiv Markowitz M, et al. IAC Abstract THLB0214. Raltegravir vs EFV: Therapy Naïve pts VL < 50 copies/mL at Week 24 (NC = F) *P <.001 for raltegravir at each dose vs EFV. Week RLG 100 mg39 RLG 200 mg40 RLG 400 mg41 RLG 600 mg40 EFV Patients With VL < 50 copies/mL (%) * *

60 clinicaloptions.com/hiv Markowitz M, et al. IAC Abstract THLB0214. *Additional AEs seen at ≥ 5% in EFV group: nightmares (11%), vomiting (8%), malaise (8%), fatigue (5%), attention disturbances (5%), lethargy (5%), anxiety (5%). Raltegravir vs EFV: Adverse Events AEs Occurring in ≥ 5% of Pts, % RLG (All Doses) (n = 160) EFV (n = 38) Nausea11 13 Headache 9 24 Dizziness 8 26 Diarrhea711 Insomnia711 Abnormal dreams618 Flatulence6--

61 clinicaloptions.com/hiv Teppler H, et al. ICAAC Abstract 256a. Raltegravir: Serum Lipids at Week 24 in Naive Patients Treatment ArmMean B/L TC, mg/dL (mmol/L) Change From B/L at Wk 24, % (95% CI) Mean B/L TG, mg/dL (mmol/L) Change From B/L at Wk 24, % (95% CI) RLG 100 mg BID* (n = 39)168 (4.35)-7 (-14 to 0) † 129 (1.46)+2 (-22 to 26) RLG 200 mg BID* (n = 34)161 (4.17)-2 (-11 to 8) † 110 (1.24)-5 (-20 to 9) † RLG 400 mg BID* (n = 40)168 (4.35)-7 (-15 to 2) † 127 (1.44)-2 (-23 to 18) † RLG 600 mg BID* (n = 35)162 (4.19)-4 (-12 to 5) † 155 (1.75)-43 (-87 to 1) † EFV 600 mg QD (n = 36)170 (4.40)+19 (8 to 30)128 (1.45)+47 (-1 to 96) *With NRTI backbone of TDF + 3TC. † Significant difference vs EFV (P <.05).

62 Challenges Still Remain

63 The Future The provider crisis The provider crisis The need for vaccines The need for vaccines New affected populations New affected populations The rise of denialists The rise of denialists –HIV denialists –Abstinence-only/ anti-condom The challenge for funding The challenge for funding The epidemic of complacency The epidemic of complacency

64 Unmet needs in HIV Care Prevention Epidemic growing ~10% per year (US) Many HIV+ do not know their status EDUCATION Address stigma Abstinence Faithfulness Safer drugs/needle exchange Safer sex/condom distribution

65 Unmet needs in HIV care Diagnosis Many HIV+ do not know their status CDC now recommends HIV testing as part of routine health care screening Must address stigma and confidentiality Delayed diagnosis facilitates: Increased disease burden Increased disease cost Increased risk of transmission

66 Unmet needs in HIV care Treatment Access to HIV treatment saves lives ADAP waitlists Expertise of care provider correlates to survival ~9% of HIV+ do not have access to primary care What prevents HIV+ from access? Lack of education Fear of stigma Fear of disclosure Fear of side effects

67 Unmet needs in HIV care Treatment Long-term tolerability/toxicity Cardiovascular disease Pregnancy Hepatitis Costs Drug-drug interactions TB Methadone

68 20 Years of Antiretroviral Therapy Antiretroviral therapies revolutionized care Newer treatments offer well tolerated options Pharmacogenetics impact management New drugs will continue to shape ART Prevention and access to care continue to challenge

69 Acknowledgements Colorado HIV community Rose Medical Center: Ken Greenberg John Hammer Amy Thomas Peggy Zellner HOPS/CDC collaborators Howard Grossman Clinical Care Options Elaine Seekins

70 Twenty Years of Antiretroviral Therapy: Lessons Learned and Unmet Needs Benjamin Young, MD PhD Rose Medical Center Division of General Internal Medicine University of Colorado Denver and Health Sciences Center Denver, Colorado


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