New Concepts and Recent Developments in HIV Therapeutics ...

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  • This slide summarizes the Early Virologic Response results for both COL40263 and for ESS30009. These results were calculated using the early virologic non-response criteria used for the ESS30009 study (I.e. the non-response rates were calculated using the criteria and the success rates were then determined from the converse of these rates). ESS30009 results are represented by the red bars and COL40263 results are represented by the yellow bars. In terms of overall response, COL40263 had a 76% success rate compared with a 51% success rate for ESS30009. For the low baseline VL group, the success rate was 83% in COL40263 vs. 56% in ESS30009. For the high baseline VL group, the success rate was 71% in COL40263 vs. 32% in ESS30009. This direct comparison with ESS30009 using the same measures therefore gave us confidence in the efficacy and safety of the study regimen. We also performed statisticial modeling to see what the eventual week 24 results would be based on the current results. Statistical modeling showed that we had a 98% probability of achieving a response rate (HIV-1 RNA <400 c/mL) of 60% when all subjects complete week 24. Both of these analyses gave us the confidence to continue with the trial.
  • Be sure to review the animation of this slide it will guide your discussion This program provides a different treatment support structure for the treatment for HIV. Medical providers from the Institute along with providers and patients from the community did a 3 day retreat to develop a model that would address the needs of the community
  • Note: This is an animated slide. In slideshow mode, initially the < 400 copies/mL results are shown, with the < 50 copies/mL results being superimposed in the second build Background Resistance mutations to NNRTIs are detectable in 19-63% of women who receive single-dose nevirapine for prevention of MTCT The prevalence depends on the number of doses, the maternal viral load, the time to testing, the viral subtype, and the sensitivity of the test The mutations quickly fall below the detectable threshold by routine bulk sequencing, but remain archived This raises great concern over whether single-dose nevirapine for prevention of MTCT will affect the woman’s future response to therapy. This study is the first to directly measure this response WHO guidelines suggest that first-line antiretroviral treatment in resource-poor settings should include ZDV or d4T, 3TC, and an NNRTI (nevirapine or efavirenz). Nevirapine is preferred for women of childbearing age. Therapy is recommended when the CD4+ cell count falls below 250 or clinical AIDS develops Study Design In this study, the PHPT-2 investigators made antiretroviral therapy available to all participants in the trial summarized on the previous slide Women were started on HAART a variable amount of time after delivery if they met the WHO criteria for HAART therapy Women who started HAART were sicker that the study population as a whole The median CD4+ cell count was 182 and the median VL was 4.5 log All women received d4T, 3TC and nevirapine, in a generically produced combination tablet called GPO-vir Three groups were defined: Those who had been in the zidovudine alone arm are shown in green Those who received nevirapine but had no detectable resistance are shown in yellow Those who had detectable NNRTI mutations (30% of the total) are shown in orange Results Women with no nevirapine exposure and those who had been on nevirapine but had no mutations had a good response using a cut-off of < 400 copies/mL Those with nevirapine mutations tended to have a worse response by 6 months, but the difference was not statistically significant, given the modest size of the study <<Show second build>> Using the < 50 copies/mL cutoff, however, the effect of prior nevirapine exposure became more clear By 6 months, 75% of those without prior nevirapine had undetectable VL, compared with 53% of the nevirapine-exposed group without mutations and only 34% of those with resistance mutations Discussion Thus, this study clearly demonstrates that women exposed to single-dose nevirapine for MTCT prevention who develop resistance mutations have a poorer response to nevirapine-based HAART Most of these women started therapy shortly after delivery, so it is not clear whether the response would be better after the amount of resistant virus declined However, other studies at this meeting also showed that archived mutations are associated with decreased response to NNRTIs Since the fixed-dose combination in Thailand costs about $30 US a month, it will be crucial to look at the effects of fully suppressive HAART in pregnant women in this setting MTCT+ programs aim to do that, by focusing on optimal therapy for the health of the pregnant woman in developing countries as well as preventing transmission
  • Key Points Considerations of forgiveness are critical for ensuring “coverage” if a dose is missed

Transcript

  • 1. New Concepts and Recent Developments in HIV Therapeutics September 27 2004 Robert R. Redfield MD Director Clinical Care and Research Institute of Human Virology
  • 2. Impact of Anti-retroviral Therapy in the US
    • Major impact on mortality and morbidity of HIV infection
      • In 2003 some patient’s with HIV will live a natural lifetime as a direct consequence of durable antiretroviral therapy
    • >90% reduction in perinatal HIV infection
    • Significant treatment failure in experienced clinics secondary to the development of drug resistance
    • Increase morbidity and mortality secondary to drug induced toxicities
    • Increase transmission of anti-retroviral drug resistant virus
    • Significant “swings” in consensus recommendation related to use of anti-retroviral therapy
  • 3. Evolution of Treatment: Main Steam Approaches
    • AZT mono-therapy
    • Combination NRTI therapy
    • Triple drug regimens (2 NRTI and 1 PI)
    • Combination PI’s with or without 1 NRTI)
    • Three drug RTI (2NRTI,1NNRTI) regimens
    • Three NRTI regimens
    • PK enhanced PI regimens
    • Four RTI regimens
  • 4. Evolution of Treatment: Main Steam Approaches
    • Salvage and Deep therapy
    • Fusion Inhibitors
    • Under Investigation
      • Entry inhibitors
        • Chemokine antagonist
        • Strategies to alter chemokine and co-receptor dynamics
      • Intergrase Inhibitors
      • Combination of chemotherapeutic drugs with candidate therapeutic vaccines
      • Cycle Therapy
        • Structured Interrupted Treatment
        • Maintenance Therapy with cell cycle agents
      • Use of cytostatic agents
      • Induction Maintenance therapy
  • 5. Mainstream Treatment Strategy: 2000
    • Sequential combination chemotherapy (rational ART sequencing based on concerns of cross resistance)
    • Preservation of future treatment options
    • Expanded use of Viral Load monitoring
    • Use of resistance testing in selected clinical settings (viral rebound, new infection) to steer drug selection
    • Delay use of ART ( due to high risk of viral failure and toxicity)
  • 6. Real Life Settings Demonstrates Limited Durability in Clinical Cohort Studies ( 1 year Antiretroviral Treatment Success Rates)
    • Baltimore (JHU) 37%
    • Cleveland Clinic 47%
    • San Francisco (UCSF) 50%
    • Amsterdam 60%
    • Ref: Lucas Annal 1999, Deeks AIDS 1999 , Casado AIDS 1998)
    • Baltimore (JHU) 36% (18 months)
      • 1999-2003 ARV naïve
    • Ref: Lucas JAIDS 2003
  • 7. Key Factors for Improved Durability:
    • Working Hypothesis: Events that occur in during the initial induction of viral control largely determine the durability of antiretroviral induced viral control.
    • Key Factors
      • Role of compartment specific ART
      • Role of enhanced treatment support especially during induction of viral control – impact of drug side effect profile on adherence
      • Use of high Mutation Threshold Regimens
        • Does the use of low mutation drugs during induction of viral control contribute to limited durability?
      • Use of antiretroviral drugs in regimen with similar
      • pk profiles
  • 8. Case 1
    • Patient is 37 year old black female with at history of HIV infection diagnosed in 1989.
    • She remained asymptomatic with CD 4 cell count in the range of 437- 526.
    • In 2000, she re-engaged in care with her PMD. She remained asymptomatic; CD4 count 444, VL 67,000.
    • After discussion with her doctor she began on treatment with AZT, 3TC and Nelfinavir.
  • 9. Case 1 continued
    • Patient did well; viral load declined to <400 copies.
    • After 3 months on treatment viral load ranged 1,300-27,000.
    • After 5 months Viral genotype was preformed. (RT mutations noted at 184. 211, 215 )
    • Plasma from 3 month sample demonstrated RT mutation at 184.
  • 10. New Concepts
    • Concept of Compartment Specific Mono-therapy
  • 11. HIV infection occurs inactivated and resting PMBC. Does state of cell cycle impact antiviral activity of approved antiretroviral drug?
  • 12. What is the Impact of Cell Cycle on the Anti-Viral Activity of RT Inhibitors? AZT has potent antiviral Activity in activated HIV infected cells HIV-1 p24 antigen (ng/ml) AZT –Activated Cell Infection 0 0.03 0.1 0.3 1 4 0 1000 2000 3000 4000 5000
  • 13. Cell Cycle and AZT Antiviral Activity AZT limited antiviral Activity in resting HIV infected cells 0 0.03 0.1 0.3 1 4 0 200 400 600 800 AZT - Resting Cell Infection HIV-1 p24 antigen (ng/ml)
  • 14. Cell Cycle and DDI antiviral activity DDI has limited antiviral Activity in activated HIV infected cells 0 0.1 0.3 1 3 10 0 1000 2000 3000 DDI - Activated Cell Infection HIV-1 p24 antigen (ng/ml)
  • 15. Cell Cycle and DDI antiviral activity DDI has antiviral activity in only resting HIV infected cells 0 0.1 0.3 1 3 10 0 200 400 600 800 DDI-Resting Cell Infection HIV-1 p24 antigen (ng/ml)
  • 16. 0 0.04 0.14 0.4 1.3 4 0 1000 2000 3000 Abacavir- Activated Cell Infection HIV-1 p24 antigen (ng/ml) Cell Cycle and Antiviral Activity: Abacavir
  • 17. 0 0.04 0.14 0.4 1.3 4 0 100 200 300 400 500 600 Abacavir- Resting Cell Infection HIV-1 p24 antigen (ng/ml) Cell Cycle and Antiviral Activity: Abacavir
  • 18. Impact of Cell Cycle on Antiviral Activity of Approved Antiretroviral Drugs 2004
    • Cell Cycle Dependent Drugs
      • AZT, D4T ( activated cells)
      • DDI (resting cells)
      • Combivir, Trizavir (activated cells for AZT)
      • Protease Inhibitors (activated cells)
    • Cell Cycle Independent Drugs
      • 3TC, FTC, Abacavir
      • Tenofovir
      • Truvada
      • Epzicom
      • NNRTIs
  • 19. New Concepts
    • Did wide scale use of compartment specific “mono-therapy” in the late 1990’s contributed to limited durability of early 2NRTI PI based regimens?
  • 20. Case 2
    • Patient is a 23 year old white male who was diagnosed with HIV infection after he presented in 2002 to his PMD for a medical evaluation increasing fatigue. He had several different sexual partners in NYC between 1982-1984; however, he has not been involved in sexual activity since his partner got sick with AIDS in 1992.
    • His CD4 ranged 190-256 cells/mm3 and viral load ranged 368,000-478,000 copies/ml. After extensive discussion with his PMD he began treatment with AZT, 3TC and Sustiva.
    • After 12 week viral load was 12,000 copies/ml.
    • Genotype was drawn.
    • Patient did not return to clinic until 8 weeks later.
    • At 20 weeks post treatment his viral load was 47,000 copies/ml. Genotype was repeated.
  • 21. Case 2
    • Genotype at 12 weeks
      • 184V
    • Genotype at 20 weeks
      • 184V
      • 103N
  • 22. How Quickly Resistance Can Occur Depends on the Viral Load Adapted from Siliciano, 2002 1,000 30 100 300 10 3,000 1 30,000 0.1 300,000 Days Before Mutation Arises Viral Load
  • 23. New Concepts
    • Does the wide scale use of low mutation threshold 3TC and NNRTI “protected” by a thymidine analog (AZT or DT4) contributed to limited durability of these regimens?
  • 24. New Concepts
    • Concept of Specific NRTI-NRTI interaction
  • 25. Recent Developments
    • High failure Rates for selected 3NRTI based regimens
      • D4T, DDI Abacavir- Gerstoff et.al AIDS 2003
      • Tenofovir, Abacavir, 3TC – Farthing et. Al 2 nd ISA Paris 2003
      • Tenofovir abacavir, 3TC- Gallant et al ICAAC Chicago 2003
      • Tenofovir, DDI, 3TC – Jemsek personal communication/Gilead Warning letter 2003
  • 26. Therapeutic Strategies to Target Cellular Enzymes and Cell Cycle RIBOSE-5P + ATP PRPP GUANINE GUANOSINE MP INOSINE MP ADENOSINE MP DEOXYGUANOSINE DP DEOXYADENOSINE DP DEOXYGUANOSINE TP DEOXYADENOSINE TP DNA DNA IMP dehydrogenase ADA Mycophenolic Acid HGPRTase PRPP Salvage Pathway PRPP Synthetase DeNovo Pathway Ribonucleotide reductase Hydroxyurea Ribonucleotide reductase AS
  • 27. Early Virologic Response*: COL40263 vs ESS30009 ESS30009 N = 80 N = 22 N = 102 COL40263 N = 36 N = 52 N = 88 (ABC/3TC + TDF QD) (ABC/3TC/ZDV + TDF QD) * Based on early virologic non-response criteria used in ESS30009: 1: <2 log drop from baseline by week 8 and HIV-1 RNA  50 copies/mL by week 8 2:  1 log increase above nadir at or before 8 weeks 56% 83% 32% 71% 51% 76% Elion R, et al . 11 th CROI, San Francisco 2004, #53.
  • 28. New Concepts
    • Concept of Dynamic Adherence Threshold
  • 29. Correlation Between Adherence* and Virologic Suppression † (N = 84) % Patients With HIV-1 RNA <400 copies/mL Level of Adherence, % *Adherence was measured by MEMScaps electronic pill monitoring device. † P = .00001.Data from Paterson et al. Poster presented at: 6th Conference on Retroviruses and Opportunistic Infections; January 31–February 4, 1999; Chicago, Ill. Poster 92. 70 60 50 40 30 20 10 0 80 90 >95 90–95 80–90 70–80 <70
  • 30. Relationship Between Adherence and HIV Suppression * Series of 886 treatment-naive HIV patients; CD4 cell count <500 x 10 6 cells/L or plasma viral load >5000 copies/mL. † Prospective, observational study of 81 HIV patients. ‡ MEMS, Medication Events Monitoring System. 1. Low-Beer S et al. JAIDS . 2000;23:360-361. Letter. 2. Paterson DL et al. Ann Intern Med . 2000;133:21-30. 2
  • 31. Consistency in viral rebound dynamics Davey et al. PNAS 1996 Davey et al. demonstrated in 18 patients that mean time to viral load rebound above 50copies/ml and 500copies/ml was 11 and 18 days respectively.
  • 32. New Concept Dynamic Adherence Threshold
    • Key variables
      • in vivo replication kinetics
      • mutation threshold of regimen
      • pk profile of regimen
  • 33. “JACQUES Initiative”
    • J Joint
    • A AIDS
    • C Community-wide
    • Q Quest for
    • U Unique and
    • E Effective treatment
    • S Strategies
    A program designed by and for the community .
  • 34. The JACQUES Initiative (J.I.) A new care delivery model Integrating treatment preparation, clinical management and treatment support for long term treatment success Jacques Initiative J.I. Staff serves as an extension to referring provider Clinical Management Treatment Preparation Treatment Support Directly Observed Therapy (DOT) Our staff will assist and observe the medicine being taken on site or in the community. HIV 101 Workshop Life Skills Workshop Care Partner Supported (CP) - This option is for someone who chooses to be supported by a friend or relative, not HIV positive Treatment Partner (TP) - This system is modeled as a buddy system where two HIV positive people plan together to support each other with therapy Treatment Coach Observed/Supported – A coach from our staff will observe and/or support you with therapy Weekly Observed Therapy (WOT) – This option involves a weekly exchange of a pre-filled pill box
  • 35. New Concepts
    • Treatment Preparation
      • Patient and support system
    • Targeted Treatment Support
      • Intensive daily treatment support for first 6-12 weeks and then de-intensify
      • Menu of treatment support options
      • Role of Treatment Specialist and Treatment Coaches
      • Integrate support groups into treatment care plan
      • Proactive treatment interruption prior to treatment failure when co-morbidities flair such as relapsed SA and depression
  • 36. Case 4
    • Patient presented (in 1997) as a 33 year old Hispanic male with a 12 year history of HIV infection complicated with PML associated with significant neurological impairment. CD 4 <20 cells/mm3; Viral load >750,000.
    • Patient had a history of antiretroviral in the late 1980’s early 1990’s to include use of AZT, DDI, 3TC; however he has not used AVR sense 1994.
    • Patient was treated with Nelfinavir, Saquinavir and Sustiva.
    • Over the next 6 years, the patient experienced progressive CD4 immune reconstitution (CD 4 450-625 range) associated with sustained viral suppression (VL < 50 copies/ml
    • After over 6 years, in 2002 simplification of patients regimen was considered.
  • 37. Case 4
    • Patient was placed on Tenofovir, DDI , 3TC
    • Viral load 2 weeks 763, at 4 weeks 3890, 6 weeks 58,000. CD4 cell count dropped to 269
    • Viral genotype at week 4 demonstrated multiple RT mutations consistent with previous NRTI history
    • High input genotype 2 week sample confirmed multiple RT mutations.
    • Initial PI NNRTI regimen was restarted. Patient re-suppressed. VL remains < 50 copies. CD4 cell count continues to increase (620-700 range 1/2004)
  • 38. ACTG 398: HIV-1 RNA response (log 10 copies/ml) by NNRTI Experience and NNRTI mutations
  • 39. New Concepts
    • Resistance is unforgiving.
    • What is the long term consequences of development of specific mutations associated with decreased antiviral susceptibility?
    • Consider the implication related to PEPFAR and MTCTP plus programs unfolding in Africa
  • 40. Case 5
    • Patient is a 19 year old African female in labor (2003) HIV diagnosis was confirmed three years earlier when she tested HIV positive during delivery of her first child. She and her child were treated with single dose Nevirapine as part of MTCT program in Cameroon.
    • Her CD4 cell count was 220; viral load 78,000 copies.ml.
  • 41. Case 5
    • During delivery she and her newborn completed AZT MTCT program. After recovering from childbirth she discussed ARV treatment option with her PMD and was started on Trizavir and Sustiva.
    • Viral load at 6 weeks was > 50 copies. By 6 months CD4 cell count had increased to 315.
    • At 14 months viral load was 3500. Repeat at month 15 was 127,000.
  • 42. Case 5
    • Viral genotype demonstrated 184V, 103N, 181Y and several TAM’s.
    • Plasma from 6, 12 and 24 weeks was evaluated for variants
      • 6 week genotype: 181Y
      • 12 week genotype 181Y
      • 24 week genotype 181Y, 103N, 184V
  • 43. Response to d4T/3TC/NVP in mothers based on previous history of single-dose NVP No NVP NVP No Mutation NVP + Mutation 42 139 81 37 112 58 28 110 50 0% 30% 60% 90% Baseline 3 months 6 months Jourdain G, et al. 11 th CROI 2004 Abstract #41 % With Virologic Suppression 7% 2% 0% 86% 88% 79% 86% 80% 68% <400 copies/mL 1% 0% 0% 59% 44% 43% 75% 53% 34% <50 copies/mL * Significant * *
  • 44. New Concepts
    • Could the current MTCT program negatively impact general ART programs. If so how could this be minimized?
    • Use alternative MTCT regimen
      • Single drug with high mutation threshold and or limited pk profile as single dose drug
      • Use drugs with matched pk profile
  • 45. Stopping drugs with different half lives 0 24 48 36 12 Time (hours) Drug concentration Zone of potential replication IC 90 IC 50 Last Dose Day 1 Day 2 S. Taylor et al. 11th CROI Abs 131 MONOTHERAPY
  • 46. New Concepts
    • Use regimens with similar Pk profile
    • Prolong tail of NNRTI post single dose NVP or discontinuation of NNRTI
    • Long acting may not always be better. Needs to be combined with drugs with similar pk profile
  • 47. Durability: Key Variables
    • Potency of primary regimen
    • Treatment Adherence especially during the induction of viral control
    • PK profile of regimen
    • Background Resistance
    • Mutation threshold of ARVs used especially during induction of viral control
  • 48. Key Factors for Improved Durability:
    • Working Hypothesis: Events that occur in during the initial induction of viral control largely determine the durability of antiretroviral induced viral control.
    • Key Factors
      • Role of compartment specific ART
      • Role of enhanced treatment support especially during induction of viral control – impact of drug side effect profile on adherence
      • Use of high Mutation Threshold Regimens
        • Does the use of low mutation drugs during induction of viral control contribute to limited durability?
      • Use of antiretroviral drugs in regimen with similar
      • pk profiles
  • 49. Key Factors for Improved Durability:
    • Prevent Chronic Toxicity – major cause of ARV regimen changes
      • Minimize long term drug induced toxicity
      • Minimize mitochondrial toxicity
      • Minimize development of chronic metabolic toxicity
      • Minimize drug induced changes in body habitus changes
  • 50. New Approaches to Treatment under Investigation at IHV: Targeting Host Cell Pathways for Therapeutic Potential
    • Modulating Cell Cycle
      • Antiretroviral activity and Cell Cycle
      • Use of cell cycle agents
        • Use of inhibitors of cellular enzymes to potentate nucleoside analogs
        • Use of S phase agents to potentate nucleoside analogs
        • Modification of chemokine and co-receptor dynamics CCR5
        • Inhibitors of specific CD kinases
    • Targeting cellular receptors
      • Entry Inhibitors ( CCR5 antagonist)
      • Role of sialic acid and sialidase inhibitors
    • Therapeutic Vaccines: non-structural protein targets and cell receptor HIV envelope complexes
  • 51. HIV Pathogenesis
    • CCR5 co-receptor usage and HIV
      • CCR5 co-receptor using virus key in HIV transmission
      • CCR5 co-receptor using virus dominant in early HIV infection
    • CCR5 co-receptor beta chemokines dynamics and HIV
      • Decrease infection rate of delta 32 CCR5 host
      • Decrease infection rate among risk populations with increase basal beta chemokine production
    • Inter-relationship between increase cellular activation and increase CCR5
  • 52.  
  • 53. High expression of activation markers and CCR5 in advanced HIV-1 infection: Percent CD4 Percent CD4 Disease progression
  • 54. CCR5 expression predicts disease progression CCR5 CXCR4 : PRESEROCONVERSION 5 YEARS AFTER SEROC . Van Rij et al. (2003) AIDS Res Hum Retrov 19:389. “ low” CCR5 “ high” CCR5 “ low” CCR5 “ high” CCR5 “ high” CXCR4 “ high” CXCR4
  • 55. Strategies to Alter CCR5 co-receptor Dynamics
    • Block CCR5 receptor (antagonist/antibody)
    • Augmentation of Beta-Chemokine production and/or extracellular Beta-Chemokine levels
    • Change or alter CCR5 expression
  • 56. Proof of Concept: In vivo anti-HIV activity of prototype CCR5 antagonist SCH C: “Monotherapy” in HIV Infected Volunteers
  • 57. Rapamycin
    • Rapamycin is a marcocyclic lactone produced by Streptomyces hygroscopicus
    • Inhibits T Lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (IL-2,IL-4 and IL-15) stimulation
    • Binds to immunophilin K binding protein 12 to generate an immunosuppressive complex
    • Inhibits progression of cell from G1 to S phase
    • Approved for use in US as an immunosuppressive agent used in solid organ transplantation
  • 58. RAPA inhibits CCR5-using HIV-1 0 20 40 60 80 100 p24 (ng/ml) No RAPA RAPA 0.01 nM RAPA 0.1 nM RAPA 1 nM IIIb ADA BaL JRCSF JRFL SF162 0.2 0.4 0.6 0.8 1.0 1.2 MTT (O.D. 490 ) 0 .01 .1 1 RAPA (nM)
  • 59. CD4 M 100 10 1 0 RAPA (nM) CCR5 18S FL2-H # Cells FL2-H # Cells FL2-H # Cells FL2-H # Cells 1 nM RAPA 100 nM RAPA Rapamycin inhibits CCR5 expression (RNA and protein levels) 1 10 100 1000 10000 0 50 100 150 200 1 10 100 1000 10000 0 50 100 150 200 1 10 100 1000 10000 0 50 100 150 200 1 10 100 1000 10000 0 50 100 150 200 10000
  • 60. RAPA-mediated reduction of CCR5 expression results in accumulation of beta-chemokines RANTES MIP 1∞ MIP 1 ß 0 10000 20000 30000 40000 50000 Chemokines (pg/ml) RAPA (nM): 0 1 10 100 0 20 40 60 80 % CCR5 RAPA (nM): 0 1 10 100
  • 61.  
  • 62. Potential Role in Treatment of HIV Infection
    • Synergize with CCR5 antagonist
    • Primary treatment for early infection alone or in conjunction with other therapy
    • Strategy to decrease dependency on standard ART
      • Cycle therapy
      • De-intensification
      • Role in induction maintenance
    • Increase durability of primary ARV regimens
  • 63. Potential Role in Prevention of HIV Infection
    • Block mother to child transmission breast milk transmission
    • Role in chemoprophylaxis
    • Potential in increase efficacy of marginal preventive vaccine
    • Potential in increase immunogenicity of HIV vaccine
  • 64. Clinical Translation to evaluate role of G1 cell cycle agents: Proof of Concept Trials in progress at IHV
    • Phase 1 Pilot Study Rapamycin in Healthy Volunteers ( completed Fall 2003)
    • Phase 1 Pilot Study: Monotherapy with Rapamycin in HIV infected volunteers with CD4 counts > 350 cells/mm
      • Enrollment closed
      • Study visits competed June 2004, analysis in progress
    • Phase 1 Pilot: Prolonged Cycle Therapy (ART plus HU cycled with HU alone
      • Initial 3 week cycle closed to enrollment ( Spring 2004)
      • Initiation of 4 week cycle ( Spring 2004) actively enrolling
    • Phase 1 Pilot: Treatment De-intensification-HADIT study using Tenofovir and HU: Actively enrolling
  • 65. New Approaches to Treatment: Targeting Host Cell Pathways for Therapeutic Potential
    • Modulating Cell Cycle
      • Antiretroviral activity and Cell Cycle
      • Use of cell cycle agents
        • Use of inhibitors of cellular enzymes to potentate nucleoside analogs
        • Use of S phase agents to potentate nucleoside analogs
        • Modification of chemokine and co-receptor dynamics CCR5
        • Inhibitors of specific CD kinases
    • Targeting cellular receptors
      • Entry Inhibitors ( CCR5 antagonist)
      • Role of sialic acid and sialidase inhibitors
    • Therapeutic Vaccines: non-structural protein targets and cell receptor HIV envelope complexes
  • 66.
    • Inhibition of HIV-1 by targeting cellular components: Key Advantage: Viral drug resistance is much less likely to emerge under drug pressure
    • Targeting of cellular enzymes in nucleotide biosynthesis pathways: Ribonucleotide Reductase (hydroxyurea), IM Dehydrogenase (Mycophenolic acid), Resveratrol
    • Targeting of virus coreceptors: CCR5 (Rapamycin and other G1 cell cycle agents)
    • Targeting of Cyclin Dependent Kinases
  • 67. (Full-length viral transcripts. Virus production) ( Short viral transcripts. No virus production) Tat is essential for HIV-1 replication HIV provirus
  • 68. Inhibition of HIV-1 by targeting CDKs with Indirubin
    • Indirubin is a compound extracted from the medicinal herb Isantis tinctoria . Its use is approved in China for the treatment of Chronic Mielogenous Leukaemia (CML)
    • Indirubin exerts anticancer activity by inhibiting CDKs
  • 69. 10000 20000 30000 day 7 day 13 day 21 day 28 RT (CPM) MTT (O.D. 490 ) day 28 a) b) IM (µM): 0 0.2 0.5 1 2 4 IM0 IM.25 IM.5 IM1 IM2 IM4 0.0 0.1 0.2 0.3 0.4
  • 70. M 16 8 4 0 IR (µM) M 16 8 4 0 IR (µM) Multiple-spliced HIV-1 transcripts Full-length, unspliced HIV-1 transcripts Indirubin inhibits HIV-1 by blocking synthesis of full-length, unspliced viral transcripts
  • 71. p 24 (ng/ml) MTT (O.D.) 74V,41L,106A,215Y (RTMDR) 46I,63P,82T,184V (PI Resistant) 103N,181C (NNRT Resistant) 305R,308P,316V,321E (SCH-C Resistant) wild type (drug sensitive) No IM 1µM IM 4µM IM 74V,41L,106A,215Y (RTMDR) 46I,63P,82T,184V (PI Resistant) 103N,181C (NNRT Resistant) 305R,308P,316V,321E (SCH-C Resistant) wild type (drug sensitive) IM inhibits drug-resistant HIV-1 0 50 100 150 200 0.0 0.2 0.4 0.6 0.8 1.0
  • 72. Clinical Development Status to evaluate role of CDK 9 inhibitors as Novel Treatment Strategy for HIV
    • IND under development
    • Phase 1 Pilot Proof of concept trial under development
      • patient population: patients with MDRV and 3 class cross class ARV drug resistance
      • Planned start date late fall 2004
  • 73. New Directions in Antiretroviral Therapy
    • Development of specific regimens for specific clinical situation
      • Treatment Naïve:
        • Development of Induction Maintenance regimens
        • Use of new fixed dose combinations
      • Viral suppressed:
        • De-intensification regimens
      • Deep Salvage:
        • Bridging regimens
        • New class of agents
      • Regimens designed for initiation of treatment early in disease course
        • Therapeutic strategies that target CCR5
        • Chemotherapy Induction/Maintenance
        • Role of new fixed dose combinations