Download presentation
Presentation is loading. Please wait.
Published byKaren Allen Modified over 8 years ago
1
Update on HIV Therapy Hail M. Al-Abdely, MD Consultant, Infectious Diseases
2
Virus in Plasma Symptoms Detectable VIRUS IN PLASMA Detectable Time 012 Years InfectionDeath Clinical, Virological and Immunological Course of HIV Infection
3
CD4 Cell Count Virus in Plasma Symptoms Detectable VIRUS IN PLASMA Detectable > 500 cells CD4 COUNTS < 200 cells Time 012 Years InfectionDeath Clinical, Virological and Immunological Course of HIV Infection
4
CD4 Cell Count Virus in Plasma Symptoms Detectable VIRUS IN PLASMA Detectable > 500 cells CD4 COUNTS < 200 cells SeroconversionAsymptomaticAIDS Time 012 Years InfectionDeath Clinical, Virological and Immunological Course of HIV Infection
5
CD4 Cell Count RNA in Plasma Virus in Plasma Symptoms Detectable VIRUS IN PLASMA Detectable > 500 cells CD4 COUNTS < 200 cells SeroconversionAsymptomaticAIDS Time 012 Years InfectionDeath Clinical, Virological and Immunological Course of HIV Infection
6
HIV infection J. Coffin, XI International Conf. on AIDS, Vancouver, 1996 Development of AIDS is like an impending train wreck Viral Load = Speed of the train CD4 count = Distance from cliff
7
Productively infected CD4 lymphocytes Latently infected CD4 lymphocytes HIV Uninfected CD4 lymphocytes Uninfected activated CD4 lymphocytes Long-lived cell populations CD4 lymphocytes infected with defective virus 2.6 days per generation 99% <1% T 1/2 ~1.6d <1% T1/2 ~5.7 hrs Viral Dynamics of HIV-1 Infection Perelson et.al. Science 271:1582 (1996)
8
Viral dynamics u It takes 2.6 days to produce a new generation of viral particles u Estimated total HIV production is 10.3 x 10 9 virions per day u 99% of the virus pool is produced by recently infected cells u Retroviral therapy should be able to reduce viral load within a few days
9
GOALS OF THERAPY Clinical goals: Prolongation of life and improved quality of life Virologic goals: Reduction in viral load as much as possible for as long as possible to: 1) halt disease progression, and 2) prevent/reduce resistant variants Immunologic goals: Achieve immune reconstitution that is quantitative (CD4 to normal range) and qualitative (pathogen-specific immune response) Therapeutic goals: Rational sequencing of drugs in a fashion that achieves virologic goals, but also: 1) maintains therapeutic options; 2) is relatively free of side effects; and 3) is realistic in terms of probability of adherence Epidemiologic goals: Reduce HIV transmission
10
19 1
11
Generic NameClassFDA Approval Date Zidovudine, AZT NRTIMarch 87 Didanosine, ddI NRTIOctober 91 Zalcitabine, ddC NRTIJune 92 Stavudine, d4T NRTIJune 94 Lamivudine, 3TC NRTINovember 95 Saquinavir, SQV, hgcPIDecember 95 Ritonavir, RTVPIMarch 96 Indinavir, IDVPIMarch 96 Nevirapine, NVPNNRTIJune 96 Nelfinavir, NFVPIMarch 97 Delavirdine, DLVNNRTIApril 97 Combivir (AZT+3TC)NRTISeptember 97 Saquinavir, SQV, sgcPINovember 97 Efavirenz, EFVNNRTISeptember 98 Abacavir, ABC NRTIFebruary 99 Amprenavir (AMP) PIApril 99 Lopinavir (LPV) PISeptember 00 EC Didanosine(EC DDI) NRTISeptember 00 Trizivir (AZT+3TC+ABC) NRTISeptember 00 Antiretroviral Drugs Approved by FDA for HIV
12
RT Provirus Proteins RNA RT Viral protease Reverse transcriptase RNA DNA Current antiretroviral targets ZDV, ddI, ddC, d4T, 3TC, ABC, DLV, NVP, EFV SQV RTV IDV NFV APV LPV
13
Monotherapy Dual therapy Triple therapy Viral Suppression with Monotherapy versus Multiple Drugs
15
**Preliminary 1998 data Trends in Age-Adjusted* Rates of Death due to HIV Infection, USA, 1982-1998 *Using the age distribution of the projected year 2000 US population as the standard.
16
Highly active antiretroviral therapy has Changed our view toward HIV from inevitably fatal to a manageable disease over several decades Good News
17
1.Incomplete response 2.Complexity of treatment 3.Short and long term side effects 4.Resistance 5.Drug-drug interactions Bad News
19
Monotherapy Dual therapy Triple therapy Viral Suppression with Monotherapy versus Multiple Drugs
20
Virologic nadir predicts duration of response
21
Bad News
23
DrugCommon Side effects Zidovudine (azt, zdv) Initial nausea, headache, fatigue, anemia, neutropenia, neuropathy, myopathy. Lamivudine (3TC) GI side effects. Didanosine (ddl) GI side effects. Peripheral neuropathy in 15%, pancreatitis. Zalcitabine (ddC) Peripheral neuropathy in 17-31% of trial participants; oral ulcers. Stavudine (d4T) Peripheral neuropathy (1-4% in early studies; 24% in expanded access patients with CD4+ counts < 50) Abacavir (ABC) About 3%-5% hypersensitivity reaction: malaise, fever, possible rash, GI. Resolves within 2 days after discontinuation. Side Effects of NRTIs
24
DrugCommon Side effects Delavirdine Transient rash. P450 3A4 inhibitor Nevirapine Transient rash, hepatitis. P450 3A4 inducer. Efavirenz Initial dizziness, insomnia, transient rash, P450 3A4 inducer. Side Effects of NNRTIs
25
DrugCommon Side effects Amprenavir Rash (20%), diarrhea, nausea Indinavir Kidney stones in 6 to 8%: good hydration essential. Occasional nausea and GI upset. Nelfinavir Diarrhea common; occasional nausea Ritonavir Nausea, diarrhea, numb lips for up to 5 weeks; occasional hepatitis. Saquinavir Nausea, diarrhea. Side Effects of PIs
26
Metabolic Complications of PIs Hyperbilirubinemia Hyperlipidemia –Coronary artery disease Insulin resistance Abnormal fat distribution. Lipodystrophy
28
Bad News
29
Drug CategoryIndinavirRitonavir**SaquinavirNelfinavirAmprenavirNevirapineDelavirdineEfavirenz Ca++ channel blocker (none)bepridil(none) bepridil(none) Cardiac(none)amioderone flecainide propafenone quinidine (none) Lipid Lowering Agents simvastatin lovastatin (none)simvastatin lovastatin (none) Anti- Mycobacterial rifampinnonerifampin rifabutin rifampin (none)rifampin rifabutin (none) Antihistamineastemizole terfenadine (none)astemizole terfenadine Gastrointestinal Drugs cisapride (none)cisapride H-2 blockers Proton pump inhibitors cisapride Neuroleptic(none)clozapine pimozide (none) Psychotropicmidazolam triazolam (none)midazolam triazolam Drugs That Should Not Be Used With Antiretrovirals
30
Bad News
31
Resistance AgentResistance mutations ZDV416769*70151210215219333 3TC69*151184333 ddI6569*74151184 ddC656969*74151184 d4T5069*75151178 ABC6569*74115151184 AgentResistance mutations DLV103181236 EFV100103108179181188190225 NV100103106108181188190 Genotypic Mutations Associated With Resistance to NRTI & NNRTIs
32
Resistance Genotypic Mutations Associated With Resistance to PIs AgentResistance mutations APV1036464748505463718284 IDV1020243236464854637173828490 NFV10303646487182848890 RTV102032333646546371828490 SQV1020243036464854637173828490 LPV103246475084
33
Overcoming Drug Resistance Change to a drug to which virus shows greater susceptibility Increase exposure to drug RESISTANCE Drug
34
Change to a drug to which virus shows greater susceptibility Overcoming Drug Resistance Guided by Genotypic resistance testing
35
Switching within a drug class Example - Switching within PI class of drugs: Primary mutation associated with reduced susceptibility to nelfinavir is D30N Timely switching of patients on a failing NFV regimen harboring D30N has resulted in good clinical response New PI regimen has increased susceptibility due to non-cross resistance to D30N
36
Switching to a different drug class Often switching within a drug class not effective due to class cross-resistance –NRTI: Q151M, 69 insertion (other multiple MU) –NNRTI: K103N (others) –PI: G48V + V82A (other multiple primary) Switching to new class of drugs not previously used most effective
37
0 5 10 15 20 25 30 35 0 36912 Randomized Study Months Percentage of patients with plasma HIV-RNA below 200 copies/ml in the VIRADAPT study ) (Adapted from Clevenbergh et al. Antiviral Therapy 2000; 5:65–70) % <200 copies/ml Control Genotypic
38
0 5 10 15 20 25 30 35 0 36912 Randomized Study Open Study Months Percentage of patients with plasma HIV-RNA below 200 copies/ml in the VIRADAPT study ) (Adapted from Clevenbergh et al. Antiviral Therapy 2000; 5:65–70) % <200 copies/ml Control Genotypic
39
Change to a drug to which virus shows greater susceptibility Increase exposure to drug RESISTANCE Drug Overcoming Drug Resistance
40
Saquinavir boosted by ritonavir Fortovase 1600 mg + ritonavir 100 mg qd Fortovase 1200 mg tid Time (hours) 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 0510152025 SQV conc (ng/mL) Kilby et al. Antimicrob Agents Chemother Vol 44 2000
41
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 0510152025 Increase - above efficacy, below toxicity Time (hours) Drug conc (ng/mL) Drug A Drug A level required to overcome WT virus
42
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 0510152025 Time (hours) Drug conc (ng/mL) Drug A Boosted Drug A Drug A level required to overcome “resistant” virus Drug A level required to overcome WT virus Increase - above efficacy, below toxicity
43
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 0510152025 Time (hours) Drug conc (ng/mL) Drug A Toxicity threshold Drug A Boosted Drug A Drug A level required to overcome “resistant” virus Drug A level required to overcome WT virus Increase - above efficacy, below toxicity
44
The benefits of therapeutic drug monitoring -1.55 -1.35 -1.15 -0.95 -0.75 -0.55 -0.35 -0.15 0.05 036 Months HIV RNA* * viral load from baseline, log 10 copies/ml Control sub-optimal concentration (Adapted from Garaffo et al. Antiviral Therapy 1999; 4 (Suppl 1):75– 76)
45
The benefits of therapeutic drug monitoring (Adapted from Garaffo et al. Antiviral Therapy 1999; 4 (Suppl 1):75– 76) -1.55 -1.35 -1.15 -0.95 -0.75 -0.55 -0.35 -0.15 0.05 036 Months HIV RNA* * viral load from baseline, log 10 copies/ml Control sub-optimal concentration Genotypic sub-optimal concentration
46
The benefits of therapeutic drug monitoring -1.55 -1.35 -1.15 -0.95 -0.75 -0.55 -0.35 -0.15 0.05 036 Months Control optimal concentration HIV RNA* * viral load from baseline, log 10 copies/ml Control sub-optimal concentration Genotypic sub-optimal concentration (Adapted from Garaffo et al. Antiviral Therapy 1999; 4 (Suppl 1):75– 76)
47
The benefits of therapeutic drug monitoring -1.55 -1.35 -1.15 -0.95 -0.75 -0.55 -0.35 -0.15 0.05 036 Months Control optimal concentration Genotypic optimal concentration HIV RNA* * viral load from baseline, log 10 copies/ml Control sub-optimal concentration Genotypic sub-optimal concentration (Adapted from Garaffo et al. Antiviral Therapy 1999; 4 (Suppl 1):75– 76)
48
Indications for the Initiation of Antiretroviral Therapy in the Chronically HIV-Infected Patient Clinical Category CD4+ T-Cell Count and HIV RNA Recommendation Symptomatic (AIDS, thrush, unexplained fever) Any valueTreat AsymptomaticCD4+ T Cells 10,000 (bDNA) or > 20,000 (RT-PCR) copies/mL Treatment should be offered. Strength of recommendation is based on prognosis for disease-free survival and willingness of the patient to accept therapy. AsymptomaticCD4+ T Cells > 350 cells/mm 3 and HIV RNA < 10,000 (bDNA) or < 20,000 (RT-PCR) copies/mL Many experts would delay therapy and observe; however, some experts would treat.
49
Recommended Antiretroviral Agents for Treatment of Established HIV Infection Column AColumn B Strongly recommended Efavirenz Indinavir Nelfinavir Ritonavir + Saquinavir (SGC or HGC*) Stavudine + Lamivudine Stavudine + Didanosine Zidovudine + Lamivudine Zidovudine + Didanosine Recommended as an alternative Abacavir Amprenavir Delavirdine Nelfinavir + Saquinavir-SGC Nevirapine Ritonavir Saquinavir-SGC Didanosine + Lamivudine Zidovudine + Zalcitabine No recommendation; insufficient data Hydroxyurea in combination with other antiretroviral drugs Ritonavir + Indinavir Ritonavir + Nelfinavir Not recommended; should not be offered (All monotherapies, whether from column A or B § ) Saquinavir-HGCStavudine + Zidovudine Zalcitabine + Lamivudine Zalcitabine + Stavudine Zalcitabine + Didanosine
50
New agents in the pipeline New agents should: 1.Exhibit high potency. 2.Adequate drug levels. 3.Activity against resistant isolates. 4.Penetration into all cellular and bodily compartments (eg, central nervous system, genital tract). 5.Favorable drug interaction profile. 6.Minimal side effects. 7.Convenient to take, with no food restrictions and minimal dosing requirements; preferably once daily.
51
RT Provirus Proteins RNA DNA RNA DNA RT Viral regulatory proteins Viral protease Reverse transcriptase Viral integrase RNA Binding, fusion and entry DNA Viral zinc-finger nucleocapsid proteins Potential new targets
52
HIV viral membrane fusion Stein et al. (1987) Cell 49: 664
53
CXCR4 CCR5 HIV CD4 Cell HIV interaction with CD4 cell
54
CD4 Attachment CXCR4 CCR5 HIV gp120 CD4 Cell gp41 HIV interaction with CD4 cell
55
CD4 Attachment CXCR4 CCR5 HIV gp120 CD4 Co-receptor Interaction Cell HIV gp41 HIV interaction with CD4 cell
56
CD4 Attachment CXCR4 CCR5 HIV gp120 Anchorage CD4 Co-receptor Interaction Cell HIV gp41 HIV interaction with CD4 cell
57
CD4 Attachment HR1-HR2 Interaction CXCR4 CCR5 HIV gp120 Anchorage CD4 Co-receptor Interaction Cell HIV gp41 HIV interaction with CD4 cell
58
Fusion Complete CD4 Attachment HR1-HR2 Interaction CXCR4 CCR5 HIV gp120 Anchorage CD4 Co-receptor Interaction Cell HIV gp41 HIV interaction with CD4 cell
59
ClassTargetExample Compounds Attachment Inhibitors gp120, CD4specific Mab, soluble CD4 and CD4-Ig Co-receptor Inhibitors CXCR-4AMD-3100 CCR-5SCH-C, specific Mab, Fusion Inhibitors gp41T-20, T-1249, D-peptides Entry inhibitors under development
60
HIV attachment inhibitors PRO 542 - Novel protein –Human IgG-2 Fv replaced with HIV binding domains of CD4 molecule –Neutralized broad range of HIV variants in vitro –Active in SCID-Hu model with primary isolates –Phase II clinical testing
61
PRO 542 (rCD4-IgG2) –Single injection dose-ranging trial ~4 doses, 3-6 subject/dose, HIV RNA > 3,000 CD4 > 50 ~Well tolerated, single dose non-immunogenic, linear pharmacokinetics ~6/6 high dose subjects had decrease in HIV RNA, infectious titers of virus declined HIV attachment inhibitors
62
Chemokine receptor inhibitors CCR-5 Inhibitors –SCH-C (Schering-Plough) –PRO 140 (anti-CCR-5 monoclonal antibody) CXCR-4 Inhibitors –AMD-3100
63
CCR-5 inhibitors: SCH-C Small molecule antagonist of CCR-5 PK profile in animals supports oral administration Active in SCID-hu Thy/Liv model against primary HIV Risk of switch to SI (CXCR-4) virus?
64
CXCR-4 inhibitors: AMD 3100 Targets CXCR-4 and dual tropic virus Resistance develops in vitro Active SCID-hu mouse (CXCR-4, dual tropic HIV) IV and SC administration well tolerated CXCR-4: importance in embryogenesis and immune function?
65
41 patients, monitored for 48 weeks after adding T-20 to failing therapy, and a mean HIV RNA decline of -1.4 log 10 copies/mL has been reported T-20 ( Fusion inhibitor)
66
New agents: 1.Emtricitabine (FTC, Coviracil) 2.DAPD/DXG 3.Emivirine (MKC-442, Coactinon). New formulations: 1.Enteric-coated didanosine (Videx EC). 400 mg once daily. 2.Extended-release formulation of stavudine. 3.Zidovudine +lamivudine + abacavir single tablet (Trizivir) New agents - NRTI
67
Emtricitabine: Fluorinated cytosine analogue with a similar resistance profile to lamivudine, but 4- to 10-fold more active in vitro. Administered once daily. Phase II study : given with didanosine and efavirenz once daily 93% of patients had HIV RNA below 50 copies/mL at week 24, and 48-week lone virologic failure in this study had rebounded from below 50 copies/mL to below 400 copies/mL. New agents - NRTI
68
DAPD: Guanosine analogue, which is metabolized to the active form, DXG. A 15-day monotherapy dose-ranging study in antiretroviral-naive patients demonstrated HIV RNA declines of 0.5-1.6 log 10 copies/mL, and 0.5-1.1 log 10 copies/mL in antiretroviral-experienced patients. No adverse events were reported during these studies. DAPD is likely to be active against HIV carrying the Q151M mutation, which confers cross-class resistance. New agents - NRTI
69
1.Lopinavir/ritonavir (ABT-378/r, Kaletra) – approved by FDA. 2.BMS-232632. 3.Tipranavir. 4.DMP-450. 5.PD 178390 New agents– Protease Inhibitors
70
Lopinavir/ritonavir (ABT-378/r, Kaletra): uses a low dose of ritonavir to achieve very high plasma levels of lopinavir, enabling it to retain activity against virus with low-to-moderate levels of resistance to PIs (including to lopinavir itself). 96% of patients with 0 to 5 PI mutations achieved HIV RNA less than 400 copies/mL at week 24 compared with 76% of those with 6 or 7 mutations and 33% of those with 8 to 10 mutations. New agents– Protease Inhibitors
71
BMS-232632: Active against 89% of virus isolates resistant to fewer than 4 PIs in vitro. Loss of sensitivity is correlated with high-level resistance to at least 4 PIs. High incidence of unconjugated hyperbilirubinemiaTipranavir Active against multi-PI resistant isolates. 87% of isolates > 10-fold resistance to 4 PIs remained completely susceptible to tipranavir in vitro New agents– Protease Inhibitors
72
New agents– NNRTI 1.Capravirine. 2.Emivirine 3.DMP-961 4.DMP-083 All show activity against viruses with 1 or more of the common NNRTI mutations.
73
Barriers to the Development of an Effective AIDS Vaccine Sequence variation Protective immunity in natural infection not clearly established Lack of adequate animal model to study vaccine protection with HIV Latency and integration of HIV into host genome Transmission by cell-associated virus Limited knowledge about mucosal transmission and immune responses Financial disincentives Ethical issues
74
Conclusion Better understanding of the HIV has allowed better treatment modalities. Cure is beyond reach at this stage, but patients can survive years to decades longer. More drugs and drug problems are on the horizon. Control of HIV replication by the host immune system may be the best outlook for future research. Intense vaccine research is ongoing and ultimately will be the major preventive measure against HIV infection
76
Immunotherapy
77
Immunotherapy Directions –Augmentation of specific immune response to control viral replication. –Preventive Vaccines.
78
Clues to immune control of HIV? Subject 161J: Sx: Fever, Rash, Headache Dx: HIV ELISA Neg. HIV ELISA Pos. F/U: No Rx Well at 19 yrs. CD4 1000 Viral Load < 500 Subject JP: Sx: Fever, Rash, Headache Dx: HIV ELISA Neg. HIV RNA >700,000 F/U: Extensive Rx AIDS at 11 mo. Rapid CD4 cell decline Viral Load >750,000
79
Acute HIV-1 infection Stimulation of HIV-1-specific immune CD4 cells (Helper cells) Infection of activated helper cells Loss of HIV-1-specific helper cells Generation of HIV-1-specific killer cells (CTL) Loss of CTL function due to inadequate HIV-1-specific helper cells Progression
80
T helper cells are the central orchestrator of the immune system CTL Function APC Function Cytokine productionAntibody Production B Cell Function NK Cell Function T helper cell
81
Acute HIV-1 infection Stimulation of HIV-1-specific immune CD4 cells (Helper cells) Protection of activated helper cells Maintenance of HIV-1- specific helper cells Generation of HIV-1-specific killer cells (CTL) Maintenance of CTL function due to adequate HIV-1-specific helper cells Antiviral Rx Nonprogression
82
HIV-1-specific T helper cells in individuals treated during acute infection (n=7) 1 10 100 MBJCKMNDSJDKKS 0 Months 2 Months
Similar presentations
© 2024 SlidePlayer.com Inc.
All rights reserved.