Update on HIV Therapy Hail M. Al-Abdely, MD Consultant, Infectious Diseases

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Update on HIV Therapy Hail M. Al-Abdely,
MDConsultant, Infectious Diseases
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Clinical, Virological and Immunological Course of
HIV Infection
Symptoms
Virus in Plasma
Infection
Death
Detectable VIRUS
IN PLASMA Detectable
Time 0
12 Years
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Clinical, Virological and Immunological Course of
HIV Infection
CD4 Cell Count
Symptoms
Virus in Plasma
Infection
Death
Detectable VIRUS
IN PLASMA Detectable
gt 500 cells CD4
COUNTS lt 200 cells
Time 0
12 Years
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Clinical, Virological and Immunological Course of
HIV Infection
CD4 Cell Count
Symptoms
Virus in Plasma
Infection
Death
Detectable VIRUS
IN PLASMA Detectable
gt 500 cells CD4
COUNTS lt 200 cells
Time 0
12 Years
Seroconversion
Asymptomatic
AIDS
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Clinical, Virological and Immunological Course of
HIV Infection
CD4 Cell Count
RNA in Plasma
Symptoms
Virus in Plasma
Infection
Death
Detectable VIRUS
IN PLASMA Detectable
gt 500 cells CD4
COUNTS lt 200 cells
Time 0
12 Years
Seroconversion
Asymptomatic
AIDS
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Development of AIDS is like an impending train
wreck Viral Load Speed of the train CD4
count Distance from cliff
HIV infection
J. Coffin, XI International Conf. on AIDS,
Vancouver, 1996
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Perelson et.al. Science 2711582 (1996)
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Viral dynamics

• It takes 2.6 days to produce a new generation of
  viral particles
• Estimated total HIV production is 10.3 x 109
  virions per day
• 99 of the virus pool is produced by recently
  infected cells
• Retroviral therapy should be able to reduce viral
  load within a few days

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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

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19
1
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Antiretroviral Drugs Approved by FDA for HIV
Generic Name Class FDA Approval Date
Zidovudine, AZT NRTI March 87
Didanosine, ddI NRTI October 91
Zalcitabine, ddC NRTI June 92
Stavudine, d4T NRTI June 94
Lamivudine, 3TC NRTI November 95
Saquinavir, SQV, hgc PI December 95
Ritonavir, RTV PI March 96
Indinavir, IDV PI March 96
Nevirapine, NVP NNRTI June 96
Nelfinavir, NFV PI March 97
Delavirdine, DLV NNRTI April 97
Combivir (AZT3TC) NRTI September 97
Saquinavir, SQV, sgc PI November 97
Efavirenz, EFV NNRTI September 98
Abacavir, ABC NRTI February 99
Amprenavir (AMP) PI April 99
Lopinavir (LPV) PI September 00
EC Didanosine(EC DDI) NRTI September 00
Trizivir (AZT3TCABC) NRTI September 00
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Current antiretroviral targets
Viral protease
SQV RTV IDV NFV APV LPV
RNA
RNA
Proteins
Reversetranscriptase
RT
RNA
RNA
ZDV, ddI, ddC, d4T, 3TC, ABC, DLV, NVP, EFV
DNA
RT
DNA
DNA
Provirus
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Viral Suppression with Monotherapy versus
Multiple Drugs
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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.
Preliminary 1998 data
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Good News
Highly active antiretroviral therapy has Changed
our view toward HIV from inevitably fatal to a
manageable disease over several decades
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Bad News

• Incomplete response
• Complexity of treatment
• Short and long term side effects
• Resistance
• Drug-drug interactions

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Bad News

• Incomplete response
• Complete RNA suppression and sustained CD4
  increase happens only in 60-80.
• Effectiveness is even lower in patients with high
  replication rates and extensive antiretroviral
  experience.
• Complexity of treatment
• Short and long term side effects
• Resistance
• Drug-drug interactions

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Viral Suppression with Monotherapy versus
Multiple Drugs
Triple therapy
Dual therapy
Monotherapy
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Virologic nadir predicts duration of response
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Bad News

• Incomplete response
• Complexity of treatment
• Too many tablets.
• Difficult schedule.
• Food factor
• Short and long term side effects
• Resistance
• Drug-drug interactions

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Bad News

• Incomplete response
• Complexity of treatment
• Short and long term side effects
• Drug-drug interactions
• Resistance

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Side Effects of NRTIs
Drug Common 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 lt 50)
Abacavir (ABC) About 3-5 hypersensitivity reaction malaise, fever, possible rash, GI. Resolves within 2 days after discontinuation.
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Side Effects of NNRTIs
Drug Common Side effects
Delavirdine Transient rash. P450 3A4 inhibitor
Nevirapine Transient rash, hepatitis. P450 3A4 inducer.
Efavirenz Initial dizziness, insomnia, transient rash,P450 3A4 inducer.
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Side Effects of PIs
Drug Common 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.
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Metabolic Complications of PIs

• Hyperbilirubinemia
• Hyperlipidemia
• Coronary artery disease
• Insulin resistance
• Abnormal fat distribution.
• Lipodystrophy

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Bad News

• Incomplete response
• Complexity of treatment
• Short and long term side effects
• Drug-drug interactions
• Resistance

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Drugs That Should Not Be Used With
Antiretrovirals
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Bad News

• Incomplete response
• Complexity of treatment
• Short and long term side effects
• Drug-drug interactions
• Resistance

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Resistance
Genotypic Mutations Associated With Resistance to
NRTI NNRTIs
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Resistance
Genotypic Mutations Associated With Resistance to
PIs
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Overcoming Drug Resistance
Increase exposure to drug
RESISTANCE
Change to a drug to which virus shows greater
susceptibility
Drug
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Overcoming Drug Resistance
Change to a drug to which virus shows greater
susceptibility
Guided by Genotypic resistance testing
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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

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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

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Percentage of patients with plasma HIV-RNA below
200 copies/ml in the VIRADAPT study
lt200 copies/ml
Randomized Study
35
30
25
Control
20
Genotypic
15
10
5
0
0
3
6
9
12
Months
(Adapted from Clevenbergh et al. Antiviral
Therapy 2000 56570)
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Percentage of patients with plasma HIV-RNA below
200 copies/ml in the VIRADAPT study
lt200 copies/ml
Open Study
Randomized Study
35
30
25
Control
20
Genotypic
15
10
5
0
0
3
6
9
12
Months
(Adapted from Clevenbergh et al. Antiviral
Therapy 2000 56570)
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Overcoming Drug Resistance
Increase exposure to drug
RESISTANCE
Change to a drug to which virus shows greater
susceptibility
Drug
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Saquinavir boosted by ritonavir
SQV conc (ng/mL)
9000
8000
Fortovase 1600 mg ritonavir 100 mg qd
7000
6000
5000
4000
Fortovase 1200 mg tid
3000
2000
1000
0
0
5
10
15
20
25
Time (hours)
Kilby et al. Antimicrob Agents Chemother Vol 44
2000
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Increase - above efficacy, below toxicity
Drug conc(ng/mL)
9000
8000
7000
6000
5000
4000
3000
2000
Drug A
1000
Drug A level required to overcome WT virus
0
0
5
10
15
20
25
Time (hours)
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Increase - above efficacy, below toxicity
Drug conc(ng/mL)
9000
8000
Boosted Drug A
7000
6000
5000
Drug A level required to overcome resistant
virus
4000
3000
2000
Drug A
1000
Drug A level required to overcome WT virus
0
0
5
10
15
20
25
Time (hours)
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Increase - above efficacy, below toxicity
Drug conc(ng/mL)
Drug A Toxicity threshold
9000
8000
Boosted Drug A
7000
6000
5000
Drug A level required to overcome resistant
virus
4000
3000
2000
Drug A
1000
Drug A level required to overcome WT virus
0
0
5
10
15
20
25
Time (hours)
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The benefits of therapeutic drug monitoring
HIV RNA
0.05
-0.15
Control sub-optimal concentration
-0.35
-0.55
-0.75
-0.95
-1.15
-1.35
-1.55
0
3
6
Months
? viral load from baseline, log10 copies/ml
(Adapted from Garaffo et al. Antiviral Therapy
1999 4 (Suppl 1)7576)
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The benefits of therapeutic drug monitoring
HIV RNA
0.05
-0.15
Control sub-optimal concentration
-0.35
-0.55
Genotypic sub-optimal concentration
-0.75
-0.95
-1.15
-1.35
-1.55
0
3
6
Months
? viral load from baseline, log10 copies/ml
(Adapted from Garaffo et al. Antiviral Therapy
1999 4 (Suppl 1)7576)
46
The benefits of therapeutic drug monitoring
HIV RNA
0.05
-0.15
Control sub-optimal concentration
-0.35
-0.55
Genotypic sub-optimal concentration
-0.75
Control optimal concentration
-0.95
-1.15
-1.35
-1.55
0
3
6
Months
? viral load from baseline, log10 copies/ml
(Adapted from Garaffo et al. Antiviral Therapy
1999 4 (Suppl 1)7576)
47
The benefits of therapeutic drug monitoring
HIV RNA
0.05
-0.15
Control sub-optimal concentration
-0.35
-0.55
Genotypic sub-optimal concentration
-0.75
Control optimal concentration
-0.95
-1.15
-1.35
Genotypic optimal concentration
-1.55
0
3
6
Months
? viral load from baseline, log10 copies/ml
(Adapted from Garaffo et al. Antiviral Therapy
1999 4 (Suppl 1)7576)
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Indications for the Initiation of Antiretroviral
Therapy in the Chronically HIV-Infected Patient
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Recommended Antiretroviral Agents for Treatment
of Established HIV Infection
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New agents in the pipeline

• New agents should
• Exhibit high potency.
• Adequate drug levels.
• Activity against resistant isolates.
• Penetration into all cellular and bodily
  compartments (eg, central nervous system, genital
  tract).
• Favorable drug interaction profile.
• Minimal side effects.
• Convenient to take, with no food restrictions and
  minimal dosing requirements preferably once
  daily.

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Potential new targets
Viral zinc-finger nucleocapsid proteins
Binding, fusionand entry
Viral protease
RNA
RNA
Proteins
Reversetranscriptase
RT
RNA
RNA
DNA
DNA
RT
Viral regulatory proteins
DNA
DNA
DNA
DNA
Provirus
Viral integrase
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HIV viral membrane fusion
Stein et al. (1987) Cell 49 664
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HIV interaction with CD4 cell
HIV
CXCR4 CCR5
CD4
Cell
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HIV interaction with CD4 cell
HIV
gp41
gp120
CD4 Attachment
CXCR4 CCR5
CD4
Cell
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HIV interaction with CD4 cell
Co-receptor Interaction
HIV
HIV
gp41
gp120
CD4 Attachment
CXCR4 CCR5
CD4
Cell
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HIV interaction with CD4 cell
Co-receptor Interaction
HIV
HIV
gp41
Anchorage
gp120
HIV
CD4 Attachment
CXCR4 CCR5
CD4
gp41
Cell
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HIV interaction with CD4 cell
Co-receptor Interaction
HIV
HIV
gp41
Anchorage
gp120
HIV
CD4 Attachment
CXCR4 CCR5
CD4
gp41
Cell
HIV
HR1-HR2 Interaction
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HIV interaction with CD4 cell
Co-receptor Interaction
HIV
HIV
gp41
Anchorage
gp120
HIV
CD4 Attachment
CXCR4 CCR5
CD4
gp41
Cell
Fusion Complete
HIV
HR1-HR2 Interaction
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Entry inhibitors under development
Class
Target
Example Compounds
Attachment Inhibitors
gp120, CD4
specific Mab,
soluble CD4 and CD4-Ig
Co-receptor Inhibitors
CXCR-4
AMD-3100
CCR-5
SCH-C, specific Mab,
Fusion Inhibitors
gp41
T-20, T-1249, D-peptides
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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

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HIV attachment inhibitors

• PRO 542 (rCD4-IgG2)
• Single injection dose-ranging trial
• 4 doses, 3-6 subject/dose, HIV RNA gt 3,000CD4 gt
  50
• Well tolerated, single dose non-immunogenic,
  linear pharmacokinetics
• 6/6 high dose subjects had decrease in HIV RNA,
  infectious titers of virus declined

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Chemokine receptor inhibitors

• CCR-5 Inhibitors
• SCH-C (Schering-Plough)
• PRO 140 (anti-CCR-5 monoclonal antibody)
• CXCR-4 Inhibitors
• AMD-3100

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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?

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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?

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T-20 (Fusion inhibitor)
41 patients, monitored for 48 weeks after
adding T-20 to failing therapy, and a mean HIV
RNA decline of -1.4 log10 copies/mL has been
reported
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New agents - NRTI

• New agents
• Emtricitabine (FTC, Coviracil)
• DAPD/DXG
• Emivirine (MKC-442, Coactinon).
• New formulations
• Enteric-coated didanosine (Videx EC). 400 mg once
  daily.
• Extended-release formulation of stavudine.
• Zidovudine lamivudine abacavir single tablet
  (Trizivir)

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New agents - NRTI

• 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.

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New agents - NRTI

• 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 log10 copies/mL, and
  0.5-1.1 log10 copies/mL in antiretroviral-experien
  ced 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.

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New agents Protease Inhibitors

1. Lopinavir/ritonavir (ABT-378/r, Kaletra)
   approved by FDA.
2. BMS-232632.
3. Tipranavir.
4. DMP-450.
5. PD 178390

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New agents Protease Inhibitors

• 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.

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New agents Protease Inhibitors

• 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 hyperbilirubinemia
  
• Tipranavir
• Active against multi-PI resistant isolates.
• 87 of isolates gt 10-fold resistance to 4 PIs
  remained completely susceptible to tipranavir in
  vitro

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New agents NNRTI

• Capravirine.
• Emivirine
• DMP-961
• DMP-083
• All show activity against viruses with 1 or more
  of the common NNRTI mutations.

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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

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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

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Immunotherapy
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Immunotherapy

• Directions
• Augmentation of specific immune response to
  control viral replication.
• Preventive Vaccines.

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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 lt 500
Subject JP Sx Fever, Rash, Headache Dx
HIV ELISA Neg. HIV RNA gt700,000 F/U
Extensive Rx AIDS at 11 mo. Rapid CD4 cell
decline Viral Load gt750,000
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Acute HIV-1 infection
Stimulation of HIV-1-specific immune CD4
cells (Helper cells)
Generation of HIV-1-specific killer cells (CTL)
Infection of activated helper cells
Loss of CTL function due to inadequate
HIV-1-specific helper cells
Loss of HIV-1-specific helper cells
Progression
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T helper cells are the central orchestrator of
the immune system
CTL Function
NK Cell Function
T helper cell
APC Function
B Cell Function
Cytokine production
Antibody Production
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Acute HIV-1 infection
Stimulation of HIV-1-specific immune CD4
cells (Helper cells)
Antiviral Rx
Generation of HIV-1-specific killer cells (CTL)
Protection of activated helper cells
Maintenance of CTL function due to adequate
HIV-1-specific helper cells
Maintenance of HIV-1-specific helper cells
Nonprogression
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HIV-1-specific T helper cells in individuals
treated during acute infection (n7)
1
0
0
1
0
1
M
B
J
C
K
M
N
D
S
J
D
K
K
S