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

Update on HIV Therapy Update on HIV Therapy

Hail M. Al-Abdely, MDHail M. Al-Abdely, MDConsultant, Infectious DiseasesConsultant, Infectious Diseases

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Clinical, Virological and Immunological Course of HIV Infection

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HIVinfection

J. Coffin, XI International Conf. on AIDS, Vancouver, 1996

Development of AIDS is like an Development of AIDS is like an impending train wreckimpending train wreck

Viral Load = Speed of the train Viral Load = Speed of the train CD4 count = Distance from cliffCD4 count = Distance from cliff

Productively infectedCD4 lymphocytes

Latently infectedCD4 lymphocytes

HIV

Uninfected CD4 lymphocytes

Uninfected activatedCD4 lymphocytes

Long-lived cell populations

CD4 lymphocytes infected with defective virus

2.6 daysper 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)Perelson et.al. Science 271:1582 (1996)

Viral dynamicsViral 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

GOALS OF THERAPY 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

191

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 (AZT+3TC) 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 (AZT+3TC+ABC) NRTI September 00

Antiretroviral Drugs Approved by FDA for HIVAntiretroviral Drugs Approved by FDA for HIV

RT

Provirus

ProteinsRNA

RNA

RT

Viral protease

Reversetranscriptase

RNA

RNA

DNA

DNA

DNA

Current antiretroviral targets

ZDV, ddI,ddC, d4T,3TC, ABC,

DLV, NVP,EFV

SQVRTVIDVNFVAPVLPV

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MonotherapyMonotherapy Dual therapyDual therapy Triple therapyTriple therapy

Viral Suppression with Monotherapy Viral Suppression with Monotherapy versus Multiple Drugsversus Multiple Drugs

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82 84 86 88 90 92 94 96 98**

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**Preliminary 1998 data

Trends in Age-Adjusted* Rates of Death due to HIV Infection,Trends in Age-Adjusted* Rates of Death due to HIV Infection,USA, 1982-1998USA, 1982-1998

*Using the age distribution of the projected year 2000 US population as the standard.

Highly active antiretroviral therapy has Highly active antiretroviral therapy has Changed our view toward HIV from Changed our view toward HIV from inevitably fatalinevitably fatal to a to a manageable diseasemanageable diseaseover several decadesover several decades

Good News

1.1. Incomplete responseIncomplete response

2.2. Complexity of treatmentComplexity of treatment

3.3. Short and long term side effectsShort and long term side effects

4.4. ResistanceResistance

5.5. Drug-drug interactionsDrug-drug interactions

Bad News

Bad News

1.1. Incomplete responseIncomplete 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.

2. Complexity of treatmentComplexity of treatment3. Short and long term side effectsShort and long term side effects4. ResistanceResistance5. Drug-drug interactionsDrug-drug interactions

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MonotherapyMonotherapy Dual therapyDual therapy Triple therapyTriple therapy

Viral Suppression with Monotherapy Viral Suppression with Monotherapy versus Multiple Drugsversus Multiple Drugs

Virologic nadir predicts duration of response

1. Incomplete responseIncomplete response

2.2. Complexity of treatmentComplexity of treatment• Too many tablets.Too many tablets.

• Difficult schedule.Difficult schedule.

• Food factorFood factor

3. Short and long term side effectsShort and long term side effects

4. ResistanceResistance

5. Drug-drug interactionsDrug-drug interactions

Bad News


2. Complexity of treatmentComplexity of treatment

3.3. Short and long term side effectsShort and long term side effects4. Drug-drug interactions Drug-drug interactions


Bad News

Drug Common Side effectsZidovudine

(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

Drug Common Side effectsDelavirdine 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

Drug Common Side effectsAmprenavir 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

Metabolic Complications of PIs

• Hyperbilirubinemia

• Hyperlipidemia– Coronary artery disease

• Insulin resistance

• Abnormal fat distribution.

• Lipodystrophy




4.4. Drug-drug interactionsDrug-drug interactions


Bad News

Drug Category Indinavir Ritonavir Saquinavir Nelfinavir Amprenavir Nevirapine Delavirdine Efavirenz

Ca++ channel blocker

(none) bepridil (none) (none) bepridil (none) (none) (none)

Cardiac (none) amioderoneflecainidepropafenonequinidine

(none) (none) (none) (none) (none) (none)

Lipid LoweringAgents

simvastatinlovastatin





(none) simvastatinlovastatin

(none)

Anti-Mycobacterial

rifampin none rifampinrifabutin

rifampin rifampin (none) rifampinrifabutin

(none)

Antihistamine astemizoleterfenadine

astemizoleterfenadine




(none) astemizoleterfenadine


GastrointestinalDrugs

cisapride cisapride cisapride cisapride cisapride (none) cisaprideH-2 blockersProton pumpinhibitors

cisapride

Neuroleptic (none) clozapine pimozide

(none) (none) (none) (none) (none) (none)

Psychotropic midazolamtriazolam

midazolamtriazolam

midazolamtriazolam

midazolamtriazolam

midazolamtriazolam

(none) midazolamtriazolam

midazolamtriazolam

Drugs That Should Not Be Used With Antiretrovirals




4. Drug-drug interactionsDrug-drug interactions

5.5. ResistanceResistance

Bad News

ResistanceResistance

Agent Resistance mutationsZDV 41 67 69* 70 151 210 215 219 333

3TC 69* 151 184 333

ddI 65 69* 74 151 184

ddC 65 69 69* 74 151 184

d4T 50 69* 75 151 178

ABC 65 69* 74 115 151 184

Agent Resistance mutations

DLV 103 181 236

EFV 100 103 108 179 181 188 190 225

NV 100 103 106 108 181 188 190

Genotypic Mutations Associated With Resistance to NRTI & NNRTIs

ResistanceResistance

Genotypic Mutations Associated With Resistance to PIs

Agent Resistance mutations

APV 10 36 46 47 48 50 54 63 71 82 84

IDV 10 20 24 32 36 46 48 54 63 71 73 82 84 90

NFV 10 30 36 46 48 71 82 84 88 90

RTV 10 20 32 33 36 46 54 63 71 82 84 90

SQV 10 20 24 30 36 46 48 54 63 71 73 82 84 90

LPV 10 32 46 47 50 84

Overcoming Drug ResistanceOvercoming Drug Resistance

Change to a drug to which virus shows greater susceptibility

Increase exposure to drug

RESISTANCE

Drug



Guided by Genotypic resistance testing

Switching within a drug classSwitching within a drug classExample - 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

Switching to a different drug classSwitching 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

(Adapted from Clevenbergh et al. Antiviral Therapy 2000; 5:65–70))

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(Adapted from Clevenbergh et al. Antiviral Therapy 2000; 5:65–70))

% <200 copies/ml

ControlGenotypic


Increase exposure to drug

RESISTANCE

Drug


Saquinavir boosted by ritonavir Saquinavir boosted by ritonavir

Fortovase 1600 mg + ritonavir 100 mg qd

Fortovase 1200 mg tid

Time (hours)

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Kilby et al. Antimicrob Agents Chemother Vol 44 2000

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Increase - above efficacy, below toxicityIncrease - above efficacy, below toxicity

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Drug A

Drug A level required to overcome WT virus

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Drug A level required to overcome “resistant” virus



The benefits of therapeutic drug monitoring

-1.55

-1.35

-1.15

-0.95

-0.75

-0.55

-0.35

-0.15

0.05

0 3 6Months

HIV RNA*

* viral load from baseline, log10 copies/ml

Control sub-optimal concentration

(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

0 3 6Months

HIV RNA*



Genotypic sub-optimal concentration


-1.55

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-0.95

-0.75

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Control optimal concentration

HIV RNA*






-1.55

-1.35

-1.15

-0.95

-0.75

-0.55

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Control optimal concentration

Genotypic optimal concentration

HIV RNA*





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 value Treat

Asymptomatic CD4+ T Cells < 350 cells/mm3 or HIV RNA > 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.

Asymptomatic CD4+ T Cells > 350 cells/mm3 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.

Recommended Antiretroviral Agents for Treatment of Established HIV Infection

Column A Column B

Strongly recommended EfavirenzIndinavirNelfinavir

Ritonavir + Saquinavir (SGC or HGC*)

Stavudine + LamivudineStavudine + Didanosine

Zidovudine + LamivudineZidovudine + Didanosine

Recommended as an alternative AbacavirAmprenavirDelavirdine

Nelfinavir + Saquinavir-SGCNevirapineRitonavir

Saquinavir-SGC

Didanosine + LamivudineZidovudine + Zalcitabine

No recommendation; insufficient data

Hydroxyurea in combination with other antiretroviral drugsRitonavir + Indinavir

Ritonavir + Nelfinavir

Not recommended; should not be offered(All monotherapies, whether from column A or B§)

Saquinavir-HGC Stavudine + ZidovudineZalcitabine + LamivudineZalcitabine + Stavudine

Zalcitabine + Didanosine

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.

RT

Provirus

ProteinsRNA

DNA

RNA

DNA

DNA

RT Viral regulatoryproteins

Viral protease

Reversetranscriptase

Viral integrase

RNA

RNA

Binding, fusionand entry

DNA

DNA

DNA

Viral zinc-fingernucleocapsid

proteins

Potential new targetsPotential new targets

HIV viral membrane fusion

Stein et al. (1987) Cell 49: 664

CXCR4CCR5

HIV

CD4

Cell

HIV interaction with CD4 cell

CD4Attachment

CXCR4CCR5

HIV

gp120

CD4

Cell

gp41


CD4Attachment

CXCR4CCR5

HIV

gp120

CD4

Co-receptorInteraction

Cell

HIV

gp41


CD4Attachment

CXCR4CCR5

HIV

gp120

Anchorage

CD4


Cell

HIV

HIV

gp41

gp41


CD4Attachment

HR1-HR2Interaction

CXCR4CCR5

HIV

gp120

Anchorage

CD4


Cell

HIV

HIV

HIV

gp41

gp41


FusionComplete

CD4Attachment

HR1-HR2Interaction

CXCR4CCR5

HIV

gp120

Anchorage

CD4


Cell

HIV

HIV

HIV

gp41

gp41


Class Target Example Compounds

AttachmentInhibitors

gp120, CD4 specific Mab, soluble CD4 and CD4-Ig

Co-receptorInhibitors

CXCR-4 AMD-3100

CCR-5 SCH-C, specific Mab,

FusionInhibitors

gp41 T-20, T-1249, D-peptides

Entry inhibitors under developmentEntry inhibitors under development

HIV attachment inhibitorsHIV 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

• PRO 542 (rCD4-IgG2)– Single injection dose-ranging trial

~ 4 doses, 3-6 subject/dose, HIV RNA > 3,000CD4 > 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 inhibitorsHIV attachment inhibitors

Chemokine receptor inhibitors

• CCR-5 Inhibitors– SCH-C (Schering-Plough)– PRO 140 (anti-CCR-5 monoclonal antibody)

• CXCR-4 Inhibitors– AMD-3100

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?

CXCR-4 inhibitors: AMD 3100CXCR-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?

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

T-20 (T-20 (Fusion inhibitor)Fusion inhibitor)

New agents:1. Emtricitabine (FTC, Coviracil) 2. DAPD/DXG3. 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

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

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-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

1. Lopinavir/ritonavir (ABT-378/r, Kaletra) – approved by FDA.

2. BMS-232632. 3. Tipranavir. 4. DMP-450.5. PD 178390

New agents– Protease InhibitorsNew 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.


BMS-232632: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 Tipranavir • Active against multi-PI resistant isolates.• 87% of isolates > 10-fold resistance to 4 PIs

remained completely susceptible to tipranavir in vitro


New agents– NNRTINew 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.

Barriers to the Development of an Barriers to the Development of an Effective AIDS VaccineEffective 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

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

Immunotherapy

ImmunotherapyImmunotherapy

• Directions– Augmentation of specific immune response to

control viral replication.– Preventive Vaccines.

Clues to immune control of HIV?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

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 functiondue to inadequate HIV-1-specific

helper cells

Progression

T helper cells are the central orchestrator of the immune system

CTL Function

APCFunction

Cytokine productionAntibody Production

B Cell Function

NK Cell Function

T helper cell

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 functiondue to adequate HIV-1-specific

helper cells

Antiviral Rx

Nonprogression

HIV-1-specific T helper cells in individuals HIV-1-specific T helper cells in individuals treated during acute infection (n=7)treated during acute infection (n=7)

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MB JC KM ND SJ DK KS

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Documents

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