Current and Future Trends in HIV Therapy Hail M. Al-Abdely Consultant, Infectious Diseases

Current and Future Trends inCurrent and Future Trends in HIV Therapy HIV Therapy

Hail M. Al-AbdelyHail M. Al-AbdelyConsultant, Infectious DiseasesConsultant, Infectious Diseases

CD4 Cell Count

Virus in Plasma

Symptoms

Detectable VIRUS IN PLASMA Detectable

> 500 cells CD4 COUNTS < 200 cells

Seroconversion Asymptomatic AIDSTime 0 12 Years

Infection Death

Clinical, Virological and Immunological Course of HIV Infection

0

200

400

600

800

1000

RNA in Plasma

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

T1/2 ~5.7 hrs

Productively infectedCD4 lymphocytes

Latently infectedCD4 lymphocytes

HIV

Uninfected CD4 lymphocytes

Uninfected activatedCD4 lymphocytes

Long-lived cell populations

2.6 daysper generation

99%T 1/2 ~1.6d

<1%

Viral Dynamics of HIV-1 Infection

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

CD4 lymphocytes infected with defective virus

1%

Latency TheoryLatency Theory

261

15

Nucleoside Reverse Transcriptase Nucleoside Reverse Transcriptase Inhibitors (NRTIs)Inhibitors (NRTIs)

Abacavir (Ziagen)

Abacavir + Lamivudine (Epzicom)

Abacavir+Lamivudine+Zidovudine (Trizivir)

Didanosine (Videx, ddI)

Emtricitabine (Emtriva, FTC)

Emtricitabine + Tenofovir DF (Truvada)

Lamivudine (Epivir, 3TC)

Lamivudine+Zidovudine (Combivir)

Stavudine (Zerit, d4T)

Tenofovir DF (Viread)

Zalcitabine (Hivid, ddC)

Zidovudine (Retrovir, AZT, ZDV)

Nonnucleoside Reverse Transcriptase Nonnucleoside Reverse Transcriptase InhibitorsInhibitors (NNRTIs)(NNRTIs)

Delavirdine (Rescriptor)

Efavirenz (Sustiva)

Nevirapine (Viramune)

Protease Inhibitors (PIs)Protease Inhibitors (PIs)

Amprenavir (Agenerase)

Atazanavir (Reyataz)

Fosamprenavir (Lexiva, 908)

Indinavir (Crixivan)

Lopinavir+Ritonavir (Kaletra)

Nelfinavir (Viracept)

Ritonavir (Norvir)

Saquinavir (Fortovase, Invirase)

Tipranavir

Fusion InhibitorsFusion Inhibitors

Enfuvirtide (Fuzeon, T-20)

Total = 25 drug or Total = 25 drug or drug combinationsdrug combinations

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

50

60

70

80

90

Monot herapy

50

60

70

80

90

Mon

othe

rapy

20

40

60

80

100

Mon

othe

rapy

MonotherapyMonotherapy Dual therapyDual therapy Triple therapyTriple therapy

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

Hospitalization Days for AIDS Patients

Ho

spit

aliz

atio

n d

ays

(n)

2,000

1,500

1,000

500

0

1993

/2

1994

/1

1994

/2

1995

/1

1995

/2

1996

/1

1996

/2

1997

/1

1997

/2

1998

/1

1998

/2

1999

/1

1999

/2

2000

/1

2000

/2

2001

/1

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 (Cancer) (Cancer)to a to a manageable disease manageable disease (Diabetes, HTN)(Diabetes, HTN)

Good News

1.1. Incomplete responseIncomplete response

2.2. Adherence & Complexity of treatmentAdherence & Complexity 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. Adherence & Complexity of treatmentAdherence & Complexity of treatment3. Short and long term side effectsShort and long term side effects4. ResistanceResistance5. Drug-drug interactionsDrug-drug interactions

50

60

70

80

90

Monot herapy

50

60

70

80

90

Mon

othe

rapy 20

40

60

80

100

Monot herapy

MonotherapyMonotherapy Dual therapyDual therapy Triple therapyTriple therapy

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

1. Incomplete responseIncomplete response

2.2. Adherence & Complexity of treatmentAdherence & Complexity 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

Predictors of Inadequate Adherence

• Regimen complexity and pill burden• Poor clinician-patient relationship• Active drug use or alcoholism • Unstable housing• Mental illness (especially depression)• Lack of patient education • Medication adverse effects• Fear of medication adverse effects


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

Metabolic Complications of PIs

• Hyperbilirubinemia

• Hyperlipidemia– Coronary artery disease

• Insulin resistance

• Abnormal fat distribution.

• Lipodystrophy

From NEJM

Risk: Benefit Analysis ofRisk: Benefit Analysis of Coronary Heart Disease and HAART Coronary Heart Disease and HAART

Average Average calculated calculated increase in increase in

CHD events = CHD events = 0.14% per year0.14% per year

RisksRisks

BenefitsBenefits

Mortality Mortality rates in HIV-rates in HIV-

infected infected patients by patients by

50%50%

Adapted from Grunfeld. 6th CROI; 1999; Chicago. Palella. NEJM 1998;338:853.




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

Change to a drug to which virus shows greater susceptibility

Overcoming Drug ResistanceOvercoming Drug Resistance

Guided by Genotypic resistance testing

Goals of Antiretroviral Goals of Antiretroviral Therapy (ART)Therapy (ART)

• Eradication of HIV? Not possible with currently available antiretroviral medications.

GOALS OF THERAPYGOALS OF THERAPY

Clinical goals

Prolongation of life and improved quality of life

Immunologic goals: Achieve immune reconstitution that is quantitative (CD4 to normal range) and qualitative (pathogen-specific immune response)

Virologic goalsReduction in viral load to:

1) halt disease progression 2) prevent/reduce resistant variants

Therapeutic goalsRational use of drugs that achieves virologic goals, but also: 1) maintains therapeutic options 2) relatively free of side effects 3) realistic in terms of probability of adherence

Epidemiologic goals

Reduce HIV transmission

Importance of Initial Therapy

Success Failure Success Failure Success Failure

Naïve patientExperienced

patient

Highly-experienced

patient

HAART: Randomized Comparative Trials*: HIV RNA <400 Copies/mL at Week 48 (ITT)

*All trials have 100 patients/arm

Study 863: LPV/r + d4T + 3TC

DuPont 006: EFV + AZT + 3TC

Study 863: NFV + d4T + 3TC

Agouron 542: NFV BID + d4T + 3TC

Atlantic: IDV + d4T + ddI

Agouron 542: NFV TID + d4T + 3TC

Atlantic: 3TC + d4T + ddI

Atlantic: NVP + d4T + ddI

DuPont 006: EFV + IDV

Patients (%)

DuPont 006: IDV + AZT + 3TC

CNAAB 3005: IDV + AZT + 3TC

CNAAB 3005: ABC + AZT + 3TC

0 10 20 30 40 50 60 70 80 90

Gilead 903: TDF + 3TC + EFV

Adapted from Bartlett J et al. 7th CROI, 2000

Correlation Between Nonadherence and Virologic Failure

Paterson DL et al. Ann Intern Med, 2000

Pat

ien

ts w

ith

vir

olo

gic

fai

lure

* (%

)

Adherence (%)

100

80

60

40

20

0 >95 90–95 80–90 70–80 <70

P<0.001, r=–0.554*Virologic failure defined as HIV RNA >400 copies/mL at last study visit

Duration of initial HAART100

80

60

40

20

0

Pat

ien

ts w

ith

ou

t ch

ang

ein

th

erap

y (%

)

0 120 240 360 480 600 720

Days

197 patients, Cologne 1997–1999 Fätkenheuer G et al. 8th ECCATH, 2001

Reasons for Modification of Initial HAART

197 patients, Cologne 1997–1999113/197 (57%) modified therapy

35

30

25

20

15

10

5

0Adverse Virologic Lost to Otherevents failure follow-up

Fätkenheuer G et al. 8th ECCATH, 2001

Pat

ien

ts (

%)

Considerations in Initiating ART: Asymptomatic HIV

• Willingness of patient to begin and the likelihood of adherence

• Degree of immunodeficiency (CD4+ T cell count)

• Plasma HIV RNA• Risk of disease progression• Potential benefits and risks of therapy

Considerations in Initiating ART: Chronically HIV-Infected Patient,

Asymptomatic

• Strong evidence of decreased mortality and morbidity with ART if CD4 <200 cells/µL or symptomatic

• Theoretical benefit of treatment at higher CD4• Few data establish clinical benefit for treatment if

CD4 >200 cells/µL; optimal point to initiate ART is unknown

• Individualize treatment decisions

Indications for ART in the Chronically HIV-Infected Patient

Treat all (regardless of viral load):

• Symptomatic (AIDS, severe symptoms)

• Asymptomatic, CD4 count <200 cells/µL


Offer treatment, after discussion of pros and cons:

• Asymptomatic, CD4 count 200-350 cells/µL


Defer Treatment:

Asymptomatic, CD4 count >350 cells/µL

– If HIV RNA >100,000 copies/mL, may consider treatment

Initial Treatment for Previously Untreated Patients: Choosing

Regimens

• Three categories:– 1 NNRTI + 2 NRTIs– 1 PI + 2 NRTIs– 3 NRTIs

• Few clinical endpoints to guide choices• Advantages and disadvantages to each type of

regimen• Individualize regimen choice

GUIDELINES

1987 AZT

1992 AZT/ddI

1995 2 NRTIs

1997 2 NRTIs + PI

1999 2 NRTI + PI/NNRTI

2002 2 NRTI + NNRTI or

PI or 3d NRTI

2004 2 NRTIs + PI/r or NNRTI

Initial Treatment: Preferred Regimens

*Avoid in pregnant women and women with pregnancy potential.

Efavirenz*

+ (lamivudine or emtricitabine)

+ (zidovudine or tenofovir)

2-5

# pills/day

Lopinavir/ritonavir (Kaletra)

+ (lamivudine or emtricitabine)

+ zidovudine

8-10

NNRTI-Based

PI-Based

Future Trends

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.

Class Target Example Compounds

AttachmentInhibitors

gp120, CD4 specific Mab, PRO 542 soluble CD4 and CD4-Ig

Co-receptorInhibitors

CXCR-4 AMD-3100

CCR-5 SCH-C, specific Mab,

FusionInhibitors gp41 T-1249, D-peptides

Entry inhibitors under developmentEntry inhibitors under development

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• HIV/AIDS is no longer a “death sentence” for infected

individuals• Cure is beyond reach at this stage, but patients can survive

years to decades longer. • Better understanding of the HIV has allowed better

treatment modalities.• 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

Documents

Current and Future Trends in HIV Therapy Hail M. Al-Abdely Consultant, Infectious Diseases