26 YEARS OF HIV EPIDEMY26 YEARS OF HIV EPIDEMY10 years HAART10 years HAART

Dan Turner, MD, Tel-Aviv Sourasky Medical Center

Case Presentation

• Male 41 years old• Weight lost• Cough• Blurred vision• Weakness – right arm and legHIV Serology +

What next?

AIDS-HIVAIDS-HIVHIV: Human Immunodeficiency

Virus

AIDS: Acquired Immuno-Deficiency Syndrome

HIV in Israel: HIV in Israel: 1980- June 20041980- June 20044141 new casesnew cases

0

50

100

150

200

250

300

350

400

80-85

87 89 91 93 95 97 99 2001

1 new patient every day

Transmission of HIVTransmission of HIV

Sexual Route: Homo-Heterosexual

Sharing Needles: Intravenous Drug Users

Blood Products: Blood Transfusion

Maternal to Child: In Utero ,During Labor and Breast Feeding

HIV in Israel: Exposure HIV in Israel: Exposure Categories (until end 2005)Categories (until end 2005)

MSM17%

IDU15%

blood2%

EPID44%

HETER3%

MTCT3%

Other16%

Groups M N O

Types HIV-1 HIV-2

Subtypes A B C D A/E F G H I J K

World World Distribution Distribution ofof different Subdifferent Subtypestypes

B

B

B , F

B, F

C

C

A/E

A/E

B

B

B

A D C C

A G, H, O

C, E

F

A,B

C

B

C

A/C/D

COJ

FAdult prevalence rate

15.0% – 36.0% 5.0% – 15.0% 1.0% – 5.0% 0.5% – 1.0% 0.1% – 0.5% 0.0% – 0.1% not available

A,CG

AA

Natural History: CD4 and VL and Natural History: CD4 and VL and clinical eventsclinical events

Acute HIV

Asymptomatic PhaseSymptomatic

weeks Years

Acute Retroviral SyndromeAcute Retroviral Syndrome

Toxoplasmosis

primary CNS lymphoma

PML

Toxoplasmosis

primary CNS lymphoma

PML

CMV retinitisCMV retinitis

Candida esophagitisCandida esophagitis

PCPPCP

CryptosporidiumCryptosporidium

carcinoma:

cervix, anal

carcinoma:

cervix, anal

Cryptococal meningitis

Cryptococal meningitis

All systems

tuberculosis

MAC

cytomegalovirus

NHL

Kaposi’s sarcoma

All systems

tuberculosis

MAC

cytomegalovirus

NHL

Kaposi’s sarcoma

SSymptoms in HIymptoms in HIVV

CMV- Cytomegalovirus, CNS- Central Nervous System, MAC- Mycobacterium aviumNHL-Non Hodgkin Lymphoma, PCP- Pneumocystis carinii Pneumonia, PML- Progressive Multifocal Leucoencephalopathy

CD4>500: mucocutaneous candida

200-500: Pneumococcal pneumonia

tuberculosis

herpes zoster

cervical neoplasia

Kaposi’s sarcoma

NHL

CD4>500: mucocutaneous candida

200-500: Pneumococcal pneumonia

tuberculosis

herpes zoster

cervical neoplasia

Kaposi’s sarcoma

NHL

100-200:

PCP

AIDS dementia

Wasting

50-100:

toxoplasmosis

cryptococcosis

<50:

CMV retinitis

MAC

cryptosporidiosis

PML

primary CNS lymphoma

100-200:

PCP

AIDS dementia

Wasting

50-100:

toxoplasmosis

cryptococcosis

<50:

CMV retinitis

MAC

cryptosporidiosis

PML

primary CNS lymphoma

According toCD4According to system

Oral thrushOral thrush

Hairy LeukoplakiaHairy Leukoplakia

Kaposi SarcomaKaposi Sarcoma

PCPPCP

CMVCMV

Cerebral Cerebral ToxoplasmosisToxoplasmosis

Progressive Multifocal Leuco-encephalopathyProgressive Multifocal Leuco-encephalopathy

(PML)(PML)

ProphylaxisProphylaxis

• PPD> 5mm: TB (INH)

• CD4 < 200: PCP (TMP/SMX)

• CD4< 50: MAC (Azyhtro/Clarythro)

Antiretroviral TherapyAntiretroviral Therapy

Treatment History• 1981: HIV discovery• 1987: AZT• 1990: DDI and TMP/SMX prophylaxis for

PCP and toxoplasmosis• 1994:AZT to prevent maternofetal

transmission • 1996: HAART- Highly Active Antiretroviral

Therapy• 2000: Viral Resistance• 2003: Fusion inhibitor (T-20)• 2006: Integrase inhibitors

HIVHIV

RT: RTIRT: RTI

Protease: PIProtease: PI

RNARNA

DNADNA

Viral RNAViral RNA

Viral proteinsViral proteins

T-helper(CD4)T-helper(CD4)

HIV- Human Immunodeficiency Virus, RT- Reverse transcriptase

RNA messegerRNA messeger

Anti HIV Drugs

Entry inhibitors

Entry inhibitors

RNaseH

Assembly

integraseintegrase

Combination Therapy-1996:Combination Therapy-1996:Decrease mortality in USA

Decrease incidence of Decrease incidence of opportunistic infectionopportunistic infection

Decrease in Morbidity since Decrease in Morbidity since HAART (EuroSida)HAART (EuroSida)

Nucleos(t)ides Reverse Nucleos(t)ides Reverse Transcriptase InhibitorsTranscriptase Inhibitors

MITOCHONDRIAL TOX• DRUG• AZT• DDI• DDC• D4T• 3TC• ABACAVIR

• TENOFOVIR

• SIDE EFFECT:• BONE MARROW• PANCREATITIS • PNP, STOMATITIS• PNP*• PNP• HYPER

SESITIVITY SYNDROME

• RENAL (RARE)

*Peripheral Neuropathy

Non Nucleosides Reverse Non Nucleosides Reverse Transcriptase InhibitorsTranscriptase Inhibitors

• DRUG• EFAVIRENZ• NEVIRAPINE• DELAVIRDINE

• SIDE EFFECT• NEUROLOGIC• RASH, LIVER• RASH

PROTEASE INHIBITORSPROTEASE INHIBITORSLipid abnormality

• DRUG• SAQUINAVIR• INDINAVIR• RITONAVIR (Rtv)• NELFINAVIR• fosAMPRENAVIR• Rtv/LOPINAVIR• ATAZANAVIR*

* No lipid abnormality

• SIDE EFFECT• GI• KIDNEY STONES• GI • GI• RASH• GI• hyperbilirubinemia

OTHERSOTHERS

• IL2

• VACCINE

• INTEGRASE

New drugsNew drugsDifferent mutational profile:

PI- TMC 114 (Darunavir) (FDA&EC approved)

NNRTI- TMC 125

New TargetsNew Targets

• Fusion inhibitors T-20 (Fuzeon)

• Entry inhibitors: CCR5 inhibitor

• Integrase inhibitor (FDA approved)

Year 1995 1998-2000 2003 CD4 (cells/mm3),

<500 <500 >500 <200 >350

VL (copies/ml) Not available Any value

>10,000 (bDNA) >30,000 (RT-PCR)

Any value

>55,000 (RT-PCR and bDNA)

Evolution of DHHS* guidelines as to the best time to begin antiretroviral therapy in asymptomatic patients

*DHHS- Department of Health and Human Services

2004>350

>100,000optional

<200

Any Value

Major problems with the Major problems with the TreatmentTreatment

10,000-20,000$10,000-20,000$//person/yearperson/year

Side Effects of the DrugsSide Effects of the Drugs

Failure TherapyFailure Therapy

Failure TherapyFailure Therapy

• COMPLIANCE!!!!!!!!!!!

• DRUG INTERACTION

• VIRAL RESITANCE

Maternal-Child TransmissionMaternal-Child Transmission

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%Placebo30%-50%

AZT8%

No difference of congenital abnormalities from general population

>2%

Effect of HAART on VL and Effect of HAART on VL and CD4CD4

0

500000

1000000

1500000

2000000

2500000

3000000

3500000

4000000

4500000

5000000VL

0

50

100

150

200

250

300

350

400

450

CD4

PCP-CMV

GCV-IV

HAART

CD4

VL

OCT 96 DEC 96 DEC 97

STOP CMV

Tx

Immune ReconstitutionImmune Reconstitution

• ELISA- screeningELISA- screening• Western Blot- confirmationWestern Blot- confirmation• P24 AgP24 Ag• CD4CD4• Viral LoadViral Load• GenotypingGenotyping• PhenotypingPhenotyping

LaboratoryLaboratory

Diagnosis

Follow up

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