26 YEARS OF HIV EPIDEMY 10 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 leg HIV Serology + What next?

AIDS-HIV  HIV: Human Immunodeficiency Virus  AIDS: Acquired Immuno-Deficiency Syndrome

HIV in Israel: June 2004 new cases HIV in Israel: June new cases 1 new patient every day

Transmission 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 Categories (until end 2005)

Groups MNO Types HIV-1HIV-2 Subtypes A B C D A/E F G H I J K

World Distribution of different Subtypes B B B, F C C A/E B B B A D C C A G, H, O C, E F A,B C B C A/C/D C O J F Adult 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,C G A A

Natural History: CD4 and VL and clinical events Acute HIV Asymptomatic Phase Symptomatic weeks Years

Acute Retroviral Syndrome

Toxoplasmosis primary CNS lymphoma PML Toxoplasmosis primary CNS lymphoma PML CMV retinitis Candida esophagitis PCP Cryptosporidium carcinoma: cervix, anal carcinoma: cervix, anal Cryptococal meningitis All systems tuberculosis MAC cytomegalovirus NHL Kaposi’s sarcoma All systems tuberculosis MAC cytomegalovirus NHL Kaposi’s sarcoma Symptoms in HIV CMV- Cytomegalovirus, CNS- Central Nervous System, MAC- Mycobacterium avium NHL-Non Hodgkin Lymphoma, PCP- Pneumocystis carinii Pneumonia, PML- Progressive Multifocal Leucoencephalopathy CD4>500: mucocutaneous candida : Pneumococcal pneumonia tuberculosis herpes zoster cervical neoplasia Kaposi’s sarcoma NHL CD4>500: mucocutaneous candida : Pneumococcal pneumonia tuberculosis herpes zoster cervical neoplasia Kaposi’s sarcoma NHL : PCP AIDS dementia Wasting : toxoplasmosis cryptococcosis <50: CMV retinitis MAC cryptosporidiosis PML primary CNS lymphoma : PCP AIDS dementia Wasting : toxoplasmosis cryptococcosis <50: CMV retinitis MAC cryptosporidiosis PML primary CNS lymphoma According toCD4 According to system

Oral thrush

Hairy Leukoplakia

Kaposi Sarcoma

PCP

CMV

Cerebral Toxoplasmosis

Progressive Multifocal Leuco-encephalopathy (PML) (PML)

Prophylaxis PPD> 5mm: TB (INH) CD4 < 200: PCP (TMP/SMX) CD4< 50: MAC (Azyhtro/Clarythro)

Antiretroviral 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

HIV RT: RTI Protease: PI RNA DNA Viral RNA Viral proteins T-helper(CD4) HIV- Human Immunodeficiency Virus, RT- Reverse transcriptase RNA messeger Anti HIV Drugs Entry inhibitors RNaseH Assembly integrase

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

Decrease incidence of opportunistic infection

Decrease in Morbidity since HAART (EuroSida)

Nucleos(t)ides Reverse Transcriptase Inhibitors Nucleos(t)ides Reverse Transcriptase 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 Transcriptase Inhibitors DRUG EFAVIRENZ NEVIRAPINE DELAVIRDINE SIDE EFFECT NEUROLOGIC RASH, LIVER RASH

PROTEASE INHIBITORS PROTEASE INHIBITORS Lipid abnormality DRUG SAQUINAVIR INDINAVIR RITONAVIR (Rtv) NELFINAVIR fosAMPRENAVIR Rtv/LOPINAVIR ATAZANAVIR* * No lipid abnormality SIDE EFFECT GI KIDNEY STONES GI RASH GI hyperbilirubinemia

OTHERS IL2 VACCINE INTEGRASE

New drugs Different mutational profile: PI- TMC 114 (Darunavir) (FDA&EC approved) NNRTI- TMC 125 New Targets Fusion inhibitors T-20 (Fuzeon) Entry inhibitors: CCR5 inhibitor Integrase inhibitor (FDA approved)

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 >100,000 optional <200 Any Value

Major problems with the Treatment 10,000-20,000$/person/year Side Effects of the Drugs Failure Therapy

COMPLIANCE!!!!!!!!!!! DRUG INTERACTION VIRAL RESITANCE

Maternal-Child Transmission Placebo 30%-50% AZT 8% No difference of congenital abnormalities from general population <2%

Effect of HAART on VL and CD4

Immune Reconstitution

ELISA- screeningELISA- screening Western Blot- confirmationWestern Blot- confirmation P24 AgP24 Ag CD4CD4 Viral LoadViral Load GenotypingGenotyping PhenotypingPhenotyping Laboratory Diagnosis Follow up

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