HIV / AIDs &Opportunistic Infections HIV RNA retrovirus ( single-stranded RNA 2 ) HIV CD4 CD4 cells 40-80 cells/mm3 CD4 count < 200 cells/mm3 (opportunisitic infections) AIDS (acquired immunodeficiency syndrome) HIV latency period 7-10 HIV life cycle gp120 envelope subunit CD4 receptors chemokine co-receptors (CCR5, CXCR4) Viral envelope cell membrane (fusion) viral core Viral RNA (transcription) proviral DNA reverse transcriptase Proviral DNA host DNA integrase host cell viral polyproteins Viral polyproteins proteases mature virions

HIV (transmission) 3 1. 90 (transfusion)2. ( 90 ) HIV 3. 20-50 4 1. Primary: (acute HIV infection) VL (> 1,000,000 cell/mm3)2. Clinical latent period: (latent phase or Asymptomatic HIV infection) 10 Window period 3 HIV antibody 3. (Symptomatic HIV infection) (AIDS related complex ARC) HIV antibodies 4. AIDs:CD4 count < 200 cells/mm3 (opportunisticinfections) 1. : 2. : 3. : virological test 3.1 antibody screening test (ELISA, PA), comfirmatory test3.2 viral load immunological test: CD4 monoclonal antibody CD4 CD4 (%CD4) CD4

CD4 = %CD4 x WBC x %Lymphocyte 10,0003.3 : 3 Genotypic drug susceptibility testing, Phenotypic drug susceptibility testing, Virtual phenotype genotype

HIV (Antiretroviral agents; ARV) ARV HIV HIV .. 1987 HIV Zidovudine (AZT) .. 1996 HIV (HAART = Hightly Active Antiretroviral Therapy) HIV 4 1. Reverse Transcription (Inhibition of Reverse Transcription) 2. Integration (Inhibition of Proviral Integration) 3. Transcription 4. Post-translation processing

HIV HIV 4 1. Nucleoside Reverse Transcriptase Inhibitor (NRTIs) nucleoside base reverse transcriptase enzyme DNA RNA AZT, ddI, ddc, 3TC, d4T, ABC 2. Non-nucleoside Reverse Transcriptase Inhibitor (NNRTIs) nucleoside base NRTI nevirapine, delavirdine, efavirenz 3. Protease Inhibitor (PIs) protease enzyme (immature) indinavir, ritonavir, saquinavir, nelfinavir, amprenavir 4. HIV-entry inhibitors Fusion inhibitors enfuvirtide (Fuzeon) HIV NRTIs 2 NNRTIs Protease inhibitor (PIs) 1 HAART NRTIs AZT d4T ddC 3TC ddI ddC ( pancreatitis, neuropathy) Protease Inhibitors (lipodystrophy)

1 CD4 cell count (cell/mm3)Viral load

(AIDS-defining illness)* HIV

**< 250 HIV

< 200 HIV

200 - 350 CD4 3

> 350 CD4 6

*AIDS-defining illness 2** (PPE) 14 10 3

2 ADIs defining illness CDC

1. Candidiasis 2. Cervical cancer, invasive3. Coccidioidomycosis 4. Cryptococcosis5. Cryptosporidiosis 1 6. Cytomegalovirus 7. Cytomegalovirus retinitis8. HIV encephalopathy HIV dementia, AIDS dementia subacute HIV encephalitis 9. Herpes simplex 1 10. Histoplasmosis 11. Isosporiasis 1 12. Kaposis sarcoma13. Lymphoma, Burkitts (or equivalent term)14. Lymphoma, immunoblastic (or equivalent term)15. Lymphoma, primary in brain16. Mycobacterium avium complex M. Kansasii17. Mycobacterium, other species or unidentified species, disseminated or extrapulmonary18. Mycobacterium tuberculosis, pulmonary or extrapulmonary19. Pneumonia recurrent (Bacteria) 1 1 20. Pneumocystis carinii pneumonia21. Penicillium marneffei infection22. Progressive multifocal leukoencephalopathy23. Salmonella septicemia 24. Toxoplasmosis 25. Wasting syndrome (emaciation, slim disease)26. Nocardiosis27. Rhodococcosis28. Serious Bacterial infection, recurrent or multiple 2 13

3

()1. d4T AZT + 3TC + NVP 1. d4T AZT + 3TC + EFV2. d4T AZT + 3TC + IDV/RTV 1 NVP EFV

*2NRTIsNNRTIs PIs

AZT + ddI + TDF + ABC +ddI3TC 3TC 3TCSQV / RTVNFVLPV / RTVATV + RTV

* 2NRTIs NNRTIs PIs 1 1. AZT+3TC d4T+3TC NRTIs 2. NVP NNRTIs 3. EFV NNRTIs 1 NVP EFV 4. IDV 400-600 ./RTV 100 . 2 NVP EFV IDV/RTV boosted PI 6 serum creatinine5. HIV6. 7. TDF HIV NRTIs TDF+3TC HIV 8. ABC+3TC NRTIs AZT, d4T, ddI TDF ABC hypersensitivity reaction NVP ABC NVP

GPO-VirGPO-VIR fixed dose combination ( HIV 1 ) GPO-VIR d4T+3TC+NVP GPO-VIR

1. 2 60 . d4T 30 . 3TC 150 . 1 GPO-VIRS30 ( d4T 30 .+ 3TC 150 . + NVP 200 .) 12 30 60 . 3TC 150 . d4T 40 . 1 GPO-VIRS40 ( d4T 40 . + 3TC 150 . + NVP 200 .) 12 30 2. 2 / GPO-VIRS30 GPO-VIRS40 2 12 30 1. 3TC NVP 12 30 2. / NVP hypersensitivity reaction NVP EFV Immune Reconstitution Inflammatory Syndrome (IRIS)IRIS HIV 6 6 IRIS HIV

HIV WHO DHHS 1) 2 2) NRTIs 3 3) d4T+AZT/ddI d4T-AZT d4T-ddI ADRs neuropathy, acidosis, pancreatitis4) 3TC+FTC 5) EFV pregnancy6) AZT+ddC effect 7) ABC+NVP hypersensitivity ARV viral load (undetectable) 20-500 copies/ml OIs

1) HAART 2NRTIs+NNRTIs2) d4T+AZT, ddC+3TC 3) ADR ddI+ddC 4) PIs second line drug ADR

ADRs ADRs

1. NTRIs

1.1 AZT1.1 (macrocytic anemia and/or neutropenia)

1.2 d4T1.2 peripheral neuropathy, lactic acidosis, lipoatrophy

1.3 3TC1.3 pancreatitis

1.4 ddI1.4 neuropathy

1.5 ABC1.5 MP rash, urticaria ( NVP)

1.6 TDF1.6 nephrotoxicity (increased Scr, proteinurea)

2. NNRTIs

2.1 NVP2.1 PPE, Hepatitis

2.2 EFV2.2 PPE, psychosis (CNS SE: 1 )

3. PIs 3. hepatitis, hyperlipidemia ( ATV RTV ), hyperglycemia, lipodystrophy, insulin resistance

3.1 IDV3.1

3.2 RTV3.2

3.3 ATV3.3 prolong PR interval (1st degree AV block)

4.PIs hypersensitivity

6 1) OIs ( TB) OIs 6 2) CD4 30% 2 OIs OIs ARV 2 CD4 ok ! DI OIs ARV CD4 (2 ) 200 cell/mm3 ARV CD4 200 cell/mm3 6 ARV OIs ARV ARV ADR, DI

1) NRTIs: 3TC (combine pill) AZT+3TC NTRIs ddI 3TC, TDF HBV HBV 3TC TDF hepatitis 2) NNRTIs: ADR PIs amino acid reversetranscriptase : EFV NVP () NVP NVP CD4 CD4 250 CD4 400 paper CD4 250 CD4 400 hepatitis CD4 250 CD4 400 NVP lead in 14 NVP autoinducer lead in (200 mg 1x2 400 mg/day) 14 14 ADR NVP 18 wk (~ 5 ) LFTs skin LFTs 3 LFTs 5 3) PIs: IDV/RTV 22% 48 wk ADR RTV enzyme inhibitor ( P450 CYP3A4) RTV low dose+PI (PI boosted) NFV ATV DI TDF EFV 2 ATV TDF (NRTIs), EFV (NNRTIs) ATV RTV low dose antacid, H2RA, PPI ATV (ATV ) 2 ARV TB 1) Drug interaction: Rifampicin (enzyme inducer) NNRTIs PIs () 2) Adherence: 2 3) ADR: ADR (skin hepatitis) 4) IRIS: ARV TB HAART IRIS TB HAART ARV TB1) anti-TB rifampicin EFV base regimen rifampicin EFV NVP (EFV 25%, NVP 37%)2) rifampicin HAART recommend regimen 3) NNRTIs (EFV NVP) PIs (PIs base regimen) anti-TB drug rifampicin 4) HAART OIs (TB) anti-TB HAART EFV NVP 5) TB CD4

CD4 level HAART TB

< 100 HAART ()

100 200 HAART anti-TB drug 2

200 350 HAART CD4 3

> 350 HAART CD4 6

1) NRTIs: AZT (ZDV), ddI (didanozine), ddC (zalcitabine), TDF (tinofovir), d4T (stavudine), ABC (abacavir), 3TC (lamivudine) 2) NNRTIs: NVP (nevirapine), EFV (efavirenz) 3) PIs: IDV (indinavir), RTV (ritonavir), NFV (nelfinavir), SQV (saquinavir), APV (amprenavir), ATV (atazanavir) 4) FIs: T-20 (enfuvirtide)

1) HIV &OI 15

2) AZT3) ddI (250< 60 kg