Maraviroc CCR5 antagonist HIV CCR5 receptor CD4+ cell HIV 1,2,3 USFDA 2007 maraviroc 4 1). maraviroc1,2,3 Bioavalibility 23%-33% Cmax 33%-60% AUC 33%-50% plasma protein 76% 14-18 CYP3A inactive metabolites3 CYP2D9 , CYP2D6 ,CYP2D19 2 20% (8% ) 76% (25% )2). 300 mg 2 CYP3A inhibitors inducers1,2,3 2.1 CYP3A inhibitors protease inhibitors ( tipranavir/ritonavir), delavirdine, ketoconazole, itraconazole, clarithromycin, nefazodone, and telithromycin maraviroc maraviroc 150 mg 2 2.2 CYP3A inducers efavirenz, rifampin, carbamazepine, phenobarbital, and phenytoin maraviroc maraviroc 600 mg 2 2.3 3).maraviroc Gulick 5 double-blind, placebo-controlled, phase 3 studies(MOTIVATE 1 MOTIVATE 2 ) ( optimized background therapy : OBT) 3 1. OBT + maraviroc 300 mg 2. OBT + maraviroc 300 mg 2 3. OBT 48 virologic immunologic response maraviroc HIV-1 RNA (P 350 cells/mm3

2.1. HAART 14 zidovudine nevirapine CD4+ count > 250 cells/mm3 ( nevirapine CD4 < 250 cells/mm3) zidovudine monotherapy ( HIV RNA levels < 1000 copies/mL) = zidovudine (300) + lamivudine (150) 1 12 lopinavir/ritonavir (200/50) 2 12

2.2. zidovudine 300 mg 1 3 600 mg nevirapine 200 mg zidovudine monotherapy

2.3. () nevirapine zidovudine (300) + lamivudine (150) 1 12 7

2.4. ()GA > 35 : zidovudine syrup 4 mg/kg/dose 12 4 GA 30 35 : zidovudine syrup 2 mg/kg/dose 12 2 zidovudine syrup 2 mg/kg/dose 8 2 GA < 30 : zidovudine syrup 2 mg/kg/dose 12 4

3. ( )

3.1. HIV antiretroviral drug-resistance testing (detectable viral load viral load > 1000 copies/mL 6 ) zidovudine zidovudine efavirenz ( efavirenz zidovudine (300) + lamivudine (150) 1 12 lopinavir/ritonavir (200/50) 2 12 )

3.2. zidovudine 300 mg 1 3 600 mg

3.3. ()

3.4. ()GA > 35 : zidovudine syrup 4 mg/kg/dose 12 4 GA 30 35 : zidovudine syrup 2 mg/kg/dose 12 2 zidovudine syrup 2 mg/kg/dose 8 2 GA < 30 : zidovudine syrup 2 mg/kg/dose 12 4

4.

4.1. zidovudine 300 mg 1 3 600 mg nevirapine 200 mg 2 nevirapine ( zidovudine 600 mg )

4.2. () zidovudine (300) + lamivudine (150) 1 12 lopinavir/ritonavir (200/50) 2 12 CD4CD4 > 350 cells/mm3 : zidovudine (300) + lamivudine (150) 1 12 lopinavir/ritonavir (200/50) 2 12 4 CD4 < 350 cells/mm3 : nevirapine ( zidovudine) zidovudine CD4 < 350 cells/mm3

4.3. ()zidovudine syrup 4 mg/kg/dose 12 lamivudine syrup 2 mg/kg/dose 12 4 6 nevirapine syrup 4 mg/kg/dose 24 2 4 ziduvudine + lamivudine NVP 2

1. (virological failure) viral load 400 copies/mL 6 viral load 50 copies/mL 12 viral load 50 copies/mL viral load 50 copies/mL

2. (immunological failure) CD4 50 cells/mm3 12 CD4 30% %CD4 3 CD4

1. CD4 6

2. Viral load 36 virus viral load 1000 copies/mL 8 12

3. CBC 4 8 (zidovudine)

4. AST/ALT 4 8 (nevirapine)

5. GCT (lopinavir/ritonavir) 24 28 4

1. Zidovudine (AZT 200 mg/tab) : , bone marrow suppression (anemia, neutropenia) 2 3 Hb < 8 g/dL Hct < 24% AZT ferrous folic acid supplementation AZT d4T

2. Lamivudine (3TC 150 mg/tab)

3. Stavudine (d4T 30 mg/tab) : peripheral neuropathy, lactic acidosisPeripheral neuropathy 50 d4T ddI Lactic acidosis lactate 5 mmol/L arterial pH d4T ddI supportive treatment d4T ddI

4. Nevirapine (NVP 200 mg/tab) : skin rash, hepatotoxicitySkin rash 2 3 diffuse maculopapular rash mucous membrane involvement antihistamine NVP Hepatotoxicity 1 2 serum transaminase elevation clinical hepatitis CD4 250 cells/mm3, AST ALT , HBV HCV NVP 200 mg 24 2 , NVP CD4 > 250 cells/mm3 AST/ALT > 2.5 upper limit NVP NVP EFV LPV/r

5. Tenofovir (TDF) : nephrotoxicity, bone mineral densityNephrotoxicity serum creatinine , proteinuria, glycosuria, hypokalemia serum creatinine TDF osteomalacia TDF (fetal growth retardation)

6. Efavirenz (EFV, stocrin 600 mg/tab) : hepatotoxicity, teratogenicityHepatotoxicity NPVTeratogenicity anencephaly, anophthalmia, microphthalmia cleft palate EFV myelomeningocele anophthalmia EFV EFV

7. PIs LPV/r : insulin resistance, hyperlipidemia, Insulin resistance PIs GCT / OGTT GDM GCT / OGTT 24 28

Hyperlipidemia PIs LDL, total cholesterol, triglyceride ATV/r PIs fasting lipid profile 3 6 hyperlipidemia PIs ergot alkaloids methergine severe vasoconstriction methergine oxytocin

1 , (Classes of antiretroviral drugs, Food and Drug Administration pregnancy (FDA) pregnancy category classification and common side effects)

Drug class FDA category

Nucleoside and nucleoside analog reverse transcriptase inhibitors (NRTIs)

Zidovudine (AZT)

Stavudine (D4T)

Lamivudine (3TC)

Abacavir (ABC)

Zalcitabine (ddC)

Tenofovir (TDF)

Emtricitabine (FTC)

Didanosine (ddI)

C

C

C

C

C

B

B

B

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Nevirapine (NVP)

Efavirenz (EFV)

Delavirdine (DVL)

B

D

C

Protease inhibitors

Lopinavir / ritonavir (LPV/r, Kaletra)

Indinavir (IDV)

Amprenavir (APV)

Fosamprenavir (FPV)

Ritonavir (RTV)

Nelfinavir (NFV)

Atazanavir (ATV)

Saquinavir (SQV)

Darunavir (DRV)

C

C

C

C

B

B

B

B

B

Entry inhibitors

Enfuvirtide (ENF)

Maraviroc

B

B

Integrase inhibitors

Raltegravir (RAL)

C

(fixed-dose combination) 1.GPO-vir Z = AZT (250) + 3TC (150) + NVP (200)2.GPO-vir S30 = d4T (30) + 3TC (150) + NVP (200)3.Zilavir = AZT (300) + 3TC (150)4.Lastavir = d4T (30) + 3TC (150)5.Kaletra = LPV (200) + RTV (50)6.Truvada = TDF (300) + FTC (200)

1.

1. Atazanavir (Reyataz) 2. Tenofovir (TDF) 3. Efavirenz GPO 4. Efavirenz (Stocrin)

5. Zidovudine (Antivir) 6. Lastavir 7. Lamivudine (Lamivir) 8. Lopinavir / ritonavir GPO

9. Stavudine (Stavir) 10. Nevirapine (Neravir) 11. GPO-vir S30 12. GPO-vir Z

2. Zidovudine (AZT)

3. Stavudine (D4T)

4. Lamivudine (3TC)

5. Nevirapine (NVP)

6. Lastavir

7. GPO-vir Z

8. GPO-vir S30

9. Efavirenz (EFV)

10. Efavirenz (EFV)

11. Lopinavir / ritonavir

12. Atazanavir (ATV)

13. Tenofovir (TDF)