1. بسم الله الرحمن الرحيم Treatment of HIV/AIDS In : Medical, health and social aspects of HIV/AIDS Alex Shnyra 2003

3. Nucleoside RT Inhibitors (NRTI) A class of nucleoside analogs Require an activation (phosphorylation) by cells Mechanism of action: –A: competitive inhibition of HIV RT –B: if incorporated – causes stop of DNA elongation

4. ZIDOVUDINE (zye-DOE-vue-deen) Azidothymidine (AZT) or deoxythymidine analog Active against HIV-1 and other mammalian retroviruses Well absorbed and distributed in the tissues (CSF:>60% of blood level) Serum T1/2 ~ 1hr, but intracellular – 3.3 hrs Excretion – primarily renal after glucuronidation by the liver. Clearance is reduced by 50% in uremic patients Drug resistance (mutations in RT gene) may limit its efficacy when used as monotherapy

5. ZIDOVUDINE: Use and Dosage Decrease the rate of clinical disease progression Prolongs survival of HIV-infected patients Used for treatment of HIV associated dementia and thrombocytopenia AgentRouteUseAdult Dosage ZIDOVUDINEORAL I.V. HIV200 mg q3d or 300 mg q2d During labor 1-2 mg/kg/h (to prevent mother-to- newborn infection)

6. ZIDOVUDINE: Adverse Effects Common Myelosuppression (anemia and neutropenia) Gastrointestinal intolerance Headache Insomnia Uncommon Thrombocytopenia Hyperpigmentation of nails Myopathy,High doses may cause anxiety, confusion. Rare Fatal lactic acidosis, severe hepatomegaly (check aminotransferase levels)

7. ZIDOVUDINE: Drug Interactions Increased serum levels of Zidovudine may occur with simultaneous administration of: –Fluconazole –Probenecid –Phenytoin –Methadone –Valproic acid Zidovudine may decrease the levels of Phenytoin Potentiating hematologic toxicity of other cytotoxic agents and myelosuppressive drugs

8. DIDANOSINE (di-DAN-oe-seen) Didanosine (ddI) is a synthetic analog of deoxyadenosine. Activated by acidic pH via hydrolysis of the glycosidic bond. Plasma protein binding is low. Excretion by renal system - T1/2 0.6-1.5 h. Activated intracellular T1/2 12-24 h Contains phenylalanine (phenylketonuria) and Na (Na-restricted diets) !

9. DIDANOSINE: Use and Dosage A chemical buffer is needed to increase absorption; proper buffer dosing depends on taking drug on an empty stomach (AUC is reduced by 55% if taken 2 h after a meal) Resistance occurs due to mutation in the viral RT gene AgentRouteUseAdult Dosage DIDANOSINEORALAntiretrovir al HIV 200 mg q12h (> 60 kg) 125 mg q12h (< 60 kg)

10. DIDANOSINE: Adverse Effects Common Anxiety, diarrhea. Uncommon Nausea and vomiting; stomach pain; pain in the hands or feet. Rare Convulsions (seizures); fever and chills; shortness of breath; skin rash

11. DIDANOSINE: Drug Interactions Decreases absorption of: –Dapsone (Use with Didanosine may increase the chance of peripheral neuropathy) –Ketoconazole –Quinolones (Didanosine decreases concentration of antibiotics via chelation effects) –Tetracycline (use with Didanosine may increase the chance of pancreatitis) Increased risk of pancreatitis with I.V. Pentamidine or Ganciclovir NB! Avoid alcohol !

12. LAMIVUDINE: (la-MI-vyoo-deen) Lamivudine (3TC) is a cytosine analog. Synergistic with other antiretroviral nucleoside analogs. Oral bioavailability ~ 80% (not food- dependent). Excretion: unchanged by renal system - T ½ ~ 2.5h. Intracellular T1/2 ~ 10-15h. High level resistance occurs – best when used in combination

13. LAMIVUDINE: Use and Dosage For treatment of HIV infection/AIDS or hepatitis B infection Side effects are typically mild (headache, insomnia, gastrointestinal). AgentRouteUseAdult Dosage LAMIVUDINEORALAntiretrovir al HIV 150 mg q12h ( > 50 kg) 2 mg/kg q12h (< 50 kg)

14. ZALCITABINE (zal-SITE-a-been) Zalcitabine – a cytosine analog with high bioavailability ~ 80% If taken with food or antacid – plasma concentration drops Excretion – T1/2 ~ 2 h by renal system – reduce the dosage in patients with renal insufficiency T1/2 intracellular ~ 10 h Resistance has been described – use in combination regimens (effective with Zidovudine) Only 4% is plasma protein bound CSF ~ 20% plasma concentration

15. ZALCITABINE: Use and Dosage Drug interactions: –Any drug with potential risk of peripheral neuropathy (e.g., ddI, Cloramphenicol, INH, Dapsone, Phenytoin etc.). –Any drug which increases risk of pancreatitis (e.g., IV Pentam) –Antacids decrease ddC absorption. –Probenecid and Cimetidine decrease elimination of ddC and may increase chance of toxicity. AgentRouteUseAdult Dosage ZALCITABIN E ORALAntiretrovir al HIV 0.75 mg q8h

16. ZALCITABINE: Adverse Effects Common Dose-dependent neuropathy, tingling, burning, numbness, or pain in the hands, arms, feet, or legs Less common Fever; joint pain; muscle pain; skin rash; ulcers in the mouth and throat. Rare Fever and sore throat; nausea and vomiting; stomach pain (severe); yellow eyes or skin

17. STAVUDINE (STAV-yoo-deen) A thymidine analog Oral bioavailability ~ 86% Blood T1/2 ~ 1.22 h T1/2 intracellular ~ 3.5h CFS ~ 55% of blood concentration Excretion – renal Resistance occurs (mutations in RT gene) Side Effects: –peripheral sensory neuropathy (may increase when used with other drugs, e.g. ddC ddI) –Pancreatitis

18. ABACAVIR (a-BAK-a-veer) A guanidine analog (the most effective drug in the group) Oral bioavailability ~ 83%, not affected by food ~50% is protein bound form Blood T1/2 ~ 1.5 h T1/2 intracellular ~ 3.5h CFS ~ 30% of blood concentration Excretion – renal – after alcohol dehydrogenase inactivation High level resistance occurs (mutations in RT gene) Side Effects: –Hypersensitivity, gastrointestinal – resolves quickly with discontinuation –Nausea, vomiting, headache, fatigue.

19. NONNUCLEOSIDE RT INHIBITORS The NNRTIs directly interact with RT – block RNA- and DNA- dependent DNA polymerase. Do not require activation for the activity. Specific for RT of HIV-1. Rapid resistance (cross-resistance with other NNRTIs) occurs due to mutations in viral RT gene – use in combination regiments. No cross-resistance between NNRTIs and NRTIs or the protease inhibitors

20. NEVIRAPINE (ne-VYE-ra-peen) A highly lipophilic drug Excellent bioavailability ~ 90% which is not food-dependent ~ 60% as protein-bound CSF concentration ~ 45% of the blood levels Metabolized by P450 – excretion primarily in urine AgentRouteUseAdult Dosage NEVIRAPINEORALAntiretrovir al HIV 200 mg/d for 2 w then 200 mg q12h Newborn from infected mother – 2 mg/kg oral

21. NEVIRAPINE: Drug Interaction ATNTAGONIZES: ketoconazole (not recommended) oral contraceptives (use nonhormonal contraception) methadone Concentration is increased by: Coadministration with Cimetidine Macrolide agents Monitor: Rifampin, Rifabutin and other drugs metabolized by CYP3A4 or CYP2B6. Inhibitors of CYP3A

22. NEVIRAPINE: Adverse Effects COMMON Skin rash (17%). Sometime severe – toxic epidermal necrolysis; hepatoxicity (fatal hepatic necrosis), abnormal liver function tests; chills, fever, or sore throat. LESS COMMON Aching joints and muscles; bleeding or crusting sores on lips; dark urine; loss of appetite; nausea; vomiting; weakness; yellow skin or eyes RARE Pain in arms, legs, or feet; sleepiness or unusual drowsiness; sores or ulcers in the mouth.

23. DELAVIRDINE (de-la-VIR-deen) Good bioavailability ~ 85% which is reduced by antacids ~ 98% as protein-bound CSF concentration only 0.4 % of the blood levels Metabolized by CYP3A and CYP2D6 P450 (monitor liver tests) Can inhibit its own metabolism via inhibition of CYP3A AgentRouteUseAdult Dosage DELAVIRDINEORALAntiretroviral HIV400 mg q8h

24. DELAVIRDINE: Drug Interaction Delavirdine may increase plasma concentrations of: Indinavir, Saquinavir, Amprenavir, Rifabutin Antihistamines. Sedative hypnotics Calcium channel blockers Delavirdine concentration may be decreased by: Antacids, Didanosine, Phenytoin, Phenobarbital, Carbamazepine, Rifabutin, Rifampin. Delavirdine concentration may be increased by: Ketoconazole Clarithromycin Fluoxetine

25. EFAVIRENZ (ef-FAH-ver-enz) Oral administration gives ~ 45% bioavailability, food-dependent T1/2 40-55 hrs with peak 3-5 hrs after administration Highly protein bound (>99%) Steady plasma concentration is established after 6-10 days of use Hydroxylated by CYP3A4 and CYP2B6 Low CSF concentration (0.3-1.2 % blood levels) AgentRouteUseAdult Dosage EFAVIRENZ ORALAntiretroviral HIV600 mg/d

26. EFAVIRENZ: Adverse Effects COMMON Psychiatric effects – depression, aggression, confusion Skin rash or itching LESS COMMON Blood in urine; difficult or painful urination; pain in lower back RARE Usually occur in the first days of therapy !

27. EFAVIRENZ: Drug Interaction Efavirenz may decrease the amount of: Indinavir Saquinavir Rifabutin Efavirenz levels may be decreased by: Rifampin Rifabutin Induces CYR3A4 – induction of its own metabolism + other drugs High rates of fetal abnormalities in primates: should be avoided in pregnancy. !

28. Protease Inhibitors Act on late stages of HIV growth cycle. Proteases are responsible for conversion (cleaving) of the proteins in to mature forms which are the components of virion core. Prevent new waves of infection. Resistance is emerging and associated with mutations (at least 4) in the genes encoding viral proteases.

29. SAQUINAVIR (sa-KWIN-a-veer) Oral administration: old formulation (hard) only 4 % bioavailability; new formulation (soft) ~ 12% bioavailability Absorption is food-dependent (fat). Drug should be taken 2h before or after meals Highly protein bound (~ 98%) Low CSF concentrations T1/2 12 hrs; Excretion in the feces Metabolized in the liver by CYP3A4 AgentRouteUseAdult Dosage SAQUINAVIR ORALAntiretroviral HIV600 mg q8h

30. SAQUINAVIR: Drug Interaction Saquinavir concentration is increased by: Ritonavir, Nelfinavir, Delavirdine, Indinavir, Ketoconazole, Clarithromycin, grapefruit juice. Saquinavir is decreased by: Efavirenz, Nevirapine, Rifampin, Rifabutin, Phenobarbital, Phenytoin, Dexamethasone, Carbamazepine. Contraindications: Concomitant Rifampin: not recommended.

31. SAQUINAVIR: Adverse Effects Selective drug RARE: Burning or prickling sensation; confusion; dehydration; dry or itchy skin; fruity mouth odor; nausea; unusual tiredness; weight loss

32. RITONAVIR (ri-TOE-na-veer) An inhibitor of HIV-1 and HIV-2 proteases High bioavailability (~ 75%) – increased with food Excretion – primarily in the feces. A potent inhibition of CYP3A and CYP 2D6 P450 ( patients with hepatic insufficiency). Resistance is emerging. AgentRouteUseAdult Dosage RITONAVIR ORALAntiretrovir al HIV 600 mg q12h

33. RITONAVIR: Drug Interaction Concentrations are reduced by: Phenobarbital, Carbamazepine, Dexamethasone, Phenytoin, Rifampin, Nevirapine, tobacco use. Concentration are increased by: Fluconazole, Efavirenz, Delavirdine, Clarithromycin Contradictions: Cardiac drugs - Amiodarone, Encainide Analgesics – Meperidine, Propoxyphene Anti-depressants – Bupropion, Desipramine Neuroleptics – Clozapine, Pimozide Sedatives – Diazepam, Chlorazepate Dosage adjustment is required !

34. RITONAVIR: Adverse Effects COMMON GI upset, asthenia, abdominal pain, headache, anorexia UNCOMMON Numbness or tingling feeling around the mouth; numbness or tingling feeling in the hands or feet RARE Confusion; dehydration; dry or itchy skin; fatigue; nausea; vomiting; weight loss

35. INDINAVIR (in-DIN-a-veer) A specific inhibitor of HIV-1 and HIV-2 proteases Oral bioavailability ~ 65%, but must be taken on empty stomach ~ 60% of drug is protein-bound CSF ~ 75% - is the highest levels among protease inhibitors Metabolized by liver (CYP3A4) – excretion in the feces Cirrhosis and other hepatic diseases cause the higher AUC for Indinavir Resistance - due to multiple codon substitutions Indinavir is a substrate and inhibitor of CYP3A4 AgentRouteUseAdult Dosage INDINAVIR ORALAntiretrovir al HIV 800 mg q8h

36. INDINAVIR: Drug Interaction Concentrations are reduced by: Rifabutin (substantially decreases AUC for Indinavir), Amprenavir, Nevirapine, Efavirenz, Fluconazole, grapefruit juice Concentration are increased by: Zidovudine, Ritonavir, Nelfinavir, Delavirdine, Ketoconazole, Contradictions: Concomitant Cisapride, Triazolam, Midazolam, Ergot derivatives. Numerous complex drug interactions !

37. INDINAVIR: Adverse Effects COMMON Blood in urine; sharp back pain just below ribs UNCOMMON Asymptomatic hyperbilirubinemia, GI upset, abdominal pain, headache, fatigue, insomnia. RARE Confusion; dehydration; dry or itchy skin; fatigue; nausea; vomiting; weight loss.

38. NELFINAVIR (nel-FIN-a-veer) A specific inhibitor of HIV-1 and HIV-2 proteases Absorption is food-dependent (food increases AUC for Nelfinavir) Bioavailability in humans is unknown Extensively protein-bound (>98%) Plasma T1/2 is 3.5-5 h Resistance is emerging AgentRouteUseAdult Dosage NELFINVIR ORALAntiretrovir al HIV 750 mg q8h with food

39. NELFINAVIR: Drug Interaction Concentrations are reduced by: Rifabutin and Rifampin (substantially decreases AUC for Nelfinavir) May be reduced by Carbamazepine, Phenobarbital, Phenytoin Concentration are increased by: Indinavir, Ritonavir, Saquinavir, Delavirdine, Efavirenz, Ketoconazole Contradictions: Cisapride, Triazolam, Midazolam, ergot derivatives. Nelfinavir is an inducer and an inhibitor of the CYP3A !

40. NELFINAVIR: Adverse Effects COMMON Diarrhea, flatulence, redistribution of body fat. LESS COMMON Intestinal gas; skin rash, diabetes, hyperglycemia. RARE Other side effects not listed above may also occur in some patients.

41. AMPRENAVIR (am-PREN-a-veer) Rapidly absorbed from the GI (food-independent) Plasma T1/2 is 7-10 hrs Especially effective in a combination with NRTIs (at least two) Resistance occurs but cross-resistance with other protease inhibitors is less prevalent AgentRouteUseAdult Dosage AMPRENAVIR ORALAntiretrovir al HIV 1200 mg q12h b.w. > 50kg 20 mg/kg q12h b.w. < 50 kg

42. AMPRENAVIR: Adverse Effects COMMON Dry or itchy skin; fatigue; increased hunger; increased thirst; increased urination; skin rash LESS COMMON Burning or prickling sensation in arms or legs; depression; mood or mental changes RARE Fever; general feeling of discomfort or illness; unexplained weight loss

43. AMPRENAVIR: Drug Interaction Concentrations are reduced by: Rifampin and Efavirenz Contradictions: Triazolam, Cisapride, Midazolam, ergot derivatives, Amiodarone, Warfarin, tricyclic antidepressants, Lovastatin, Nelfinavir is an inhibitor of the CYP3A4 ! NB! Use of antacids or may keep Amprenavir from working properly.