بسم الله الرحمن الرحيم

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

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

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 ! NB! Avoid alcohol • 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

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).

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.

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

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

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)

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

27. EFAVIRENZ: Drug Interaction ! Induces CYR3A4 – induction of its own metabolism + other drugs Efavirenz may decrease the amount of: • Indinavir • Saquinavir • Rifabutin Efavirenz levels may be decreased by: • Rifampin • Rifabutin 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

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.

33. RITONAVIR: Drug Interaction Dosage adjustment is required 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 !

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

36. INDINAVIR: Drug Interaction ! Numerous complex drug interactions 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.

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

39. NELFINAVIR: Drug Interaction ! Nelfinavir is an inducer and an inhibitor of the CYP3A 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.

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

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