بسم الله الرحمن الرحيم treatment of hiv/aids in : medical, health and social...

بسم الله الرحمن بسم الله الرحمن الرحيمالرحيم

Treatment of HIV/AIDSTreatment of HIV/AIDS

In : In :

Medical, health and social Medical, health and social aspects of HIV/AIDSaspects of HIV/AIDS

Alex Shnyra

2003

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

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

NH

N

O

CH3

O

OOH

N3

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

Agent Route Use Adult Dosage

ZIDOVUDINE ORAL

I.V.

HIV 200 mg q3d or 300 mg q2d

During labor 1-2 mg/kg/h

(to prevent mother-to-newborn infection)

ZIDOVUDINE: Adverse EffectsCommon • 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)

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

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

N

NNH

N

O

OOH

Contains phenylalanine (phenylketonuria) and Na (Na-restricted diets)!

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


DIDANOSINE ORAL Antiretroviral

HIV

200 mg q12h (> 60 kg)

125 mg q12h (< 60 kg)

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

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 !

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

N

N

NH2

O

S

O

OH

LAMIVUDINE: Use and Dosage

• For treatment of HIV infection/AIDS or hepatitis B infection

• Side effects are typically mild (headache, insomnia, gastrointestinal).


LAMIVUDINE ORAL Antiretroviral

HIV

150 mg q12h ( > 50 kg)

2 mg/kg q12h (< 50 kg)

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

N

N

O

NH2

O

OH

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.


ZALCITABINE

ORAL Antiretroviral

HIV

0.75 mg q8h

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

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

NH

N

OOH

CH3

O

O

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.

N

NN

N

OH

NH2

NH

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

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


NEVIRAPINE ORAL Antiretroviral

HIV

200 mg/d for 2 w then

200 mg q12h

Newborn from infected mother – 2 mg/kg oral

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

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.

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


DELAVIRDINE

ORAL Antiretroviral HIV 400 mg q8h

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

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)


EFAVIRENZ ORAL Antiretroviral HIV 600 mg/d

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!

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.

!

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.

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


SAQUINAVIR ORAL Antiretroviral HIV 600 mg q8h

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.

SAQUINAVIR: Adverse Effects

Selective drugRARE:

• Burning or prickling sensation; confusion; dehydration; dry or itchy skin; fruity mouth odor; nausea; unusual tiredness; weight loss

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.


RITONAVIR ORAL Antiretroviral

HIV

600 mg q12h

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

!

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

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


INDINAVIR ORAL Antiretroviral

HIV

800 mg q8h

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!

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.

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


NELFINVIR ORAL Antiretroviral

HIV

750 mg q8h with food

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!

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.

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


AMPRENAVIR ORAL Antiretroviral

HIV

1200 mg q12h b.w. > 50kg

20 mg/kg q12h b.w. < 50 kg

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

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.

بسم الله الرحمن الرحيم treatment of hiv/aids in : medical, health and social...

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