Treatment of HIV

Question 1

HIV-1

Answer 1

Principle form of epidemic

Question 2

HIV-2

Answer 2

Closely related to simian immunodeficiency virus
Concentrated in western Africa
Non-nucleoside reserve transcriptase inhibitors are not active against HIV-2

Question 3

Highly active anti-retroviral therapy (HAART)

Answer 3

Three to four drugs
None alone or combined eradicate HIV
Decrease viral replication, improve immunological status and prolong life
Immunological status is based on normal HIV progression not on normal HIV response.

Question 4

NRTIs

Nucleoside reverse transcriptase inhibitors

Answer 4

Inhibit HIV reverse transcriptase
Inhibitor of viral life cycle following lethal synthesis to nucleotide analog.
Converted to active triphosphate form that competes for nucleoside triphosphates for access to reverse transcriptase. Missing essential 3’-hydroxyl group prevents additional nucleoside addition to DNA chain.
Blocks viral replication and infection of new cells
Inhibition of cellular and mitochondrial DNA polymerases and kinases accounts for potentially lethal toxicity. Primary Toxicities are lactic acidosis, severe hepatomegaly with hepatic steatosis, myopathy, fat redistribution and accumulation, pancreatitis

Question 5

NTRTIs

Nucleotide reverse transcriptase inhibitors

Answer 5

Tenofovir disoproxil fumarate (Viread) - Tenofovir converted to tenofovir diphosphate that competes with deoxyadenosine triphosphate (dATP) for access to reverse transcriptase - Results in DNA chain termination
Potentially useful in patients with NRTI-resistant HIV

Question 6

NNRTIs

Non-nucleoside reverse transcriptase inhibitors

Answer 6

Inhibit reverse transcriptase by binding near the active site and inducing a conformational change that blocks enzyme activation
No activation required
Resistance develops rapidly to this class when used alone. All cause rash, sometimes severe
Rashes can vary from mild to severe, even life-threatening.

Question 7

Didanosine (Videx)

Answer 7

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Tablets contain phenylalanine (avoid use in phenylketonurics)
Tablets are heavily buffered - to avoid acid breakdown in the stomach - which may affect absorption of some drugs
Combined use with stavudine or zalcitabine associated with increased toxicity

Question 8

Stavudine (Zerit)

Answer 8

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Peripheral neuropathy with high dose use
Lactic acidosis incidence is highest for stavudine of all NNRTIs
Very high in pregnant women or in combination with other NNRTIs
Avoid use in patients with hepatic or pancreatic disease
Cannot be given with zidovudine both drugs lose benefit

Question 9

Zidovudine (AZT, Retrovir

Answer 9

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Good oral absorption
Good penetration into all tissues
Eliminated by biotransformation and renal systems
Dosage adjustment may be necessary in patients with renal or hepatic impairments
Probenecid (blocker of tubular secretion) inhibits renal elimination (pharmacokinetic – not clinically effective)
Ribavirin inhibits zidovudine activation
Zidovudine inhibits stavudine’s activation
Use in prevention of HIV after needle stick, sexual exposure , or maternal-neonate transmission
Bone marrow function suppression up to 30% of patients, VB12 deficiency, severe anemia, granulocytopenia
Can not be given with stavudine

Question 10

Emtricitabine (Emtriva)

Answer 10

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Long duration of action allows for once daily dosing - desirable
Causes hyperpigmentation of soles and palms
Patient becomes yellow-ish

Question 11

Lamivudine (Epivir)

Answer 11

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Generally regarded as the best tolerated NRTI
EpiVir HBV – used to hepatitis B virus. Not able to use in HIV patients.
Same drug but different dosages. Epivir is higher dosage
Increase risk of pancreatitis when used in children
Not recommended for use with zalcitabine (inhibit each other)

Question 12

Abacavir (Ziagen)

Answer 12

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Higher incidence of hypersensitivity
5% may be severe; Type 1 and Type 2. Repeat exposure in hypersensitive patient results in more severe hypersensitivity
Avoid use in patients with hepatic disease or alcohol use

Question 13

Tenofovir (Viread)

Answer 13

Nucleotide Reverse transcriptase inhibitor (NTRTI)
Generally well tolerated - once daily oral dosing
Lower incidence of mitochondrial toxicity than NRTIs (doesn’t work well with other treatments)

Avoid use in patients with renal disease

Avoid concurrent use with didanosine and atazanavir (Increases plasma levels on one or both agents)

Question 14

Efavirenz (Sustiva)

Answer 14

Non-nucleoside Reverse Transcriptase Inhibitor (NNRTIs)
Indicated for HIV therapy and postexposure prophylaxis
Once a day, well tolerated
Central toxicity in half of patients

Question 15

Nevirapine (Viramune)

Answer 15

Non-nucleoside Reverse Transcriptase Inhibitor (NNRTIs)
Black Box Warnings:
Rash - Avoid rash by using low dose therapy initially
Hepatic toxicity
FDA Pregnancy Category D

Question 16

Saquinavir (Fortovase)

Answer 16

Protease Inhibitors (PI)
Well-tolerated with mild gastrointestinal effects the primary complaint
Bioequivalence is Black Box Warning
Therapeutic equivalence is not guaranteed. (do not allow for generic substitution)

Question 17

Ritonavir (Norvir)

Answer 17

Protease Inhibitors (PI)
Not well-tolerated at high doses
Drug Interactions a Black Box Warning
Most potent CYP3A4 inhibitor of protease inhibitors
Also inhibits CYP2D6 and other CYP isoforms

Question 18

Indinavir (Crixivan)

Answer 18

Protease Inhibitors (PI)
Renal toxicity seen in children (30%) and adults (10%) that consume less than 1.5 liters of water daily

Question 19

Atazanavir (Reyataz)

Answer 19

Protease Inhibitors (PI)

Question 20

Tipranavir (Aptivus)

Answer 20

Protease Inhibitors (PI)
Hepatotoxicity (Black box warning)
Intracranial hemorrhage (Black box warning)
Most common with ritonavir – tipranavir combination

Question 21

Amprenavir (Agenerase)

Answer 21

Protease Inhibitors (PI)
High incidence of rash
Oral solution contains propylene glycol (Black box warning) - Avoid in children and pregnant women
Propylene glycol can produce hyperosmolality, lactic acidosis, seizures and respiratory depression
Sulfonamide sensitive patients should avoid
Preparations contain high levels of vitamin E

Question 22

Nelfinavir (Viracept)

Answer 22

Protease Inhibitors (PI)
Low incidence of serious adverse reactions make it the most often used protease inhibitor
Most tolerated – commonly abused

Question 23

Lopinavir – Ritonavir (Kaletra)

Answer 23

Protease Inhibitors (PI)

Question 24

Darunavir (Prezista)

Answer 24

Protease Inhibitors (PI)

Question 25

Fosamprenavir (Lexiva)

Prodrug of amprenavir

Answer 25

Protease Inhibitors (PI)
Lower toxicity than amprenavir
Rash most common adverse reaction
Avoid use with patients with sulfa allergy

Question 26

Protease Inhibitors (PI)

Answer 26

(All end in -inavir)
Inhibits the human immunodeficiency virus aspartic protease enzyme
Blocks posttranslational processing of the essential viral protein products
Impairs viral replication and proliferation
Typically used with HIV reverse transcriptase inhibitors
Serious Adverse reactions: hyperglycemia, hyperlipidemia, elevated transaminases, increase in bleeding in hemophiliacs, CYP3A4 biotransformation (grapefruit), Paresthesia

Question 27

Enfuvirtide (T-20, Fuzeon)

Answer 27

Fusion Inhibitor, prevents virally induced conformational change in transmembrane glycoprotein subunit (GP41) - which permits viral-host membrane fusion to inject RNA into the cell. Less cell to cell transmission.
Requires twice daily subcutaneous injections
potential hypersensitivity reaction

Question 28

Maraviroc (Selzentry)

Answer 28

Interferes with entry of HIV into host cells by inhibiting fusion with outer membrane (only effective with CCR5-tropic HIV strains.)
Oral dosing
Adverse reactions: hypersensitivity, cardiovascular events (MI, hypotension), hepatotoxicity, suppresses immune response.
Thioridazine (old antipsychotic) increases risk of serious cardiovascular events

Question 29

Raltegravir (Isentress)

Answer 29

(integrase) - HIV-1 integrase strand transfer inhibitor - prevents viral DNA from integrating with host genome. Resistance related to mutations in integrase.