HIV NRTI

retrovirus

DS RNA

HIV replication cycle

1. GP120 bind CD4- attach and fuse

2. uncoating and rna is RT to DNA

3. into nucleus and incorporated by integrase

4. DNA transcribed by RNA polymerase

5. mRNA traslated

6. viral proteins/ genome released

zidovudine

zidovudine brand

retrovir

zidovudine analog, use, moa

analog of 2'-deoxythymidine

oral form- used in combo w other antiretroviral agents

MOA: AZT triphosphate compete w 2'-deoxythymidine to inhibit HIV-RT, terminate elongation

zidovudine warning

Major toxicities follow from inhibition of mitochondrial DNA polymerase gamma, leading to mitochondrial DNA depletion

lactic acidosis/ hepatomegaly w stenosis

bone marrow suppression, neutropenia, anemia

myopathy

zidovudine azt, didanosine ddl , stavudine 4dt

less preferred agents

2-3x daily dosing

warnings for actic acidosis, hepatomegaly w steatosis

azt- bone marrow suppression

ddl- less mitochondrial tox, pancreatitis risk

4dt- less mitochondrial tox, peripheral neuropathy, lipoatrophy

lamivudine

lamivudine brand

epivir

lamivudine analog, use, moa warning and ci

-analog of 2'-deoxycytidine

oral/sol used in combo w other antiretroviral agents

MOA: 3tc triphosphate compete w 2'-deoxycytidine for HIV-RT, terminate elongation

resistance- mutation M184I/V

1x daily dosing

warning: well tolerated, few side effects

CI- hep B infection

abacavir

abacavir brand

ziagen

abacavir analog, use, moa

analog of of 2'-deoxyguanosine

oral/sol for combo use w antiretroviral for HIV-1

MOA: CBV triphosphate competes with 2'-deoxyguanosine triphosphate to inhibit HIV-RT, terminate elongation

abacavir warning

-Patients who carry the HLA-B*5701 allele are at high risk for a serious and sometimes fatal multi-organ hypersensitivity syndrome (HLA = Human Leukocyte Antigen) -> otherwise well tolerated

hypersensitivity likely from metabolic oxidation, isomerization

tenofovir

Tenofovir disoproxil fumarate

tenofovir alafenamide

tenofovir analog, use

-analog of 2'-deoxyadenosine

oral form used in combo for HIV/ Hep B

tenofovir moa and resistance

prodrug triger metabolism of TDF and TAF

TVF- substrate for host cell kinase from TFV-DP

compete w 2'-deoxyadenosine to inhibit RT and terminate elongation

resistance: single mutation (K65R) in HIV RT

low in treatment-naive

activity restored when M184V (associated with 3TC, FTC) present

TDF prodrug metabolism to TFV

carboxyesterases, phosphodiesterases - gut and liver

TAF to prodrug conversion to TFV

CES-1 carboxyesterase 1 Cat-A cathespin a in liver and PBMC- peripheral blood monoclear cells

adme Tenofovir

TDF/TAF enhance F- once daily

TFV- favorable distribution to lymphoid tissue

t1/2 60-100 hrs

TDF vs TAF- dose, F, site of activation, toxicities

TDF- 300mg, 25-40, gut/liver, kidney, bone tox

TAF- 10mg, 65%, liver PBMC, inc ldl cholesterol

Emtricitabine

Emtricitabine brand

emtriva

emtritiabine analog, use, moa, warnings CI

analog of 2'-deoxycytidine

oral/sol combo w antiretrovirals to treat HIV

MOA: FTC triphosphate compete w 2'-deoxycytidine to inhibit hiv-ti, terminate elongation

resistance- mutation (M184I/V) in HIV-RT

warnings: well tolerated, few side effects

CI hep B

NRTI medication 5

zidovudine, lamivudine, abacavir, tenofovir, emtricitabine