Download NRTIs NNRTIs PIs Entry Inhibitor Integrase Inhibitors MOA Inhibits

ANTIRETROVIRAL DRUGS FOR HIV AND AIDS
NRTIs
MOA
NNRTIs
Inhibits HIV reverse transcriptase
enzyme by competing with
adenosine, guanosine, thymidine,
and cytosine to grow proviral DNA
chain.
-Lactic Acidosis and hepatic
steatosis (abdominal distention,
n/v/d, low CO2, anion gap >16)
-Stavudine and Didanosine have the
greatest risk for ADR
Inhibits HIV-1 reverse transcriptase
by binding adjacent to the active
site, inducing a conformational
change that inactivates the enzyme
Indications
HIV-1 and HIV-2
Comments
ADR
DRUG:
PIs
Entry Inhibitor
Integrase Inhibitors
Inhibits the enzyme HIV protease
by binding to its active site.
Prevents the cleavage of gag-pol
precursorincomplete & noninfectious “virions”
-Significant GI effects
-Paresthesia
-Hyperglycemia & insulin
resistance
-Dyslipidemia
-Hepatotoxicity
-Lipohypertrophy
CCR5 receptor antagonist—
prevents CCR5 tropic HIV entry
into cells
HIV integrase strand transfer
inhibitor
Maraviroc- Dizziness, orthostatic
hypotension, hepatoxicity
N/D, h/a
HIV-1 only
HIV-1 and HIV-2
CCR5-trophic HIV-1, any pt
resistant to multiple AR agents
Combination therapy in pts
resistant to other ARV drugs
-NRTIs must undergo
phosphorylation to be active vs. virus
-First class of ARV drug approved.
-All are renally eliminated
-Parent molecule is active (unlike
NRTIs)
-2nd class of drug to be approved
- CYP3A4 substrate
-CI in CVD, Liver disease,
Infection
-CYP450 substrate
-Expensive ($900-$1000 per
month)
Raltegravir (Isentress)
Zidovudine (AZT)
Lamivudine (3TC)
Abacavir (ABC)
Emtricitabine (FTC)
Tenofovir (TDF)
Efavirenz (EFZ)
Ritonavir (RTV)
Nelfinavir (NFV)
Lopinavir-Ritonavir
Atazanavir (ATV)
Maraviroc (Selzentry)
Enfuvirtide (Fezeon)
Raltegravir
All can cause rashes and
hepatotoxicity
-Ritonavir is most potent
inhibitor (Boosted therapy--used
in combo with other PIs to
increase their levels)
Enfuvirtide- Inj site Rxn.
Expensive ($1000 per month)
Nucleoside/Nucleotide Analogue Reverse Transriptase Inhibitors (NRTIs)
MOA: Inhibits HIV reverse transcriptase enzyme by competing with adenosine, guanosine, thymidine, and cytosine to grow proviral DNA chain.
ZIDOVUDINE(Retrovir)
LAMIVUDINE(Epivir)
ABACAVIR(Ziagen)
EMTRICITABINE(Emtriva)
TENOFOVIR DF (Viread)
Indications
-Adults & Children
-Post-exposure prophylaxis
-Prenatal/perinatal transmission to
baby by HIV infected mother, NOT as
monotherapy for mother
-HIV 1, 2 pts
-Hep B
ADR
-h/z, n/v/d, anorexia, fatigue
-Bone marrow suppression
-Nail discoloration
-Lipoatrophy
GI effects-(biggest
complaint)
Comments
-First ARV for HIV
-Post exposure prophylaxis (basic) in
combo with Lamivudine
-Cytosine analogue
-Best tolerated of all NRTIs
-HIV 1, 2
-Dual NRTI drug
-Preferred initial HAART
regimen
QD dosing
-Hep B
-Dual NRTI
-Preferred intial HAART regimen
-Fatal hypersensitivity rxn (35% of pts)fever, rash, GI,
cough
-Black box warning
-Similar to other NRTIs
-Caution with h/a and unique
hyperpigmentation of the palms
-Renal insufficiency –RARE
-Osteoporosis
-Guanosine Analogue
-Cytosine analogue
-Long half-life- Can take w/o
regards to meals
-Adv: Already has one phosphate group so
it only requires diphosphorylation to be
activated
-Adenosine analogue
-Hep B
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTIs)
MOA: Inhibits HIV-1 reverse transcriptase by binding adjacent to the active site, inducing a conformational change that inactivates the enzyme
Indications
EFAVIRENZ (Sustiva) EFZ
-NNRTI portion of initial preferred HAART regiment
-HIV-1 ONLY
ADR
-Rash (MC)
-CNS effects: dizziness, h/a, insomnia, AMS, vivid dreams, nightmares, hallucinations
Comments
Adm: MUST be taken on an empty stomach
CI in 1st trimester of preg
Use with caution in pts with unstable psychiatric dz.
Protease Inhibitors (PIs)
MOA: Inhibits the enzyme HIV protease by binding to its active site. Prevents the cleavage of gag-pol precursorincomplete & non-infectious “virions”
RITONAVIR (RTV)
NELFINAVIR(NFV)
LOPINAVIR-RITONAVIR
ATAZANAVIR (ATV)
Indications
HIV 1,2
HIV 1,2
HIV 1,2
-Can be used as PI portion for initial
preferred HAART regimen
HIV 1,2
ADRs
-GI effects
-Altered taste sensation
-Paresthesias
-Hypertriglyceridemia
-Pancreatitis
-Diarrhea
-Flatulence
-Hyperlipidemia
-Diarrhea
-Similar to other PI except less dyslipidemia
-Hyperbilirubinemia (d/c if total BIR >5x ULN or
Jaudice)
Comments
-Not well tolerated in high doses
Boosted therapy—used, in low dose, in
combo with other PIs to increase their
levels
-Potent CYP3A4 inhibitor, also CYP2D6
**Does not have to be boosted with
Ritonavir—Can boost with food**
-No cross resistance to other PIs
-Ritonavir inhibits the rapid inactivation of
Lopinavir by CYP3A4
-Greater specificity for HIV protease than other
available PIs
-Do not use once-daily in preg
-Metabolized/Inhibitor of CYP3A4
-Requires an acidic medium
-CI with PPI
-Separate dosing required w/ H2
blockers & antacids
Entry/Fusion Inhibitors
MOA: CCR5 receptor antagonist—prevents CCR5 tropic HIV entry into cells
MARAVIROC (MVC)
ENFUVIRITIDE (T-20)
Indications
CCR5-trophic HIV-1, any pt resistant to multiple AR agents
Pts resistant to multiple ARV agents
Preg Cat (B)
ADRs
-Injection site RXN
-Dizziness, orthostatic hypoTN, hepatotoxicity
Comments
Inj Adm:
-Supplied as Dry powder for reconstitution
-Stored as room temp prior to reconstitution
-Syringe, diluents, alcohol supplied with product
-Caution in CVD, Liver Dz, Infxn
-CYP450 substrate
Integrase Inhibitors
MOA: HIV integrase strand transfer inhibitor- Prevents HIV from getting into host DNA
RALTEGRAVIR (ISENTRESS)
Indications
Combination therapy in pts resistant to other ARV drugs
ADRs
N/V, Headache
Comments
-Less DDIs
-$1,000 per month
ARV TX FAILURE:
VIROLOGIC FAILURE (MC!)
o
HIV RNA is still in the blood 1 year after initiation of treatment OR if it is
detected again after ARVs had previously lowered it to undetectable.
IMMUNOLOGIC FAILURE
o
CD4 increase of <25-50 cells/uL in the first year of therapy, or a decline in CD4
count to below the baseline.
CLINICAL PROGRESSION
o
The occurrence of HIV-related events or a decline in physical health after >3
months of therapy
CAUSES OF TX FAILURE
Patient factors
o
CD4, Viral load, co -morbidities)
Suboptimal adherence
ARV toxicity and intolerance
Pharmacokinetic problems
Suboptimal drug potency
Viral resistance
Antiretroviral Combination Regimen consists of either:


1-NNRTI + 2-NRTI OR
1-PI(w/ boost of ritonavir) + 2-NRTI
NNRTI:
 Efavirenz
PI:
 Atazanavir + Ritonavir (CI in PPIs)
 Darunavir + Ritonavir
 Fosamprenavir + Ritonavir
 Lopinavir/Ritonavir
2-NRTI:
 Tenofovir + Emtricitabine