Antiretroviral agents (6) Flashcards
Antiretroviral agents: mechanisms
- entry/fusion/attachement inhibitor
- Protease inhibitor
- maturation inhibitor
- integrase inhibitor
- nucleoside/nucleotide and Non-nucleoside reverse transcriptase inhibitor
Antiretroviral agents - NRTIs
Nucleoside / nucleotide RT inhibitors: NRTI
- Thymidine analogues: zidovudine (AZT), (stavidine)(D4T)
- Cytidine analogues : lamivudine (3TC), emtricitabine (FTC)
- Purine analogues: abacavir (ABC), tenofovir (TDF)
combinations: a cytidine: 3TC or FTC and a purine ABC, TDF
Mechanism of action:
- Prodrugs, converted by host cell kinases to triphosphates
- Competitively inhibit binding of natural nucleotides to reverse transcriptase (RNA-dependent DNA polymerase enzyme); act as chain terminators via their
insertion into the growing DNA chain (lacking a 3’ -OH group) - Resistance emerges rapidly when used as a single agent, via mutations in the Pol gene
General (common) toxicity and side effects:
- GI distress (nausea, vomiting, diarrhea)
- Headache, fatigue
- Hepatotoxicity (steatosis, hepatomegaly, elevated transaminases); risk factors include obesity, prolonged treatment, pre-existing liver disease
- Lactic acidosis
- Mitochondrial toxicity
Zidovudine
Indication: HIV-1 and HIV-2 infection
- High genetic barrier: for complete resistance more mutations are needed
- no cross-resistance
- Hepatic metabolism + renal elimination
(dose adjustment in hepatic and renal dysfunction) - Drug of choice during pregnancy and lactation
• side effects:
•GI problems (nausea, vomiting, diarrhea),
-lactic acidosis,
-lipodystrophy,
headache,
malaise,
hepatitis (elevated transaminases)(mitochondrial toxicity)
+anemia and leukopenia
- Bone marrow suppression (most toxic of all agents); effect may be severe to require blood transfusions
lamivudine
Indication: HIV-1 and HIV-2 infection
for HBV as well
Least potent and least toxic agent
- High genetic barrier: for complete resistance more mutations are needed
- no cross-resistance
• side effects: •GI problems (nausea, vomiting, diarrhea), -lactic acidosis, -lipodystrophy, headache, malaise, hepatitis (elevated transaminases)(mitochondrial toxicity) - Peripheral neuropathy (mild)
emtricitabine
Indication: HIV-1 and HIV-2 infection
for HBV as well
- Newer form of lamivudine (more potent)
- Contraindications: pregnancy, children, renal or hepatic dysfunction
- High genetic barrier: for complete resistance more mutations are needed
- no cross-resistance
• side effects:
•GI problems (nausea, vomiting, diarrhea),
-lactic acidosis,
-lipodystrophy,
headache,
malaise,
hepatitis (elevated transaminases)(mitochondrial toxicity)
abacavir
- Guanosine analogue
Indication: HIV-1 and HIV-2 infection
- High genetic barrier: for complete resistance more mutations are needed
- no cross-resistance
• side effects: •GI problems (nausea, vomiting, diarrhea), -lactic acidosis, -lipodystrophy, headache, malaise, hepatitis (elevated transaminases)(mitochondrial toxicity) \+hypersensitivity reaction
- Allergy (in up to 5% of patients, potentially severe); strongly-associated with the HLA-B*57:01 allele
tenofovir
• AMP analogs
- Nucleotide analogue (requires less phosphorylation steps for activation)
• Can be nephrotoxic
• no cross-resistance
• teno: less primary resistance, higher efficacy
Indication: HIV-1 and HIV-2 infection
for HBV as well
- High genetic barrier: for complete resistance more mutations are needed
- no cross-resistance
oral administration
• side effects: •GI problems (nausea, vomiting, diarrhea), -lactic acidosis, -lipodystrophy, headache, malaise, hepatitis (elevated transaminases)(mitochondrial toxicity) \+nephrotoxicity
which NRTis for HBV
Lamivudine, emtricitabine and tenofovir:
for HBV as well
Antiretroviral agents - NNRTIs
Non nucleoside RT inhibitors: (Nevirapine, Efavirenz,)
2nd gen: Etravirine, (Rilpivirine, Doravirine)
Mechanism of action:
- Bind to a site on reverse transcriptase different from the binding site of NRTI’s
- Do not require activation via phosphorylation
- Resistance emerges rapidly when used as a single agent, via mutations in the Pol gene
- No cross resistance with NRTI’s
- Additive or synergistic effect is achieved when used in combination with NRTI’s and/or PI’s
*NNRTI’s are not active against HIV-2 strains (common cause of disease in west Africa)
Nevirapine: (NOT ON THE LIST)
- Used to suppress HIV vertical transmission – single dose to mother at the onset of labor, and to neonate post-partum
- Part of HIV drug regimens
- Hypersensitivity reaction (rash, Stevens-Johnson syn.)
- Hepatotoxicity
- Inducer of CYP450 (extensive drug-drug interactions)
Delavirdine: (NOT ON THE LIST)
- Teratogenic
- Skin rash
- Extensive drug-drug interactions (substrate of P450)
Efavirenz: (NOT ON THE LIST)
- Teratogenic (specifically 1st trimester)
- Skin rash
- CNS effects (including sleep-cycle alterations, insomnia,
nightmares)
Etravirine
Non nucleoside RT inhibitor
- The newest NNRTI approved for HIV treatment (2nd gen’); may be effective against strains resistant to other NNRTI’s
• HIV-1 only
• gen1: A single point-mutation causes total cross-resistance
• gen2: higher potency, longer half-life, less side effects
• metabolized in the liver, (nevirapin penetrates the CNS)
-inhibitor binds to the reverse transcriptase and denatures it -> enzyme cannot produce viral DNA
• General adverse effects: • liver and GI disorders • skin reactions, even Stevens-Johnson syndrome, efavirenz: teratogenic - Rash, nausea, diarrhea - Inhibitor + inducer of CYP450 enzymes (extensive drug-drug interactions)
Antiretroviral agents - Protease inhibitors
- Ritonavir,
- Lopinavir,
(Fosamprenavir,)
(Atazanavir,) - Darunavir,
(Tipranavir,)
(Asunavir,) etc.
• No general cross-resistance between PI-s
Mutations in HIV proteases leading to resistance
Mechanism of actions:
- Aspartate protease (Pol gene encoded) is a viral enzyme that cleaves precursor polypeptides to form the final structural proteins of the mature virus core
- The enzyme contains a dipeptide structure not seen in mammalian proteins; PI’s bind to this dipeptide, inhibiting the enzyme
- Resistance occurs via specific point mutations in the Pol gene, such that there is no complete cross-resistance between different PI’s
- All of the PI’s are substrates and inhibitors of cytochrome P450 enzymes (extensive drug-drug interactions)
*The use of PI’s as part of HIV drug regimens has led to the development of metabolic disorder (believed to occur via PI’s inhibiting lipid-regulating proteins). Characterised by hyperglycemia, insulin resistance, hyperlipidemia, and altered fat distribution.
Ritonavir
- HIV protease: viral maturation
- structure, mechanism unlike mammalian proteases
- Most commonly used protease inhibitor
- May be used to ‘boost’ other drug concentrations by inhibiting P450
• Ritonavir: only as a booster
- Adverse effects:
- insulin-resistance (5% in 5 years)
- hyperlipidemia
- peripheral lipodystrophy
- transaminase elevation (hepatotoxicity)
- GI and neurological disorders
- allergic reactions
Most potent inhibitor of P450 enzymes
• Different mutations result in resistance
- Kinetics:
- various oral availability
- no CNS penetration
- Half-life: variable
- metabolized in liver CYP3A4;
- Boosters:
- increased oral availability and elevated plasma levels of other PIs
- Ritonavir: blocks CYP3A4 (induces CYP1A2) and P-glycoprotein
- Cobicistat: inhibits CYP3A4, MDR
• No general cross-resistance between PI-s
Mutations in HIV proteases leading to resistance
Lopinavir
- HIV protease: viral maturation
- structure, mechanism unlike mammalian proteases
• Adverse effects: - Well tolerated • insulin-resistance (5% in 5 years) • hyperlipidemia • peripheral lipodystrophy • transaminase elevation • GI and neurological disorders • allergic reactions
• Different mutations result in resistance
- Kinetics:
- various oral availability
- no CNS penetration
- Half-life: variable
- metabolized in liver CYP3A4;
• Boosters:
• increased oral availability and elevated plasma levels of other PIs
- Used in combination with a subtherapeutic dose of ritonavir (ritonavir acts as pharmacokinetic enhancer by inhibiting lopinavir metabolism)
• No general cross-resistance between PI-s
Mutations in HIV proteases leading to resistance
Darunavir
- HIV protease: viral maturation
- structure, mechanism unlike mammalian proteases
- Used in combination with ritonavir in patients resistant to other PI’s
• Adverse effects: • insulin-resistance (5% in 5 years) • hyperlipidemia • peripheral lipodystrophy • transaminase elevation • GI and neurological disorders • allergic reactions - skin rash - Sulfonamide hypersensitivity reaction
• Different mutations result in resistance
- Kinetics:
- various oral availability
- no CNS penetration
- Half-life: variable
- metabolized in liver CYP3A4;
- Boosters:
- increased oral availability and elevated plasma levels of other PIs
• No general cross-resistance between PI-s
Mutations in HIV proteases leading to resistance
Antiretroviral agents – integrase inhibitors
- Elvitegravir
- (Raltegravir)
- (Dolutegravir)
- Pyrimidine derivative that binds integrase
- Integration of transcribed viral DNA into host cell chromosomes is inhibited
