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
Elvitegravir
• Elvitegravir
- Pyrimidine derivative that binds integrase
- Integration of transcribed viral DNA into host cell chromosomes is inhibited
spectrum:
- In combination with other antiretroviral drugs
- Safe during pregnancy
kinetics:
- Oral
- Hepatic metabolism
Adverse effects:
- Nausea, headache, dizziness
- Elevated CK, myopathy, rhabdomyolysis
- PO QD with „booster” cobicistat (CYP3A inhibitor: ritonavir)
- Cross-resistance with raltegravir
• combined product: elvitegravir (+cobicistat) + emtricitabin
+ tenofovir: handy with many side effects
blocks insertion of HIV DNA into cd4+ cell DNA
Raltegravir and Dolutegravir
not on the list
Raltegravir
• Inhibits integration of vDNA into human DNA.
- PO, twice daily
- well-tolerated
- Resistance develops relatively fast
Dolutegravir
• Low cross-resistance, higher genetic barrier
• Side effect: Severe hypersensitivity reactions, insomnia
Antiretroviral agents - entry inhibitors
Maraviroc
Enfuvirtid
(Ibalizumab)
(Fostemsavir)
Maraviroc
• CCR5 coreceptor antagonist
• CCR5 coreceptor:
• mainly macrophage-infecting viruses
• mainly present in earlier stage of the disease
• only after tropism testing of HIV
- CCR5 receptor inhibitor → prevent interaction between viral gp120 and CD4 on target cell
Spectrum:
- In combination with other antiretroviral agents in adult patients
Kinetic:
- Oral
- Hepatic metabolism
Adverse effects:
- allergic liver disorder,
- increased prevalence of malignancies
- Cough
- Diarrhea
- Muscle and joint pain
- Elevated liver enzymes
• P.o., metabolized in liver (CYP3A4 – interactions)
Enfuvirtid
Ibalizumab
Fostemsavir
(not on the list)
• Enfuvirtid
• Binds to Gp41 of HIV
• Polypeptide (36AA) structure, s.c. • well-tolerated
- Gp41 antagonist → prevent the conformation change required for the fusion of viral and cellular membranes
- In combination with other antiretroviral drugs, against resistant strains
*Not active against HIV-2 strains
- Subcutaneous injection
- Injection site reaction
- Hypersensitivity reaction
- Ibalizumab
- monoclonal antibody for CD4, blocks interaction with co- receptors
- not immunosuppressant
- For multi-resistant patients; i.v., twice monthly
- Fostemsavir
- prodrug, binds to gp120 of HIV-1
- extended release tablet
- For multi-resistant or -intolerant patients
- immune reconstitution syndrome, long-QT
Treatment strategies for HIV infection
- cART: combined Anti-Retroviral Therapy
- right after diagnosis
- starting with 2 NRTI +1 integrase inhibitor, or NNRTI or PI
- ritonavir or cobicistat as a booster
- fixed combination products: better compliance
- important to keep treatment timing
- pregnancy: no dolutegravir, children: more aggressive treatment • post-exposure prophylaxis for health care staff: 4 weeks
- other name: HAART: Highly Active Antiretroviral Therapy
Treatment of HIV infection requires a combination of different antiretroviral agents.
Highly-active antiretroviral therapy (HAART) involving drug combinations can slow or reverse the increase in viral RNA load that normally accompanies disease progression.
It reduces (do not eliminate) the risk of transmitting the virus, slows or reverses the decline in CD4 cells, and decrease the incidence of opportunistic infections.
Current approach to treatment is the initiation of treatment with 3 antiretroviral drugs (‘2+1 role’), if possible, before symptoms appear:
- Tenofovir + Emtricitabine + Efavirenz (NNRTI)
- Tenofovir + Emtricitabine + Ritonavir (PI)
- Tenofovir + Emtricitabine + Raltegravir (integrase inhibitor)
Further aspects to address when treating AIDS patient:
- Multiple drug-drug interactions between antiretroviral agents
- Prophylaxis treatment against opportunistic infections (Mycobacterium avium complex, Mycobacterium tuberculosis, CMV reactivation, Pneumocystis
pneumonia, Toxoplasmosis, Cryptococcal meningitis, JC virus infection)
Antiretroviral prophylaxis:
- PrEP (pre-exposure prophylaxis) → Tenofovir + Emtricitabine
- PEP (post-exposure prophylaxis) → Tenofovir + Emtricitabine +/- Raltegravir
- Pregnancy prophylaxis (prevent vertical transmission) → ‘2+1 regimen’ + Zidovudine
- life-long treatment, controlling viral load
- complete eradication is very rare
- vaccines are under development:
- ALVAC/gp120/MF59: HVTN 702/”Uhambo„ study: no benefit in prevention
- Ad26.Mos4.HIV/cladeC gp140: phase 3 HVTN 706/”Mosaico„ study is ongoing
