Antiretrovirals

Question 1

Enfuvirtide
Type
Mechanism
Use
Toxicity
Resistance

Answer 1

• Fusion inhibitor.
• Mechanism - Blocks gp41-mediated membrane fusion. Conformational change usually occurs in gp41, w/ HR1 folding upon the HR2 domain to form a 6-helix bundle, bringing the 2 membranes w/in proximity of each other. Enfuvirtide is identical in sequence to a region in HR2, so it competitively inhibits HR2 from binding to HR1.
• Use - Mainly used in pxs w/ multi-drug resistance to other drugs
• Toxicity – injection site rxn occurs in almost all pxs
• Resistance – mutations in gp41 gene

Question 2

Maraviroc
Type
Mechanism
Toxicity
Resistance

Answer 2

• Entry inhibitor.
• Mechanism - Blocks gp120-CCR5 binding via an allosteric mechanism. Targets a HOST protein (CCR5). Blocks entry of R5 HIV, not X4 HIV.
• Toxicity – hepatotoxicity, muscle pain, sleep disturbance, GI
• Resistance – mutation in gp120, allowing the virus to bind to CCR5

Question 3

NRTI’s
2 main drugs
Mechanism
Specific adverse rxs of these 2 drugs

Answer 3

Zidovudine and Abacavir
•NRTI’s lack a 3’ OH necessary for chain elongation
•Initial lack of phosphorylation leads to increased absorbtion of NRTIs, relative to nucleotide analogs
•NRTI’s need to be phosphorylated to a triphoshpate to become activated and incorporated into the DNA.
•Zidovudine – bone marrow suppression
•Abacavir – HYPERSENSITIVITY involving fever, rash, headache, nausea, abdominal pain, cough, and SOB

Question 4

Class-wide toxicity of NRTI’s

Answer 4

• MITOCHONDRIAL TOXICITY, LACTIC ACIDOSIS, and hepatic steatosis (due to FA accumulation).
• Host cell polymerases have much lower affinity for binding these drugs than viral polymerase. If one of these nucelotides is incorporated, there are enzymes that can fix it. The exception is mitochondria DNA polymerase gamma, which has much higher affinity → lack of electron transport chain enzymes → buildup of lactate and TGs. Elevated aniong gap, low bicarb, elevated LFTs, pancreatitis. Sxs may include nausea, vomiting, abdominal pain, malaise, dyspnea (acidosis).

Question 5

2 main resistance mechanisms to NRTI’s

Answer 5

• Mutation in RT that allows enzyme to discriminate against NRTIs during DNA synthesis
• Mutation in RT that promotes hydrolytic removal (primer unblocking) of NRTI
• Significant cross-resistance exists for this class

Question 6

Efavirenze
Type
Use
Mechanism
Class-wide toxicity
Specific toxicity to Efavirenze
Resistance

Answer 6

• NNRTI
• Use - Not effective against HIV-2
• Mechanism - Allosterically blocks RT by binding a hydrophobic pocket adjacent to active site in p66 → conformational change. NNRTI’s do NOT need to be phosphorylated, as do NRTI’s.
• Toxicity (class-wide) – rash and hepatotoxicity. All NNRTIs are CYP3A4 substrates.
• Efavirenz – CNS (vivid dreams, feelings of disconnect, sleep disturbance, mental health disorders) and teratogenicity
• Resistance – mutation in NNRTI binding pocket. High level of cross-resistance.

Question 7

Synergy b/w NRTI’s and NNRTI’s (2)

Answer 7

• Resistance mutations caused by NNRTIs hypersensitize HIV-1 to zidovudine via interference w/ hydrolytic removal of NRTI.
• HIV-1 containing multiple NRTI-resistance mutations are more susceptible to NNRTIs.

Question 8

Raltegravir
Type
Mechanism
Toxicity

Answer 8

• Integrase inhibitor.
• Mechanism - Drug docks in the acceptor DNA binding site, blocking strand transfer.
• Little toxicity.

Question 9

Protease Inhibitors
2 main drugs
Normal use of HIV proteases
Mechanism
Class-wide toxicity
Toxicity to drug that starts w/ A
Resistance

Answer 9

• Atazanavir and Ritonavir (not used alone due to terrible taste at required dose). (Lopinavir only exists as a coformuation w/ ritonavir; Small dose of ritonavir is used to inhibit CYP3A4 metabolism of Lopinavir)
• Protease normally cleaves HIV-1 polyproteins (Pol and Gag-Pol) into functional units.
• Mechanism - Mimic the natural cleavage sites for HIV-1 protease by reversibly binding to the active site. Peptidomimetic.
• Toxicity (class-wide) – hepatotoxicity, GI, lipodistropy (severe metabolic complications, including fat redistribution, hyperlipidemia, and insulin resistance).
• Atazanavir – hyperbilirubinemia and QT prolongation. Lower lipid raising / insulin resistance effects, so good in px w/ metabolic problems or CVD.
• Resistance – mutations impacting bindings site w/ protease pocket → cross-resistance

Question 10

What does mutation in RNAseH do?

Answer 10

Mutations in RNaseH that reduce rate of RNA degradation → increased time available for excision of incorporated NRTIs.

Question 11

What does mutation in HR1 pocket of gp41 do?

Answer 11

Fusion inhibitor resistance (Enfuvirtide)