Antiretroviral Drugs Flashcards Preview

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Flashcards in Antiretroviral Drugs Deck (24):

List the Antiretrovirals

NRTI – zidovudine, abacavir
NNRTI – efavirenz
Protease Inhibitor – ritonavir, atazanavir
Membrane Fusion – enfuvirtide
CCR5 (entry inhibitor) – maraviroc
Integrase Inhibitor - raltegravir


Nucleoside reverse transcriptase inhibitors (NRTIs)

Ex: Zidovudine, Abacavir

Normal HIV-1 RT:
• 2 subunits (p66 & p55) derived from proteolytic cleavage of p66 homodimer
• N-terminal of p66 = polymerase
• C-terminal of p66 = endonuclease (RNaseH) activity to degrade RNA strand of RNA/DNA intermediate
• P55 = structural role

• Synthesize negative strand of DNA (uses viral RNA as template)
• Hydrolyzes positive strand viral RNA
• Synthesizes the positive strand of DNA

NRTIs = nucleoside analogs that lack 3’OH needed for chain elongation
• When incorporated = terminate chain elongation
• Note: need to be phosphorylated to be active


Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Ex: Efavirenz

Binds hydrophobic pocket adjacent to active site in p66 → conformational change → blocks RT activity
o Do NOT need phosphorylation to be active


Protease Inhibitors (PIs)

Active HIV-1 protease = homodimer

PIs mimic natural cleavage sites of HIV-1 protease
• Bind active site with high affinity
• Prevents protease cleavage of Gag-Pol and Pol polyproteins into mature/functional units

Ex: lopinavir/ritonavir, atazanavir
• Small amount of Ritonavir used to inhibit CYP3A4 metabolism of Lopinavir = make Lopinavir viable


Fusion Inhibitors (FIs)

o Normal HIV fusion requires interactions between HIV gp41 and gp120 and host cell CD5, CCR5, and CXCR4 receptors

o Note: if mutant CCR5 receptor = HIV-1 infection is blocked
• Physiologically normal but 32 bp deletion in coding region → frameshift → non-functional receptor → no HIV-1 entry and infection

Ex: Enfuvirtide
• Binds to gp41 → blocks gp41-mediated membrane fusion
• Competitively inhibits folding of HR1 to HR2 (segments on gp41) → disrupts formation of 6-helix bundle needed for membrane fusion


Entry Inhibitors (EIs)

o Ex: Maraviroc

• Targets host protein
• Blocks gp120-CCR5 → prevents entry of CCR5-tropic (R5) virus
• BUT does NOT prevent entry of CXCR4-tropic (X4) virus


Integrase Inhibitors (IIs)

o Ex: Raltegravir
o Docks in acceptor DNA binding site = interferes with strand transfer


Explain how phosphorylation of NRTIs can cause drug interactions among NRTIs.

• For activity = require phosphorylation by cellular enzymes in cytoplasm
• Can have common or different pathways of phosphorylation → drug interactions

• Lack of phosphorylation → increased absorbance of NRTIs (relative to nucleotide analogs)

Negative drug interaction:
o Thymidine kinase has higher affinity for zidovudine than stavudine
o Result: zidovudine antagonizes effects of stavudine


How to detect resistance in anti-HIV drugs?

Phenotypic testing
Sample of HIV is grown in the laboratory
• Add dose of 1 drug
The growth rate of the HIV is compared to the rate of wild type virus
• If the sample grows more than wild type = it is resistant to the drug.
Phenotypic resistance is reported as "fold" resistance.

Genotypic testing
o The sequence of the sample virus is compared to the wild type virus


Resistance in NRTIs

Mutated RT that is able to discriminate against NRTIs during DNA synthesis
• Associated with decreased HIV-1 replication in vitro

Mutations in RT that promotes hydrolytic removal (primer unblocking) of chain-terminating NRTI = able to continue DNA synthesis
• Can lead to cross-resistance


Resistance in NNRTIs

o Single mutation in NNRTI-binding pocket
o With monotherapy treatment = rapid resistance emerges


Resistance in PIs

Mutations in binding in protease pocket → cross-resistance within class

Individual “signatiure” mutations to drugs (not cause resistance to entire class)
• Allow sequential use of other PIs as resistance emerges


Resistance in FIs

o Mutations in region of gp41 envelope protein


Resistance in EIs

o From emergence of mixed-tropic or CXCR4 tropic viruses


Resistance in IIs

o Mutations in integrase gene


Major Toxicities in NRTIs

Significant cross-resistance
Mitochondrial toxicity and lactic acidosis/hepatic steatosis
• Inhibition of mitochondrial DNA polymerase gamma (has high affinity for NRTIs)
o Used in mitochondrial DNA replication
• Leads to mitochondrial electron transport chain protein depletion
• Result: shift in pyruvate: lactate ratio → build-up of lactic acid and TAGs
• Mild reaction: elevated serum lactate without academia or symptoms
• Sever: lactic acidosis associated with academia, heapti steatosis, heptatomegaly (can be fatal)
• Clinical presentations: non-specific
o Nausea
o Vomiting
o Abdominal pain (often severe)
o Malaise
o Dyspnea (from acidosis)
• Labs: elevated anion gap, low HCO3-, elevated lactate, elevated CK, elevated LFT’s, often pancreatitis
• Therapy: DC the NRTIs, supportive care.

Individual toxicities:
Zidovudine: bone marrow suppression
Didanosine: pancreatitis and peripheral neuropathy
Stavudine: peripheral neuropathy
• Hypersensitivity syndrome of fever, rash, headache, nausea, abdominal pain, cough, SOB
• Genetic marker HLA B*5701 predicts risk
Tenofovir: renal impairment, Faconi syndrome


Major Toxicities in NNRTIs

o High levels of cross-resistance
o CYP3A4 substrates = drug interactions (can inhibit or induce)

• Rash
• Hepatotoxicity

• CNS effects: vivid dreams, feelings of disconnect, sleep disturbance, worsening of mental health disorders
• Teratogenicity


Major Toxicities in PIs

All = CYP3A4 substrates
• Most = inhibitors; some also inducers
• Ritonavir = pharmacokinetic enhancer of other PIs

GI upset and diarrhea
• Fat redistribution
o Accumulation in abdomen, dorsal-cervical (buffalo hump) and breasts
o Atrophy in buccal fat pads, proximal extremities, buttocks
• Hyperlipidemia = high cholesterol and TAGs
• Insulin resistance
• Exception: Atazanavir = no lipid raising or insulin resistance effects

Individual drugs:
• Indinavir: nephrolithiasis, hyperbilirubinemia
• Atazanavir: hyperbilirubinemia, QT prolongation
• Nelfinavir: high rates of diarrhea


Major Toxicities in FIs

o Quickly degraded so needs frequent injections → injection site reactions
o Hypersensitivity reactions
o Bacterial pneumonia


Major Toxicities in EIs

o CYP3A substrate
o Hepatotoxicity
o Muscle pain
o Sleep disturbances
o GI side effects


Major Toxicities in IIs

o NO cross-resistance with other anti-viral classes
o Side effects relatively uncommon:
• Nausea, diarrhea, headache
o NO CYP3A4 drug interactions


Identify molecular reasons why combination drug therapy is more effective than monotherapy.

• Combining drugs from different classes = suppresses viral replication at different points in life cycle
• Combining nucleoside analogs with different bases → increases chances of drug incorporation by viral RT

Possible favorable interactions between NRTIs and NNRTIs:
o Resistance mutations from NNRTIs hypersensitize HIV to zidovudine and tenofovir = Interferes with removal of chain-terminating NRTI
o HIV with multiple NRTI-resistance mutations are more susceptible to NNRTIs = Unknown mechanism


Describe some types of therapies:

PI: Lopinavir/Ritonavir
NRTI backbone: Zidovudine (T); Lamivudine (C)

NNRTI: Efavirenz
NRTI backbone: Tenofovir (A); Emitricitabine (C)

II: Elvitegravir
NRTI backbone: Tenofovir (A); Emitricitabine (C)


Anti-retroviral combinations NOT recommended

Stavudine + Zidovudine = both thymidine analogs; antagonistic

Emtricitabine + Lamivudine = similar resistance profiles; no potential benefit

Lopinavir = should be combined with Ritonavir (not used alone!)