EXAM 2- KHAN - HIV

What is the function of the following enzymes:

• integrase

• protease

• reverse transcriptase

• integrase: “integrates” viral DNA into host cell DNA

• protease: how proteins become functional

• reverse transcriptase: converts viral RNA into double stranded DNA

What is the HIV genome made up of?

• -gag for structure

• -pol for enzymes

• -env for envelope

How is HIV virus transmitted?

• IV drug users

• sexual

• perinatal/vertical

What is the MOA of NRTIs?

• inhibits reverse transcriptase

  • phosphorylated to 5’ triphosphate by HOST cell

    • (exception: tenofovir already monophosphate)

  • is incorporated into viral DNA= chain termination

What are the class BBW of NRTIs?

• lactic acidosis

• hepatomegaly

• steatosis (fatty liver)

What is the MOA of NNRTIs?

• inhibits reverse transcriptase

  • binds to ALLOESTERIC SITES on reverse transcriptase

  • induces conformational change to RT= reduces activity

How does the MOA of NTRIs compare to NNRTIs?

• BOTH act on reverse transcriptase—> but in different ways

  • NRTIs—> compete with nucleoside triphosphates, incorporated into viral DNA, cause chain termination

    • need phosphorylation

  • NNRTIs—> bind to allosteric sites on reverse transcriptase, inactivate the enzyme

    • do NOT need phosphorylation

What are the class ADRs of NNRTIs? drug interactions?

• rash

• hepatotoxicity

• D/I—> CYP3A4 SUBSTATES!!!!!!!!! (1 exception)

What is the MOA of protease inhibitors?

• PREVENTS PROTEASE from making functional proteins

  • prevents protease from cleaving the viral precursor polypeptide and blocks maturation

What are the class ADRs of protease inhibitors? drug interactions?

• SEVERE GI—> n/v/d

• metabolic syndrome

  • hyperglycemia

  • hyperlipidemia

  • fat redistribution

• increased liver enzymes

• hypersensitivity

• D/I—> CYP3A4 SUBSTRATES

What is the MOA of Integrase Inhibitors?

• inhibits catalytic activity of HIV INTEGRASE

  • Integrase integrates HIV DNA into the host cell genome—> we inhibit this

What are the class ADRs of Integrase Inhibitors?

• weight gain

• insomnia

• rare risk—> depression/psych conditions

How is Abacavir activated?

• KNOW: TO BE ACTIVE—> PHOSPHORYLATION THEN DEAMINATION

  • Abacavir to Abacavir MP using adenosine phosphotransferase

  • Abacavir MP to Carbovir MP using deaminase

How is Tenofovir activated?

• KNOW: ester hydrolysis then diphosphorylated

  • Tenofovir AF or DF to tenofovir by ester hydrolysis

  • Tenofovir to Tenofovir diphosphate by HOST CELL

What is an ADR specific to EMTRICITABINE?

hyperpigmentation of the skin

What ADRs are specific to Tenofovir? AF vs. DF?

• Tenofovir

  • reduced renal function

  • osteomalacia/decreased bone density

  • AF has less risk than DF

How does the structure of Lamivudine compare to Embrictabine? IDENTIFY STRUCTURES

What mutations are responsible for NRTI resistance?

RT mutations

Which NRTIs are cross resistant to each other? WHY?

• LAMIVUDINE AND EMTRICITABINE—> bc of similar structures

How are each of the following effected by food? aka unaltered, no food, take with food

• Zidovudine

• Efavirenz

• Rilipivirine

• Atazanavir

• Zidovudine- unaltered by food

• Efavirenz- take on empty stomach

• Rilipivirine- take with food

• Atazanavir- absorption is pH dependent, increases in acidic pH

What NRTIs undergo metabolism? What route?

• Zidovudine- glucuronidation

• Abacavir- 5’ carboxylate derivative and glucuronidation

What NRTIs inhibit mitochondrial DNA polymerase gamma?

What adverse reactions are observed?

• ABACAVIR AND ZIDOVUDINE inhibit mitochondrial polym of HOST CELLS

• causes s/e: mitochondrial TOXICITIY, anemia, granulocytopenia, myopathy, peripheral neuropathy, pancreatitis

What NRTI requires HLA*5701 genotype screen prior to use? Because of what BBW?

• ABACAVIR!!!!!!

  • Bc of BBW for hypersensitivity rxns

Is there any advantage of using rilpivirine over other NNRTIs like Efavirez?

NOT A CYP3A4 substrate like the rest of the class

What are specific ADRs of Efavirenz? What’s important about taking it on an empty stomach?

• teratogenic in primates

• increased cholesterol and TGs

• CNS DISTURBANCES (INCLUDES SUICIDALITY)—> WHY WE TAKE ON EMPTY STOMACH TO DECREASE

What are specific ADRs of Rilpivirine? C/I with what?

• CNS disturbances—> depression

• C/I with antacids, PPIs, and H2RA

NNRTIs are effective against…

a. HIV-1

b. HIV-2

c. both

a.

What is the resistance rate of PI compared to NRTIs and NNRTIs?

• resistance rate in between NRTIs and NNRTIs

  • mutations at active site or secondary mutations

What are the names of the boosters used at subtherapeutic doses to increase the bioavailability of PIs?

Ritonavir and Cobicistat

Ritonavir is resistant to what? What group allows this? BE ABLE TO IDENTIFY

• resistant to metabolism—> bc of THIAZOLE GROUPS

• 

Ritonavir interacts with many drugs like…

• antiarrhythmics

• anticoagulants

• azoles

• hypolipemics

What is a UNIQUE ADR of Atazanavir? What is a UNIQUE ADR of Darunavir?

Atazanavir—> hyperbilirubinemia (whites of your eyes turn yellow)

Darunavir—> Rash/SJS/TEN

What PI should be avoided in sulfa allergy because it has a sulfa group?

a. Ritonavir

b. Atazanavir

c. Darunavir

c

What group does Darunavir have that allows it to have tighter binding at enzyme site?

• bis-tetrahydrofuran group

• 

Answer the following about FUSION INHIBITORS:

• name

• MOA

• ADRs

• Enfuvirutide

• MOA: blocks fusion of host cell and HIV membrane

  • peptide binds to gp41 of viral envelop protein, prevents conformational changes required for fusion of viral and cell membrane

• ADRS:

  • injection site rxns

  • erythema, pain

  • NODULES—> TENNIS BALL SIZED

Answer the following about CCR5 Antagonist:

• name

• MOA

• ADRs

• testing before use?

• Maraviroc

• MOA: Stops HIV binding to CCR5 co-receptor on HOST CELL

  • prevents interaction of HIV gp120 and CCR5 needed for HIV to enter cells

  • BINDS TO CCR5 ON HOST CELL MEMBRANE NOT THE VIRUS

• ADRS:

  • BBW—> for hepatoxicity

  • URI, cough, myopathy, orthostatic hypotension, increased CV risk, rash

• trophism testing before beneficial

Answer the following about Attachment Inhibitors:

• name

• MOA

• ADRs

• Fostemsavir

• MOA: Prevents HIV attachment to CD4

  • active form Temsavir binds to viral envelope protein gp120—> inhibits attachment to CD4 cells—> inhibits host cell entry

• ADRS:

  • Increases LFT and QTc

Answer the following about Post-attachment Inhibitor:

• name

• MOA

• Ibalizumab

• MOA: INHIBITS HIV ENTRY/FUSION

  • binds to extracellular domain 2 of CD4+ cells

  • produces steric hinderance for conformational change of gp120 and CD4+ cells—> inhibits HIV entry

  • note: doesn’t block HIV from binding attaching to host cell, inhibits the fusion/entry of HIV into the host cell

What are the functions of diketoenol group in the structures of integrase inhibitors?

• required for drug action

• binds to multivalent cations

What is the effect of food on each of the following? no effect, take with, take without, etc.

• Raltegravir

• Dolutegravir

• Elvitegravir

• Raltegravir- bioavailability not food dependent, increased fat in food increases absorption

• Dolutegravir- take with or without food

• Elvitegravir- take WITH food

What should be avoided with integrase inhibitors?

multivalent cations (2hrs before, 6 hrs after)

What are the brand names of the agents used for PrEP?

• Truvada

• Descovy

• Apretude (IM Cabotegravir)

What are the brand names of the agents used for oPEP?

• Truvada + Tivicay (Dolutegravir)

• Truvada + Isentress (Raltegravir)

Know the single agent brand names?