Exam 4

Question 1

What is the replication cycle of HIV?

Answer 1

1. A mature extracellular virion attaches/fuses with the cell (just needs to have a CD4)
2. Penetration & uncoating - Nucleocapsid enters the cell
3. Reverse transcription - RT makes copy strand, then RNA is degraded, DNA is synthesized
4. Integration - DNA attempts to integrate into the nucleus
5. Transcription & translation - viral RNA and proteins are made in nucleus
6. Budding and release - proteases allow infection HIV to form & infect more cells

Question 2

What is a genetic barrier to resistance? Which antiretroviral drugs have high vs. low genetic barriers?

Answer 2

NRTIs have a low genetic barrier to resistance, meaning mutations are pretty common due to their structure/mechanism. Integrase inhibitors also have a low barrier.

High genetic barrier means that the mutations that cause resistance are pretty hard to develop.

Question 3

What are the human or viral targets, reasons the class is selective for the virus/viral cells, affected step in viral cycle, and MOA of these drugs: entry/fusion inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors

Answer 3

Entry/fusion inhibitors - enfuvirtide binds to HIV GP41 & blocks GP41 conformational change that is needed for fusion, maraviroc binds to human CCR5 and blocks GP120 binding. Overall this blocks the first step of the cycle by inhibiting the virus to enter the cell.

NRTIs - RTs can do these 3 things: (1) RNA dependent DNA polymerase, (2) Ribonuclease H, (3) DNA dependent DNA polymerase. RT copies plus-strand RNA and produces minus-strand RNA. It then degrades the RNA template and synthesizes plus-strand DNA from the minus-strand DNA template. NRTIs have 2 effects: (1) compete w/ nucleotides for reverse transcriptase, (2) DNA chain terminator

NNRTIs - These block RNA and DNA-dependent DNA polymerase activities by binding to an allosteric site on the reverse transcriptase.

Question 4

What are the targets and mechanisms by which maraviroc and enfuvirtide block HIV entry?

Answer 4

Maraviroc - Selective CCR5 antagonist that binds CCR5 and causes a conformational change that prevents gp120 binding. Has no effect on cell surface levels of CCR5, so there’s little/no side effects. Can only be used in pts with HIV strains that utilize CCR5. Potentially can select for viral mutants that bind to CXCR4 (bad).

Enfuviritide - Only active against HIV-1. Causes a conformational change that inhibits the necessary binding insertion, thus inhibiting viral fusion. Mutations are easily acquired

Question 5

How are nucleoside RT inhibitors activated metabolically before enzyme inhibition can occur?

Answer 5

The DNA must be tri-phosphorylated in order for viral RT to do it’s functions.

All of the nucleoside RT inhibitors are prodrugs that need to be activated by cellular kinases to the triphosphate form. (These enzymes are thymidine kinase, thymidylate kinase, and NDP kinase)

Question 6

What are the key structural differences between nucleoside analogues and the normal nucleosides used by reverse transcriptase?

Answer 6

NRTIs look almost exactly like nucleotides, but they don’t have an OH group that would be needed to make a new bond in the DNA.

Question 7

How can you describe the structure on tenofovir, emtricitabine, and zidovudine?

Answer 7

tenofovir - deoxyadenosine analog, but acyclic

emtricitabine - deoxycytidine analog with no OH, does have a sulfur in the ring and a fluorine at the top

zidovudine -deoxythymidine analog with N=N=N

Question 8

What are the differences in structure and activation between tenofovir and the other nucleoside RT inhibitors? How does this contribute to the longer half-life of tenofovir?

Answer 8

Azidothymidine - instead of OH on normal deoxythymidine, it has an azole group (three N)
Stavudine - instead of OH on normal deoxythymidine, it has no OH, it does have a double bond in the ring structure
Tenofovir - deoxyadenosine analog, but acyclic; activated by cellular enzymes; already monophosphorylated
- Not sure how this contributes to a longer half-life of tenofovir

Question 9

What are the differences in activation pathways for tenofovir disoproxil fumarate and tenofovir alafenamide? What are the effects of these differences on dosage, plasma and intracellular tenofovir concentrations, and tenofovir side effects?

Answer 9

tenofovir disoproxil fumarate (TDF) - Converted to tenofovir (TFV) by cellular esterases, then two more phosphorylations need to occur.
- Long intracellular half life
- plasma esterases (not cellular) can activate TDF -> TFV, which can cause kidney toxicity & reduction in bone mineral density

tenofovir alafenamide - activated by a different pathway than TDF. Plasma esterases don’t metabolize TAF.
- Lower concentrations of TFV -> less toxicity
- Increased accumulation of lymphocytes
- May be better at targeting HIV!
- Less side effects
- High lipid levels than TDF

Question 10

Why are tenofovir and emtracitabine preferred NRTI for initial antiretroviral therapy? (5)

Answer 10

TFV has a long intracellular half-life
once daily dosing
equivalent to other NRTI combinations w/ less toxic effects
less fat maldistribution
different resistant mutation profiles

Question 11

What hypersensitivity reaction can be caused by abacavir? What is the role of the HLA-B*5701 polymorphism?

Answer 11

Black Box Warning: hypersensitivity reaction -> can be fatal
- symptoms: malaise, dizziness, headache, GI disturbances
*must d/c immediately if symptoms develop

It’s highly associated with the HLA-B*5701 allele, so testing for this is recommended before initiating treatment with abacavir.

Question 12

How can HIV become resistant to the RT inhibitors (discriminatory vs. excision mutations)? Does resistance to one RT inhibitor confer resistance to all drugs in this class? How can combinations of RT inhibitors be used to manage resistance?

Answer 12

HIV polymerase is error prone and there’s large amounts of virus present. The rate at which mutations appear is inversely related to the serum drug concentration.
- Discriminatory mutations: selectively impair the ability of reverse transcriptase to incorporate analogues into the DNA
- Excision mutations: ATP molecule mediates the removal of a nucleoside analogue after its been incorporated (happens to thymidine analogues)

Question 13

Why are NRTI monotherapy and some combos of NRTIs not recommended?

Answer 13

The combinations need to be different analogs (T analog and C analog, not two T analogs).

NRTIs are preferred in combination for initial therapy to take advantage of some mutations making RT more susceptible to inhibition by some analogues over others.

Monotherapy not recommended due to mutations that may arise
Dual NRTI therapy w/ no other antiretroviral not used, usually use another agent as well
3-NRTI regmimen not normally done, but there are some options.

Question 14

How do the non-nucleoside RT inhibitors inhibit RT?

Answer 14

These bind directly to the site on RT near the catalytic site. This is near but different than where the NRTIs bind. These are noncompetitive inhibitors (allosteric) that block RNA and DNA dependent DNA polymerase activities.

**FYI these have CYP450 interactions

Question 15

How do the second generation NNRTIs (ertavirine and rilviripine) differ from the first generation NNRTIs with regards to their structural changes and interactions with HIV RT?(+ what are 2 1st gen and 2 2nd gen agents)

Answer 15

1st gen - nevirapine, efavirenz
2nd gen - ertavirine, rilpivirine; diaryl-pyrimidine-based molecule. These are designed to be inherently flexible, so they can bind even if the site is mutated.

Question 16

How does HIV become resistant to the non-nucleoside RT inhibitors?

Answer 16

Resistance to NNRTIs can be acquired through a single mutation. Mutations that confer resistance to NNRTIs do not cause resistance of NRTIs

Question 17

By which mechanism do raltegravir, dolutegravir, and elvitegravir inhibit HIV integrase?

Answer 17

Integrase inhibitors - These inhibit the insertion of HIV DNA into the human genome. These block the strand transfer step of integrase.

Integrase uses divalent metal ions to catalyze insertion. Raltegravir chelates both of the metal ions and stabilizes the enzyme-DNA complex, which prevents it from binding to the chromosomal DNA.

• Elvitegravir is metabolized by CYP3A4, so it’s given with cobicistat to inhibit the CYP3A4 and increase elvitegravir effect
• Dolutegravir has once daily dosing and doesn’t require cobicistat boosting. Also has higher barrier of resistance.

Question 18

How does HIV become resistant to integrase inhibitors?

Answer 18

Resistance can be caused by primary and secondary mutations.

These have a low genetic barrier to resistance (dolutegravir has higher barrier). They also have extensive, but incomplete cross resistance (dolutegravir less affected).

Question 19

How can you recognize the structure of HIV protease inhibitors atazanavir and darunavir, and which are the noncleavable bonds? How does the structure of tipranavir, a non-peptidomimetic PI, differ?

Answer 19

HIV protease inhibitors are transition state mimetics (except tipranavir). PIs have non-cleavable linkages (hydroxyethylene bond) instead of the amide bond in HIV protease.

atazanavir -
- most potent PI (except darunavir)
- different resistant mutation profile

darunavir - preferred PI for initial antiretroviral combinations
- makes extensive hydrogen bonds w/ protease backbone
- inhibits HIV protease dimerization

tipranavir - nonpeptidic
- Doesn’t need ritonavir (PI boosting)
- Retains activity against proteases in highly treated patients, even those resistant to darunavir

Question 20

By which mechanism do protease inhibitors block HIV protease activity?

Answer 20

PIs have non-cleavable linkages (hydroxyethylene bond) instead of the amide bond in HIV protease. The inhibitors bind at the interface of the protease active site. This causes a conformational change in the protease to reduce its activity (inhibit substrates from entering).

Question 21

How does resistance to protease inhibitors arise and how can the development of resistant viral strains be minimized? How do darunavir and atazanavir differ from other PIs in regards to PI resistance mutations? What is the basis for these differences for darunavir?

Answer 21

PIs have the highest genetic barrier of antiretrovirals. Mutations can be in the active site or far away and these modify the contact between protease and inhibitor. Some mutations could actually increase the susceptibility of others.

Use CYP3A4 inhibitors like ritonavir and cobicistat to reduce mutations

Atazanavir shows a different resistance mutation profile than the other PIs.

Darunavir can display strong hydrogen bonds with the peptide backbone of HIV protease, so it’s less affected by changes in amino acid side chains. It also inhibits HIV protease dimerization.

Question 22

What are the main toxic effects of protease inhibitors? (6)

Answer 22

Hyperlipidemia
Insulin resistance and diabetes
Lipodystrophy
Elevated liver function tests
Possible increased bleeding risk in hemophiliacs
Drug-drug interactions

Question 23

What are the effects of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors on CYP3A4?

Answer 23

NRTIs - no info on these with CYPs

NNRTIs - All metabolized by CYP3A4, potential for interactions with other drugs that are metabolized by CYP3A. Ertavirine inhibits 2C9 and 2C19.

Integrase inhibitors - Elitegravir metabolized by CYP3A4. Dolutegravir has no CYP3A4 interactions

Protease inhibitors - all are substrates and some are inhibitors of CYP3A4. The levels of PI can be influenced by other CYP3A4 inhibitors
- Delavirdine (NNRTI) increases indinavir and saquinavir levels
- Efavirenz (NNRTI) reduces indinavir and saquinavir levels

Question 24

Why do the structures of ritonavir and cobicistat act on CYP3A4 to act as PI boosters?

Answer 24

Ritonavir
- Ritonavir is the most potent PI inhibitor of CYP450s
- All initial PI treatment regimens use ritonavir combinations
- Low doses used
- Also reduces emergence of resistant viruses by keeping the serum drug concentrations high

Cobicistat
- Peptidomimetic that was designed to inhibit CYP3A4

Question 25

What is the currently recommended initial anti-retroviral drug regimen?

Answer 25

HAART preferred: dolutegravir (integrase inhibitor) + abacavir/lamivudine (NRTI)

Question 26

What is the MOA, mechanism of resistance, and spectrum of activity of these: acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, and valganciclovir

Answer 26

These bind to DNA polymerase to inhibit DNA replication. acyclovir - selectively accumulates in infected cells, competitive inhibitor of viral DNA polymerase. It competes w/ dGTP, incorporates into DNA irreversibly, and acts as a chain terminator. Resistance due to mutations in viral thymidine or DNA polymerase. Spectrum is HSV1&2 and VZV valacyclovir - prodrug of acyclovir -> improved efficacy penciclovir & famciclovir - famciclovir is the prodrug of penciclovir. Competitive inhibitor of viral DNA polymerase, but does NOT cause immediate chain termination b/c it still has the OH group (is a short-chain terminator). Similar antiviral potency to acyclovir ganciclovir - similar structure to penciclovir, same MOA as penciclovir, *better substrate for cytomegalovirus kinase than acyclovir*, more toxic than acyclovir valganciclovir - monovalyl ester of ganciclovir

Question 27

What is the MOA, mechanism of resistance, and spectrum of activity of these: foscarnet, cidofovir, and letermovir

Answer 27

foscarnet - pyrophosphate compound that inhibits viral DNA polymerase, RNA polymerase, and HIV RT. It doesn't require phosphorylation and blocks the pyrophosphate binding site of the viral DNA polymerase (different binding site than the others) to inhibit cleavage of pyrophosphate from dNTPs. cidofovir - cytosine analog. Already has 1 phos, so only needs to be phosphorylated 2 more times. Has a broad spectrum of activity, is highly selective for viral DNA pol. It's a competitve inhibitor and chain terminator letermovir - **non-nucleoside** that is used for prophylaxis of CMV. Well tolerated due to selective toxicity. Inhibits the terminase complex to prevent herpes virus genomes to be cut out properly.

Question 28

Which herpes meds are DNA chain terminators? (acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, valganciclovir, foscarnet, cidofovir, and letermovir)

Answer 28

acyclovir/valacyclovir cidofovir NOT: - famciclovir/penciclovir - ganciclovir/valgancyclovir - foscarnet (?) - letermovir

Question 29

Which herpes meds can be incorporated into DNA? (acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, valganciclovir, foscarnet, cidofovir, and letermovir)

Answer 29

acyclovir/valacyclovir penciclovir/famciclovir ganciclovir/valganciclovir cidofovir

Question 30

Which herpes meds are prodrugs? (acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, valganciclovir, foscarnet, cidofovir, and letermovir)

Answer 30

*they are all prodrugs b/c they need to be triphosphorylated before being active acyclovir - activated by **viral** thymidine, which selects for viral cells, then diphophorylated by cellular kinases valacyclovir - prodrug of acyclovir famciclovir - prodrug of penciclovir that gets converted through first pass metabolism in the intestine and liver valganciclovir - monovalyl ester of ganciclovir that is rapidly hydrolyzed to ganciclovir by esterase in intestine and liver cidofovir - requires 2 phosphorylations (not 3) NOT: foscarnet, letermovir

Question 31

How are these activated & how does that contribute to their specificity?: acyclovir, penciclovir/famciclovir

Answer 31

acyclovir - activated by viral thymidine, which selects for viral cells famciclovir/penciclovir - activated by viral and cellular kinases

Question 32

Which herpes drugs are able to cause cross-resistance? (acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, valganciclovir, foscarnet, cidofovir, and letermovir)

Answer 32

famciclovir/penciclovir - some cross-resistance with acyclovir (think of viral thymidine activation) ganciclovir - assuming there's cross resistance with penciclovir b/c they have very similar structures and the same MOA foscarnet - resistance due to mutations in DNA polymerase or HIV RT. Resistant CMV isolates are cross-resistant to ganciclovir, probably because there are multiple mutations, or a single mutation could effect the pyrophosphate AND active site. Usually still effective against cidofovir-resistant CMV though. letermovir - no cross resistance to other CMV drugs

Question 33

What is the binding side of foscarnet on DNA polymerase?

Answer 33

Foscarnet blocks the pyrophosphate binding site of the viral DNA polymerase, which traps the polymerase in a closed formation, inhibiting the cleavage of pyrophosphate from dNTPs. Therefore, the DNA is unable to translocate.

Question 34

Why are viral thymidine kinase mutants that are resistant to ganciclovir not resistant to cidofovir or foscarnet? Why are foscarnet-resistant versus likely to be cross-resistant to ganciclovir?

Answer 34

Viral thymidine kinase mutants that are ganciclovir-resistant are not resistant to cidofovir because they are different analogues (?). Not resistant to foscarnet because it's a different binding site. Acyclovir - mutations in viral thymidine kinase inhibits the production of the active acyclovir molecule Ganciclovir - resistance due to mutations in CMV or CMV DNA polymerase. The mutations in the viral kinase are not cross-resistant to cidofovir or foscarnet. Foscarnet - resistance due to mutations in DNA polymerase or HIV RT. Resistant CMV isolates are cross-resistant to ganciclovir, probably because there are multiple mutations, or a single mutation could effect the pyrophosphate AND active site. Usually still effective against cidofovir-resistant CMV though.

Question 35

How is cidofovir metabolized to form the biologically active species?

Answer 35

Cidofovir is phosphorylated by cellular kinases to form the biologically active species

Question 36

Why do valacyclovir and valganciclovir have greater bioavailability than acyclovir and ganciclovir, respectively?

Answer 36

Valacyclovir is the L-valyl ester of acyclovir, which makes it easier to absorb. Then it gets converted to acyclovir by esterases in the intestine and liver. Valganciclovir is the monovalyl ester of ganciclovir. It's hydrolyzed to ganciclovir by esterases in the intestines and liver.

Question 37

What is the influenza virus life cycle? Which steps are targeted by anti-influenza drugs?

Answer 37

Influenza enters through endosomal pathway. Virus uncoating occurs and the virus enters the nucleus. Replication of the virus occurs in the nucleus (unlike other viruses where replication happens in the cytoplasm). Synthesis of viral mRNAs also in nucleus. Proteins synthesized in ER. Proteins/virus relased from the cells. Amantadine - blocks viral uncoating (M2 protein that allows uncoating) Neuraminidase inhibitors - Inhibits release of new virions (inhibits cleaving from the sialic acid containing receptor) Baloxavir - inhibit transcription

Question 38

What is the MOA, mechanism of resistance, and spectrum of these influenza drugs: oseltamivir, zanamavir, peramivir, baloxavir

Answer 38

Neuraminidase inhibitors - Transition state analogues that inhibit the release of new virions (inhibits neuraminidase cleaving from the sialic acid containing receptor). oseltamivir - prodrug converted to active form by liver. Binds to active site of neuraminidase. Active against influenza A and B (less). Resistance is associated with mutations in the active site of neuraminidase. Resistance develops more easily against oseltamivir than zanamavir because the binding with oseltamivir is more dependent on certain proteins compaired to zanamivir zanamavir - same MOA as oseltamivir. Effective against influenza A and B. peramivir - newest neuraminidase inhibitor that cannot be absorbed PO. Active against A and B. baloxavir - inhibits viral "cap-snatching," meaning it blocks transcription. (influenza steals mRNA cap from host cell mRNA to make its own mRNA.) baloxavir binds to PB2 subunit of RNA polymerase of the virus to inhibit the cap-snatching.

Question 39

What are the life cycles of Hep B and Hep C? Which steps are targeted by anti-HBV and HCV drugs?

Answer 39

Hep C - HCV lipoparticle binds and is endocytosed. Viral RNA is released. Translation of viral RNA in the cytoplasm generates an HCV polyprotein. The polyprotein is eventually processed by the viral protease. As the virus matures, it forms a replication complex (uses NS5A). RNA polymerase replicates the genome (NS5B). The virion is assembled and released. - Anti HCV: interferon (nonspecific), ribavirin (RNA polymerase), RNA polymerase inhibitors, NS5A inhibitors Hep B - partially double-stranded DNA virus. The viral genome replications includes an RNA intermediate that is converted to viral DNA by reverse transcriptase. - tenovoir, lamivudine, telbivudine, entecavir, adefovir

Question 40

What is the MOA, mechanism of resistance, and spectrum of activity of these HCV inhibitors: ribavirin, simeprevir, paritaprevir, grazoprevir, voxilaprevir, sofosbuvir, dasabuvir, daclatasvir, velpatasvir, pibrentasvir

Answer 40

ribavirin - guanosine analog. Broad spectrum of activity (flu, Hep A/B/C, etc.). Inhibits Inosine monphosphate dehydrogenese (host enzyme), which reduces GTP levels. It directly inhibits viral RNA polymerase. HCV protease inhibitors: Resistance if mutations in NS3 active site (low genetic barrier) - simeprevir (2nd gen P1-P3) - paritaprevir (2nd gen P1-P3) - grazoprevir (2nd gen P2-P4) - voxilaprevir (2nd gen P2-P4) sofosbuvir - HCV RNA polymerase inhibitor. (Nucleoside) Converted to monophosphate by liver enzymes, then di and tri phosphorylated. It's incorporated into viral RNA chain and causes chain termination. Single mutation (S288T) causes resistance. dasabuvir - non-nucleoside RNA polymerase inhibitor. Doesn't bind to active site, binds to palm I site of RNA polymerase to prevent conformation changes, thus blocking nucleotide incorporation into viral RNA. Not active against all HCV genotypes. Pretty good genetic barrier for resistance. HCV NS5A inhibitors: binds tighly to NS5A, inhibits both viral RNA replication and assembly or release of infectious viral particles. Mutations more common for 1st gen. 2nd gen retains activity against common resistance-associated substituations - daclatasvir (1st gen) - velpatasvir (2nd gen) - pibrentasvir (2nd gen)

Question 41

What is the MOA, mechanism of resistance, and spectrum of activity of these HBV inhibitors: lamivudine, tenofovir

Answer 41

lamivudine - antiretroviral (NRTI), incorporated into RT to cause chain termination tenofovir - bind to active site of RT to cause chain termination

Question 42

Which HCV protease inhibitors and which HCV NS5A inhibitors are second generation? What are the advantages of second gen inhibitors vs. the first gens?

Answer 42

HCV protesase inhibitors target the HCV protease NS3. This blocks the cleavage of the HCV polyprotein. 1st generation - linear peptide mimics. Form covalent bonds. Discontinued now. - Telaprevir - Boceprevir 2nd generation - Macrocyclic peptides. non-covalent inhibitors. Advantages: These have once daily dosing, are better tolerated, and are activated against all genotypes. - Paritaprevir (P1-P3) - Simeprevir (P1-P3) - Voxilaprevir (P2-P4) - Grazoprevir (P2-P4) - Gelcaprevir (P2-P4)

Question 43

What the CYP interactions with HCV protease inhibitors?

Answer 43

Second gen HCV Protease Inhibitors are all substrates and weak inhibitors of CYP3A4

Question 44

What are the proposed MOAs of ribavirin? What viruses are susceptible to ribavirin? How is ribavirin like the NRTIs? Would any NRTIs be expected to compete with ribavirin? If so, how?

Answer 44

Ribavirin is a guanosine analog that causes inhibition of inosine monphosphate dehydrogenase (IMPDH) that reduces GTP levels, causing direct inhibition of viral RNA polymerase. It's also incorporated into viral RNA, leading to error catastrophe. Lots of viruses are susceptible to ribavirin (ex. influenza A & B, Hep A/B/C, genital herpes, herpes zoster, etc.) Similar to NRTIs becuase it is a nucleoside analog that gets incorporated into the DNA to cause chain termination. The guanosine analogs would likely compete with ribavirin because they are the same analog.

Question 45

What are the basics of the possibility of HBV reactivation during HCV treatment in patients with a known prior HBV infection?

Answer 45

HBV reactivation - abrupt increase in HBV replication HBV reactivation has been seen in patients co-infected with HCV which undergoing treatment with direct acting antivirals (DAAs) for HCV. This is observed with DAAs used without interferon. Reactivation of HBV replication is often followed by hepatitis, and potentially hepatic failure and death. The mechanism is unknown. To decrease the risk of HBV reactivation, pts should be screened to see if HBV infection previously occurred, monitor for symptoms, and consult physicians with expertise in managing hep B.

Question 46

What are the MOAs, prodrug/metabolism, and side effects of these SARS-CoV-2 drugs: remdesivir, nirmatrelvir, molnupiravir

Answer 46

remdesivir - prodrug that is bio-transformed to a ribonucleotide analog that can inhibit viral RNA polymerase (adenosine analog). Approved for emergency use for COVID-19. nirmatrelvir - Peptidomimetic that inhibits active site of SARS-CoV-2 3CLpro to inhibit production of nonstructural proteins. This was approved for emergency use for COVID-19. molnupiravir - prodrug of synthetic nucleoside derivative that serves as a polymerase inhibitor and chain terminator. Emergency use authorization for COVID-19.

Question 47

What are the differences between opportunistic fungal pathogens and those considered to be true pathogens?

Answer 47

True pathogens - cutaneous infective agents, subcutaneous infective agents, systemic infective agents Opportunistic infections require the host to be impaired before causing an infections.

Question 48

What are the definitions of dermatophytosis and onchomycosis? What fungi are associated with these conditions?

Answer 48

dermatophytosis - classic skin and hair infections like ringworm, athlete's foot, jock itch, etc. These involve 3 genera of mold that grow on keratin on a living host. - ex. *Epidermophyton*, *Trichophyton*, and *Microsporum* - Tinea capitis is ringworm of the scalp, Tinea pedis is athlete's foot onychomycosis - non-dermatophyte nail infections or any fungal nail infection caused by any fungus

Question 49

What are the differences between fungal and human cells? How are these differences exploited in antifungal drugs?

Answer 49

Fungal cells need ergosterol (not cholesterol) to survive. If we can inhibit this, the membrane can be weakened and cause it to become leaky b-glucan synthesis occurs in fungal cells but not human cells we can target fungal microtubules

Question 50

Which steps are inhibited by the allylamines and the azole antifungals in ergosterol synthesis?

Answer 50

allylamines - inhibit conversion of squalene to lanosterole azole - inhibit conversion of lanosterol to ergosterol

Question 51

Family, MOA, basis for selective inhibition of fungi, major toxicities, spectrum: echinocandins, griseofulvin, tavaborole

Answer 51

echinocandins (caspofungin, micafungin, anidulafungin) - These inhibit the synthesis of b(1-3) glucan in the fungi cell wall (not in human cells, so this is the reason for specificity). These will cause leaky membranes -> fungicidal. Can be used in combination if needed. griseofulvin - disrupts fungal microtubles tavaborole - inhibits leucyl transfer RNA synthetase (leuRS), which inhibits protein synthesis

Question 52

How can you recognize these structures: Amphotericin B, terbinafine, ketoconazole, itraconazole, fluconazole, voriconazole, posaconazole, tavaborole, caspofungin, anidulafungin, flucytosine

Answer 52

amphotericin B - large molecule with polar side, that forms H-bonds with warer, lipophilic side that liked the lipid bilayer. Also has a mycosamine group that binds to cholesterol. terbinafine - small molecule with 2 rings and a carbon-carbon triple bond Azoles - 5-membered aromatic azole ring (key nitrogen that helps to inhibit the 14 a-demethylase) - ketoconzaole has dioxalane ring on asymmetric carbon - itraconazole is a triazole instead of imidazole - fluconazole has 2 azole rings - voriconazole has a fluoropyrimidine ring instead of the 2nd triazole - posaconazole has a furan ring - isavuconazole is structurally similar to voriconazole but is a prodrug echinocandins - large lipopeptides that are all delivered IV Flucytosine - pyrimidine analog griseofulvin - 3 ringed molecule, nothing special tavaborole - small molecule with a Boron that is essential for activity

Question 53

What regions of amphotericin B are lipophilic and hydrophilic?

Answer 53

The top chain is lipophobic (no double bonds, lots of OH), the bottom chain is lipophilic (double bonds)

Question 54

What are the solubility properties of amphotericin B and how have these problems been overcome to increase bioavailability? What type of delivery is needed for treatment of fungal meningitis?

Answer 54

Very poorly absorbed (need IV for systemic infections). Can use PO if treating a GI infection. Need intrathecal therapy for fungal meningitis. Lipid formulations have been used to reduce nephrotoxicity.

Question 55

What is the toxicity of amphotericin B? How does this relate to flucytosine therapy?

Answer 55

Infusion-related: fever, chills, muscle spasms, vomiting, headache, hypotension -> reduce rate of infusion to help Renal damage: occurs in nearly all patients. - reversible: reduced renal perfusion - irreversible: renal tubular injury (usually after prolonged administration >4g) Since flucytosine is renally excreted, you need to make sure that the amphotericin B isn't causing renal damage that results in a toxic level of flucytosine.

Question 56

What are the CYP450 interactions with the azole agents? How does this affect other drug therapies? Why can this be a problem?

Answer 56

Azoles are metabolized extensively by CYP450s. This means we can't use them systemically unless the drug doesn't get metabolized by CYP450s. Triazole concentrations can be increased by other drugs metabolized by this pathway. Concentrations of other drugs that use CYP enzymes may be elevated. Inducers of CYPs can decrease triazole levels. - Ketoconazole - 3A4 inhibitor - Itraconazole - metabolized by 3A4 - Voriconazole - metabolized most by 2C19 All are inhibitors of CYP3A4.

Question 57

Why can some azole antifungals only be used topically whereas others can be used systemically?

Answer 57

Only the azoles with reduced metabolism are used for systemic infection (because we need to avoid the CYP metabolism) - ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole

Question 58

What is the azole functional group and what is its significance for the MOA?

Answer 58

5-membered aromatic azole ring (key nitrogen that helps to inhibit the 14 a-demethylase). The nitrogen is what binds to the Fe3+ in the CYP450 to inhibit the conversion to ergosterol.

Question 59

How does the metabolism of flucytosine in fungal cells differ from that in animal cells?

Answer 59

Animal cells are unable to convert flucytosine to the active metabolite.

Question 60

What reaction is catalyzed by thymidylate synthase? How does flucytosine inhibit this reaction?

Answer 60

dUMP is converted to dTMP by thymidylate synthase. Flucytosine inhibits this by being converted to %-GU, then 5-FdUMP, which inhibits thymidylate synthase. In 5-FdUMP, there is an F in place of an H that is in dUMP. This traps the thymidylate in the inactive form.

Question 61

What antifungal drugs are able to penetrate the cerebrospinal fluid?

Answer 61

- intrathecal amphotericin B - flucytosine

Question 62

What are the two reasons why amphotericin B and 5-fluorocytosine are often used in combination?

Answer 62

He didn't say much about this - 5-fluorocytosine is synergistic with amphotericin B (maybe because they both effect the cell wall?)

Question 63

By which mechanisms do fungi become resistant to antifungal drugs?

Answer 63

Natural resistance (intrinsic) vs. Induced (acquired) - *Candida krusei*, *Candida glabrata*, and *Aspergillus terreus* all have intrinstic resistance. - Acquired resistance is not transferred between strains as in bacteria. Azoles - target site alterations accounts for most resistant strains, reduced drug concentration via efflux pumps, target enzyme upregulation, development of bypass pathways Polyenes - reduced ergosterol content Echinocandins - rare, but target site mutations Flucytosine - cytosine deaminase or UPRT (cytosine permease) so it can't get into the cell/get activated Allylamines and griseofulvin - not well characterized yet

Question 64

What fungal classes/drugs cause these toxicities: hepatic (4), renal (2), CNS (1), photopsia (1), cutaneous (2), GI (3), cardiac (2), infusion reactions (2), bone marrow suppression (2)

Answer 64

hepatic - all azoles, amphotericin B, 5-FC, echinocandins renal - amphotericin B, IV voriconazole CNS - voriconazole Photopsia - voriconazole Cutaneous - rash (all), photosensitivity/malignancy (voriconazole) GI - Itraconzaole, posaconazole, 5-FC Cardiac - cardiomyopathy (itraconazole), QTc prolongations (all azoles, esp. with drug interactions) Infusion reactions - amphotericin B, echinocandins Bone marrow suppression - 5-FC, amphotericin B

Question 65

What is the MOA, spectrum (HSV, VZV, CMV, influenza, SARS-CoV-2, etc.), PK (absorption, 1/2 life, elimination, dose adjustments, etc.) for acyclovir?

Answer 65

MOA - After being converted to the monophosphate form by viral enzymes, acyclovir is triphosphorylated, then inhibits viral DNA polymerase resulting in inhibition of viral replication. It's also incorporated into viral DNA to cause premature chain termination. Spectrum - Herpes simplex virus (HSV) 1 and 2, Varicella zoster virus (VZV) - HSV-1 > HSV-2 > VZV > EBV > CMV PK - 10-20% PO bioavailability, dose-dependent oral absorption; 1/2 life 2.5-3.5hrs; widely distributed in tissues/body fluids, can penetrate CSF if dose is doubled, adjust for renal dysfunction

Question 66

What are the therapeutic indications, adverse events, and monitoring for acyclovir?

Answer 66

Therapeutic indications - 1. Herpes simplex virus infections (inc. HSV encephalitis [IV dose 10mg/kg q8h], mucocutaneous disease in immunocompromised host) 2. Varicella zoster virus infections (severe VZV in immunocompromised host 10mg/kg q8h IV) Adverse events - - Nephrotoxicity (crystalline nephropathy) - Thrombophlebitis Monitor - - Renal function (prevent nephrotoxicity)

Question 67

What is the MOA, spectrum (HSV, VZV, CMV, influenza, SARS-CoV-2, etc.), PK (absorption, 1/2 life, elimination, dose adjustments, etc.) for valacyclovir?

Answer 67

MOA - same as acyclovir (inhibit DNA polymerase to inhibit replication/chain termination) Spectrum - HSV, VZV PK - 3-5x greater PO absorption than acyclovir, adjust for renal dysfunction

Question 68

What are the therapeutic indications and adverse events for valacyclovir?

Answer 68

Indications - 1. Varicella zoster virus (preferred over PO acyclovir) Adverse events - same as acyclovir 1. Nephrotoxicity 2. Thrombophlebitis

Question 69

What is unique about famciclovir?

Answer 69

Oral famciclovir undergoes rapid and extensive conversion to penciclovir. Penciclovir is phosphorylated by viral thymidine kinase to penciclovir monphosphate and eventually to penciclovir triphosphate by cellular enzymes, which then inhibits viral replication (other than this he said he doesn't ever use this)

Question 70

What is the MOA (what specific gene monophosphorylates it), spectrum (HSV, VZV, CMV, influenza, SARS-CoV-2, etc.), PK (absorption, 1/2 life, elimination, dose adjustments, etc.) for ganciclovir?

Answer 70

MOA - In HSV or VZV, thymidine kinase will activate ganciclovir. In CMV, UL97 gene monophosphorylates ganciclovir. After being triphosphorylated, the viral DNA polymerase is inhibited and it incorporates into viral DNA to inhibit viral replication. Spectrum - **cytomegalovirus (CMV)**, HSV-1 and 2, VZV, EBV PK - Low PO bioavailability, half like 3.5hrs adjust for renal dysfunction

Question 71

What are the therapeutic indications, adverse events, and monitoring for ganciclovir?

Answer 71

Indications - 1. CMV Adverse effects - - bone marrow suppression Monitor - CBC/differential

Question 72

What is the MOA, spectrum (HSV, VZV, CMV, influenza, SARS-CoV-2, etc.), PK (absorption, 1/2 life, elimination, dose adjustments, etc.) for valganciclovir?

Answer 72

MOA - L-valyl ester of ganciclovir, inhibits viral DNA replication. Spectrum - **CMV**, HSV, ZVZ PK - 60% PO absorption, administer with food to improve absorption, adjust for renal dysfunction

Question 73

What are the therapeutic indications, adverse events, and monitoring for valganciclovir?

Answer 73

Indications - 1. Treatment of CMV retinitis in pts with AIDS 2. CMV prevention in high risk patients Adverse effects - - Hematologic toxicity Monitor - - CBC

Question 74

What is the MOA, spectrum (HSV, VZV, CMV, influenza, SARS-CoV-2, etc.), PK (absorption, 1/2 life, elimination, dose adjustments, etc.) for letermovir?

Answer 74

MOA - Inhibits CMV replication and prevents CMV infection Spectrum - **ONLY CMV** PK - Well absorbed orally with cyclosporine, 1/2 life 12 hours, IV formulation contains hydroxypropyl betadex, **no adjustment for CrCL > 10mL/min, monitor if <50mL/min due to IV vehicle

Question 75

What are the therapeutic indications, adverse events, and drug interactions for letermovir?

Answer 75

Indications - 1. Prophylaxis of CMV in allogeneic hematopoietic stem cell transplant Adverse effects - - **no bone marrow toxicity** - nothing crazy Drugs Interactions - nightmare - CYP3A4 - Lots of consequences of the CYP interactions (inc. QTc prolongation, bleeding, etc.)

Question 76

What is the MOA, spectrum (HSV, VZV, CMV, influenza, SARS-CoV-2, etc.), PK (absorption, 1/2 life, elimination, dose adjustments, etc.) for foscarnet?

Answer 76

MOA - Directly inhibits viral DNA polymerase, this **is not a prodrug** Spectrum - HSV-1 and 2, VZV, CMV PK - <20% PO bioavailability, bone sequesters 10-20% of a dose, 1/2 life 4-8hrs, adjust for renal dysfunction

Question 77

What are the therapeutic indications and adverse events (5) for foscarnet?

Answer 77

Indications - 1. CMV retinitis 2. HSV and VZV (resistant) Adverse events - 1. **Nephrotoxicity** 2. Metabolic - hypocalcemia, hypo/hyperphosphatemia, hypokalemia, hypomagnesemia 3. CNS 4. GI 5. Hematologic

Question 78

What is the MOA, spectrum (HSV, VZV, CMV, influenza, SARS-CoV-2, etc.), PK (absorption, 1/2 life, elimination, dose adjustments, etc.) for amantadine and rimantadine?

Answer 78

MOA - Prevents the virus from taking off its coat Spectrum - Influenza A (not prophylaxis) PK - - Amantadine: Well absorbed orally, 1/2 life 12-18 hours, adjust for renal dysfunction - Rimantadine: 1/2 life 24-36 hrs, **adjust for hepatic and renal insufficiency**

Question 79

What are the therapeutic indications and adverse events for amantadine and rimantadine?

Answer 79

Indications - 1. Treatment of influenza A Adverse events - 1. CNS: more common w/ amantadine 2. GI

Question 80

What is the MOA, spectrum (HSV, VZV, CMV, influenza, SARS-CoV-2, etc.), PK (absorption, 1/2 life, elimination, dose adjustments, etc.) for neuraminidase inhibitors?

Answer 80

zanamivir (dry powder), oseltamivir, peramivir MOA - NA inhibitors prevent the virus from leaving the cell, which halts the spread of the virus Spectrum - Influenza A and B - Influenza B: zanamivir > oseltamivir PK - - Zanamavir: <5% PO, is an inhaled product, 1/2 life 2.5-5hrs, **no adjustments for renal/hepatic** - Oseltamivir: 80% PO absorption, 1/2 life 6-10hrs, dose adjust for renal insufficiency, no adjustment in obesity

Question 81

What are the therapeutic indications and adverse events for neuraminidase inhibitors?

Answer 81

Indications - - Zanamivir: treatment if ≥ 7 yo, prophylaxis ≥ 5yo; *don't give flu vaccine until 48hrs after cessation* - Oseltamivir: treatment (≥ 2 weeks old) and prophylaxis (≥ 1 year old); *don't give flu vaccine until 48 hours after cessation* Adverse events - - Zanamivir: bronchospasm, worsening COPD, neuropsychiatric events - Oseltamivir: transient neuropsychiatric events

Question 82

What are the stages of COVID?

Answer 82

Early infection: Viral replication for 10 days, may see fever and dry cough, lymphopenia Pulmonary Phase: may see SOB Hyperinflammation: no more viral replication (antivirals will not work), host-inflammatory response, may be ARDS, SIRS/shock/cardiac failure, elevated inflammatory markers, etc.

Question 83

When should we use glucocorticoids with COVID-19

Answer 83

*a study found that dexamethasone decreases mortality Recommended among hospitalized critically ill patients. Dexamethasone 6mg IV/PO once daily for 10days (or equivalent) Suggested (not recommended) if only mild-to-moderate Inhaled: do not use these

Question 84

When should be use interleukin-6-inhibitors in COVID-19?

Answer 84

Tocilizumab is suggested in addition to steroids in hospitalized adults with progressive severe or critical COVID-19 who have elevated markers of systemic inflammation If tocilizumab not available, sarilumab is suggested in addition to steroids.

Question 85

When should we use remdesivir for COVID-19?

Answer 85

Remdesivir is suggested if the pt has mild-to-mod COVID-19 and are at high risk for progression. Should be initiated w/in 7 days of symptom onset In pts on supplemental oxygen but not mechanical ventilation or ECMO, 5 days of remdesivir is suggested In pts with severe COVID-19, remdesivir is suggested If patient is on invasive ventilation and/or ECMO, do not use remdesivir

Question 86

Why is remdesivir not recommended in CrCL less than 30?

Answer 86

It has the cyclodextrin vehicle (so does voriconazole) that can accumulate in renal dysfunction

Question 87

When should we use baricitinib for COVID-19?

Answer 87

If patient has severe COVID-19, baricitinib is suggested to use with steroids

Question 88

When should be use Paxlovid (nirmatrelvir/ritonavir) for COVID-19?

Answer 88

ritonavir - inhibits metabolism of the active drug In ambulatory pts with mild-to-mod COVID-19 at high risk for progression to severe disease, paxlovid is suggested to be initiated within 5 days of symptom onset. (watch out for CYP3A4 interactions) But no significant decrease in mortality in hospitalized patients

Question 89

What are the fungal organism that are more common in the midwestern states vs. southeastern vs. south western states?

Answer 89

Midwest - Histoplasma capsilatum Southeastern/Midwest - Blastomyces Southwestern - Coccidioides immitis/posadasii

Question 90

What is the MOA, spectrum, and PK for amphotericin B?

Answer 90

MOA - Binds to ergosterol and gets insterted into the fungal cytoplasmic membrane eventually causing cell death Spectrum - 1. Candida (not C. lusitaniae "doesn't sink the ship") 2. Cryptococcus neoformans 3. Histoplasma capsulatum 4. Aspergillus 5. Mucor 6. Blastomyces, Coccidioides PK - differs based on formulation, not absorbed orally (may be used for oral infections), widely distributed, poor penetration into CSF (but we still use for meningitis), **no adjustments w/ insufficiency**

Question 91

What are the therapeutic indications, adverse events, and monitoring for amphotericin B?

Answer 91

Indications - Disseminated candidiasis, cryptococcosis, aspergillosis, histoplasmosis, blastomycosis, coccidioidomycosis, mucormycosis Adverse events - - Deoxycholate: infusion related (can pretreat w/ APAP, diphenhydramine, steroids, tolerance develops over times), nephrotoxicity (do sodium repletion), hypokalemia, hypomagnesemia *less nephrotoxicity with lipid-associated formulations Monitor - - electrolytes - kidney function

Question 92

What is the MOA, spectrum, and PK for flucytosine?

Answer 92

MOA - flucytosine gets converted to 5-FU, which then interferes with protein synthesis. It also inhibits thymidylate synthetase to interfere with DNA synthesis Spectrum - cryptococcus neoformans PK - well absorbed orally, penetrates CSF, adjust in renal impairment

Question 93

What are the therapeutic indications, adverse events, and monitoring for flucytosine?

Answer 93

indications - used in combo w/ amphotericin B for cryptococcal meningitis adverse events - 1. Bone marrow suppression monitoring - - CBC, platelets, SCr, BUN - Therapeutic drug monitoring

Question 94

What is the MOA, spectrum, and PK for ketoconazole?

Answer 94

MOA - inhibits the synthesis of ergosterol via inhibition of the CYP450 dependent enzyme lanosterol 14-a-demethylase. This causes inhibition of fungal growth. Spectrum - 1. Candida albicans 2. Cryptococcus neoformans 3. Histoplasma capsulatum 4. Dermatophytes PK - absorption is inversely related to gastric pH (gastric acid). Better absorbed with a high fat meal. Lower pH = better absorption

Question 95

What are the therapeutic indications, adverse events, and drug interactions for ketoconazole?

Answer 95

indications - - never used orally first line due to hepatoxicity and drug interactions - used more commonly for topical uses adverse reactions - - hepatotoxicity - endocrine - dose-dependent inhibition of adrenal steroid and testosterone synthesis, menstrual irregularities drug interactions - CYP3A4 inhibitor!!

Question 96

What is the MOA, spectrum, and PK for itraconazole (and suba-intraconazole)?

Answer 96

MOA - inhibits the synthesis of ergosterol via inhibition of the CYP450 dependent enzyme lanosterol 14-a-demethylase. This causes inhibition of fungal growth. Spectrum - 1. Aspergillus (but we don't use much) 2. **Histoplasma capsulatum** (DOC if not super severe) 3. Sporothrix schenckii (seen with rose garden workers) 4. Blasto, candida, coccidioides, crytococcus PK - capsules good oral administration (dependent on gastric acidity, so take with food), oral solution better absorbed and not affected by gastric acidity, SUBA-itraconazole capsule is super-bioavailable, not affected by gastric acidity, still recommend to give with food; active metabolite (hydroxyitraconazole), clearance decreases with higher doses

Question 97

What are the therapeutic indications, adverse events, monitoring, and drug interactions for itraconazole (and suba-itraconazole)?

Answer 97

indications - 1. Histoplasmosis (1º choice) 2. Aspergillosis (not 1st choice) 3. Blastomycosis adverse events - 1. Hepatotoxicity 2. **Congestive heart failure** 3. **QTc prolongation** monitoring - - TDM: troughs associated with efficacy drug interactions - - H2RAs, PPIs, antacids decrease absorption - CYP3A4 inhibitor

Question 98

What is the MOA, spectrum, and PK for fluconazole?

Answer 98

MOA - inhibits the synthesis of ergosterol via inhibition of the CYP450 dependent enzyme lanosterol 14-a-demethylase. This causes inhibition of fungal growth. Spectrum - 1. Candida species (not C. krusei) 2. Cryptococcus neoformans 3. Coccidioides immitis PK - well absorbed orally, independent of gastric acidity, switch to PO if the gut works; dose adjustment in renal insufficiency; gets good concentrations in the urine; dosed based off of total body weight

Question 99

What are the therapeutic indications, adverse events, and drug interactions for fluconazole?

Answer 99

indications - 1. noninvasive/invasive candidiasis 2. prophylaxis in pts undergoing bone marrow transplant 3. candida urinary tract infections 4. cryptococcal meningitis adverse reactions - 1. QT prolongation drugs interactions - 1. CYP2C9 inhibitor 2. CYP3A4 inhibitor

Question 100

What is the MOA, spectrum, and PK for voriconazole?

Answer 100

MOA - inhibits the synthesis of ergosterol via inhibition of the CYP450 dependent enzyme lanosterol 14-a-demethylase. This causes inhibition of fungal growth. spectrum - 1. **Aspergillus** (drug of choice) 2. Fusarium 3. Others (inc. candida) PK - very good oral availability, not affected by GI acid, metabolized by CYP450 enzymes, *PK is non-linear*, **no dose adjustments, but avoid IV voriconazole if CrCL < 50mL/min due to vehicle**, dose with adjusted body weight

Question 101

What are the therapeutic indications, adverse events, and monitoring and drug interactions for voriconazole?

Answer 101

indications - 1. Aspergillis adverse events - 1. Visual disturbances 2. Elevated liver function tests 3. QTc prolongation 4. Phototoxic skin reactions 5. Diffuse, painful periostitis monitoring - - TDM drug interactions - need to look at drug list - CYP3A4, CYP2C9, CYP2C19

Question 102

What is the MOA, spectrum, and PK for posaconazole?

Answer 102

MOA - inhibits the synthesis of ergosterol via inhibition of the CYP450 dependent enzyme lanosterol 14-a-demethylase. This causes inhibition of fungal growth. spectrum - 1. aspergillus 2. mucor (voriconazole doesn't cover this) 3. others (inc. candida) PK - PO tablets preferred, **no adjustment in renal insufficiency, but avoid IV if CrCL < 50mL/min due to vehicle**

Question 103

What are the therapeutic indications, adverse events, monitoring, and drug interactions for posaconazole?

Answer 103

indications - 1. prophy for aspergillus and candida 2. oropharyngeal candidiasis 3. refractory oropharyngeal candidiasis 4. salvage therapy for aspergillosis or Mucor infections adverse events - - QTc prolongation monitoring - TDM drug interactions - - CYP3A4 inhibitor

Question 104

What is the MOA, spectrum, and PK for isavuconazole?

Answer 104

MOA - inhibits the synthesis of ergosterol via inhibition of the CYP450 dependent enzyme lanosterol 14-a-demethylase. This causes inhibition of fungal growth. spectrum - 1. aspergillus 2. mucor 3. rhizopus PK - liner PK!!, **no dose adjustment or IV vehicle**, long half-life

Question 105

What are the therapeutic indications, adverse events, drug interactions, and contraindications for isavuconazole?

Answer 105

indications - 1. invasive aspergillosis 2. invasive mucormycosis adverse events - **no QTc prolongation!!** 1. hepatic 2. infusion drug interactions - - CYP3A4 substrate - inhibitor of 3A4, 2C8, 2C9, @c19, 2D6 contraindications - - administration w/ strong CYP3A4 inhibitors - administration w/ strong CYP3A4 inducers - patients with *short* QT syndrome (isavuconazole shortens QT interval)

Question 106

What is the MOA, spectrum, and PK for echinocandin agents? (caspofungin, micafungin, anidulafungin)

Answer 106

caspofungin, micafungin, anidulafungin MOA - glucan synthesis inhibitor that inhibits 1,2-b-D-glucan, which is necessary for the cell wall (fungicidal) spectrum - 1. aspergillus 2. candida (really good, inc. azole-resistant strains [glabrata]) - Limited activity against histoplasma capsulatum, cryptococcus neoformans, fusarium, and mucor (don't use for these) PK - all IV formulations, no adjustments needed

Question 107

What are the therapeutic indications and adverse events for echinocandin agents? (caspofungin, micafungin, anidulafungin)

Answer 107

indications - - prophy of candida infections in HSCT - candidiasis - aspergillosis adverse reactions - 1. histamine-mediated symptoms (non severe) - nothing crazy *no CYP interactions*

Question 108

What is the MOA, spectrum, and PK for triterpenoid agents? (ibrexafungerp)

Answer 108

MOA - inhibits 1,3-b-D-glucan synthesis to cause cell lysis spectrum - similar to echinocandins 1. candida 2. aspergillus 3. pneumocystic jiroveci - not active against mucor, fusarium, cryptococcus, or endemic fungi PK - only available PO right now, PO absorption dependent on GI acid, take with food, **no adjustments**

Question 109

What are the therapeutic indications, adverse events, contraindications, and drug interactions for triterpenoid agents? (ibrexafungerp)

Answer 109

indications - - vulvovaginal candidiasis adverse effects - nothing important contraindications - pregnancy, use effective contraception during and for 4 days after treatment drug interactions - 1. metabolized by and weak inhibitor of CYP3A4 and CYP2C8

Question 110

What is the primary line of host defenses for superficial candida infections?

Answer 110

1st line of defense - T-cell mediated immunity (this is what HIV attacks, so they have decreased CD4 cells)

Question 111

What are local and systemic risk factors for ora-pharyngeal candidiasis and esophageal candidiasis?

Answer 111

Local - use of inhaled steroids and antibiotics, dentures, xerostomia due to drugs/chemo/HSCT/radiotherapy, smoking Systemic - drugs, neonates/elderly, HIV/AIDS, diabetes, malignancies, nutritional deficiencies

Question 112

What are the differences in clinical presentation between OPC and EC?

Answer 112

OPC - cottage-cheese appearance, no severe symptoms like dysphagia or odynophagia EC - dysphagia and odynophagia, fever

Question 113

How do we treat OPC?

Answer 113

Mild infection: - topical therapy for 7-14 days: clotrimazole, nystatin, miconazole Refractory, can't tolerate topicals, mod-severe disease, pts with HIV, high-risk for systemic disease: - systemic therapy fluconazole 100mg daily fluconazole-refractory: - treatment for 14-28 days: itraconaozle, posaconazole, amphotericin B, voriconazole, caspofungin, micafungin, etc.

Question 114

How do we treat esophageal candidiasis?

Answer 114

Treat for 14-21 days. **Systemic therapy** is always required. - fluconazole 200mg PO/IV daily - itraconazole solution - echinocandin - voriconazole - posaconazole suspension - amphotericin C Fluconazole-refractory: treat for 21-28 days - inraconazole, posaconazole, voriconazole, amphotericin B, echinocandin

Question 115

What is the difference between uncomplicated and complicated VVC?

Answer 115

uncomplicated - sporadic infection that is susceptible to all forms of antifungal therapy regardless of treatment duration complicated - recurrent VVC, severe disease, non-candida albicans infection, host factors (DM, immunosuppression, pregnancy)

Question 116

What are risk factors for VVC? (4)

Answer 116

sexually active oral-genital contact contraceptives antibiotic use

Question 117

How do we treat VVC? (uncomplicated, complicated, pregnancy, recurrent, anti-fungal resistant)

Answer 117

uncomplicated - topical or oral azoles, nystatin, PO fluconazole, ibrexafungerp complicated - duration of therapy is 10-14 days, regardless of ROA. - fluconazole 150mg x 2-3 doses, 72 hours apart - other topical, oral agents pregnancy: topical agents x7 days ideal recurrent - >4 episodes w/in 12 months 1. topical or oral azole x10-14 days 2. followed by fluconazole 150mg PO once weekly for 6 months antifungal-resistant VVC - - boric acid intravaginally x14 days, then 1 cap 2x/week - flucytosine cream intravaginally x7 days

Question 118

What are risk factors for candidiasis? (9)

Answer 118

- broad-spectrum antibacterial agents - use of central venous and urinary catheters - parenteral nutrition - HD and renal replacement therapy in ICU patients - neutropenia (ANC ≤ 500 cells/mm) - implantable prosthetic agents - immunosuppressive agents - surgery - ICU length of stay

Question 119

How do we treat candidemia for non-neutropenic adults?

Answer 119

1. Echinocandin (caspofungin, micafungin, anidulafungin) - Fluconazole - use if not critically ill (uncommon) Azole susceptibility testing is recommended on all bloodstream and other clinically relevant isolates (glabrata and parapsilosis) - switch from echinocandin to fluconazole if susceptible to fluconazole Treat for 14 days after the first negative blood culture

Question 120

How do we treat candidemia for neutropenic adults? (+ if culture came back as C. glabrata, C. parapsilosis, or C. krusei)

Answer 120

1. Echinocandin - lipid amphotericin B If not critically ill and no prior azole exposure: fluconazole, voriconazole C. glabrata - echinocandin C. parapsilosis - fluconazole or lipid amphotericin B C. krusei - echinocandin, lipid amphotericin B, voriconazole Treat for 14 days after documented clearance of candida from the blood, resolution of symptoms, and resolution of neutropenia

Question 121

How do we treat chronic disseminated (hepatosplenic) candidiasis?

Answer 121

- lipid amphotericin B OR echinocandin for several weeks - follow by fluconazole 400mg PO daily

Question 122

Does growth of candida from respiratory secretions require antifungal therapy?

Answer 122

Usually no! Only if there's tissue invasion (which there's probably not)

Question 123

When do we treat candida UTIs?

Answer 123

Treatment not recommended unless high risk of dissemination High risk: neutropenic, very low-birth-weight infants, undergoing urologic procedure - fluconazole Symptomatic: fluconazole

Question 124

What are differences in clinical presentation between acute pulmonary histoplasmosis vs. chronic pulmonary histoplasmosis vs. disseminated?

Answer 124

Acute: - low inoculum exposure results in asymptomatic or mild pulmonary infection - high inoculum exposure results in an acute, self-limited illness with flu-like pulmonary symptoms Chronic: - opportunistic infection imposed on a pre-existing medical condition - chronic pulmonary symptoms: apical lung lesions that progress with inflammation, calcified granulomas, fibrosis Disseminated: - seen especially if decreased cell-mediated immunity. May be seen in pts exposed to large inoculum.

Question 125

How do we treat an immunocompetent host if the pt has histoplasmosis?

Answer 125

If it is asymptomatic/resolved -> no treatment Mild-mod w/ symptoms >4 weeks: - itraconazole for 6-12 weeks mod-severe - lipid amphotericin for 1-2 weeks, then itraconazole for 12 weeks - also give methylprednisolone

Question 126

How do we treat an immunocompromised host if the pt has histoplasmosis?

Answer 126

disseminated: lipid amphotericin B for at least 12 **months** less severe: itraconazole for 12 months

Question 127

How do we treat pulmonary blastomycosis in an immunocompetent host? What if it's in the CNS?

Answer 127

Mild-moderate: itraconazole for 6 months Mod-severe: Start with amphotericin B for 1-2 weeks, then itraconazole for 6-12 **months** total CNS: lipid amphotericin B for 4-6 weeks, then flu/itra/voriconazole for at least 12 months

Question 128

How do we treat blastomycosis in an immunocompromised host?

Answer 128

acute: lipid amphotericin B for 1-2 weeks, then suppressive therapy for at least 12 months suppressive: itraconazole for at least 12 months total - life long therapy may be necessary

Question 129

How do we treat coccidioidomycosis? (primary infection, disseminated)

Answer 129

Primary respiratory infection: most people recover without therapy - if concurrent risk factors (HIV, organ transplant, pregnancy, high doses of corticosteroids) or severe infection, treatment maybe necessary - Treatment: fluconazole or itraconazole for 3-6 months Disseminated: - Nonmeningeal: itraconazole or fluconazole, amphotericin B - Meningeal: fluconazole is treatment of choice

Question 130

What is likely to see in the clinical presentation of cryptococcus?

Answer 130

meningitis (HIV symptoms less severe because they don't have a good inflammatory response) pulmonary symptoms

Question 131

How do we treat cryptococcal meningitis? (non-HIV, HIV)

Answer 131

Non HIV: - induction: amphotericin B + flucytosine for at least 4 weeks - consolidation: fluconazole for 8 weeks - maintenance: fluconazole for 6-12 months HIV - induction: lipid amphotericin B + flucytosine for at least 2 weeks - consolidation: fluconazole for at least 8 weeks - maintenance: fluconazole for at least 1 year

Question 132

What is the most important predisposing risk factor for aspergillosis? What is important for aspergillus indentification?

Answer 132

Prolonged neutropenia (ex. bone marrow transplant) - not common in HIV infection! (here, cell mediated immunity if decreased, not neutropenia) Aspergillus has **septate hyphae** branched at 45º angles

Question 133

What are the signs and symptoms of aspergillosis?

Answer 133

aspergillosis - mold lung - vascular invasion -> thrombosis - pleuritic chest pain - fever - coughing up blood - friction rubs survival beyond 2 and 3 weeks is uncommon CT scan - halo sign or crescent sign

Question 134

How do we treat aspergillosis?

Answer 134

Invasive pulmonary aspergillosis - voriconazole for a minimum of 6-12 weeks. - trough concentrations between 1.15 - watch out for non-linear kinetics!! - alternative: lipid amphotericin B, isavuconazole - maybe combo voriconazole plus echinocandin for salvage therapy or amp B, echinocandin, or posaconazole

Question 135

When do we give prophylaxis for aspergillosis and what are our agents for prophy?

Answer 135

Done in pts who we know are going to be neutropenic for a long period of time. posaconazole - also voriconazole, itraconazole, micafungin, aerosolized amp B

Question 136

What are the different modes of transmission, risk factors, methods of prevention, and potential for chronic infection of hepatitis A, B, and C?

Answer 136

Hep A - - transmission: fecal-oral - risk factors: direct contact with someone with HAV - prevention: vaccine (safe in pregnancy) - potential for chronic infection: no Hep B - - transmission: blood, sexual (percutaneous or mucosal contact) - risk factors: born to an infected mother; also injection drug users, incarcerated people, people with HIV or HCV, men who have sex with men, STIs, on maintenance dialysis - prevention: vaccine (everyone) - potential for chronic infection: yes Hep C - - transmission: blood - risk factors: injection drug use - prevention: avoid sharing toothbrushes, shaving equipment, illicit drugs, do not donate blood/organs - potential for chronic infection: yes

Question 137

How do you interpret hep B serologic test results?

Answer 137

Hepatitis B surface antigen (HBsAg): marker of presence of ongoing infection (is the patient infectious) Antibody to hepatitis B surface antigen (anti-HBs): marker of immunity (is the patient immune) Antibody to hepatitis B core antigen (Total anti-HBc): marker of exposure to the infection (has the patient been exposed to the virus) Immunoglobulin M class of antibody to hepatitis B core antigen (ImG anti-HBc): marker of acute or recently acquired HBV infection (has the pt been recently exposed to the virus in the past 6 months)

Question 138

What are the goals of therapy and fundamental principles of treatment with antiviral agents for chronic hep B and C?

Answer 138

Hep B: - Goals of therapy: prevent long-term outcomes, achieve sustained suppression of HBV replication, remission of liver disease, prevent cirrhosis/hepatic failure/HCC, functionally cure - Principles of treatment: The greater the amount of Hep B DNA (≥ 2000 IU/mL), the more likely the pt is to have bad long term outcomes. Treatment does not eradicate HBV, combo therapy isn't better than mono therapy. Hep C: - Goals of therapy: obtain virological cure by achieving a sustained virological response (SVR) [HCV RNA undetectable 12 weeks after cessation of treatment], prevent complications (cirrhosis, HCC) and death - Principles of treatment: Mostly use oral regimens. Combo therapy of direct acting antivirals (DAAs) prevent resistance. Treatment is recommended for all persons with chronic HCV, except those w/ <12 mo life expectancies *unrelated to liver disease*. Initiation of DAAs is almost exclusively done outpatient. Treatment has high costs. All DAAs carry a warning of risk of Hep B virus reactivation

Question 139

What is the upper limit of normal for alanine aminotransferase (ALT) for females and males?

Answer 139

females: 25 U/L males: 35 U/L

Question 140

How can you use HBeAg serology, ALT, and HBV DNA to classify the patient in these clinical phases of chronic HBV: e+ immune-tolerant, e+ immune-active, e- inactive (carrier), e- immune reactivation

Answer 140

e+ immune-tolerant: liver is handling it - normal ALT - elevated HBV DNA e+ immune-active: see liver inflammation - elevated ALT - elevated HBV DNA e+ cirrhosis - elevated ALT - elevated HBV DNA - low albumin, low platelets e- inactive (carrier) - normal ALT - low/undetectable HBV DNA e- immune reactivation - elevated ALT - elevated HBV DNA e- cirrhosis - elevated ALT - elevated HBV DNA - low albumin, low platelets

Question 141

Who gets Hep B treatment (based on the 6 phases)?

Answer 141

e+ immune-tolerant and e-inactive: just monitor e+ immune-active: treat if ALT > 2x ULN AND HBV DNA > 20,000 IU/mL, otherwise MONITOR e- immune reactivation: treat indefinitely if ALT > 2x ULN and HBV DNA > 2,000 IU/mL, otherwise MONITOR e+ or e- cirrhosis: treat indefinitely if HBV DNA > 2,000 IU/mL, otherwise monitor

Question 142

How do you develop treatment and monitor chronic hepatitis B?

Answer 142

1. Nucleoside analogs - tenofovir disoproxil fumarate 300mg PO daily - tenofovir alafenamide 25mg PO daily - entecavir 0.5mg PO daily in nucleoside-naïve patients, 1mg PO daily in nucleoside-experienced 1. cytokines - peginterferon alfa 180mcg SQ qweek for 48 weeks: contraindicated in pts with currert psychosis, severe depression, neutropenia, thrombocytopenia, symptomatic heart disease, decompensated liver disease, uncontrolled seizures Monitoring: - immune tolerant patients: monitor ALT q3-6mo & eAg q6-12mo to see if they switch from tolerant to active - e- inactive patients: monitor ALT q6-12mo - pts on therapy: HBV DNA levels q3mo on NA until undetectable, then q3-6mo

Question 143

How do you develop treatment and monitor for chronic hepatitis C?

Answer 143

All treatments should be 12 weeks, unless otherwise noted (some are 8 weeks). Treatment is based upon genotype (1a, 1b, 2-4, 5/6). Combo therapy is recommended. Always recommended: pibrentasvir/glecaprevir (8 weeks) velpatasvir/sofosbuvir Somewhat recommended: ledipasvir/sofosbuvir (not for genotypes 2 & 3) elbasvir/grasoprevir (only for 1b and 4, alternative for 1a) If Y93H is present (velpatasvir screening): velpatasvir/sofosbuvir/voxilaprevir or vel/sof for genotype 3 monitoring: symptoms of hypoglycemia if taking diabetes drugs, INR if on warfarin, LFTs if pt has cirrhosis or on grazoprevir; then test HCV RNA 12 weeks after treatment to assess for SVR - ribavirin: monitor CBC - grazoprevir: monitor ALT

Question 144

What are the common adverse effects associated with these drugs for hep B and C: nucleoside analogs, cytokines, NS3/4A protease inhibitors, ribavirin

Answer 144

- Nucleoside analogs: TDF associated with kidney and bone marrow toxicities - Cytokines: flu like symptoms, mood disturbances NS3/4A protease inhibitors - grazoprevir: ALT elevations ribavirin: hemolytic anemia, pancreatitis, pulmonary dysfunction, insomnia, pruritis

Question 145

Where are the guidelines published by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America?

Answer 145

www.hcvguidelines.org/

Question 146

What MOA do these direct-acting antiviral Hep C agents have: [grazoprevir, glecaprevir, voxilaprevir], sofosbuvir, [ledipasvir, elbasvir, velpatasvir], ribavirin

Answer 146

NS3/4A protease inhibitors - "previr"; inhibit the viral NS3/4A serine protease which cleaves the HCV RNA-encoded polyprotein into its functional units -> prevents RNA replication - grazoprevir, glecaprevir, voxilaprevir NS5B polymerase inhibitors - "buvir"; inhibit RNA NS5B polymerase responsible for replication of HCV. The nucleoside agents compete with the active site & the nonnucleoside agents bid allosterically. - sofosbuvir NS5A replication complex inhibitors - "asvir"; inhibit the protein NS5A which is needed for HCV RNA replication and assembly - ledipasvir, elbasvir, velpatasvir, pibrentasvir Ribavirin - guanosine analog, exact mechanism is unknown

Question 147

What is the special pre-treatment testing to consider prior to initiation of elbasvir and velpatasvir?

Answer 147

perform an NS5A genotype to screen for the presence of resistance-associated substitutions (RASs) at baseline. Any presence of mutations requires an extended 16 week course + ribavirin

Question 148

What is the special on-treatment monitoring parameter for grazoprevir?

Answer 148

Patients should have ALT checked at 8 weeks and discontinue if they at over 5x ULN

Question 149

What is the pathogenesis of the HIV infection, including the stages of the infection?

Answer 149

Pathogenesis - HIV has receptor proteins (gp120) that preferentially bind to CD4 receptors on T cells, macrophages, and dendritic cells (primary target is CD4 T helper/inducer lymphocyte). CD4 cells are key components of cell-mediated immunity & assist with antibody production and secreting cytokines to protect the host against bacterial/viral infections. These CD4 cells are ultimately destroyed by a direct cytolytic effect from HIV. Stages of HIV infection - - acute retroviral syndrome (stage 0) - seen w/in 2-6 weeks after initial infection. See flu-like symptoms - chronic HIV infection (asymptomatic, stage 1/2) - reached w/in 3-6 months after infection. Antibodies developed against HIV reduce the virus in the serum. Baseline pt has 800-1500 CD4 cells/mm, but see a progressive loss of CD4 cells between 30-90 cells/mm/year - acquired immunodeficiency syndrome (AIDS, symptomatic, stage 3) - see profound immunosuppression. When CD4 count <500, may be thrush, VVC, etc., when CD$ count <200, **opportunistic infections** can occur.

Question 150

What are the 3 routes of transmission of HIV?

Answer 150

1. Exposure of mucous membrane or damaged tissue to infected body fluids (ex. blood, semen, pre-seminal fluid, rectal fluids, vaginal secretions, breast milk, CSF, synovial fluid, amniotic fluid, pleural fluid, peritoneal and pericardial fluid) 2. Blood-stream exposure (injection drug use) 3. Mother-to-child (risk has greatly decreased)

Question 151

What are the methods of HIV diagnosis and how do you counsel a patient on an at-home HIV test?

Answer 151

A diagnosis of HIV can be made from either positive results from a multitest algorithm or a positive virologic test (ex. viral load, qualitative HIV NAT) - HIV-1/2 antigen/antibody immunoassay is the preferred method for HIV diagnosis (4th gen test) - if HIV 1/2 antigen/antibody immunoassay is positive, then use the HIV-1/HIV-2 antibody differentiation immunoassay to see which types of antibodies are detected. *remember that no info from anything during the eclipse period will be provided (~14-20 days for 4th gen immunoassay) *OraQuick* In-Home test is a 3rd gen test that results in 20 mins (still recommended that they get the 4th gen testing as well) - These are preliminary screens, pts should seek out their medical provider for confirmatory testing - Patients with non-reactive results should know about the 3 month seroconversion window, so they need to repeat for testing if the risk event occurred within that period - Counsel on methods of risk reduction

Question 152

What are two surrogate markers used in assessing the progression of a patient's infection and the effectiveness of a patient's antiretroviral regimen?

Answer 152

CD4 lymphocyte cell count - used to assess the pt's overall immunocompetence, particularly useful before initiation of antiretroviral therapy, <200 is indicative of the potential for opportunistic infections. - stage 1 ≥ 500 CD4 count (generally) - stage 2 200-499 CD4 count (generally) - stage 3 < 200 (generally) HIV RNA - used to assess the effectiveness of therapy, most useful after the initiation of antiretroviral therapy, pre-treatment viral load play a role in the selection of drug therapy (some are less effective with a higher baseline of viral load)

Question 153

What is the difference between HIV infection and AIDS?

Answer 153

The classification of HIV infection is primarily based on CD4 count. Stage 0 is established if a positive result is found w/in 180 days of a negative or indeterminate result, regardless of CD4 count. AIDS is established if an AIDS-defining opportunistic infection is diagnosed, regardless of CD4 count.

Question 154

What are the MOAs of these antiretrovirals: NRTIs (which drugs are which analogues), NNRTIs, Protease Inhibitors

Answer 154

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) - purine and pyrimidine analogues that must undergo phosphorylation. Then, these NRTIs compete with native nucleotides for incorporation into the growing DNA chain, but they don't have a 3'-OH group, so it causes chain termination - Adenosine: tenofovir, didanosine - Cytidine: lamivudine, emtricitabine - Thymidine: stavudine, zidovudine - Guanosine: abacavir Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) - bind to an *allosteric site* of the RT enzyme, inducing a conformational change that results in reduced functionally of the enzyme - CYP 3A4 inducers Protease Inhibitors - competitively inhibit viral protease, which is responsible for cleavage of precursor polypeptides into functional structural and enzymatic viral proteins. So these prevent the assembly, maturation, and release of new infectious virions - These are metabolized by CYP3A4, so boosting with ritonavir or cobicistat is important.

Question 155

What are the MOAs of these antiretrovirals: INSTIs, attachment inhibitor, post-attachment inhibitor, CCR5 antagonist

Answer 155

Integrase Strand Transfer Inibitors (INSTIs) - inhibit the HIV integrase enzyme, preventing the proviral DNA integration into the host cell genome - INSTIs are subject to chelation, elvitegravir (1st gen) requires boosting Attachment inhibitor - fostemsavir; binds to gp120 on the surface of HIV, blocking the attachment to the CD4 T-cell co-receptor - contraindicated with strong CYP3A4 inducers as coadministration results in significant decreases in temsavir concentrations, these are rarely used clinically Post-Attachment inhibitor - binds to domain D2 of the CD4 T-cell co-receptor to interrupt the post-attachment steps required for entry of HIV into the host cell - monoclonal antibody, rarely used clinically Chemokine coreceptor 5 (CCR5) antagonist - miraviroc; binds to CCR5 on CD4 cell surface, which blocks the binding of gp120, preventing entry of HIV into the host cell - need tropism assay to ensure virus only uses CCR5 before initiating - CYP3A4 substrate

Question 156

What are the MOAs of these antiretrovirals: fusion inhibitor, capsid inhibitor,

Answer 156

fusion inhibitor - enfuviritide; binds to gp41 and prevents the fusion and entry of HIV into the CD4 cell - rarely used clinically capsid inhibitor - lenacapavir; binds to the interface between capsid protein (p24) subunits. This inhibits HIV-1 replication by interfering with multiple steps of the viral life cycle, including update of proviral DNA, virus assembly and release, and capsid core formation - half-life is 8-12 weeks - substrate of CYP34 - only approved for MDR infections who are failing their antiretroviral regimen

Question 157

What are the FDA-approved adult doses of these initial regimens for most people with HIV: Biktarvy, Dovato, Triumeq, dolutegravir, maraviroc

Answer 157

Biktarvy: bictegravir, emtricitabine, TAF - bictegravir 50mg - emtricitabine 200mg - TAF 25mg Dovato: dolutegravir, lamivudine - dolutegravir 50mg - lamivudine 300mg Triumeq: abacavir, dolutegravir, lamivudine - abacavir 600mg - dolutegravir 50mg - lamivudine 300mg dolutegravir: - 50mg daily for INSTI naive - 50mg BID for INSTI experienced maraviroc: (give tropism assay) - 300mg BID - 150mg BID if CYP3A4 inhibitor +/- inducer - 600mg BID if CYP3A4 inducer

Question 158

What are the special administration requirements/adverse reactions for efavirenz, neviripine, rilpivirine, etravirine, atazanir

Answer 158

efavirenz - take at bedtime on an empty stomach (may cause CNS reactions) neviripine - need dose titration for 14 days rilpivirine - take with a large, fatty meal etravirine - take with food atazanir - take with food. may cause indirect hyperbilirubinemia

Question 159

What are the special administration requirements for elvitegravir, ibalizumab, enfuviritide, lencapavir

Answer 159

elvitegravir - take with food, must be boosted with something ibalizumab - IV enfuviritide - SQ lencapavir - SQ

Question 160

What are common adverse effects of these antiretrovirals: NRTIs, NNRTIs, protease inhibitors, INSTIs

Answer 160

NRTIs: mitochondrial toxicity (anemia, granulocytopenia, myopathy, peripheral neuropathy, pancreatitis [seen less with TEAL tenofovir, emtricitabine, abacavir, lamivudine]), TDF associated with renal impairment and decreased bone mineral density, CAD/MI, lactic acidosis NNRTIs: rash Protease inhibitors: GI intolerance, insulin resistance, lipodistrophy INSTIs: weight gain

Question 161

How do you manage clinical relevant drug interactions between antiretrovirals and acid reducers, benzodiazepines, corticosteroids, HMG-CoA reductase inhibitors, biguanide, PDE5 inhibitors, polyvalent cation supplements?

Answer 161

acid reducers: separate antacides from PO INSTIs by 6 hours, never give raltegravir with Al or Mg. Atazanavir and PO rilpivirine are reduced by acid reducers. Rilpivirine is contraindicated with PPIs benzodiazepines: with protease inhibitors + cobicistat, preferred benzos are LOT lorazepam, oxazepam, and remazepam corticosteroids: beclomethasone is preferred with protease inhibitors + cobicistat HMG-CoA reductase inhibitors: with protease inhibitors + cobicistat, low doses of atora/rosuva/pitava/pravasatin are preferred. With NNRTIs, dose may beed to be increased biguanide: dolutegravir increases metformin, so dose decrease if necessary PDE5 inhibitors: with protease inhibitors + cobicistat, use very low doses q48-72 hours polyvalent cation supplements: with integrase inhibitors, space apart by 6 hours. Coadministration with Ca/Fe w/ dolutegravir or bictegravir is OK if also taken with food

Question 162

Which antiretroviral class requires dosage adjustments in renal insufficiency?

Answer 162

NRTIs - all except abacavir require adjustment in renal insufficiency Not: - NNRTIs (hepatic metabolism) - protease inhibitors (CYP metabolism) - INSTIs (UGT1A1 glucuronidation elimination)

Question 163

What lab tests are required prior to initiation of abacavir and maraviroc?

Answer 163

Screening for HLA-B*5701 which is predictive of a potentially fatal hypersensitivity reaction

Question 164

Which website has the federally approved HIV/AIDS medical practice guidelines?

Answer 164

clinicalinfo.hiv.gov

Question 165

What are the goals and general principles of treatment with antiretroviral agents?

Answer 165

Goals: 1. Maximally and durably suppress plasma HIV RNA to be below the lower level of detection of the assay used (aka undetectable) 2. Restore and preserve immunologic function 3. Reduce HIV-associated morbidity and prolong the duration and quality of survival 4. Prevent transmission

Question 166

What are the recommendations surrounding timing of initiation of treatment in HIV infection?

Answer 166

ART should be initiated immediately. ART is recommended for all individuals with HIV, regardless of CD4 count

Question 167

What is the appropriate first-line antiretroviral regimen (including dose and counseling points)?

Answer 167

Triple drug combination regimens. Monotherapy does NOT work. - generally two NRTIs + [INSTI OR NNRTI OR PI boosted] Most common: TAF/FTC (tenofovir alafenamide/emtricitabine) + BIC (bictegravir) OR DTG (dolutegravir) - backbone can also be [abacavir + lamivudine] - TDF/FTC or TDF/3TC (rarely) also - lamivudine + dolutegravir (Dovato) is an option, but has many caveats Dosing: - Biktarvy [TAF/FTC + BIC]: bictegravir 50mg + emtricitabine 200mg + tenofovir alafenamide 25mg daily - Dovato [DTG/3TC]: dolutegravir 50mg + lamivudine 300mg - Triumeq [ABC/DTG/3TC]: abacavir 600mg + dolutegravir 50mg + lamuvidine 300mg daily Due to CYP3A4 interactions and higher pill burden, PI or NNRTI regimens are not currently recommended for initial treatment.

Question 168

What are positive predictors to adherence and negative predictors of adherence?

Answer 168

Positive: knowledge about the medication, motivation to maintain therapy, once daily regimens, comprehensive, multidisciplinary care settings, strong patient-provider relationship Negative: high viral load, untreated major psychiatric disorders, neurocognitive impairment, active substance abuse, unstable housing, other unfavorable social circumstances, patient concerns about side effects, poor adherence to clinical visits

Question 169

In which clinical scenarios is obtaining a resistance test recommended?

Answer 169

- At entry to care (regardless of whether ART is initiated immediately or deferred): standard genotype of RT and PR genes preferred - If virologic failure or suboptimal virologic response: genotype recommended when failing first or second regimens, sequence integrase gene if failing an INSTI-based regimen, phenotypes should be considered in pts with extensive treatment hisotry, particularly to PIs

Question 170

What viral load is needed for the best likelihood of yielding a successful standard resistance test result?

Answer 170

the specimen should contain >500 copies/mL for the best likelihood of yielding a successful standard resistance test results (should still be considered for >200 copies/mL

Question 171

What are the differences in genetic barrier to resistance for the NNRTIs and boosted PIs?

Answer 171

NNRTIs - high-level resistance develops easily and quickly Protease inhibitors - when boosted, these have a highly favorable resistance profile

Question 172

What is the recommended post-exposure prophylaxis regimen (including dose, duration, monitoring, counseling points)?

Answer 172

emtricitabine/tenofovir disoproxil fumarate 200/300mg PO daily + raltegravir 400mg PO BID or dolutegravir 50mg PO daily for 28 days - start as soon as possible, must be within 72 hours monitoring: rapid testing at baseline (if positive, don't initiate PEP), repeat testing at 4-6 weeks and 3 months, should also be tested for HBV and HCV (if exposure non-occupational) counseling: use precautions to prevent secondary transmission, especially during first 6-12 weeks, possible drug toxicities, importance of adherence, ongoing risk for recurring HIV should undergo consideration for PrEP once the 28 day course of PEP is completed

Question 173

What is the recommended pre-exposure prophylaxis regimen (including dose and monitoring)?

Answer 173

Contraindications to PrEP: HIV infection, weight <77lbs, CrCL < 60 for TDF/RTC or <30 for TAF/FTC, possible HIV exposure w/in the last 72 hours (instead offer PEP) Duration: not life-long, just while the high risk persists a. TDF/emtriciabine (Truvada) - 300/200mg 1 tab PO daily for not more than 90 days b. On-Demand or 2-1-1 oral PrEP (for men who have sex with men infrequently) - TDF/FTC (Truvada) 300/200mg 2 tabs PO taken 2024 hours prior to having sex, then 1 tab PO 24 hours after the first 2 tabs were taken, then 1 tab PO 48 hours after the first 2 tabs were taken, then 1 tab PO daily until 28 hours after last sexual encounter c. injection PrEP - cabotegravir 500mg IM, 2nd dose 1 month after 1st dose, then every 2 months - check for Hep B before starting PrEP Monitoring: HIV test within 1 week before starting PrEP, HIV RNA if possibly infected within the past 2-4 weeks, STI testing, creatinine/hep B test - test for HIV infection every 3 months - test lipids and triglycerides for PO regimens (TAF/FTC)