Antivirals 1 and 2

Question 1

Five major classes of antiretroviral meds:

Answer 1

1. nucleoside reverse transcriptase inhibitors (NRTI’s); subset is nucleotide RTI’s (tenofovir)
2. Non-nucleoside reverse transcriptase inhibitors (NNRTI’s)
3. Protease inhibitors (PI’s)
4. Entry inhibitors: enfuvirtide and CCR5 antagonists
5. Integrase inhibitors

Question 2

List NRTI’s:

Answer 2

Lamivudine, abacavir, tenofovir, emtricitabine;

TEAL

Question 3

Mech of action of NRTI’s and analog posers:

Answer 3

viral DNA chain termination via inhibition of reverse transcriptase enzyme;
thymidine: zidovudine and stavudine (STarZ)
adenosine: didanosine, tenofovir (TAD)
Cytosine: zalcitabine, lamivudine, emtricitabine (CELZer)
Guanine: abacavir

Question 4

List NRTI SE’s and the class SE’s:

Answer 4

1. Tenofovir: nephrotoxicity (Fanconi, RTA)
2. Abacavir: hypersens reaction (immune-mediated: if stopped do NOT restart; maybe HLA allele associated)
3. Lamivudine/emtricitabine: few
4. Zidovudine: anemia;

Lactic acidosis (much less common with new agents), and GI SE’s (N/V, diarrhea)

Question 5

List of NNRTI’s, mech of action, and SE’s:

Answer 5

Efavirenz, nevirapine, rilpivirine, etravirine;
bind directly to reverse transcriptase and inhibits its action;
efavirenz: CNS symptoms like vivid dreams and drowsiness, and TERATOGENIC
Nevirapine: rash; hepatitis and hepatic necrosis
Etravirine: rash, increased LFT’s
Rilpivirine: rash, QT prolongation

Question 6

Protease inhibitors and mech of action and class toxicities:

Answer 6

Ritonavir, fosamprenavir, lopinavir/ritonavir, atazanavir, darunavir;
Mech: bind within active pocket of protease, inhibiting binding of virus; without protease clevage, virus cannot cause infection (more flexibility regarding resistance);
Class toxicities: GI intolerances like N/V, diarrhea, with metabolic toxicities: dyslipidemia, hyperglycemia, lipodystrophy

Question 7

What’s good about ritonavir:

Answer 7

Ritonavir at low doses ENHANCES blood levels of other PI’s when given together;
Inhibits P4503A4 inhibition in liver and gut, and inhibition of P-glycoprotein transport;
1. reduce dosing freq
2. improve adherence/reduce ADR’s
3. suppress strains of resistant virus
4. improve efficacy of regimen

Question 8

Fusion inhibitors:

Answer 8

Enfuvirtide (salvage drug that can help after resistance develops); injection;
SE’s: local injection sight reaction, increased rate of bacterial pneumonia, hypersens rxn;

Maraviroc (CCR5 inhibitors)
SE’s: hepatotoxicity (rare); cough, fever, URI’s, rash, musculoskeletal symptoms, abdo pain, dizziness

Question 9

Integrase inhibitors:

Answer 9

Raltegravir, elvitegravir, dolutegravir;
Mech: inhibits viral enzyme (integrase), which is necessary for insertion of viral DNA into human genomic DNA;
SE’s: Usually few adverse effects; nausea, headache, diarrhea, pyrexia; some MYOPATHY and RHABDO

Question 10

Strength of recommendation for ART depends on; basics of HAART involves; examples for HAART

Answer 10

pre-treatment CD4 count;

combo therapy with at least 3 active agents (try to get 3 agents representative of 2 classes of agents);

1. PI (maybe with ritonavir boosting) and 2 NRTIs
2. NNRTI + 2 NRTIs
3. Integrase inhibitor + 2 NRTIs

Question 11

Goals of HAART:

Answer 11

1. Undetectable viral load (within 24-48 wks of therapy, and if goal not reached, maybe change)
2. CD4 response: should see rise in this count, but this will lag behind VL response
3. Improve quality of life
4. Reduce HIV-related morbidity and mortality
5. Minimize resistance (if you develop it to antiretroviral it’s permanent, and cross-resistance can occur within classes; it’s directly associated with adherence and attainment of virologic goals)

Question 12

When can we stop HIV treatment?

Answer 12

WE DON’T!!

Question 13

HCV basics:

Answer 13

1. No effective vaccine available
2. Curable with effective drug therapy
3. About 20% of individuals exposed to HCV will clear infection and not develop chronic HCV

Question 14

From acute HCV infection, can progress to

Answer 14

chronic HCV infection, compensated cirrhosis, decompensated cirrhosis, and HCC, transplantation and death

Question 15

For HCV, what is equivalent to a viral cure?

Answer 15

Sustained viral response (get undetectable HCV RNA 12-24 wks after therapy completion)

Question 16

Interferon:

Answer 16

Mech: induce IFN-stimulated genes that help establish an antiviral state within cells (think pegylated form, and response not virus-specific);
SE’s: flu-like symptoms, cytopenias, depression, fatigue (FFCD); tough to finish treatment course; think contraindications

Question 17

Ribavarin:

Answer 17

Nucleoside analog

SE: hemolytic anemia (major), teratogenic

Question 18

Sofosbuvir:

Answer 18

Mech: inhibitor of HCV NS5B RNA-dependent RNA polymerase; once phosphorylated, competes with naturla viral nucleotide (uridine) to cause chain termination of HCV RNA (active across ALL HCV genotypes);
Toxicity: think fatigue, headache, GI SE’s, anemia

Question 19

Ledipasvir

Answer 19

Mech: inhibits HCV NS5A, a viral phosphoprotein required for viral replication; combined with sofosbuvir;
SE’s: fatigue, headache, GI SE’s

Question 20

Simeprevir, boceprevir, telaprevir

Answer 20

Mech: prevent viral maturation through inhibition of protein synthesis;
SE’s: anemia, rash, itching, GI SE’s, drug interactions (GRAID)

Question 21

Approach to HCV therapy:

Answer 21

combo therapy is standard;
e.g. sofosbuvir and pegylated IFN and ribavarin for 12 wks
sofosbuvir and simeprevir w/w/o ribavirin for 12 wks

Question 22

Acyclovir: what are some associated therapies also?

Answer 22

Mech: after phosphorylation by cellular enzymes, acyclovir triphosphate competes with DNA analogues to cause viral DNA chain termination
Thera: think HSV and VZV
SE’s: CNS (malaise, headache, confusion), N/V, diarrhea, renal dysfunction (high doses)
Misc: IV, oral, and topical formulations;

valacyclovir (prodrug of acyclovir converted to acyclovir after oral admin),
penciclovir has structure and MOA similar to acyclovir and given topically often;
famciclovir: prodrug of penciclovir that is given ORALLY!!

Question 23

Ganciclovir:

Answer 23

Thera: HSV, VZV, and DEF CMV!!
Misc: IV/PO (valganciclovir is the prodrug with better bioavailability with food)
SE’s: myelosuppression (neutropenia), CNS toxicity (headaches, seizures, confusion), hepatoxicity and GI intolerance

Question 24

Foscarnet

Answer 24

Mech: directly inhibits herpesvirus DNA polymerase or HIV reverse transcriptase; active against acyclovir/penciclovir/ganciclovir resistant viruses
Thera: inhibitory effect on herpesviruses and HIV
SE’s: nephrotoxicity, hypo/hypercalcemia, hypo/hyperphosphatemia, hypomagnesemia, hypokalemia; CNS SE’s (Hallucinosis, Irritability, SEIZURES, Tremors: HISTory), myelosuppression

Question 25

____ is the best strategy to combat influenza infection and related morbidity/mortality; when should drug therapy start?

Answer 25

Vaccination;

start early, and moderately limit the length of illness with some benefit for critically ill patients

Question 26

Oseltamivir and Zanamivir

Answer 26

Mech: inhibit viral neuraminidase (enzyme critical in penetration of respiratory tract mucus and in release of virus from infected cells)
Thera: active against influenza A and B
SE’s: GI SE’s including N/V and diarrhea; also agitation, anxiety, altered mental status; zanamivir is inhaled and leads to bronchospasms
Misc: significantly reduces rates of influenza complications (pneumonia, bronchitis); start therapy within 48 hrs of symptom onset, continue for 5 days

Question 27

Chemoprophylaxis situations:

Answer 27

1. Seasonal prophylaxis (flu season)
2. Post-exposure prophylaxis (short period of time following exposure);
   think someone vaccinated after influenza activity has begun, unvaccinated people providing care to high risk, those with immune deficiencies, those experiencing an influenza outbreak, and unvaccinated people wishing to avoid influenza illness