Antivirals and Antiretrovirals

Question 1

Antivirals for treating HSV 1 and 2 and Varicella Zoster Virus

Answer 1

Systemic
• Acyclovir - comes topically 
• Valacyclovir
• Famciclovir
Topical
• Penciclovir; Docosanol
• Trifluridine

Question 2

Antivirals for treating CMV in immunosuppressant or transplant patients

Answer 2

Ganciclovir 
Valganciclovir
Foscarnet
Cidofovir
Letermovir

Question 3

Acyclovir

Answer 3

Oral, IV, topical - low bioavailability with wide distribution

If therapy is initiated during prodromal phase then healing time may be shortened

Causes inhitibition of Viral Thymidine Kinase - eventual stopping of viral DNA synthesis and chain termination

For Rx Hsv1/2, VZV requires higher dose because acyclovir is less potent against Vericella

Question 4

What are the resistance mechanisms drugs have against antivirals for HSV and VZV?

Answer 4

mutations in viral thymidine kinase or viral DNA polymerase, absent or def. viral thymidine kinase or altered substrate specificty

There is low degree of resistance to Acyclovir / Valcyclovir; but resistant virus are cross-resistant to penciclovir

Question 5

Valacyclovir

Answer 5

Oral prodrug - hydrolysis to acyiclivr bioavil 55% with wide distribution

therapy can shorten healing time of HSV or VZV infections

Inhibits Viral thymidine kinase -> inhibition of viral synthesis and chain termination

HSV-1, HSV-2, VZV - provides higher systemic levels of drug than acyclovir

Question 6

Famciclovir

Answer 6

Oral prodrug or Penciclovir bioavailability ~75%

Initiate during prodromal stage ⇒ may shorten healing time, duration of pain, and period of viral shedding

Inhibits viral thymidine kinase - inhibits viral DNA synthesis and inserts self into DNA causing chain termination

RX – HSV-1, HSV-2, VZV, EBV, HBV

Question 7

Acyclovir, Valacyclovir, Famciclovir Adverse Effects

Answer 7

In the Rx of HSV, VZV, CMV the drugs can cause adverse effect with high IV or oral doses — normally safe and well tolerated

cystalline nephropathy

CNS - delirium, seizures, tremors, EPS, myoclonus

thrombocytopenia

Question 8

Topical Rx for HSV infection

Answer 8

frequent application

Acyclovir, penciclovir and docossanol all come in topical cream version

Trifluidine is for ophthalmic solutions in Rx of Primary keratoconjunctivitis and Recurrent epithelial keratitis

Question 9

Ganciclovir

Answer 9

Valganciclovir is prodrug

deoxy-guanosine analog

Active against all herpes viruses but especially effective against CMV

preferrentially inhibits viral dna polymerases

uses - CMV retinitis, acute herpetic keritiits

valgan - oral for CMV retinitis and propholaxis of CMV infection

Question 10

Ganciclovir / Valganciclovir - Toxicities and Contraindications

Answer 10

Toxicities include myelosuppression, (dose-limiting: Neutropenia, thrombocytopenia), Gi effects and CNS effects

Contraindication - teratogenic, embryotoxic, inhibits spermatogensis

Blocks renal tubular secretion

Question 11

Foscarnet

Answer 11

pyrophosphate analog

given IV, treatment of CMV retinitis

Reversible noncompetitive block of pyrophosphate binding site of viral polymerase

AEs – nephrotoxicity is the major dose-limiting effect, hypocalcemia

mutatgenic so caution with pregnancy

Question 12

Cidofovir

Answer 12

Cytidine Analog -

1. Inhibits viral DNA synthesis,
2. Incorporation into DNA causes chain termination

cross-resistance with ganciclovir

THERAPEUTIC USE – IV, Treatment of CMV retinitis

Cautions - can cause proximal tubule injury leading to metabolic acidosis – administer with probenecid and saline

probenecid inhibits OAT which slows the tubular secretion of the drug

embryotoxic, mutagenic, gonadotoxic

Question 13

Letermovir

Answer 13

CMV DNA terminase complex

Given oral and IV, low bioavialbiltiy but greatly increases w/ cyclosporine

high plasma protein binding, Substrate of P-glycoprotein, OATP1B1/1B3, glucuronidation with fecal excretion

Letermovir blocks the pUL56 in CMV DNA terminase complex&raquo_space;> eventual alteration in genome length

used for the prophylaxis of CMV infection and disease, given to adult seropositive recipents of allogeneic bone marrow transplant

Question 14

Letermovir - Drug Interactions and Adverse Effects

Answer 14

CYP3A4, P-gp, OATP inhibitor
CYP2C9, 2C19 inducer

CONTRAINDICATED drug
combinations
• pimozide
• ergot alkaloids
• simvastatin
• pitavistatin

Nausea, vomiting, diarrhea, abdominal pain, headache, fatigue, peripheral edema, tachycardia, decrease platelet count and hemoglogin

Question 15

Standard of care for HIV infection

Answer 15

2 NRTIs + an INSTI, or an NNRTI, or a boosted PI

Outcome of initial therapy - undetectable viral load and a CD4 count increase of 50-150 cells in he first year

Question 16

Name some general adverse effects on antiretroviral therapy?

Answer 16

Immune reconstitution inflammatory syndrome

lipodystrophy syndrome

drug interaction - with inhibitors or inducers of metabolic enzymes

Question 17

What are the NRTI’s - Nucleoside/tide Reverse Transcriptase Inhibitors

Answer 17

activity against HIV-1 and HIV-2, some have activity against HBV

zidovudine (ZDV)*
stavudine (d4T)
zalcitabine (ddC)
lamivudine (3TC)*
emtricitabine (FTC)*
abacavir (ABC)*
didanosine (ddi) 
tenofovir (TFV)*

Question 18

Viral Resistance to NRTIs - single amino acid substitution: M184V/I

Answer 18

lamivudine and emtricitabine

Question 19

Mitochondrial Toxicity - antivirals

Answer 19

NRTIs - Zalcitabine, didanosine, stavudine, zidovudine

associated with DNA polymerase-γ inhibition

common effects - myopathy, lipoatrophy, hepatic steatosis and lactic acidosis

Question 20

antiviral therapy should be discontinued when which mitochondrial toxic effects occur?

Answer 20

(NRTIs)

inc ALT/AST, progressive hepatomegaly, metabolic acidosis with unknown origin, peripheral neuropathy or pancreatitis

Question 21

NRTI Drug Interactions

Answer 21

Renal OAT inhibition - causes decreased renal clearance of one or both drugs
-effects probenecid, acyclovor, other anti-herpes drugs, and anti-HBV drugs

mechanisms of DI’s through competition at active site and additive toxicities

Question 22

why is zidovudine + stavudine a bad combination for antiviral drugs

Answer 22

they are both thymidine analogs which have antagonistic effects

Question 23

why are the antiviral drugs Didanosine + Stavudine a bad combination?

Answer 23

fatal lactic acidosis

Question 24

Didanosine + Zalcitabine = bad effects, why?

Answer 24

Additive peripheral neuropathy

Question 25

Didanosine + Tenofovir --- why are these drugs contraindicated?

Answer 25

They are both adenosine analogs that compete at the site of function and lead to virologic failure

Question 26

Lamivudine + Zalcitadine = bad effects, why?

Answer 26

They are both cytidine analogs and are antagonist to each others efficacy - inhibit the intracellular phosphrylation of one another

Question 27

Lamivudine + Emtricitabine ---- contraindicated together for what reason?

Answer 27

they are analogs leading to enhanced toxicity

Question 28

Zidovudine

Answer 28

NRTIs - Alternative agent for antiretroviral therapy - thymidine analog HIV-1, HIV-2, and human T-cell lymphotrophic viruses (HTLV) I and II Used IV for prevention of mother-to-child HIV transmission exhibits mitochondrial toxicity

Question 29

Lamivudine

Answer 29

NRTI - cytidine analog in antiretroviral: at a higher dose once daily dosing and lower doses twice daily dosing. Used for HIV-1, HIV-2, HBV Rebound HBV infection can happen in patients if lamivudine is d/c and replaced with a drug not also effective against HBV

Question 30

Emtricitabine

Answer 30

NRTI - cytidine analog. Fluorinated version of lamivudine. Antiretroviral Rx daily dose used for HIV1, HIV2, HBV- supresses not approved for treatment of HBV -rebound HBV infection when d/c hyperpigmentation of palms or soles

Question 31

Abacavir

Answer 31

antiretroviral treatment, NRTI- guanosine analog, used for both HIV-1 and HIV-2 Associated with a gene - HLA-B 5701 that causes hypersensitivity syndrome metabolized by alcohol dehydrogenase - alcohol increases abacavir levels

Question 32

Tenofovir

Answer 32

antiretroviral - NRTI, adenosine analog used for HIV1 and HIV2, HBV rebound HBV fanconi syndrome and decreased bone marrow density

Question 33

NNRTI's - Non-nucleoside Reverse Transcriptase Inhibitors

Answer 33

highly effective HIV infection when used with 2 NRTIs They bind to allosteric site on reverse transcriptase ``` Efavirenz* Nevirapine* Etraverine* Rilpivirine* Delavirdine ```

Question 34

Viral Resistance to NNRTIs

Answer 34

Efavirenz, nevirapine, delavirdine, and rilpivirine Resistance is seen to these drugs with a single point mutation in the HIV virus Nervirapine can induce resistance with just a single dose cross-resistance is seen K103N and Y181C Etravirine - 2 mutation, cross resistance with rilpivirine

Question 35

NNRTI Class Toxicities

Answer 35

antiretroviral drugs NNRTI toxicities are rashes - usually in the first 4 weeks of treatment, usually mild and self-limited with rare SJS/TEN long term use causes fat redistribution Nevirapine - fatal hepatitis NNRTI's have high potential for drug interactions

Question 36

Efavirenz

Answer 36

Antiretroviral, alternate with 2 NRTIs tolerable and potent displays CNS symptoms - impaired concentration, dysphoria, vivid or disturbing dreams, insomnia and psychosis 1teratogenic - causes neural tube and CNS defects Efravirenz is a inducer of CYP2B6 and CYP3A4 and inhbitor of CYP2C9/19

Question 37

Nevirapine

Answer 37

NNRTI, antiretroviral, used for initial therapy in HIV, salvage therapy and in neonates adverse effect is hepatitis, considered safe during pregnancy -risk factor is pregnant women with CD4 counts greater than 250 cells Nevirapine is autometabolic inducer at CYP3A4, also induces CYP2B6

Question 38

Rilpivirine

Answer 38

NNRTI, antiretroviral HIV treatment in naive adults (ones who have not been treated yet) virologic failure is common in patients with a high baseline plasma viral load adverse effects - CNS effects, QT interval prolongation no evidence of fetal harm in animal studies substrate of CYP3A4

Question 39

Etravirine

Answer 39

NNRTI, antiretroviral Treatment in experienced HIV infected adults only no evidence of harm during pregnancy can be used in pediatric patients Etravirine - inducer of CYP3A4 and UGTs (maraviroc dose should be doubled in concurrent therapy) and inhibitors of CYP2C9/19

Question 40

NNRTI Drug Interactions

Answer 40

Efavirens/Nevirapine cannot be used with Tenofovir and Didanosine Efravirenz is a inducer of CYP2B6 and CYP3A4 and inhbitor of CYP2C9/19 Nevirapine is autometabolic inducer at CYP3A4, also induces CYP2B6 Etravirine - inducer of CYP3A4 and UGTs (maraviroc dose should be doubled in concurrent therapy) and inhibitors of CYP2C9/19 Rilpivirine is a substrate of CYP3A4

Question 41

HIV Protease Inhibitors

Answer 41

Activity against HIV-1 and HIV-2 subtrates of P-glycoprotein, cleared by CYP3A4 Fosamprenavir Lopinavir-Ritonavir Atazanavir Darunavir Prevent proteolytic cleavage of HIV gag and pol proteins

Question 42

what is the purpose of ritonavir and cobicistat with protease inhibitors?

Answer 42

potent CYP3A4 / P-glycoprotein inhibitors ↑concentrations, ↑duration of action and improve virologic activity of the protease inhibitor all PI's are given with these except Nelfinavir

Question 43

What are the mechanisms of resistance against PI's?

Answer 43

acculmulation of at least 4 or 5 codon substitutions primary mutations in enzymatic active site causes a 3 to 5x decreased sensitivity Cross-resistance to other PIs due to 2° mutations

Question 44

Effects Protease Inhibitors on HIV

Answer 44

Favorable long-term suppression of viremia ↑ CD4 lymphocyte counts Reduce disease progression Improve long-term survival must be balanced against short- and long-term toxicities, including the risk of insulin resistance and lipodystrophy

Question 45

HIV PIs Class Toxicities

Answer 45

Nausea, vomiting, diarrhea Cushingoid appearance, e.g. central obesity, buffalo hump, Triglyceride and LDL increased levels, and hyperglycemia skin rashes, SJS, TEN Peripheral neuropathy, myalgia Cardiac conduction abnormalities

Question 46

Protease Inhibitor Drug Interactions

Answer 46

CYP3A4 inhibition → drugs with narrow TI, increase statin levels and muscle toxicity, increase digitoxin, decreased oral contraceptive efficacy and decreases methadone levels

Question 47

Ritonavir

Answer 47

``` Pharmacokinetic enhancer (low doses) (antiretroviral effects at higher doses) • dose-dependent GI toxicities • Paresthesias, metabolic toxicities ``` adverse effects - paresthesia, asthenia, hepatitis, PR interval prolongation

Question 48

Fosamprenavir

Answer 48

Prodrug, protease inhibitor dephosphorylated to amprenavir in the intestinal mucosa, better tolerated than amprenavir GI effects common fatigue, depression, rash

Question 49

Lopinavir/r

Answer 49

protease inhibitor adverse effects - GI and metabolic effects are common, cardiotoxicity, lactic acidosis, CNS depression, respiratory complications, acute renal failure and death toxic to neonates

Question 50

Atazanavir

Answer 50

protease inhibitor, formulated with cobicstat Lowest pill burden of PIs (once daily) Can cause unconjugated bilirubinemia through UGT inhibition Also causes pancreatitis, asthenia, increase in transaminases, PR or QT prolongation interacts with tenofovir increases the levels, and PPIs and H2 inhibitors

Question 51

Darunavir

Answer 51

protease inhibitor, formulated with cobicstat Use: Treatment-naïve and treatment-experienced patients has sulfonamide moiety - rash in up to 10% of patients Causes hepatitis and elevations in serum transaminases

Question 52

HIV Integrase Strand Transfer Inhibitors

Answer 52

Raltegravir Elvitegravir / cobicistat Dolutegravir Bictegravir Activity against HIV-1 and HIV-2 block HIV-encoded integrase prevents integration of virus DNA into the host chromosome

Question 53

Raltegravir

Answer 53

used in treatment-naive and experienced patients, safe in children Metabolized UGT1A1 and excreted in the feces and urine, taken orally Resistance is through integrase gene mutations well tolerated but adverse effects possible are myopathy and hypersensitivity reactions

Question 54

Entry Inhibitors

Answer 54

Enfuvirtide Maraviroc Ibalizumab-uiyk

Question 55

Enfuvirtide - MOA and Uses

Answer 55

Entry Inhibitors - Synthetic peptide, binds to a hydrophobic groove of the gp41 subunit SubQ; Metabolized by proteolytic hydrolysis Treatment-experienced: Adults and children ≥ 6 years old, not effective as monotherapy - needs to be given with 2 other antiretroviral drugs

Question 56

Enfuvirtide - Adverse Effects and Resistance

Answer 56

Injection site reactions; Hypersensitivity reactions, and Pneumonia resistance - mutations in the codon which binds domain gp41, increased with more changes

Question 57

Maraviroc

Answer 57

HIV Entry Inhibitor oral, variable bioavailability, CYP3A4, fecal and urine excretion Mechanism: Maraviroc blocks gp120 to CCR5 receptor resistance through changing tropism to CXCR4 Used for CCR5 HIV virus infected patients older than 16, in combination with other agents Prior to therapy, tropism testing should be performed

Question 58

Maraviroc Cautions

Answer 58

``` Adverse effects: • Dizziness; depression; paresthesias • Hepatotoxicity with allergic features • Hypersensitivity reaction • Orthostatic hypotension • Bacterial respiratory infection / Herpes ``` Drug interactions: • Strong CYP3A4 inducers and inhibitors

Question 59

Ibalizumab-uiyk

Answer 59

HIV Entry Inhibitor IV every 14 days, blocks CD4 2nd extracellular domain away from MHC2 prevents HIV attachment and entrance preserves normal immune function Used for therapeutic experienced patients