Antiretroviral Drugs

Question 1

What are the different stages of the HIV lifecycle where drugs can be used?

Answer 1

1. Binding of the virus to the host cell membrane- blocked by CCR5 receptor antagonists
2. Fusion and uncoating of the virus- blocked by fusion inhibitors
3. Reverse transcription- blocked by NRTIs and NNRTIs inhibitors
4. Viral DNA integration- blocked by integrase inhibitors
5. Budding and maturation of the virus- blocked by protease and maturation inhibitors

Question 2

Maximally suppressive antiretroviral therapy

Answer 2

Requires combo of at least 3 drugs

Question 3

What does a typical treatment regimen for HIV look like?

Answer 3

“Backbone” – typically 2 NRTIs

“Base” – NNRTI, protease inhibitor, integrase strand transfer inhibitor, CCR5 antagonist

Question 4

Selection Criteria for Drugs within a Class

Answer 4

Results of resistance testing (treatment-naïve vs -experienced)

Allergy history (screening for presence of HLA*5701)

Hypersensitivity to abacavir

Pregnancy status (efavirenz pregnancy category D)

Patient convenience (once-daily dosing and combo products reduce “pill burden”)

Comorbidities: hepatitis B, tuberculosis, cardiovascular disease, osteoporosis, psychiatric disorders, kidney disease

Side effect profiles

Potential drug interactions: many HAART drugs are CYP450 substrates and/or inducers- inhibitors

Question 5

Specific drug combos used

Answer 5

Backbone: 2 NRTIs
Tenofovir-Emtricitabine preferred

Base: plus

An integrase inhibitor (Dolutegravir)

or a boosted (+ ritonavir) PI combination (Atazanavir or Darunavir preferred)

or an NNRTI (Efavirenz preferred

or a CCR5 antagonist (Maraviroc)

Question 6

NRTIs- Mechanism of action

Answer 6

Nucleoside–tide Reverse Transcriptase Inhibitors (Tenofovir disoproxil fumarate, Emtricitabine)

Activation by intracellular kinases to active triphosphate (REQUIRES ACTIVATION)

Phosphorylated analogs competitively inhibit viral RT and when incorporated into viral DNA causes chain termination

Prevents genome replication and establishment of provirus

Question 7

How does HIV develop resistance to NRTIs?

Answer 7

Associated with mutations at various AA positions on RT

Cross resistance within class is common and is basis for avoiding certain NRTI combinations

Question 8

What’s important when considering NRTI plasma concentration?

Answer 8

plasma levels falling too low: risk of resistance

too high- risk of toxicity

Question 9

Which NRTIs are hepatically metabolized and which are renally excreted?

Answer 9

Know organ of elimination: avoid DDIs – dosage changes

Hepatic glucuronidation: Abacavir and Zidovudine

Renal excretion: All Others

Question 10

Adverse Drug Reactions of NRTIs

Answer 10

Class Effects:

Related to varying levels of NRTI activity against mitochondrial DNA polymerase γ: anemia, myopathy, granulocytopenia, neuropathy

Lactic acidosis – hepatic steatosis, potentially fatal

Renal impairment potential with tenofovir

Question 11

What are the two best-tolerated NRTIs?

Answer 11

Lamivudine (3TC) and emtricitabine (FTC)

Both agents are also active against HBV in co-infected patients

Question 12

What are the pros and cons of dual NRTI therapy?

Answer 12

Advantages:

Established backbone of combination therapy
Minimal drug interactions

Disadvantages:

Lactic acidosis and hepatic steatosis: highest with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC (rarely used now)

Lipodystrophy: highest with d4T

Question 13

NNRTIs- Mechanism of action

Answer 13

Non-Nucleoside Reverse Transcriptase Inhibitors (Efavirenz)

Possess variety of dissimilar structures

Do NOT require activation by intracellular kinases

Bind to NON-CATALYTIC hydrophobic region and non-competitively inhibit HIV Reverse Transcriptase

Prevents genome replication - establishment of provirus

Question 14

How does HIV develop resistance to NNRTIs?

Answer 14

Associated with single AA substitutions at various positions on RT

Developing resistance to one NNRTI confers cross-resistance to remaining class members

Newer member etravirine appears to have higher barrier to resistance

Question 15

DDIs of NNRTIs

Answer 15

All are substrates of CYP450: innumerable DDIs due to induction-inhibition of CYP450 and potential for altered levels of co-administered PIs

Efavirenz: induces CYP3A4 (decreased methadone levels)

Etravirine: induces CYP3A4 – inhibits CYP2C9-19

Nevirapine: induces CYP3A4

Question 16

Efavirenz (what is it and side effects)

Answer 16

NNRTI

Most common are rash, dizziness, headache, insomnia, impaired concentration; more severe CNS effects possible

Only anti-retroviral agent in pregnancy category D

Question 17

Emtricitabine

Answer 17

NRTI

Question 18

Tenofovir disoproxil fumarate

Answer 18

NRTI

Hard on pts with kidney disease

Question 19

Pros and cons of NNRTIs

Answer 19

Advantages:

Long half-lives
Less metabolic toxicity than PIs
PIs and INSTIs preserved for future use

Disadvantages:

Low genetic barrier to resistance - single mutation
Cross resistance among most NNRTIs
Rash, hepatotoxicity (esp. nevirapine)
Potential CYP450 drug interactions
Transmitted resistance to NNRTIs more common than resistance to PIs

Question 20

PIs- Mechanism of action

Answer 20

Protease Inhibitors (Atazanavir, Darunavir)

Noncleavable peptidomimetic agents that selectively target retroviral aspartyl proteases (not host proteases)

HIV protease cleaves and processes HIV gag and pol proteins necessary for survival and replication, thus inhibition prevents viral maturation

Question 21

How does HIV develop resistance to protease inhibitors?

Answer 21

Drug resistance to most PIs requires multiple mutations - seldom develops “boosted” PI-based regimens

Relatively high barrier to resistance compared with NNRTIs and integrase inhibitor

Question 22

Atazanavir

Answer 22

PI

dosed once daily

less adverse effects on lipid profiles; reversible jaundice; mild-moderate rash (20%)

Question 23

Darunavir

Answer 23

PI

dosed once daily

incidence of side effects similar to other PIs, but rash can be severe (S-J Syndrome)

Question 24

DDIs of PIs

Answer 24

Metabolized by CYP3A4 and innumerable DDIs occur due to inhibition of CYP3A4

Question 25

Side effects of PIs

Answer 25

Many PIs can cause GI distress, hyperglycemia, insulin resistance, hyperilipidemia and increased risk of CAD Can see peripheral lipoatrophy - central fat accumulation Hepatotoxicity more common in patients with HBV-HCV

Question 26

Pros and Cons of PIs as part of initial therapy

Answer 26

Advantages: Higher genetic barrier to resistance PI resistance uncommon even with sub-optimal adherence (boosted PI) NNRTIs and INSTIs preserved for future use Disadvantages: ``` Metabolic complications (fat maldistribution, insulin resistance, dyslipidemia) GI intolerance Potential for CYP450 drug interactions (esp. ritonavir) ```

Question 27

INSTIs- mechanism of action

Answer 27

Integrase Strand Transfer Inhibitors (Raltegravir, Dolutegravir) Viral integrase involved in processing of DNA strands and catalyzing direct insertion of viral DNA into host cell DNA Raltegravir inhibits integrase activity preventing HIV-1 replication No effect on human DNA polymerases α, β, or γ

Question 28

Dolutegravir

Answer 28

INSTI unlikely to develop resistance mutations Eliminated via phase 2 glucuronidation – levels decreased by inducers (e.g., rifampin) once daily

Question 29

Raltegravir

Answer 29

INSTI eliminated via phase 2 glucuronidation – levels decreased by inducers (e.g., rifampin) Twice daily

Question 30

HIV resistance to INSTIs?

Answer 30

Raltegravir and elvitegravir have low genetic barrier Dolutegravir unlikely to develop resistance mutations: high barrier

Question 31

Adverse Drug Reactions of INSTIs

Answer 31

Generally well tolerated Diarrhea, nausea, headache

Question 32

Pros and cons of INSTIs as part of initial HIV therapy

Answer 32

Advantages: Neutral effects on triglycerides and cholesterol High barrier for resistance with dolutegravir Fewer adverse events than efavirenz Fewer drug interactions than with NNRTIs or PIs NNRTIs and PIs preserved for future use Disadvantages: Twice daily dosing (once a day for dolutegravir) Lower genetic barrier to resistance than PIs (RAL-EVG) Myopathy, rhabdomyolysis, and skin reactions reported but rare

Question 33

Maraviroc

Answer 33

Entry Inhibitor HIV-1 virions using CCR5 called “R5 tropic”, present during initial and chronic phases HIV-1 virions using CXCR4 called “X4 tropic”, associated with later stages and disease progression Maraviroc is small molecule antagonist of CCR5 receptor that inhibits its interaction with viral gp120 Indicated for treatment experienced adults with R5-tropic virus (assay to determine R5, X4, or dual tropism) Dosed twice daily Substrate of CYP3A4 – DDIs possible with strong CYP3A4 inducers or inhibitors (e.g., NNRTIs or DDIs)

Question 34

Resistance to maraviroc

Answer 34

Has been observed, esp. when X4 strains are present; also associated with mutations in viral gp120

Question 35

Adverse rxn to maraviroc

Answer 35

Generally well tolerated, mild effects include cough, fever, URI, dizziness, abdominal pain Hepatotoxicity possible with higher doses

Question 36

Pros and cons of maraviroc in initial HIV therapy

Answer 36

Advantages: Virologic response noninferior to efavirenz Fewer adverse events than efavirenz NNRTIs, PIs, and IIs preserved for future use Disadvantages: Requires tropism testing before use (CCR5 vs CXCR4) Twice daily dosing Less experience than with PI- or NNRTI-based ART - limited data with NRTIs other than ZDV-3TC CYP3A4 substrate - dosage adjustment required with concomitant inducers or inhibitors

Question 37

Enfuvirtide

Answer 37

Fusion Inhibitor Enfuvirtide is a synthetic peptidomimetic of the viral gp41 HR2 sequences Binds to HR1 sequences - unavailable for hemiperfusion stalk Prevention of viral entry into cell and infection MUST BE ADMINISTERED SUBCUTANEOUSLY

Question 38

Resistance to enfuvirtide

Answer 38

Reported to result from mutations in gp41 binding regions

Question 39

DDIs with enfuvirtide

Answer 39

Eliminated by proteolytic hydrolysis – no CYP involvement, thus NO potential for DDIs

Question 40

Adverse Drug Reactions of Enfuvirtide

Answer 40

Injection site reactions occur in almost all patients Eosinophilia Hypersensitivity reactions Increase in bacterial pneumonia

Question 41

"FOVIR"

Answer 41

nucleotides