Anti-Retrovirals

Question 1

What are the two key components of antiretroviral therapy?

Answer 1

Backbone and base

Question 2

What is “backbone” therapy?

Answer 2

Normally two nucleoside reverse transcriptase inhibitors (NRTIs)

Question 3

What sort of drugs are used in “base” therapy?

Answer 3

Non-nucleoside reverse transcriptase inhibitors (NNRTIs), Protease Inhibitors (PIs), CCR5 antagonists, and integrase strand transfer inhibitors (INSTIs)

Question 4

What are the preferred regimens for drug naive patients?

Answer 4

The “backbone” of all regimens tenofovir and emtricitabine.

Potential “base” therapies:

1. Efavirenz (NNRTI)
2. Ritonavir (PI) boosted darunavir (PI)
3. Ritonavir-boosted atazanavir (PI)
4. Raltegravir (INSTI)

Question 5

What is the preferred regimen for pregnant women?

Answer 5

Ritonavir/Liponavir (PIs) + zidovudine/lamivudine (NRTIs)

Question 6

What are the primary goals of antiretroviral therapy?

Answer 6

Reduce HIV-associated morbidity
Restore and preserve immune function
Maximally reduce serum viral load
Prevent transmission

Question 7

How can resistance to antiretrovirals be minimized?

Answer 7

Combination therapies minimize the development of resistances. When resistance is acheived, there is normally cross-resistance for the drug class.

Question 8

In what patients should antiretroviral therapy be initiated?

Answer 8

1. Patients with a hx of HIV-defining illness or CD4 count below 350.
2. Consider in patients with counts between 350 and 500
3. Immediately in pregnant women, HIV-associated nephropathy, and hepatitis B coinfection.

Question 9

What is the significance of CD4+ T-cell counts?

Answer 9

These are used to determine when to initiate therapy (antiretroviral and prophylactic), and monitor response to therapy. Normally monitor for 3-4 months initially.

Also used to determine progression and immunodeficiency.

Question 10

What is the significance of HIV RNA serum testing? What is a level indicating successful treatment?

Answer 10

HIV RNA serum testing assesses the viral load and is the best indicator of the effectivity of antiretroviral therapy. Levels should be measured at baseline and regularly throughout treatment.

A decrease of 3 fold or below detection (40-75 copies/mL) indicates successful treatment. Most patients reach these levels with 1-2 years.

Question 11

How is drug resistance testing performed? In which situations is this indicated?

Answer 11

This is performed by genotypic assay of reverse transcriptase and protease genes to assess for known mutations.

Indicated when initiating therapy, therapy failure, switching therapies, and entering pregnancy.

Question 12

What drug class does tenofovir belong to? Describe its MOA. What is an important drug interaction for tenofovir and triple-NRTI therapies?

Answer 12

NRTIs - this is the only nucleotide RTI

Competitive inhibition of the reverse transcriptase. Incorporates into the DNA chain causing terminations.

Tenofovir should not be used in triple NRTI therpies which include abacavir/lamivudine or didanosine/lamivudine. Can cause virologic failure.

Question 13

What is emitracibine? What is the drug class? What are the adverse effects? What mutation confers resistance to emitracibine?

Answer 13

Emitracibine is the 5-fluoronated form of lamivudine. It is parts of the NRTIs class. Its adverse effects are limited to hyperpigmentation of the palms and soles, especially in dark-skinned patients.

Mutation M184V causes resistance to the whole class.

Question 14

What is the drug class of zidovudine? What is the important drug interaction of zidovudine? What are the adverse effects of zidovudine?

Answer 14

Drug Class - NRTIs

drug interactions - Can be combined with any NRTI except stavudine, which is antagonistic

Adverse Effects - anemia, neutropenia, constitutional symptoms, hyperpigmentation of the oral mucosa and nailbeds.

Question 15

What is the MOA of efavirenz?

Answer 15

Binds directly to the reverse transcriptase at a site separate from NRTIs and inhibits DNA polymerase activity.

Note: Resistance develops quickly when used as a monotherapy

Question 16

What are the indications and contraindications of efavirenz?

Answer 16

Use as initial therapy in drug-naive patients. Avoid in pregnancy because of embryotoxicity.

Question 17

What are the toxic effects of efavirenz?

Answer 17

CNS disturbances - insomnia, dizziness, drowsiness, headache, amnesia, delusions, etc.

Note: Psychiatric symptoms may be rare.

Can also cause Stevens-Johnson syndrome

Question 18

Describe ritnovir boosting.

Answer 18

All protease inhibitors (PIs) are metabolized and inhibit CYP3A4. Low-dose ritonavir is used to increase the concentrations of other PIs in the serum.

Question 19

Describe the MOA of protease inhibitors.

Answer 19

Gag-Pol genes encode polyprotein products which are cleaved into mature proteins by the viral protease. PIs inhibit the production of mature proteins.

Note: Not to be used as a monotherapy due to development of class resistance

Question 20

What are the adverse effects of PIs?

Answer 20

Hepatotoxicity, GI disturbances, increased bleeding in hemophiliacs, hyperglycemia, insulin resistance, hyperlipidemia, and increased risk of CAD

Question 21

What are the interactions of atazanavir and gastric pH?

Answer 21

As pH increases in the stomach the absorption of atazanavir is decreased. Proton-pump inhibitors, H2-antihistamines, and antacids can all increase gastric pH.

Question 22

What is the significant adverse effect of atanzavir?

Answer 22

Causes an asymptomatic hyperbilirubinemia, which sometimes produces jaundice.

Question 23

What are the adverse effects of darunavir?

Answer 23

All side effects associated with PIs
Can cause erythema multiforme (precursor to SJS?)
Possesses a sulfamide moiety, beware sulfa allergies

Question 24

What class is raltegravir and describe its mechanism of action?

Answer 24

Raltegravir is part of the integrase strand transfer inhibitors (InSTIs). HIV integrase inserts the viral DNA into the human genome. This enzyme is inhibited by raltegravir.

Question 25

What are the adverse effects of raltegravir?

Answer 25

Seems to be well tolerated. Most commonly cause GI disturbances and headache. In trials has been shown to cause increased creatinine kinase, myopathy, and rhabdomyolysis.

Question 26

What is the MOA and drug class of Maraviroc?

Answer 26

Maraviroc is the first CCR5 antagonist. CCR5 is used by HIV to gain entry into cells, CXCR4 is also used. This can be used to treat “R5 tropic” HIV.

Question 27

What are the adverse effects of maraviroc?

Answer 27

cough, URI, rash, and MSK symptoms

Question 28

What is enfuviritide?

Answer 28

This is a fusion inhibitor which binds to gp41 on the viral envelope. It inhibits the conformational change necessary for virion fusion with the host cell.