Antiretroviral Questions Flashcards
What was the first antiretroviral available in the mid-1980s?
Zidovudine
What are challenges with complex antiretroviral drug regimens?
- adherence
- resistance
- toxicities
- interactions
What are NRTIs?
Nucleoside reverse transcriptase inhibitors
- oldest class of antiretrovirals
- a combination of two of these typically forms the backbone of most anti-HIV regimens
What is Tenofovir disoproxil fumarate / Tenofovir alafenamide?
NRTI
- TDF
- TAF
- technically a nucleotide but grouped with these agents
What is Emtricitabine?
NRTI
-FTC
What is Lamivudine?
NRTI
-3TC
What is Abacavir?
NRTI
-ABC
What is zidovudine?
NRTI
-ZDV, AZT
What is stavudine?
NRTI
-d4T
What is didanosine?
NRTI
-ddI
What is in Truvada?
- Emtricitabine
- TDF
What is in Epzicom?
- Abacavir
- Lamivudine
What is in descovy?
- emtricitabine
- TAF
What is in combivir?
- lamivudine
- zidovudine
What is in trizivir?
- abacavir
- lamivudine
- zidovudine
What is the MOA of NRTIs?
Inhibit the action of the virally encoded protein reverse transcriptase
- take the place of nucleotides in the elongating strand of viral DNA
- leads to early termination of the viral DNA strain
Which NRTIs have clinically useful activity against hepatitis B virus?
- tenofovir
- emtricitabine
- lamivudine
Which NRTIs that are most problematic from a toxicity perspective are uncommonly used now?
- didanosine
- stavudine
- zidovudine
What are the categories of adverse effects of NRTIs?
- extremities
- GI
- hematologic
- hypersensitivity
- metabolic
- renal
Describe NRTI extremity adverse effects.
Peripheral neuropathy
- delayed, slowly progressive adverse effect
- didanosine
- stavudine
- especially in combination
Describe NRTI GI adverse effects.
Less GI toxicity than many antiretrovirals
- nausea
- vomiting
- diarrhea
- zidovudine
- didanosine
Describe NRTI hematologic adverse effects.
Bone marrow suppression
- anemia
- neutropenia
- zidovudine (frequently)
- rarely with other NRTIs
Which NRTI is associated with a hypersensitivity reaction in a minority of patients?
Abacavir
- fever
- rash
- flu-like symptoms
- days to weeks after starting therapy
- continuation or rechallenge can be fatal
Presence of which allele is predictive of abacavir hypersensitivity toxicity in a genotype screening?
HLA-B*:5701 allele
- routine screening recommended before starting therapy
- if positive test: do not offer abacavir
Describe NRTI metabolic adverse effects.
Complex of toxicities suspected to be of mitochondrial origin
- lactic acidosis
- hepatic steatosis
- pancreatitis
When do NRTI metabolic effects show up?
- symptoms typically delayed (for months) in onset
- may be nonspecific in initial presentation
- mortality can be high if symptoms not recognized early
Which NRTIs have a higher propensity for metabolic effects?
- stavudine
- didanosine
- zidovudine
What other metabolic effects may didanosine and zidovudine contribute to?
- hyperlipidemia
- insulin resistance
- lipoatrophy
Describe lipoatrophy.
Loss of fat causing changes in appearance, primarily in the:
- face
- buttocks
Which NRTI is associated with nephrotoxicity?
Tenofovir
- increased serum creatinine
- renal electrolyte and protein wasting
Which formulation of tenofovir appears to confer less risk of nephrotoxicity?
TAF
- new formulation
- less commonly used alone or in combination pills compared to TDF
What adverse effects does didanosine cause?
- extremities
- GI
- metabolic
- other metabolic
What adverse effects does stavudine cause?
- extremities
- metabolic
What adverse effects does zidovudine cause?
- GI
- hematologic
- metabolic
- other metabolic
Do NRTIs require dose adjustment in renal dysfunction?
Yes, most do
-may need to avoid the fixed dose combinations
How do NRTI drug interactions compare with other antiretroviral classes?
Fewer metabolic drug interactions
What two NRTIs should not be coadministered together?
- tenofovir with didanosine
- tenofovir with atazanavir (may require dosage adjustment of atazanavir)
Describe NRTI resistance.
Various patterns of cross-resistance occur
- expert interpretation of susceptibility required
- NRTIs may confer a therapeutic benefit even for resistant viruses in some cases
How do the two formulations of tenofovir differ in dosing?
Newer TAF has much lower dose than TDF
What does typical treatment for treatment-naïve HIV patients involve?
-two NRTIs
+
-drug from another class
What does typical treatment for treatment-experienced HIV patients involve?
3 or more NRTIs as part of a salvage regimen
What should one look for when reviewing an HIV regimen?
Patient should be on two NRTIs or something is weird
What are the NNRTIs?
Non-nucleoside reverse transcriptase inhibitors
- inhibit the same enzyme as NRTIs but:
- work through a different mechanism
- have greatly different pharmacologic properties
What is Efavirenz?
- EFV
- NNRTI
What is etravirine?
- ETR
- NNRTI
What is rilpivirine?
- RPV
- NNRTI
What is nevirapine?
- NVP
- NNRTI
What is in Atripla?
- efavirenz
- tenofovir
- emtricitabine
What is in complera?
- rilpivirine
- tenofovir
- emtricitabine
What is the MOA of NNRTIs?
Bind to a different part of the reverse transcriptase enzyme compared to NRTIs (do not pretend to be regular nucleosides)
- causes a change in the conformation of the enzyme
- interferes with its ability to form the viral DNA chain
Are NNRTIs used for any other viral infections besides HIV?
No
-only HIV
What are the categories of adverse effects of NNRTIs?
- CNS
- dermatologic
- hepatotoxicity
- hypersensitivity
- metabolic
- pregnancy/lactation
Which NNRTI can cause a broad spectrum of adverse effects?
Efavirenz
What are common efavirenz CNS effects?
- dizziness
- drowsiness (or sometimes insomnia)
- abnormal (especially vivid) dreams
What are LESS common efavirenz CNS effects?
- depression
- psychosis
- suicidal ideation
What is the time frame of efavirenz CNS effects?
- onset usually very rapid (with first few doses)
- often subsides after several weeks of therapy
How can efavirenz CNS effects be minimized?
Taking the drug:
- on an empty stomach
- at bedtime or 2-3 hours before
What is a relative contraindication to the use of efavirenz?
History of:
- mental illness
- depression
Describe NNRTI dermatologic effects.
Rashes
-mild forms can be treated with antihistamines
What NNRTI dermatologic effect represents an absolute contraindication to rechallenge?
Lesions involving mucous membranes SJS or similar eruptions
-must be managed urgently
Which NNRTI appears to have the highest likelihood of causing a dermatologic reaction?
Nevirapine
Describe NNRTI hepatotoxicity.
Spectrum of hepatotoxicity
- asymptomatic transaminase elevations
- clinical hepatitis
- fulminant hepatic failure
What needs to be monitored for to watch for NNRTI hepatotoxicity?
- signs/symptoms of hepatitis
- liver enzymes
What NNRTI may cause hepatotoxicity in the context of a hypersensitivity reaction?
Nevirapine
Describe nevirapine-induced hypersensitivity reactions.
- flu-like symptoms
- fever
- jaundice
- abdominal pain
- with or without a rash
What are the most feared manifestations of nevirapine hypersensitivity reactions?
- fulminant hepatic failure
- severe rash (ex: toxic epidermal necrolysis)
In what patients is nevirapine hypersensitivity syndrome more frequent when starting therapy?
Patients who are less immunocompromised
-have higher CD4 counts
How can the risk of nevirapine hypersensitivity syndrome be reduced?
Use reverse taper upon initiation
- start with lower dose
- escalate to full dose over 2 weeks (when risk is highest)
Describe NNRTI metabolic effects.
Lipohypertrophy
- gradual accumulation of fat in the:
- abdomen
- chest
- neck (buffalo hump)
What metabolic effects are efavirenz and nevirapine associated with?
Hyperlipidemia
With regards to metabolic effects, how does rilpivirine compare to efavirenz?
Rilpivirine showed less of an effect on lipid profiles
What pregnancy category is efavirenz?
Category D
-should not be offered to pregnant women
or
-those trying to conceive
or
-not using effective birth control
What pregnancy category is rilpivirine?
Category B
What pregnancy category are other NNRTIs besides efavirenz and rilpivirine?
Category C
What adverse effects is efavirenz specifically associated with?
- CNS
- hyperlipidemia
- category D
What is a key limitation of NNRTIs?
Low genetic barrier to resistance
- single point mutation can lead to high level resistance to the entire class
- even stricter adherence is necessary
What are the advanced generation NNRTIs?
- etravirine
- rilpivirine
- possess activity against viruses with some NNRTI mutations
- may have roles for patients who have failed either efavirenz or nevirapine
How does the drug interaction profile of NNRTIs compare to NRTIs?
- much broader profile
- concentrations of NNRTIs can themselves be affected by inhibitors or inducers of drug metabolizing enzymes
What is the drug interaction profile of nevirapine?
Inducer
What is the drug interaction profile of efavirenz and etravirine?
Mixed inducing and inhibitory properties
What is the drug interaction profile of rilpivirine?
-does not yet appear to have significant effects on metabolism of other drugs
What is a recommended alternative regimen for initial treatment of treatment-naïve patients with HIV?
Atripla
- efavirenz
- tenofovir
- emtricitabine
- first one pill, once daily HIV regimen
Why WAS Atripla a preferred initial regimen?
New integrase strand transfer agents also offer this option now
- lesser degree of toxicity
- possibly lower genetic barrier to resistance
What are other NNRTIs (besides efavirenz) used for?
2nd line therapy in treatment-experienced patients
What must patients be counseled on when starting an NNRTI?
- adverse effects (skin reactions; symptoms of hepatotoxicity)
- strict adherence to prevent resistance
- dose titration schedule for nevirapine
- CNS effects of efavirenz
What are PIs?
Protease inhibitors
- now entering 3rd generation
- more potent agents with fewer acute toxicities
- long term toxicities are arising
What is HAART?
Highly active antiretroviral therapy
- began with combination regimens that included PIs
- have had a major impact on prolonging lifespan among HIV patients
What is boosting?
Using potent inhibition of ritonavir or the PK booster cobicistat to increase serum concentrations and half lives of other PIs
-now routine for essentially all PIs
How does boosting work?
-take an additional pill of a low dose of ritonavir with their PI (/r)
or
-co-formulation with cobicistat (/c) or ritonavir (/r)
What is Atazanavir?
PI
-ATV
What is Darunavir?
PI
-DRV
What is Ritonavir (boosting dose)?
PI
-/r
What is fosamprenavir?
PI
-FPV
What is saquinavir?
PI
-SQV
What is indinavir?
PI
-IDV
What is nelfinavir?
PI
-NFV
What is tipranavir?
PI
-TPV
What is ritonavir (full dose)?
PI
-RTV
What is in Prezcobix?
- darunavir
- cobicistat
- DRV/c
What is in Evotaz?
- atazanavir
- cobicistat
- ATV/c
What is in kaletra?
- lopinavir
- ritonavir
- LPV/r
What does the viral enzyme HIV protease do?
Hijacked HIV infected cell uses the cell’s ribosomes to synthesize its own proteins
- some are created in long chains that need to be cut up into their component parts to work correctly
- protease enzymes are like a pair of scissors that cut out prefabricated shapes from a piece of cardboard paper
What is the MOA of PIs?
Selectively inhibit HIV protease
Are PIs active against HIV also active against Hepatitis C virus?
No; those PIs are different drugs
What are the categories of adverse effects of PIs?
- cardiovascular
- GI
- hepatotoxicity
- metabolic
- nephrotoxicity
Describe PI cardiovascular effects.
Interact with conventional CV risks factors to increase risk for MI and stroke beyond that expected from just prolonging lifespan
How are PI CV risks managed?
With all the mainstays of CV risk prevention
- diet
- exercise
- drugs
Which PIs may confer somewhat LOWER CV risk compared with other PIs?
- atazanavir
- darunavir
Describe PI GI effects.
Pretty hard on the GI tract
- nausea
- vomiting
- diarrhea
How can PI GI effects be reduced?
- taking with food may reduce symptoms somewhat
- many find the effects more tolerable with time
How are severe cases of PI GI effects managed?
Administration with
- antiemetics
- antidiarrheals
Describe PI hepatotoxicity.
Ranges from
-asymptomatic transaminase elevations
to
-clinical hepatitis
Which PI may have the highest risk of hepatotoxicity?
Boosted tipranavir
Describe PI metabolic effects.
- adverse effects on the lipid profile (one way in which CV risk is increased)
- lipodystrophy: fat accumulation in
- abdomen
- breasts
- neck
Describe PI nephrotoxicity.
Certain PIs cause precipitation in the kidneys or ureters
Which PI most commonly associated with nephrotoxicity?
Indinavir
-now infrequently used
Which PIs is nephrotoxicity rarely reported with?
- atazanavir
- fosamprenavir
What strategy is recommended to prevent PI nephrotoxicity?
Adequate fluid intake
How are PIs against resistance compared to NNRTIs and INSTIs?
More robust
- several mutations in the target enzyme required to confer high level resistance
- PI based regimens may be slightly more forgiving of less than perfect adherence
What is the drug interaction profile of PIs?
-all are susbtrates of the common drug metabolizing enzymes
What drugs can PI regimens boosted with ritonavir or cobicistat affect?
Drugs that are P450 substrates
- statins
- macrolides
- benzodiazepines
- calcium channel blockers
- etc
- can lead to increased levels
- also more unpredictable effects can occur (result of shunting to alternative pathways or mixed inhibition/induction): voriconazole-ritonavir interaction can lead to reduction of voriconazole
How is ritonavir now usually always used?
As a PK booster
-much lower dose than originally approved
What is ritonavir’s originally approved dose?
400mg BID
- not well tolerated at this dose
- majority of prescriptions for it are in error
Which PI-based regimen is preferred for treatment of initial HIV infection?
Darunavir-based combinations
Which PI-based regimens are alternatives for treatment of initial HIV infection?
Regimens with
-atazanavir
or
-lopinavir
Which PI is the only one that can be used unboosted?
Only atazanavir (only for selected patients)
-other regimens should have at least some ritonavir or cobicistat
What factors need to be taken into consideration when prescribing a PI?
Balance the
-durable viral suppression
against
- long term toxicities (particularly CV effects)
- patients should be prepared to make appropriate lifestyle changes
What are the INSTIs?
Integrase inhibitors (integrase strand transfer inhibitors)
-are the anchor of most of the preferred regimens for initial therapy
What are the benefits of INSTIs?
- excellent tolerability
- fewer drug interactions (except elvitegravir)
- one pill once daily convenience (except raltegravir)
- novel MOA provides new option for treatment experienced patients
What is Dolutegravir?
INSTI
-DTG
What is Raltegravir?
INSTI
-RAL
What is in stribild?
- elvitegravir
- cobicistat
- emtricitabine
- TDF
What is in genvoya?
- elvitegravir
- cobicistat
- emtricitabine
- TAF
What is in triumeq?
- dolutegravir
- abacavir
- lamivudine
What does the viral protein integrase do?
HIV reverse transcriptase creates a strand of viral DNA
-integrase facilitates the transfer of the HIV DNA into the host cell’s genome
What is the MOA of INSTIs?
Inhibit integrase
- prevents the viral DNA from becoming a part of the host cell genome
- this is an important step in HIV replication
Are INSTIs used for any other viral infection besides HIV?
No
-only HIV
Which INSTI has been associated with musculoskeletal adverse effects?
Raltegravir
- increases in creatine phosphokinase
- most cases have been asymptomatic
- clinically evident myositis or rhabdomyolysis is rare
What kind of renal dysfunction does cobicistat cause?
Fake
- inhibits renal secretion of creatinine
- leads to increased levels of serum creatinine without a decline in GFR
- must differentiate between true renal dysfunction caused by tenofovir
Is cobicistat an antiviral?
No
- is a PK enhancer
- used to boost concentrations of other drugs
Is elvitegravir available alone?
No, only with
-cobicistat
and
-tenofovir
and
-emtricitabine
Has concerns for drug interactions (similar to ritonavir boosted regimens)
What is the drug interaction profile of raltegravir?
Few documented drug interactions
What is the drug interaction profile of dolutegravir?
More on the raltegravir end of the spectrum
-should still check for interactions (as with all antiretrovirals)
What OTC interaction do INSTIs have?
Reduced absorption when given with divalent and trivalent cations (as with FQ and tetracyclines)
- give at least 2 hours before or 6 hours after oral administration of products containing
- aluminum
- magnesium
- calcium
- iron
- zinc
Describe the genetic barrier of resistance to INSTIs.
- relatively low barrier
- less forgiving of imperfect adherence than a PI based regimen
Which form of tenofovir is elvitegravir available with?
Both TDF and TAF
What is an important factor to monitor when giving an INSTI?
Interactions
-a drug that decreases its concentration can put it at risk for development of resistance due to low level of resistance
Which class of antiretrovirals has rocketed to the top of the preferred list of antiretrovirals?
INSTIs
-have many favorable characteristics
What is Maraviroc?
Entry inhibitor
-MVC
What is enfuviritide?
Fusion inhibitor
-T20
How are entry and fusion inhibitors different from other classes of antiretrovirals?
- other classes affect the HIV life cycle after infection of the cell
- these classes attempt to block HIV from infecting the cell
What does the process of HIV binding to and entering a cell involve?
A handshake between viral proteins and proteins on the host cell target
What does the MOA of maraviroc involve?
Targets a human protein that serves as a coreceptor for the virus
What human protein does maraviroc target?
CCR5
What does the MOA of enfuviritide involve?
Binds to a viral protein involved in fusion
Are the entry and fusion inhibitors active against any viral infections besides HIV?
No
-only HIV
What are the dermatologic effects of enfuviritide?
Is a subcutaneous injection; causes injection site reactions
- occur in essentially all patients
- pain
- erythema
- pruritis
- nodule formation
What does maraviroc have a black box warning for?
Hepatotoxicity
- based on case reports from healthy subjects who received the drug in early clinical trials
- seems to be rare in patients treated with maraviroc
For what infections is enfuviritide reserved for?
Most difficult to treat, multidrug resistant strains
-administered as SC injection associated with substantial injection site reactions
What test must be used before starting maraviroc?
Tropism test
- to see whether the virus prefers CCR5 (maraviroc-yes) or CXCR4 (maraviroc-no)
- there are two coreceptors for HIV viral entry
Is maraviroc affected by CYP enzymes?
Yes
- is a substrate for P450 drug metabolizing enzymes
- different dosage recommendations depending on which other potentially interacting drugs patient is taking
When are entry and fusion inhibitors mainly used?
In treatment experienced patients
