Entry inhibitor approved for patients with CCR5-tropic HIV; it is used as 2nd-line or salvage therapy. Its bioavailability is decreased by food.
Maraviroc
NRTI main drug interaction:
NRTIs require an acidic gastric environment to be absorbed. ?���?���?���?��? (omeprazole, ketoconazole) will raise the pH in the stomach, preventing adequate absorption of NRTIs.
Which NRTI is hepatically eliminated?
Abacavir
Which NNRTI must be taken on an EMPTY STOMACH in order to be adequately absorbed?
Efavirenz
Which 2 NNRTIs must be taken WITH FOOD in order to be adequately absorbed?
Etravirine - take with food
Rilpivirine - take with LARGEST MEAL
Which NNRTI is contraindicated with PPIs, due to the fact that they raise gastric pH and thus decrease absorption of the NNRTI?
Rilpivirine
Which PI is contraindicated with PPIs, due to the fact that they raise gastric pH and thus decrease absorption of the PI?
Atazanavir
In addition to being INHIBITORS of CYP3A4, all PIs are also inhibitors of what?
P-glycoprotein
Which PI is also an inhibitor of CYP2D6?
Ritonavir
Which 2 PIs are also inhibitors of OATP?
#NAME?
The metabolism of these types of medications will be decreased when taken in combination with PIs, leading to increased serum concentrations and toxicities such as myopathy and rhabdomyolysis:
Statins!
(max atorvastatin should be 20mg)
The metabolism of these types of medications will be decreased when taken in combination with PIs, leading to increased serum concentrations and toxicities such as bradykinesia, tremor, and stooped posture:
Antipsychotics (aripiprazole, quetiapine)
The metabolism of these 2 types of medications will be decreased when taken in combination with PIs, leading to increased serum concentrations and toxicities such as increased bleeding risk:
Antiplatelets (clopidogrel) and anticoagulants (rivaroxaban)
Other drugs whose metabolism will be decreased when taken in combination with PIs, leading to increased serum concentrations and toxicities:
#NAME?
The metabolism of this medication will be decreased when taken in combination with PIs, leading to increased serum concentrations and toxicities such as adverse CNS effects and Cushing's syndrome:
Fluticasone (OTC!)
The metabolism of this medication will be decreased when taken in combination with PIs, leading to increased serum concentrations and toxicities such as increased risk of arrhythmias:
Dronedarone
The metabolism of these 2 medications will be decreased when taken in combination with PIs, leading to increased serum concentrations and toxicities such as bradycardia and hyperkalemia:
Ivabradine, eplerenone
The metabolism of these 2 medications will be decreased when taken in combination with PIs, leading to increased serum concentrations and toxicities such as increased QTc interval prolongation:
Ranolazine, salmeterol
The metabolism of these 3 medications will be decreased when taken in combination with PIs, leading to increased serum concentrations and toxicities such as excessive sedation, confusion, and respiratory depression:
Lurasidone, midazolam, triazolam
The metabolism of this medication will be decreased when taken in combination with PIs, leading to increased serum concentrations and toxicities such as increased drowsiness and decreased coordination & cognitive ability:
Lunesta (max 1mg)
What 5 drugs can increase the metabolism of PIs, leading to subtherapeutic concentrations and increased risk of resistance developing?
- Carbamazepine
- Phenobarbital
- Phenytoin
- Rifampin
- St. John's Wort
Which HIV drugs require renal dosage adjustments?
#NAME?
INSTI main drug interaction:
?���?��??��??��??��??���?��??���?��??��? ?���?���?��??��??��??��??��? (calcium supplements, antacids) will prevent adequate absorption of INSTIs in the stomach.
What can we do when a patient is taking both an INSTI and a form of polyvalent cation?
?���?���?��??���?���?��� 1:
Take the INSTI either 2 hours before, or 6 hours after the polyvalent cation
?���?���?��??���?���?��� 2:
Take the INSTI and the polyvalent cation at the same time, WITH FOOD
Dolutegravir inhibits which 2 renal transporters?
OCT2 & MATE
Which two drugs are dependent on OCT2 & MATE for elimination, and thus cannot be adequately eliminated when a patient is taking dolutegravir? Which one is absolutely C/I?
- Dofetilide: C/I
- Metformin: max 1000mg daily
Which HIV drug class has the fewest drug-drug interactions?
INSTIs
Which is the only HIV drug that must be taken on an empty stomach?
Efavirenz (?���?���?���?���?��?)
Which HIV drugs must be taken with food?
?���?���?���?��??���: none
?���?���?���?���?��??���:
- Etravirine
- Rilpivirine (take w largest meal)
?���?��??���:
- All
?��??���?���?���?��??���:
- Elvitegravir
T/F: HIV has the largest genome of almost all viruses.
FALSE; HIV has the SMALLEST genome of almost all viruses.
The only natural hosts of the HIV virus are:
Humans & primates
HIV is a lentivirus. What does this mean?
It establishes chronic, persistent infection with GRADUAL onset of symptoms (years)
Why is reverse transcriptase the target of HIV in the host cell?
Reverse transcriptase is a "promiscuous" enzyme that makes a lot of mistakes when copying viral RNA into cDNA. The virus will become rapidly mutated, giving it ability to escape drug therapy. This is why we do not have an HIV vaccine.
HIV can only bind to CD4 receptors, which are only present on which human cells?
Helper T-cells and macrophages
HIV binding to CD4 on helper T-cells and macrophages requires a respective co-receptor for each. What are they?
Helper T-cells: CD4 + CXCR4
Macrophages: CD4 + CCR5
Steps of HIV life cycle in the human body (5):
1) Virus binds to CD4 receptor on host cell membrane, activating the cell
2) Virus fuses with host cell membrane & releases viral RNA into cytoplasm
3) Viral RNA is reverse-transcribed into cDNA via VIRAL REVERSE TRANSCRIPTASE
4) Viral cDNA is integrated into the host cell genome
4) Replication & mutation of host genome containing viral cDNA
5) Assembly & release of viral components
Enzyme unique to retroviruses that is absolutely essential for viral replication:
Viral reverse transcriptase
The outer shell glycoproteins encoded for by the env gene are first synthesized as polyproteins. These polyproteins are then spliced into individual enzymes by what enzyme?
Human cellular protease
The inner-core proteins encoded for by the gag-pol gene are first synthesized as polyproteins. These polyproteins are then spliced into individual enzymes by what enzyme?
HIV protease
HIV-1 vs. HIV-2: Which is more closely related to simian immunodeficiency virus (SIV) and only really seen in West Africa?
HIV-2
HIV-1 vs. HIV-2: Which is less likely to cause AIDS?
HIV-2
HIV-1 vs. HIV-2: Which is prevalent worldwide?
HIV-1
HIV transmission routes:
#NAME?
Can HIV be transmitted from mother to child during pregnancy?
YES
HIV infection rates are higher in what races?
#NAME?
Prime test for INITIAL HIV diagnosis:
HIV serum antibody test (ELISA)
How long after infection does the patient develop antibodies to HIV En or Gag-pol proteins?
~3 weeks after infection - antibodies form
What generation of HIV serology tests do we use for HIV diagnosis today? Why?
4th generation - this test can detect HIV antibodies within 2 WEEKS
4th generation antibody tests can detect HIV antibodies within 2 weeks. Which antibodies does it detect this early? Which ones can only be detected later on?
4th generation tests can detect the p24 antigen at 2 weeks. 1st generation tests could only detect IgG, which is formed 6 weeks after infection.
Most RAPID serology tests are which generation? Which antibodies do they detect?
3rd generation - they detect the HIV-1 and HIV-2 antibodies
Test used to confirm a positive HIV serology test:
Western Blot
Test to determine an HIV patient's stage of progression:
CD4 cell counts
Test to determine the efficacy of therapy:
RNA viral load via RT-PCR (will be low if therapy is effective)
T/F: An HIV-positive person receiving therapy may never develop AIDS.
TRUE
Goal of HIV therapy:
Suppress viral replication as much as possible for as long as possible
To prevent mutation, we must always use how many HIV drugs in combination?
3 HIV drugs in combination (HAART)
T/F: Treatment (1 combo drug once daily) decreases the likelihood of HIV transmission from person to person.
TRUE
Who needs to be screened for HIV?
- All patients aged 13-64 at least once
- All pregnant patients (2x)
- MSM, sex workers, those with multiple partners, partners of HIV patients, and IVDUs need to be screened YEARLY
This might occur 2-4 weeks after HIV infection. Symptoms are similar to the flu/mono (fever, headache, sore throat, muscle aches, enlarged lymph nodes). Symptoms will resolve on their own.
Acute HIV Syndrome
Other symptoms of Acute HIV Syndrome:
#NAME?
A man with symptoms characteristic of Acute HIV Syndrome has a negative HIV antibody test result at the hospital. What is the best course of action?
Perform an HIV viral load! If you have every reason to believe the patient has HIV, but the Ab test is negative, do a viral load test.
Once a person's HIV infection progresses to the chronic stage, what symptoms do they usually experience?
#NAME?
After years of chronic HIV infection, a patient may develop AIDS. How do we define AIDS?
?���?���?��� ?���?��??��??��??��? < ?���?���?��� ?��??��? < ?���?���%
OR
?���?��??���?��??���?��??���?��� ?��??��� ?��??��??��� ?��??��� ?��??��??��� ?���?��??��??��??��??��??��??��??���:
- Cryptococcosis
- CMV
- Candidiasis (esophageal)
- Chronic HSV ulcers
- Histoplasmosis/toxoplasmosis
- PCP/PJP pneumonia
- MAC infection
- Kaposi sarcoma
- T-cell lymphoma
T/F: the presence of herpes lesions is a risk factor for HIV.
TRUE - spreads easily through blood/sexual fluids
5 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
1) Zidovudine
2) Abacavir
3) Lamivudine
4) Emtricitabine
5) TDF/TAF
The first anti-HIV medication approved; it is also still used to prevent HIV transmission to newborns.
Zidovudine
Which 2 NRTIs are analogues of cytidine, mimicking it in order to be incorporated into viral cDNA?
Lamivudine & emtricitabine
Which NRTI is an analogue of adenosine, mimicking it in order to be incorporated into viral cDNA?
TDF
Which NRTI is an analogue of guanosine, mimicking it in order to be incorporated into viral cDNA?
Abacavir
MOA of NRTIs:
?���?���?���?���?��� ?���?���?���?���?���?���?���?���?���?���?���
1) The drug is phosphorylated by human cellular enzymes, which converts it into a chain terminator with HIGH affinity for viral reverse transcriptase (RT).
2) Via viral RT, the drug is randomly incorporated into viral cNDA. Nothing else can bind after the drug is incorporated, so the rest of the cDNA cannot be made.
What must occur in order for the NRTI to be activated?
PHOSPHORYLATION BY HOST CELLULAR ENZYMES
What is significant about TDF/TAF that sets them apart from the other NRTIs?
Tenofovir is nucleoTIDE, not a nucleoSIDE
Which tenofovir formulation was developed FIRST? It is an ester pro-drug, which must be activated by cleavage of its 2 ester bonds via the esterase enzyme.
TDF
How is TAF different from TDF?
TAF is 1000-fold more potent and has lower incidence of renal & bone adverse effects, because it enters cells to a much greater degree than TDF does. The majority of TDF will remain in the plasma rather than entering cells, so it is less potent.
Which NRTI do we no longer prescribe due to its inhibition of mitochondrial DNA polymerases, leading to off-target toxicities such as macrocytic anemia, myopathy, and lipoatrophy?
Zidovudine
T/F: The appearance of a person with lipoatrophy will not revert back to its before-treatment state.
TRUE
Which 3 NRTIs are also active against HBV?
#NAME?
Which NRTI has the longest half-life, so that it doesn't have to be dosed as frequently?
TDF/TAF
HIV is more likely to rapidly develop resistance against which 2 NRTIs?
Lamivudine & emtricitabine (because they are both cytidine analogues)
NRTI that can cause hyperpigmentation of the palms and soles of the feet.
Emtricitabine
NRTI that can cause increased risk of MI:
Abacavir
NRTI that can cause decreased BONE MINERAL DENSITY, increased SCr, proteinuria, glucosuria, and hypokalemia:
TDF (do not give to patient with osteoporosis!)
5-7% of patients taking this NRTI will experience a hypersensitivity reaction, characterized by rash, fever, N/V/D, fatigue, myalgia, sore throat, cough, and/or SOB.
Abacavir
Since abacavir can have a higher risk of hypersensitivity, what test should be performed BEFORE prescribing this therapy? What does a positive result indicate?
HLA-B*5701 test ?�? positive result means that the patient is likely to experience hypersensitivity to abacavir
What do we do if a patient on abacavir begins to experience a hypersensitivity reaction?
STOP taking the drug and contact physician immediately. DO NOT RECHALLENGE.
4 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
1?���?��? ?���?���?���?���?���?���?��??���?���?���
- Efavirenz
2?���?��� ?���?���?���?���?���?���?��??���?���?���
- Etravirine
- Rilpivirine
- Doravirine
MOA of NNRTIs:
?���?���?���?���?���?���?���?���?���?��� ?���?���?���?���?���?���?���?���?���?���
The drug binds to the ALLOSTERIC site of the viral reverse transcriptase. This causes it to change conformation and become ineffective. Viral RNA is unable to be incorporated into cDNA.
What is the main difference between the 1st and the 2nd generation NNRTIs?
1st generation (efavirenz) is more prone to RESISTANCE and side effects.
T/F: Cross-resistance is common between the NRTI class and the NNRTI class.
FALSE - if HIV is resistant to one RTI, it will usually be sensitive to the other class!
How are the NNRTIs metabolized?
Hepatic metabolism
Adverse effects of 1st generation NNRTIs (efavirenz):
#NAME?
Adverse effects of 2nd generation NNRTIs:
#NAME?
Which NNRTI can cause depression in rare instances?
Rilpivirine
For pregnant patients, which NNRTI can only be taken AFTER the first 8 weeks of gestation to prevent the risk of congenital abnormalities?
Efavirenz
Which NNRTIs are CYP3A4 inducers?
Efavirenz & etravirine
T/F: NNRTIs are active against both HIV-1 and HIV-2.
FALSE - NNRTIs are NOT active against HIV-2
Which HIV drug class was directly attributable to the sharp drop in AIDS deaths in 1995?
Protease inhibitors
3 HIV Protease Inhibitors (PIs):
1?���?��? ?���?���?���?���?���?���?��??���?���?���
- Ritonavir
- Atazanavir
2?���?��� ?���?���?���?���?���?���?��??���?���?���
- Darunavir
MOA of PIs:
The drug binds to the ACTIVE site of the viral protease enzyme. It competes with the other substrates, preventing them from activating the protease enzyme. This inhibits protease from cleaving smaller viral enzymes from large gag-pol proteins.
Describe the adverse off-target effects of 1st generation PIs.
By inhibiting protease, these drugs may also inadvertently inhibit glucose transporters, as well as cholesterol metabolism. This can lead to lipodystrophy syndrome and insulin resistance.
Which PI generation has more GI side effects?
1st generation (take with food!)
Though it is no longer used as a PI, what is significant about ritonavir?
It is a strong CYP3A4 inhibitor, so it is used as a pharmacokinetic enhancer in combination with other antiretrovirals that are substrates for CYP3A4. It delays the metabolism of the other drugs so that they can work for longer against the virus.
It still has some protease activity, so it does have some adverse effects due to that. Cobicistat, a PK enhancer with NO protease activity, was derived from ritonavir and has fewer side effects.
ADRs of ritonavir:
#NAME?
ADRs of atazanavir:
#NAME?
ADRs of darunavir:
#NAME?
4 Integrase Strand Transfer Inhibitors (INSTIs):
#NAME?
MOA of INSTIs:
The drug binds to the HIV integrase enzyme, preventing the formation of the covalent bond between viral and host DNA (strand transfer). It binds by attaching to Mg2+ in the active site of the integrase enzyme.
Which INSTI is preferred for pregnancy?
Raltegravir
T/F: INSTIs are active against both HIV-1 and HIV-2.
TRUE
Raltegravir side effects:
#NAME?
Elvitegravir side effects:
#NAME?
Dolutegravir side effects:
#NAME?
Which INSTI should we NOT recommend to women of childbearing age due to the risk of neural tube defects?
Dolutegravir
A patient presents to the ER one week after starting TDF/emtricitabine/etravirine with a diffuse, maculopapular rash and fever. Labwork reveals LFT elevations.
Which medications could be the cause of these problems?
Etravirine - can cause rash/fever and elevated LFTs
A patient presents to the ER one week after starting TDF/emtricitabine/etravirine with a diffuse, maculopapular rash and fever. Labwork reveals LFT elevations.
How should this be managed?
1) Stop ALL therapy
2) Recheck in 1-2 weeks to see if patient has normalized
3) Restart therapy, but replace etravirine with either a PI or an INSTI
A patient on atazanavir experiences hyperbilirubinemia. At what point should the patient need to discontinue atazanavir?
The manufacturer recommends to discontinue atazanavir if bilirubin levels reach 5x the upper limit of normal.
Which HIV drugs are C/I with PPIs?
?���?���?���?��??���:
- All
?���?���?���?���?��??���:
- Rilpivirine
?���?��??���:
- Atazanavir
?��??���?���?���?��??���: none
HIV is a RETROVIRUS. What does this say about its genome?
It has an RNA genome.
If a patient is resistant to one NRTI, will they typically exhibit cross-resistance to all other NRTIs?
NO; cross-resistance only occurs between lamivudine & emtricitabine.
If a patient is resistant to one NNRTI, will they typically exhibit cross-resistance to all other NNRTIs?
YES
If a patient is resistant to dolutegravir, will they typically exhibit cross-resistance to all other INSTIs?
NO
If a patient is resistant to raltegravir or elvitegravir, will they typically exhibit cross-resistance to all other INSTIs?
YES
A patient is taking TDF/emtricitabine/efavirenz. His resistance report indicated he was resistant to the emtricitabine and efavirenz in his current regimen.
What other ARV therapies is he likely cross-resistant to?
Resistance to emtricitabine = resistance to LAMIVUDINE too
Resistance to efavirenz = resistance to all other NNRTIs too
What should we counsel patient to NEVER do in regards to their HIV medications?
NEVER take a partial regimen! ALL OR NONE!
T/F: We only start HIV patients on therapy when their CD4 count reaches a certain point.
FALSE - we offer HIV therapy to all patients regardless of initial CD4 count. Do not delay!
Patients starting HIV therapy should use another form of protection for at least the first ________ months of treatment, until sustained suppression has been documented.
6 months
In order to prevent transmission to sexual partners, an HIV viral load must be maintained at or below ______________ with HIV therapy.
200 copies/mL
After positive HIV diagnosis, what baseline labwork must be documented when initiating HIV therapy?
- CD4 count
- HIV viral load
- Resistance testing
- CBC w/ differential
- HepB and HepC antigens/antibodies
- HLA-B*5701 test
- Pregnancy test
If a patient presents with HIV-HBV coinfection, what is the therapy of choice?
TDF/TAF + lamivudine or emtricitabine
Treatment-naive HIV therapy recommendation for MOST PEOPLE (has a high genetic barrier to resistance):
TDF/TAF + emtricitabine + INSTI
or
Abacavir + lamivudine + dolutegravir
Most dangerous HIV drug for pregnant patients:
Dolutegravir - do a pregnancy test first!
A 46yo man has been treated for HIV infection for 24 years. He has been virologically controlled for the past 8 years on lopinavir/ritonavir, abacavir/lamivudine. His triglycerides have gradually worsened over time, despite diet and exercise, and secondar
Ritonavir, a PI, has been known to cause dyslipidemia. Switch from lopinavir/ritonavir to dolutegravir (an INSTI).
Recommended therapy for HIV Post-Exposure Prophylaxis (PEP):
TDF/TAF + emtricitabine + raltegravir
?���?��??���?��??��? ?��??��??��??��??��??��? ?���?��� ?���?���?���?���?���
?���?���?��??��??��??���?��??��? ?���?��??��? ?��� ?���?���?���?���?���
Recommended therapy for HIV Pre-Exposure Prophylaxis (PrEP):
TDF/TAF + emtricitabine
1 tab daily
HIV drug used to prevent transmission from mother to fetus:
Zidovudine
At what time should zidovudine treatment be initiated in HIV-positive pregnant women?
NO LATER than 28 weeks gestation
Under what conditions should IV zidovudine be administered to pregnant women with HIV?
Administer zidovudine if the viral load is >1000 or unknown AT ONSET OF LABOR
Recommended infant PEP therapy:
?���?��??���?��??��??��??���?��??��??��� ?��??��??��??��??��? ?��??��??��??��??��??��? ?���-?���?���?��? ?��??��� ?���?��??��??��??��? ?��? ?��� ?��??���?���?��??��?
Should HIV-positive mothers breastfeed their children?
NO - high transmission risk to baby