Antiretrovirals Flashcards
HIV is a lentivirus that can lead to AIDs. There are two types of HIV-1 and 2. What are some features?
HIV-1: more virulent, more infective, and is the cause of majority of HIV infections
HIV-2: lower infectivity and poor capacity for transmission. Confined to West Africa
How does HIV progress to AIDS?
Infects CD4T cells, macrophages and dendritic cells
–HIV destroys so many of these cells that the body cant fight off infections and therefore leads to AIDS
Describe the basics of tx for HIV
Called: Highly Active Antiretroviral Therapy (HARRT)
–prolong the lives of many ppl infected
HIV replication?
Watch the video online (HHMI)
What is the most common pattern of HIV?
3 stages:
initial infection ,marked by an acute mononucelosis-like or flu-like viral infection
disease free latency period (8 years)
AIDs develops and most patients die within 2 years without therapy
HIV-1 testing is initially by what?
ELISA (Enzyme linked immunosorbent assay)
–this detects antibodies (However dont forget the window period where antibodies arent made yet)
Confirm with Western Blot
HIV RNA can be measure via PCR: used as a prognostic factor to monitor disease and effects of tx
What are the features of viral load and CD4 lymphocytes?
Higher RNA viral load
–greater risk of opportunistic infection, progression to AIDS and risk of death
CD4+ lymphocytes in the blood is a marker of disease progression and the best predictor of a patients current risk for particular opportunistic infections (normal 800-1200)
Moving on to treatment of HIV. What is the central goal of HIV treatment?
Decrease morbidity and mortality through maximum suppression of HIV replication
Second goal: increase CD4+ T cells
Viral load reduction to below limits of assay detection in an HAART-naive patient usually occurs within?
The first 12-24 weeks of therapy
What are the current guidelines in regards to starting therapy?
Initiating therapy in all patients to reduce the risk of disease progression
What conditions increase the urgency for therapy?
Pregnancy AIDS defining conditions Acute opportunistic infections HIVAN Acute recent infection HIV/HBV coinfection HIV/HCV coinfection Rapidly declining CD4 counts Higher viral loads
Prevention of perinatal transmission should be around what time?
Before 28 weeks gestation and an HIV RNA level less than 50copies/ml near delivery
–HAART is recommended for all HIV infected pregnant women
Selection of initial combination regimen should be decided how?
Regimens should be tailored for the individual patients to enhance adherence and thus improve long term treatment success
Pre treatment drug resistance testing?
6-16% prevalence of HIV drug resistance in naive patients
–therefore pre treatment testing should be done for optimal initial regimen
There are 20 approved antiretroviral drugs in 6 classes. What are these 6 classes?
NRTIs NNRTIs PIs FIs CCR5 antagonists INSTIs --for naive patients tx generally consists of two NRTIs in combo with either an INSTI, NNRTI or PI with a pharmacokinetic enhancer --results in HIV RNA decrease and CD4 increase
First up are the Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs). What are these drugs?
Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine
What is the MOA of NRTIs?
HIV encoded, RNA dependent DNA polymerase (aka reverse transcriptase) converts viral RNA into proviral DNA that is then incorporated into a host cell chromosome.
- -Available inhibitors of this enzyme are either NRTIs or NNRTIs
- –remember that NRTIs prevent infection of susceptible cells but have no impact on cells that already harbor the virus
The selective toxicity of these drugs depend on their ability to inhibit the HIV reverse transcriptase without inhibiting host cell DNA polymerase. Some are capable, however, of inhibiting DNA polymerase gamma which is the mitochondrial enzyme. Therefore inhibition of mitochondrial DNA synthesis. What toxicities result?
Anemia, granulocytopenia, myopathy, pancreatitis
- -Didanosine and Stavudine have the highest affinity for mitochondrial polymerase (Not recommended for initial therapy)
- -Zidovudine is associated with bone marrow suppression in individuals with advanced HIV disease, dont use with ganciclovir can cause neutropenia
What are some drug interactions for NRTIs?
Not cytochrome P450
Tenofovir and Didanosine
–tenofovir increases concentrations of concurrent didanosine by 25% to 40% and a reduction of the didanosine dose is recommended when agents are given together
What is the resistance for NRTIs?
High level resistance require accumulation of a min of three to four codon substitutions
Often given in pairs and are available as coformulations
Now I will go through each drug and name the adverse effects and drug interactions. First is Abacavir
AE:
Hypersensitivity reactions with fever, rash, malaise, resp and/or GI symptoms
Drug Interactions:
Avoid Alcohol
Second is Didanosine
AE:
Peripheral neuropathy, pancreatitis, GI disturbances, insulin resistance, retinal changes and optic neuritis
Drug Interactions:
Tenofovir and avoid concurrent neuropathic drugs
Third is Emtricitabine
Well tolerated compared to other NRTIs
Can cause hyperpigmentation of the palms and soles particularly in dark skinned patients
Fourth is Lamivudine
Well tolerated compared to other NRTIs
Fifth is Stavudine
AE:
hyperlipidemia, peripheral neuropathy, increased serum aminotransferase levels, diabetes, pancreatitis, fatal lactic acidosis
Drug Interactions:
Avoid in concurrent neuropathic drugs
Sixth is Tenofovir
AE:
generally well tolerated; renal toxicity, decreased bone density and osteomalacia can occur
Drug Interactions:
Tenofovir lowers serum concentrations of atazanavir, combined used with didanosine has been associated with CD4+ decline
Seventh is Zidovudine.
AE:
Bone marrow suppression, n/v, headache, fatigue, confusion, malaise, hepatitis and diabetes
Drug Interaction:
Myelosuppresion may increase with coadministration of ganciclovir, interferon alpha, ribavirin and other bone marrow suppressive agents. Coadministration with doxorubicin or stavudine should be avoided
The last set of drugs for this card deck are the Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) — Efavirenz, Nevirapine, Rilpivirine. What is the MOA?
Bind to a hydrophobic pocket in a subunit of the HIV-1 reverse transcriptase
–this pocket site is not essential for the function of the enzyme and is distant from the active site
This complex induces a conformational change in the 3D structure of the enzyme that reduces its activity and thus are noncompetitive inhibitors
–no activity against DNA polymerases
What is the resistance for NNRTIs?
More susceptible to high level drug resistance bc a single amino acid change in the NNRTI binding pocket renders the virus resistant to all available drugs in the class
What are the pharmacokinetics for NNRTIs?
Metabolized in the liver by CYP3A4 (therefore sub therapeutic concentrations of concomitantly administered drugs that are metabolized by CYP enzymes)
Efavirenz and Nevirapine are substrates of CYP2B6
Each card will go through the NNRTI drug and the AE and drug interactions. First is Efavirenz
AE: --rash, dizziness, headache, insomnia, difficulty concentration, vivid dreams, nightmares (possible associated with suicidality), reductions in vitamin D levels, hyperlipidemia, and teratogenic (Avoid in 1st trimester) Drug Interactions: Substrate of CYP3A4 Inducer of CYP3A4 and 2B6
Second is Nevirapine
AE:
–rash, fever, nausea, headache, severe hepatotoxicity, hepatic failure and death
Drug Interactions:
Inducer of CYP3A4 and 2B6
Third is Rilpivirine
AE:
–Rash, insomnia, depression, increased liver enzymes
Just a quick note on side effects, what is the common side effect?
Rashes occur frequently
- -during the first 4 weeks of therapy
- usually mild
- -rare cases potentially fatal Stevens Johnson Syndrome (more with nevirapine and efavirenz)
