Exam 2 - HIV, STDs, Hepatitis Flashcards
HIV
..
Main monitoring of HIV
- CD4 cell count
- Viral load
CD4 count
Extent of destruction of immune system
Viral load
How extensive virus propagation is; goal is optimal viral suppression.
When is the optimal time to start HIV treatment?
Immediately upon diagnosis; want to minimize immune destruction.
Nucleoside reverse transcriptase inhibitors
- Backbone for HIV regimens
- 2 NRTIs + 1 other drug (typically)
-Based off of purine and pyrimidine nucleotides and nucleosides
- Stavudine (d4T) (Zerit)
- Zidovudine (AZT or ZVD) (Retrovir)
- Emtricitabine (FTC) (Emtriva)
- Lamivudine (3TC) (Epivir)
- Abacavir (ABC) (Ziagen)
- Didanosine (ddI) (Videx)
- Tenofovir (TDF) (Viread)
Nucleoside reverse transcriptase inhibitors
NRTI
- Backbone for HIV regimens
- 2 NRTIs + 1 other drug (typically)
-Based off of purine and pyrimidine nucleotides and nucleosides
- Stavudine (d4T) (Zerit)
- Zidovudine (AZT or ZVD) (Retrovir)
- Emtricitabine (FTC) (Emtriva)
- Lamivudine (3TC) (Epivir)
- Abacavir (ABC) (Ziagen)
- Didanosine (ddI) (Videx)
- Tenofovir (TDF) (Viread)
ADR Nucleoside Reverse Transcriptase inhibitors
NRTI
-Mediated by fact they’re not specific to only reverse transcriptase; can affect mitochondrial DNA and RNA synthesis.
Newer agents have less side effects: Abacavir, tenofovir, emtricitabine, lamivudine
ADR: lactic acidosis, fatty liver, pancreatitis, peripheral neuropathy
Before putting a patient on Abacavir, what do you have to test for?
Abacavir -
Pts with HLA-B5701; need to test for that, bc those patients will have a severe anaphylactic reaction.
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
- MOA: Bind to reverse transcriptase and change the conformation so it can’t interact with viral RNA
- Regimens have 2 NRTIs + 1 other class, this could be that other class used.
-Delavirdine (DLV) (Rescriptor)
-Efavirenz (EFV) (Sustiva)
-Nevirapine (NVP) (Viramune)
MOST USED:
-Etravirine (ETR) (Intelence)
-Rilpivirine (RPV) (Edurant)
ADR:
- Rash, transaminitis,
- Single viral mutation can confer resistance to entire class!!!!! (except etravirine)
Protease Inhibitors
-MOA: Viral DNA is incorpoprated and cells are producing viral proteins. Meds will inhibit protease enzyme preventing virus from making mature proteins. Inhibit further HIV spread from cell to cell.
- Atazanavir (ATV) (Reyataz)
- Darunavir (DRV) (Prezista)
- Fosamprenavir (FPV) (Lexiva)
- Indinavir (IDV) (Crixivan)
- Lopinavir (LPV) (Kaletra w/ Ritonavir)
- Nelfinavir (NFV) (Viracept)
- Ritonavir (RTV) (Norvir)
- Saquinavir (SQV) (Invirase)
- Tipranavir (TPV) (Aptivus)
- Ritonavir - used for PK interaction for positive effects
- Ritonavir plus Darunavir
ADR:
-GI distress, increased lipids, glucose intolerance (diabetes), and altered fat distribution (“buffalo hump” when on PI for a long time).
-Metabolized in liver
Why is Lopenavir added to Ritonavir (Coletra)?
Ritonavir is a potent CYP3A4 inhibitor, by inhibiting CYP3A4, protease inhibitor drugs metabolized by it will go up.
Allows us to use less frequent dosing with medication. Increases levels and keeps them around for longer.
-Also done with cobicistat
What happens if you put a patient on simvastatin on ritonavir as well????
- CYP3A4 inhibitor
- Don’t mix with simvastatin. Can increase dose and cause myalgia.
Enfuvirtide (ENF) (Fuzeon)
- Fusion Inhibitor
- MOA: Inhibits HIV-1 envelope fusion to human cell. No activity against HIV-2, so won’t be used in Africa.
-Not given orally, its an amino acid. Given subQ.
-ADR: injection site reactions! Nodules can develop over time.
36-amino acid peptide
No oral administration
Given SC, injection site reactions very frequent
Pain, erythema, nodules
Maraviroc (Selzentry)
CCR5 antagonist
- Works on HIV-1 and 2. Blocks the CCR5 human receptor and not the virus.
- Can only use against the correct strain of virus
- Must do testing prior to starting therapy
ADR: rash and hepatotoxicity
Integrase Inhibitors
Raltegravir (RAL) (Isentress)
Dolutegravir (DTG) (Tivicay)
Elvitegravir (EVG) (Viteka)
»Coformulated with cobicistat, a CYP3A4 inhibitor to iincrease levels and dose drug less frequently.
- MOA: Bind to integrase and prevent viral DNA from being incorporated into chromosomal DNA.
- ADR: Rash, nausea, and headache (more recommended)
What NNRTI induce CYP3A4?
What class inhibits CYP3A4?
How does Rifampin impat drugs metabolized by CYP3A4?
- Some are on purpose (ritonavir). Most interactions occur through CYP3A4.
- NNRTI: Efavirenz, etravirine, and nevirapine induce CYP3A4
- Most protease inhibitors inhibit CYP3A4
- Keep interactions in mind with anti-TB drugs (Rifampin induces CYP3A4 and can make HIV drugs less effective)
- Food-drug interactions
- Some drugs require an acidic environment to be absorbed (don’t take with food, because it’ll increase pH of the stomach).
Initial HIV treatment should be managed with a minimum of ___ antiretroviral agents including a 2 NRTI backbone.
Give an example.
3
Protease Inhib. + 2 NRTI
- Darunavir (boosted by ritonavir)
- Tenofovir
- Emtricitabine
Integrase inhibitor + 2 NRTI -Raltegravir -Tenofovir -Emtricitabine recommended together, bc of truvada (combo pill).
NNRTI + 2 NRTI (less preferred)
- Efavirenz
- Tenofovir
- Emtricitabine
Adherence
- Major impact on resistance and ultimate success or therapy.
- Once you become resistant to a drug or class, you can’t use that drug again in the future, because the function is lost.
-Reasons for poor adherence: >Psychiatric illness >Substance abuse >Adverse effects - diabetes, weight gain >Unstable social circumstances - poor access to medical care
-Use combination formulations whenever possible
When dosing HIV meds, its important to use combination formulations whenever possible to increase patient adherence and decrease food interactions.
What combination therapies can you use?
-Efavirenz, Emtricitabine, and Tenofovir (Atripla)
- Elvitegravir, cobicastat, emtricitabine, tenofovir (Genvoya)
- Cobicastat - inhibits CYP3A4 to boost integrase inhibitor
-Emtricitabine, rilpivirine, and tenofovir (Complera)
Phenotype testing –
Who do you do this on?
Determines concentration of drug to inhibit growth by 50% replication of the virus (IC50). Concrete data on what it will respond to.
Results are compared to wild type virus
Provides resistance information for complex mutation patterns
Higher cost, slower turnaround
-More established patient that probably has more mutations
Genotype testing -
Who do you do this on?
- Checks for specific genetic mutations that are known to confer resistance to specific drugs
- Not as informative as phenotyping
-Pt with new onset, few mutations
HIV monitoring
Use genotype testing, monitor CD4 cell count, and viral load to determine if the drug regimen is effective or not.
Pt on a drug regimen:
- Viral load undetectable
- CD4 maintaining
- Over time, viral load is starting to increase.
What happened?
Could have had a mutation occur making regimen ineffective.
If they’re compliant, you know they have a new mutation and you have to switch over to a protease inhibitor or an integrase inhibitor. Need to have a reason to test.
How do you treat HIV in pregnancy?
Treat as if they were NOT pregnant:
- High viral loads in mom means baby will be exposed
- Need to suppress load as much as possible.
What drug CANNOT be used in pregnancy due to neural tube defects?
Efavirenz
-will effect early on in pregnancy
Frequently, HIV patients in intra-partum period, onset of labor to delivery, doctor will give mom and newborn _____________.
Zidovudine
- Prevents perinatal transmission
- Fetuses receive 4-6 weeks after birth
- AVOID BREASTFEEDING. Without immune system, HIV is more likely to have oral transmission. Normally, less likely bc AA are broken down.
When is chemoprophylaxis for HIV used?
Good for healthcare workers (postexposure prophylaxis) after high risk exposures.
-ADR: GI toxicity
Helpful to know HIV status of patient, if not possible go with worst case scenario.
Start as early as possible (1-2 hours).
Used to use tenofovir, now they recommend RATEGRAVIR for being better tolerated.
What combination therapy is initiated for chemoprophylaxis when exposed to HIV?????
Tenofovir, emtricitabine, raltegravir for 4 weeks.
Initiate ASAP to stop HIV cells from replicating and initiating infection.
What is used for pre-exposure prophylaxis?
Daily tenofovir / emtricitabine (Truvada)
-If pt knows they’ll be exposed, pre-exp. prophylaxis = “morning after pill”
When is pre-exposure using: Daily tenofovir / emtricitabine (Truvada) used?
2 NRTIs used daily.
Those at high risk:
- MSM
- Sero-discordant couples
- IV drug abusers
- Patients need to be seronegative prior to initiation
Evaluating treatment outcomes of HIV HAART:
-Baseline CD4 and HIV RNA load = tells propagation of virus
- HIV resistance test is recommended at initiation!
- Monitored every 3 months!!!! UNTIL HIV RNA is undetectable……
Why would you change a HAART regimen?
Reasons for changing regiment:
- Intolerable side effects
- Treatment failure (viral RNA > 200 copies/mL)
- Documented resistance to agents via testing
COMPLICATIONS OF HIV/AIDS
…
CD4 < 200
What are they at risk for?
What prophylaxis do you put them on?
Risk of PJP
BACTRIM
CD4 < 50
What are they at risk for?
What do you put them on?
Risk of Mycobacterium Avium Complex
MACROLIDES
Using CD4 count:
Lets us know what to use for prophylaxis.
Latent TB can be reactivated with low CD4 counts
Today, emphasis is placed on treating HIV infection and recovering CD4 count
Goals:
- Prevent exposure to opportunistic pathogens
- Vaccinate to prevent first-episode disease
- Chemoprophylaxis at certain CD4 thresholds to prevent first-episode disease
- Treat emergent OI
- Use secondary prophylaxis to prevent RECURRENCE
- Discontinue prophylaxis once immune recovery is sustained
**Prophylaxis used for chemo patients as neutrophils drop; put them on prophylaxis for same opportunistic infections
If you have a patient with a CD4 < 40, start on bactrim for PCP, and they get PCP. What do you do?
Treat the PCP and put them on Bactrim for secondary propylaxis.
If CD4 rebounds and is sustained, D/C prophylaxis.
Immune Reconstitution Syndrome (IRIS)
- Latent infection
- Do not have a good immune system to attack it
- Reconstituting immune system with HAART, CD4 count goes up and they can fight the infection.
- Inflammation starts, which can make them feel even worse.
-Can be treated symptomatically; antipyretics.
PCP Tx:
- Pneumocystic jirovecii pneumonia
- Most common life threatening OI in AIDS pts.
Treated with sulfamethoxazole-trimethropin given thrice weekly
- Bactrim chronically, every MWF or on weekend
- Weird dosing = prophylaxis for PCP pneumonia
If they get actual pneumonia, IV Bactrim - very sick, difficult to treat. Need 3 weeks worth of treatment. Then put back on secondary prophylaxis until CD4 count goes back up.
Candidiasis Tx:
- Oral and esophageal thrush
- Treated based on severity
- Candidiasis in oral pharynx: worry about systemic infection.
- Can lead to fungal pneumonia or septicemia.
Tx:
- Fluconazole (Diflucan)
- Nystatin oral liquid, swish, and spit - NOT absorbed. Swish and swallow if esophageal.
Other OI
Cryptococcal meningitis Toxoplasmosis encephalitis Mycobacterium avium complex (MAC) Herpes-zoster Cytomegalovirus
Complications of HIV
- Diabetes, CV disease, HTN, hyperlipidemia, HIV associated nephropathy, cancer
- Always check for drug interactions
STIs
..
Gonorrhea Tx:
-Neisseria gonorrhoeae – gram negative diplococcus.
Gonorrhea:
- IM single dose
- Ceftriaxone (Rocephin)
- 3rd generation CS
Chlamidya:
-Azithromycin 1g PO once
OR
-Doxy 7x days (compliance issue)
Can have a chlamydial coinfection - when treating for gonorrhea, you have to treat for chlamidya at the SAME time.
If you have a patient with a TRUE cephalosporin allergy, how would you treat gonorrhea?
Can’t have ceftriaxone
- Give gemifloxacin (FQ)
- IM gentamycin (aminoglycoside)
For newborns with gonorrhea-infected mothers, how do you prevent perinatal transmission?
-Oral erythromycin (opthalmic)
Chlamidya Trachomatis
-2nd most frequently reported STD behind HPV
-Tx: Azithromycin 1g PO once
OR
-Doxy 7x days (compliance issue)
Tetracyclines and FQ can be used as secondary agents, but should be avoided in pregnancy
Syphillis Tx:
Treponema pallidum – spirochete
Treatment – parenteral penicillin G
T. pallidum reproduces slowly, so single doses of short acting meds won’t eliminate infection.
Benzathine PCN G (Bicillin) is effective for single dose therapy (IM can be given; 1 dose).
Serious forms = IV PCN G (Continuous infusion or Q4hrs).
How do you treat Syphillis iif a patient has a PCN allergy?
PCN allergy – doxycycline or tetracycline for 2-4 weeks
Aqueous penicillin G (IV) given intermittently or continuously for more advanced cases or neurosyphilis
Genital Herpes
Pain and discomfort
- Warm saline baths, analgesics, antipyretics, antipruritics
- Good hygiene can prevent bacterial superinfection
Tx: Acyclovir, valicyclovir, famicyclovir
IV acyclovir can be used for those immunosupressed
Episodic therapy HSV
Prodromal symptoms or outbreak is coming or lesions start occuring
- Not as much drug used
- Less SE
Chronic therapy HSV
- Decrease recurrences
- Better off for pts
- Less asymptomatic shedding
Trichomoniasis Tx:
Trichomonas vaginalis
- Metronidazole - NO ETOH
- Tindazole - antiprotozoal; damages the DNA.
- Single 2 gram dose of either med works
- Treat partners to prevent reoccurence
HEPATITIS
..
Hepatitis A
- Self-limiting disease
- Fecal-oral transmission
- Contaminated water
- Prevented by vaccine
- Usually resolved in 6 months.
- Reduce complications: liver failure, diarrhea, transaminitis, bilirubin, jaundice
- Responsible for making clotting factors
-Vaccines: HAVRIX, VAQTA
Warfarin
- Works against factor 2, 7, 9, 10
- Poor liver function: not producing clotting factors
What measures liver function?
- Measure PT/INR
- Warfarin induces limited function of the liver.
Overdose of acetaminophen:
- Hepatotoxicity
- Check LFTs and PT/INR to see how well liver is functioning.
What forms of Hepatitis have vaccines?
- Hep A and B
- NOT Hep C
When a patient is immunocompromised from hepatitis A, how can you treat?
Immunoglobulin (IgG)
-Will mount immune response for patient
Post exposure prophylaxis for patients exposed to Hep A, not previously vaccinated, tx:
IgG treatment
Hepatitis B
- Highly infectious! 50-100x more than HIV.
- Chronic infection; a reservoir for transmission/spread and leads to cirrhosis, hepatocellular carcinoma.
- Spread sexually, parenteral (IVDA), and vertical transmission.
-Vaccine: Recombivax, Engerix-B, TWINRIX
Which vaccine contains antigens for HBV and HAV for adults?
TWINRIX
Which vaccines first protected against human cancer?
HBV vaccines; prevent liver cancer.
On test:
Will not have to remember brand names for each vaccine that goes with hepatitis
Why do you have to immunize multiple times with vaccines?
- Kids have developing immune system; first dose may not have full immunity.
- Vaccines require multiple doses to challenge immune system to develop full immunity.
- Vaccine response is low and requires three doses for optimal protection.
Hep B treatment goals:
- Maintenance of viral suppression
- Seroconversion to anti-HBeAg and loss of HBeAg (if initially present)
- Prevent progression to hepatic complications
Who should receive treatment for Hep B?
- Can be cleared naturally; may do a watchful waiting approach to see if they can clear it on their own.
- Look at risk of liver M&M
If a patient has Hepatitis B, when is it apropriate to start treatment?
- ALT of 200-300
- indicates significant damage
Know which drugs treat Hep B and which treat Hep C.
Interferon-alpha (IFN-alpha, intron A)
- First approved and MAINSTAY therapy for HepB
- Interferons prime host immune system to mount a better response against virus and clear it
- Anti-viral, anti-proliferative
- Protein; cannot be taken orally.
- Must be injected 3x/week.
What interferon is used most often to treat Hep B? Why?
Largely supplanted by peginterferon-alpha (Pegasys)
- Dosed once weekly
- Better efficacy
- Have added polyethylene glycol, which allows product to last longer.
Interferon-alpha ADRsssss
IFN-alpha, intron A
- Risk for infection in decompensated cirrhotic patients.
- BLACK BOX warnings for fatal neuropsychiatric disorders, AI disorders, ischemia, and infection risks.
- Risk for anaphylaxis, flu-like symptoms, depression, SI, aggression, and blood dyscrasias.
Lamivudine (Epivir)
-MOA: NRTI, prevents viral DNA from being elongated.
- Some activity against HBV
- NOT a first-line therapy (interferons are first line).
- Patients that can’t clear infection themselves can be given this indefinitely.
- Worry about relapse and resistance.
Adefovir (Hepsera)
- Activity against Lamivudine resistant HBV.
- Similar MOA.
- Monitor serum creatinine and NEPHROTOXICITY has been reported.
Entecavir (Baraclude)
- Used in lamivudine resistant strains
- Safety similar
- Considered flirst line for HBV due to the safety and low resistance.
Telbivudine
More effective than lamivudine, but high rate of resistance…
Tenofovir (Viread)
- Also considered first line for HBV
- Low resistance rates
Hepatitis C
- Usually have a chronic infection. Usually unable to clear themselves.
- NO vaccine for it.
- New meds have been developed to help prolong cirrhosis.
- “Cure card” - you don’t have HepC anymore.
What is the main goal of HepC?
Sustained virologic response - reach non-detectable HCV RNA for at least 12 weeks after the end of their treatment; “virologic cure”.
- Helps prevent end stage liver disease and complications.
- Need genotype to determine what drug to use to treat.
What was previously used for HepC therapy?
Interferon therapy
- No longer used, too many SEs.
- Riboviron-interferon dosed occasionally, but can cause depression, agressiveness. Not used as often.
What is the current standard for treating HepC?
- All oral regimen for 3-4 mos. depending on the viral genotype.
- GT1-6 (GT1-a and GT1-b are the most common subtypes in US).
Direct Acting Antivirals (DAA)
NS5A inhibitors - Prevent breakdown of protein chain or inhibit different components (enzyme activity) to prevent replication of viral RNA in HepC.
Stage 1
Can test in a few healthy patients.
Stage 2
Test in sick people to look for dosing and efficacy.
Stage 3
Thousands of patients with disease are tested on.
Stage 4
Drug is approved and is out on the market; customers are participants in stage 4 trials.
Daclatasvir (Daklinza)
- Effective against HepC GT1 and GT3.
- Do testing beforehand to make sure drug isn’t ineffective.
- MOA: prevents RNA replication and virion assembly by binding to NS5A protein to distort protein structure and impair its function.
- Oral drugs, don’t need renal/hepatic dose adjustments.
- ADR: headache, nausea, diarrhea
- $20,000 a month
Test
Will not have a patient that walks in with GT#2,4,5,6,etc. and have to treat.
Ledipasvir/Sofosbuvir (Harvoni)
-Broad activity: GT1, 4, 5, and 6 (most of the varieties seen in US).
Ledipasvir MOA
-inhibits NS5A to block viral replication
Sofosbuvir MOA
- Nucleotide prodrug that inhibits NS5B RNA polymerase (acts as a chain terminator once incorporated into viral HepC RNA).
- Availble by itself as Sovaldi.
- No organ adjustment needed
- ADR: headache/fatigue
- $30,000 a month
Simeprevir (Olysio)
- MOA: inhibits NS3/4A protease, without cleavage, can’t produce functional HCV proteins (NS4A, 4B, 5A, 5B)
- ADR: rash
-Not used by itself; usually included with sofosbuvir or interferon/ribuviron therapy.
Ombitasvir
-MOA: NS5A inhibitor; treats Hep C.
Given in combination with:
- Paritaprevir - NS3/4A inhibitor
- Ritonavir - boost drug levels of pariaprevir (Technivie = brand name).
Given with or without dasabuvir (combo of 3 is Viekira).
Ribavirin (Rebetol)
CAT X DRUG
- MOA: drug will increase mutation of RNA, becomes so mutated that it can’t function inducing “error catastrophe”.
- Immunostimulatory; helps to clear virus.
- Injectable.
- Used to be given with interferon, but caused psychiatric effects; can see increase SI, depression, insomnia.
- Risk for HEMOLYTIC anemia.
- AVOID when possible.
- CATEGORY X: Pt must use 2 types of birth control for 6 months after discontinuing drug.
When is Ribavirin preferred?
Difficult to treat patients; ex: if you had previous treatment for HepC and failed due to mutations or having underlying cirrhosis.
Ribavirin can be added to treatment to overcome resistance or underlying cirrhosis.
When is it apropriate to use peg-interferon?
Use has gone down substantially since direct antiviral agents (DAAs) were developed.
Cirrhosis
- Fibrotic, scarred liver
- Difficult to achieve a sustained virologic response.
- Some DAAs have to be adjusted for varying degrees of cirrhosis.
What drugs need to their dose adjusted for patients affected by cirrhosis?
- Ombitasvir
- Paritaprevir
- Ritonavir c/s dasabuvir
NEED to be adjusted for late stage or severe cirrhosis so that their levels aren’t too high.
For patients that have failed treatment previously FOR HEPC; what do you do?
- Consider resistance testing
- Try adding Ribavirin and extending the treatment
How do you treat patients with acute exposure to HepC, i.e. nurses with unexpected needle sticks?
50% of patients clear spontaneously within 6 months, should defer therapy until then.
- HIV exposure: Do NOT wait to start PEP.
- HepC you can wait to treat, bc we have a cure.
Patient with HCV G1a, might have cirrhosis as well. What drugs should you add to their treatment?
Ribonavir: full-cure
Treatment changes based on what genotype you have.
