25 - HIV Flashcards
What is the difference between HIV and AIDS?
- HIV = Human Immunodeficiency Virus
- Retrovirus
- HIV-1 is the type in North America
- Chronic infection causing progressive destruction of CD4+ T-lymphocytes (crucial for normal function of human immune system)
- AIDS = Acquired Immunodeficiency Syndrome
- Person is HIV-positive & has CD4+ cell count below 200
- Person can go between having AIDS & not, so try to refrain from using this term; also stigmatizing
What is the mechanism of immunologic deficiency for HIV?
- CD4 cells are the target of HIV
- HIV interacts w/ CD4 receptors, enters CD4 cell -> replicates -> destroys CD4 cell => CD4 depletion
- CD4 cells direct & activate immune response
- Depletion of CD4 = degradation of immune function; w/o tx will result in death
- Combination tx w/ antiretrovirals decreases mortality & morbidity
- When HIV enters CD4, brings in RNA which is transcribed into DNA & then becomes part of the host DNA, so host is reproducing the virus, making it very hard to treat
Stages of HIV infection
- Viral transmission – contact w/ infectious body fluids (ex: blood, serum, vaginal secretions, breast milk)
- Urine is sterile, so isn’t transmitted through urine unless blood is present
- Primary/acute HIV infection – sx last ~ 2 weeks (fever, sore throat, fatigue, weight loss, myalgia); high viral load (may > 1,000,000 copies/mL) & persistent decrease in CD4 lymphocytes
- Very severe flu-like sx for 2 weeks, then goes away
- Seroconversion (development of HIV antibody) – 95% convert w/in 6 months
- Chronic asymptomatic HIV infection (viral replication is more controlled by immune response)
- Chronic symptomatic HIV infection
- AIDS – CD4 cell count < 200/mm3 regardless of presence/absence of sx
- Advanced HIV infection – CD4 cell count < 50 cells/mm3
Main routes of HIV transmission
- Sexual
- Parenteral (intravenous)
- Perinatal or mother-to-child transmission/ vertical
- Think sex, drugs, & rock a bye baby
Describe sexual transmission of HIV
- Most common = receptive anal & receptive vaginal
- Oral is low risk (only transmit if break in mucous membrane or blood is present)
Factors that increase risk of sexual transmission
- Increased viral load
- Vaginal bleeding during intercourse
- Genital ulcers
- STI’s
- Lack of circumcision in males
- Genetic & host factors
Factors that decrease risk of sexual transmission
- Condoms
- Tx of STIs
- Male circumcision
Describe vertical transmission of HIV
- Overall risk in absence of drug therapy & other interventions ~20-25%
- 50-70% of transmission occurs just before or during birth process/delivery
- In-utero transmission rare
- In resource rich countries, where formula feedings readily available, breast feeding is not recommended
- In resource poor countries, breast feeding recommended b/c formula feeding not feasible
Tx for vertical transmission of HIV
- Screen for HIV during pregnancy
- Tx mother w/ antiretroviral therapy during pregnancy (pre-exposure prophylaxis PrEP)
- Antiretroviral tx during labour & delivery to mother & to baby post-delivery
- Baby gets antiretrovirals after birth for 4-6 weeks (post-exposure prophylaxis PEP)
Describe parenteral tranmission of HIV
- Exposure to contaminated blood products (most common = IV injection w/ used needles & other injection paraphernalia)
- Decrease risk of transmission – free needle exchange programs, not sharing injection paraphernalia, & use of PEP
What is pre exposure prophylaxis? What is the recommended tx?
- Antiretrovirals taken by a person who doesn’t have HIV to prevent HIV before possible exposure
- Tenofovir DF 300 mg/ Emtricitabine 200 mg (Truvada) – 1 tablet PO daily
- Major barrier in MB = cost
- Requires prior and post testing for HVI
What is post exposure prophylaxis? What is the recommend tx?
- Antiretrovirals taken by person who doesn’t have HIV to prevent HIV infection after possible exposure (occupational or not)
- 28 days course of 3 antiretrovirals started w/in 72 h of exposure
- In MB – 3 day starter kit available through ER & remaining 25 days Rx through community pharmacy ($$$)
Four tx strategies known to prolong survival
- Antiretroviral therapy
- P. jiroveci prophylaxis (PCP)
- M. avium complex prophylaxis (MAC)
- Care by healthcare team specializing in HIV
What are the 6 classes of antiretrovirals? Which 4 are most common?
- Protease inhibitor (PIs)*
- Integrase strand transfer inhibitors (INSTIs)*
- Nucleoside reverse transcriptase inhibitor (NRTIs)*
- Non-nucleoside reverse transcriptase inhibitor (NNRTIs)*
- CCR5 receptor antagonist
- Fusion inhibitors
Analogies for life cycle of HIV
- ARVs = birth control for HIV b/c prevents new infectious virus from being made (if taken daily & able to achieve & maintain therapeutic blood levels)
- HIV like an intruder in a factory (HIV enters CD4 factor, hijacks production line to make viral components instead of CD4 components => thousands/millions of new virus
Examples of antiretrovirals from the 4 main classes
- NRTIs = tenofovir DF, tenofovir AF, abacavir, emtricitabine, zidovudine
- NNRTIs = efavirenz, etravirine, nevirapine, rilpivirine
- PIs = darunavir + ritonavir; atazanavir + ritonavir; “avir”
- INSTIs = dolutegravir, raltegravir; “gravir”
Goals of therapy for HIV
- Reduce HIV-associated morbidity & prolong duration & quality of survival
- Restore & preserve immunologic function
- Maximally & durably suppress plasma HIV viral load
- Prevent HIV transmission
Surrogate markers of disease progression
- Viral load = HIV RNA in blood
- Average viral burden w/o therapy = 30,000-50,000
- CD4+ T cell lymphocyte counts (and %)
- Normal CD4+ count in non-HIV pt = 800-1050 cells/mm3
- Average rate of decline of CD4 cells ~ 50 cells/mm3 per year after first year of infection
- Increased risk of morbidity at 200 cells/mm3
- < 50 cells/mm3 median survival = 12-18 months w/o tx
Who is antiretroviral therapy recommended for? When should it be initiated?
- Recommended for all HIV-infected individuals to reduce disease progression & for prevention of transmission
- Therapy should be initiated ASAP, but may be deferred on a case-by-case basis
Pt evaluation prior to initiation of HAART
- Physical – evidence of symptomatic HIV disease, evidence of opportunistic infections, fever, malaise, skin rashes or lesions, etc.
- Psychosocial – substance abuse, housing, access to meds, psychiatric
- Lab – CD4+ count, serology for hep A, B, & C; CBC, BUN, sCr, LFTs, cholesterol (protease inhibitors can worsen cholesterol)
- Certain antiretrovirals will also cure hep B, so if pt is hep B positive would choose a drug that will also treat it
- Other tests – syphilis, tuberculin skin test, chest x-ray, gynecologic exam w/ Pap
- HLA *B5701 – if pt has this allele are at increased risk of having hypersensitivity reaction to abacavir; if can’t do the test then just avoid abacavir
- HIV drug resistance testing – genotyping of virus to look for drug resistant strain
Initial tx in tx naïve pt
- Combination therapy – usually need at least 3 antiretrovirals (low dose ritonavir or cobicistat for boosting doesn’t count)
- 3 types of regiments
1) 2 NRTIs + 1 NNRTI
2) 2 NRTIs + 1 PI (preferably boosted w/ ritonavir or cobicistat)
3) 2 NRTIs + INSTI - Individualize regimen based on HIV characteristics & pt
Recommended initial regimens for most people (based on guidelines)
- All have emtricitabine (could also use lamivudine; these 2 considered interchangeable so never used together)
- All have tenofovir DF or AF (AF preferred)
- All have INSTI as 3rd drug due to side effect profile; either raltegravir, dolutegravir, or elvitegravir + cobicistat
Factors to consider for selection of ARVs
- Drug resistance
- Viral load
- CD4 count (some regimens require CD4 above a certain level)
- HLA B5701
- Co-morbidities (renal function, hep B status)
- Drug interactions
- Pt preference
- Formulation
Integrase strand transfer inhibitors - advantages
- Less negative effects on lipids
- If unboosted, less potential for drug interactions via CYP
- Raltegravir – not metabolized through CYP, so less likely to have drug interactions
- Dolutegravir – highest genetic barrier of the class
INSTI - disadvantages
- Raltegravir – low genetic barrier (missing doses can cause virus to generate a mutation, and one mutation will make the virus totally resistant to raltegravir)
- Elvitegravir – needs booster
- Dolutegravir – oral absorption can be reduced by simultaneous administration w/ products containing polyvalent cations
INSTI – adverse effects
- Raltegravir = insomnia, headache, nausea, fatigue, creatine kinase elevation, rhabdomyolysis, myositis
- Dolutegravir = insomnia
Protease inhibitors – advantages
- Higher genetic barrier for resistance (multiple mutations to confer resistance)
- PI resistance uncommon w/ failure (boosted PIs)
PI - disadvantages
- GI adverse effects
- Greater potential for drug interactions (CYP) especially w/ ritonavir or cobicistat
PI – adverse effects
- Hyperlipidemia
- Insulin resistance & diabetes
- Lipodystrophy
- Elevated liver function tests
- Drug interactions
- Atazanavir = hyperbilirubinemia
- Ritonavir = diarrhea; only used for boosting other PIs at 100-200 mg/day, so low chance of side effects
NNRTI – advantages
- Less dyslipidemia & fat maldistribution than PIs
- Long half life
NNRTI – disadvantages
- Low genetic barrier
- Potential for CYP drug interactions
- Transmitted resistance to NNRTIs more common than resistance to PI
NNRTI – adverse effects
- Efavirenz = CNS/neuropsychiatric (nightmares, vivid dreams, insomnia, agitation, impaired concentration); usually gets better w/ time; recommend taking at bedtime to sleep through side effects & on empty stomach to avoid elevated levels
- Nevirapine – hepatotoxicity (may be severe & life threatening)
- Increased risk in women w/ CD4 > 250 & men w/ CD4 > 400
Etravirine (2nd gen NNRTI) – MOA? When is it used? Adverse effects?
- Binds to reverse transcriptase & inhibits replication
- Used in tx experienced px w/ resistance to other classes of ARVs
- Adverse effects = less CNS effects than efavirenz
Potential adverse effects from NRTIs
- Lactic acidosis & hepatic steatosis (fatty liver) – rare
- Lipodystrophy – uncommon
- Higher risk for these w/ older (no longer used) NRTIs
- Tenofovir = renal impairment
What is lipodystrophy? What should be done when a pt experiences this?
- Loss of fat in cheeks, arms, buttocks; “beer belly” for no reason
- Mechanism not understood
- May be associated w/ dyslipidemia, insulin resistance, and/or lactic acidosis
- Switch to other agents may slow progression
- Can be prevented by using new NRTIs
CCR5 receptor antagonists – MOA? When are they used? What is required before initiation? ADRs?
- Bind to CCR5 co-receptor of CD4 cell preventing entry into cell
- Used in tx experienced px w/ resistance to other classes of ARVs
- Requires tropism test to see if it will be effective (not available locally)
- Only effective if virus uses CCR5 exclusively
- ADRs = cough, rash, upper respiratory infection, fever
Fusion inhibitors – administration? When are they used?
- Subcut injection twice daily
- Used in tx experienced px w/ resistance to other classes of ARVs
Hyperglycemia as an adverse effect of ARV. Onset, risk factors, and management
- Onset = weeks to months
- Risk factors = underlying hyperglycemia, family hx
- Not really high risk, but compared to other classes, this is something to look out for when taking protease inhibitors
- Management – diet & exercise; consider switching off PI
Hyperlipidemia as an adverse effect of ARV. Onset, risk factors, and management
- Onset ~ 3 months
- Boosted PI > NNRTI > INSTI
- Avoid PI & choose INSTI if pt already has high cholesterol or has family hx
- Management – atorvastatin or rosuvastatin
Drug interactions w/ antiretrovirals
- Antiarrhythmics, anticonvulsants, anticoagulants
- CCBs, corticosteroids
- Methadone
- Psychotropics
Describe an example of a desirable drug interaction
- Ritonavir/ cobicistat boosting of PI
- Both are strong inhibitors of CYP 3A4
- Both used at low dose to “boost” concomitant PI serum levels to achieve higher trough levels
- Allows for less frequent dosing
Ritonavir/cobicistat regimens & steroids important
Fluticasone (inhaled, intranasal)
- Extensively metabolized by CYP3A4
- Increased fluticasone plasma concentration & decrease plasma cortisol concentration
- Can cause sx of corticosteroid excess including Cushing syndrome & adrenal insufficiency (if tx > 14 days)
- Recommend switching to beclomethasone
- *Do not withhold/ delay systemic steroids for tx of acute disease (asthma, COPD)
Ritonavir/cobicistat & statins
- Statins metabolized via CYP 3A4
- Concomitant use of ritonavir w/ atorvastatin may cause significant increases in plasma concentrations of atorvastatin & increase risk of myopathy & rhabdomyolysis
- Management – use lowest dose possible & monitor for signs & sx of myopathy/rhabdo
Limitations to ARV tx safety & efficacy
- Adherence – decreased resistance & improved survival w/ high rates of adherence
- Drug interactions
- Adverse effects
When to switch/ modify ARV tx
- Virologic failure (failure to achieve viral load < 50 copies/mL by 48 weeks or any sustained return of viral load to > 50)
- Causes = incomplete adherence, inadequate ARV potency, development of drug resistance, failure of drugs to reach target site
- Toxicity
- Difficulty adhering to regimen
- Suboptimal current ARV regimen
Define opportunistic infections (OIs)
Infections that are more frequent or more severe b/c of immunosuppression
Influence of HAART on OIs
- OIs directly related to overall immune function (CD4+ T cells)
- HAART reduces OIs & improves survival, independent of antimicrobial prophylaxis
- Doesn’t replace need for antimicrobial prophylaxis in severe immune suppression
Management of OI for pt taking no ART
- OI normally presenting sx of HIV; leads to test for HIV
1) Start tx for OI (if tx exists)
2) Start HAART during tx of acute OI - Timing of start of HAART dependent on particular OI
Immune reconstitution inflammatory syndrome (IRIS)
- Hyperactivity of immune system after initiation of ARV therapy that recognizes a dormant infection or worsens current infections (why you look for signs of other infections before starting ARVs)
- Characterized by fever, worsening clinical signs of OI or sx of new OI
- Occur in first weeks after starting ARV
- May occur w/ PCP, hep B/C, tuberculosis, etc.
Managing acute OIs in the setting of ART
1) OI occurs shortly after initiation (w/in 12 weeks) of ART
- Start tx for OI & continue ART
2) OI occurs > 12 weeks after ART initiation in px w/ CD4 count > 200 & suppressed HIV RNA
- May be difficult to determine whether IRIS or new OI due to incomplete immunity
- Start tx for OI, continue ART
- Consider modifying ART if CD4 response to ART is suboptimal
3) OI in pt w/ immunologic & virologic failure on ART
- Start tx for OI & modify ART for better virologic control
Describe mucocutaneous candidiasis as an OI w/ HIV
- Usually caused by Candida albicans
- Oropharyngeal & esophageal are common (most common in px w/ CD4 count < 200, but can occur at higher CD4 counts)
Tx of mucocutaneous candidiasis
Treat for 7-14 days w/ oral fluconazole (bactericidal, more convenient & generally better tolerated compared to topical)
Prophylaxis for mucocutaneous candidiasis
Routine primary prophylaxis not recommended
Primary vs. secondary prophylaxis
- Primary prophylaxis = prevention before development of disease
- Secondary prophylaxis = prevention of re-occurrence (after tx of OI)
Describe PCP pneumonia
- Cause by pneumocystis jiroveci
- Common in the environment (2/3 of healthy children have antibodies by age 2-4 y/o)
- PCP may result from reactivation or new exposure
- Most common life-threatening OI
- Majority of cases occur among px who are unaware of their HIV infection or aren’t receiving ongoing HIV care or among those w/ advanced immunosuppression (CD4 < 200)
PCP tx
- Untreated = 100% mortality (can’t clear it w/o tx)
- Tx started before definitive diagnosis
- Tx duration = 21 days
- Tx of choice = TMP/SMX 15-20 mg/kg/day (TMP) IV
- Can use oral TMP-SMX for mild-to-moderate disease
- If not on ART, initiate w/in 2 weeks of diagnosing PCP (when possible, if signs of clinical improvement)
PCP – primary vs. secondary prophylaxis
- Initiate primary prophylaxis in px CD4 < 200 or hx of oropharyngeal candidiasis
- Primary/secondary prophylaxis for life unless immune reconstitution on ART
- Preferred = TMP/SMX 1 DS or SS tab daily
- Alternative = TMP/SMX 1 DS tab 3 times/week
- D/c prophylaxis in px on ART w/ sustained increase in CD4 count > 200 for at least 3 months
- Restart maintenance therapy if CD4 count decreases to < 200 or if PCP recurs at CD4 count > 200
Describe toxoplasma gondii encephalitis
- Must have really weak immune system for this to develop
- Disease usually caused by reactivation of latent tissue cysts
- Primary infection may be associated w/ acute cerebral or disseminated disease
- Primary infection acquired from tissue cysts in raw or undercooked meat
- Rarely occurs in px w/ CD4 > 200; primarily occurs in px w/ CD4 < 50
- Clinical presentation – fever, headache, CT/MRI shows multiple lesions often w/ edema; need definitive diagnosis through detection of organism by brain biopsy
Toxoplasma gondii encephalitis – tx
- Preferred = pyrimethamine + sulfadiazine + leucovorin
- TMP-SMX can be considered if valid reason not to use preferred regimen
- Duration = > 6 weeks
Toxoplasma gondii encephalitis – primary prophylaxis
- Primary if CD4 < 100 & positive IgG T. Gondii serology -> TMP/SMX 1 DS tab daily
- D/c primary if CD4 count > 200 for > 3 months on ART
- Reintroduce if CD4 count decreases to < 100
Mycobacterial infections tx and drug interactions
- Tx = concomitant but staggered start of HAART in pt not already on HAART due to adverse effects from meds & risk of severe IRIS (start of HAART based on CD4 count)
- Significant drug interactions between ARV & TB meds (need to modify TB meds or HAART)
Describe mycobacterium avium complex
- Organisms very present in environment
- Generally, occurs among px w/ CD4 counts < 50
Describe disseminated MAC tx
- Initial tx followed by chronic maintenance therapy
- Initial tx (> 12 months) at least 2 effective drugs (to prevent resistance)
- Preferred = clarithro 500 mg BID + ethambutol 15 mg/kg daily
- Alternative = azithro 500-600 mg daily + ethambutol
- If not on ART, initiate ASAP after effective tx
Disseminated MAC – primary prophylaxis
- Indication = CD4 count < 50
- Azithro 1200-1250 once weekly
- D/c in pt on ARV when CD4 > 100 for > 3 months
Disseminated MAC – prevention of recurrence/ secondary prophylaxis
- Lifelong chronic maintenance therapy after completion of initial tx unless immune reconstitution on ART
- Consider d/c of secondary if treated > 12 months, no signs & sx, and sustained (> 6 months) increase in CD4 count to > 100
- Restart secondary if CD4 count decreases to < 100
