7487 Week 3, Day 1 HIV PPT (NEWSOME)

What are the signs and symptoms of HIV?
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What are the signs and symptoms of HIV?
Most Common:
- fever
- HA
- sore throat
- fatigue
- GI upset
- weight loss
- myalgia
- morbilifor or maculopapular rash usually involving the trunk
- lymphadenopathy
- night sweats

Less Common:
- aseptic meningitis
- oral ulcers
- leukopenia

Other:
- high viral load
- persistent decrease in CD4 lymphocytes

**HIV can present as the "worst flu ever", then can be asymptomatic for years
**AIDS can present with the rash, weight loss, and other more advanced symptoms
HIV POC tests are testing for...
antibodies (not the actual virus)

**a negative POC test does not mean the patient does not have HIV, it means they don't have the antibodies (may take up to six months to develop)
What type of virus is HIV?
retrovirus

**GP-120 and GP-41 are used for attachment, along with CCR-5 and CCX-4
What parts of the viral cell life cycle do HIV medications interfere with?
Entry Inibitors:
- fusion and penetration inhibitors (e.g., enfurvitide, fostemsavir, ibalisumab-uiyk)
- chemokine antagonists (e.g., maraviroc)

Reverse Transcription Inhibitors:
- reverse transcriptase inhibitors (e.g., efavirenz, rilpivirine, abacavir, tenofovir, emtricitabine)

Integration, Transcription, and Translation Inhibitors:
- integrase inhibitors ("-gravir"s)

Viral Maturation Inhibitors:
- protease inhibitors ("-navir"s)

Capsid Assembly Inhibitors:
- GS-CA1
What drug classes are used for HIV treatment?
- NRTIs
- NNRTIs
- protease inhibitors (PIs)
- integrase strand transfer inhibitors (INSTIs)
- entry inhibitors
- fusion inhibitors
What are the first-generation NRTIs?
- didanosine
- stavudine
- zidovudine

**not usually used (except zidovudine for neonatal transmission during pregnancy from infected mother)
What are the second-generation NRTIs?
- tenofovir (disoproxil or alafenamide)
- abacavir
- emtricitabine
- lamivudine

**cornerstone of ART regimens (usually have two of these drugs in each regimen)
What are some toxicities associated with NRTIs?
mitochondrial toxicities:
- peripheral neuropathy
- pancreatitis
- lipoatrophy
- myopathy
- anemia
- lactic acidosis

**these are more common with first-generation NRTIs
What important factors must be considered before using abacavir?
- HLA-B*5701 testing should be done prior to initiating therapy (cannot use for positive results; monitor/counsel if negative)
- metabolized by alcohol dehydrogenase (competes with alcohol; may increase concentrations of either)
- avoid in CVD (associated with MI)
What should be done for patients on NRTIs who also have HBV?
NRTIs with activity against HBV should not be interrupted or discontinued in patients with HBV co-infection.

**use NRTIs that have activity against both (e.g., tenofovir, emtricitabine)
What should be considered before starting a patient on emtricitabine?- may cause hyperpigmentation of palms and solesDifferentiate tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF).- TAF is newer - TDF is associated with a higher risk for bone demineralization and renal impairment (both may cause it, TDF has a higher risk; use TAF in patients that require tenofovir but have CKD, osteoporosis, etc.) - TDF is contraindicated with probenecid - TDF is formulated with lactose - TAF requires CrCl ≥30 - TDF requires CrCl ≥60What are the second-generation NNRTIs?- doravirine - etravirine - rilpivirineWhat are the older NNRTIs?- delavirdine - efavirenz - nevirapineDescribe the NNRTIs.- second-generation have higher potency, longer half-lives, and reduced ADR profiles - low genetic barrier except etravirine (resistance develops easily; do not use in non-adherent patients) - all are substrates of CYP3A4 - rilpivirine requires an acidic environment for absorption (avoid concurrent use with QT-prolonging drugs and take with a meal; no PPIs, but may use antacids/H2RAs with separation of dosing times) - etravirine should be taken with a mealDescribe protease inhibitors.- "-navir"s - GI intolerance and lipodystrophy are common ADRs (also glucose level changes, fat maldistribution, buffalo hump, etc.) - avoid with agents associated with PR- and QT-interval prolongation - all PIs are extensively metabolized by CYP3A4 (ritonavir is a potent inhibitor of 3A4 and is given with all PIs) - high genetic barrier drugs - often used for people who failed therapyWhat should be considered before starting a patient on atazanavir?- main PI in clinical practice - requires an acidic environment for absorption (no PPIs; separate antacids/H2RAs per instructions in guides) - does not appear to be associated with dyslipidemia or hyperglycemia like other PIs (better choice for CVD, DM, etc. if PIs are needed)What should be considered before starting a patient on darunavir?- main PI in clinical practice - contains a sulfa moiety - take with a mealWhat should be considered before starting a patient on tipranavir?- contains sulfonamide moiety - inhibits and induces CYP3A4 - supplemental Vitamin E is contraindicated with the oral solution - increased risk of intracranial hemorrhage when used with ritonavirWhat INSTIs are used for HIV/AIDS?- bictegravir - dolutegravir - elvitegravir - raltegravir - cabotegravirWhat should be considered before starting a patient on INSTI-based regimens?- cabotegravir has a very long half-life and is given injection-only (usually used in PREP); other four are given orally - bictegravir/dolutegravir are the strongest (important because if someone develops resistance to the other elvitegravir/raltegravir, they more than likely will still be sensitive to bictegravir/dolutegravir but NOT the opposite - if resistant to bictegravir/dolutegravir, they will be resistant to elvitegravir/raltegravir) - elvitegravir is a major CYP3A4 substrate à must be given with cobicistat (no activity against HIV) or ritonavir - separate INSTIs from other polyvalent cations - high genetic barrier drugs - dolutegravir inhibits the renal organ cation transporter OCT2How should INSTIs be separated from polyvalent cation-containing compounds?- bictegravir should be separated by 2 hours before or after dose - other oral agents should be separated by 2 hours before or 6 hours afterDescribe the entry/fusion inhibitors used for HIV/AIDS.- last-line - not the basis of any therapy - enfurvitide binds to gp41 (prevents attachment) - ibalizumab blocks HIV by causing conformational change (prevents gp/CCR binding) - maraviroc is a CCR5 antagonist (prevents binding) **must do a tropism test before initiating maraviroc (if no activity against the receptor, it will not work)What are the initial characteristics to consider in all people with HIV?- pre-treatment HIV viral load (ripilvirine cannot be used if >100,000 copies; two-drug regimens require <500,000 copies) - pre-treatment CD4 count (CD4 <200 is AIDS; prophylaxis is often started) - prior hx of cabotegravir for PrEP (long-acting; if they received cabotegravir and still got HIV, then a specific type of regimen must be used) - HIV genotypic drug resistance test results (test for mutations in reverse transcriptase and protease genes; test for INSTI resistance → if treatment-naive, start empiric therapy; if treatment-experienced and failed, must have resistance test results) - HLA-B*5701 status (positive results should not receive abacavir) - individual preferences - anticipated adherence (no NNRTIs for poor adherence due to low genetic barrier) - timing of ART initiation after diagnosisWhat drugs should you not use if the patient presents with the following conditions? I. osteoporosis II. CVD III. DM IV. dyslipidemia V. CKD VI. psychiatric illness VII. drug abuse/dependencyI. tenofovir (definitely not TDF) II. abacavir, PIs increase lipids (except atazanavir) III. PIs worsen glucose control (not contraindicated, but not first-line) IV. PIs increase lipids (except atazanavir) V. tenofovir (definitely not TDF) VI. efavirenz VII. efavirenzWhat are regimen-specific considerations for HIV/AIDS?- barrier to resistance - potential ADRs and toxicities - known/potential drug interactions - convenience - cost and accessWhat are the recommended initial regimens for most people with HIV?all three-drug regimens will have TWO NRTis (backbone of every three-drug regimen) and the most common combos are: - tenofovir disoproxil (TDF) with emtricitabine OR tenofovir alafenamide (TAF) with emtricitabine - abacavir and lamivudine - then add INSTI (first-choice; bictegravir/dolutegravir preferred) OR PI (second-choice; atazanavir/darunavir preferred) OR NNRTI (last-line due to high resistance) **two-drug regimens are never a go-to unless there are specific issues such as adherence or they are well-controlled and patient requests, etc. usually always do three-drug regimens **two-drug regimens are usually 1 NRTI and 1 INSTI (viral load must be <500,000 copies to use; no HBV coinfection, and you must have resistance-testing)What regimen should be given to someone who was treated with cabotegravir but still got HIV?- must get resistance testing - if provider wants to start a regimen prior to resistance testing, use DRV/cb or DRV/r with (TAF or TDF) plus (emtricitabine or lamivudine) **DRV = darunavir **cb = cobicistat **r = ritonavirWhat drugs should be first choice for patients in which first-line options will not work?- atazanavir - darunavirWhat is considered virologic failure?- inability to achieve or maintain a viral load <200 copies/mL **resistance testing must be doneWhat is salvage therapy?- used for virologic failure - resistance testing must be done - should include a boosted PI (PI with ritonavir or cobicistat) + 2 NRTIs **if patient failed raltegravir/elvitegravir, you can use bictegravir/dolutegravir instead of a boosted PIWhat is considered treatment failure?- inability to reach undetectable (<50 copies/mL) viral loadsWhat is the preferred regimen for pregnant patients with HIV/AIDS?2 NRTIs as a backbone PLUS: - dolutegravir - raltegravir - atazanavir - darunavir **bictegravir has not been studied enough **elvitegravir was associated with more complicationsDifferentiate PrEP and PEP.PrEP: - pre-exposure, high-risk behaviors - given to HIV-negative, at-risk patients - only approved treatments are Truvada (TDF + emtricitabine), Descovy (TAF + emtricitabine), and cabotegravir - must be adherent due to high chance of developing resistance PEP: - post-exposure - ideally initiated within 1-2 hours of exposure - true regimen (INSTI + 2 NRTIs) - treats patients as if they have HIV - duration of therapy should be for 28 days or until suspect is proven negativeHow should patients on ART therapy be monitored?- monitor viral load and CD4 count/percentage every 3 months until levels are undetectable - may increase to every 6 months once stabilized (<50 copies/mL) - if CD4 >350, therapy is working (though >500 is the technical point) - need both viral load <50 copies/mL and CD4 >350 to drop to 6 monthsWhat makes someone a "non-progressor"?- people with high viral load count, but also continue to have high CD4 counts - usually due to mutations in CCX4 or DDR5 receptorsWhat makes someone a "lead controller"?- people for whom the viral load always stays low/undetectable without therapy