CDM III Exam III Study Guide.docx

Exam Date: December 14, 2023 Viral Hepatitis- Dr. Lancaster (November 2, 2023) Hepatitis types A (HAV): RNA Picornavirus, foodborne B (HBV): Hepadanavirus, more virulent, higher resistance, bloodborne C (HCV): Flavivirus, more virulent, higher resistance, bloodborne D: hepatitis delta virus, uncomm...

Exam Date: December 14, 2023 Viral Hepatitis- Dr. Lancaster (November 2, 2023) Hepatitis types A (HAV): RNA Picornavirus, foodborne B (HBV): Hepadanavirus, more virulent, higher resistance, bloodborne C (HCV): Flavivirus, more virulent, higher resistance, bloodborne D: hepatitis delta virus, uncommon, bloodborne E: non-enveloped , single stranded RNA virus, uncommon, foodborne Hepatitis C 6 major genotypes: 1A, 1B, and 2 are most common in north america and western europe Risk factors: IVDU, people with HIV, patient who received blood transfusions before 1992, healthcare professionals with blood exposure to someone with HepC, liver disease symptoms, babies of mothers who have HepC, prision, tattoos/piercings with unclean equipment ⅓ of all IVDU age 18-30 have HepC, screening should be every 6-12 months Clinical presentation: latency is 4-12 weeks (but can be 2-24 weeks) 30% of patients experience mild symptoms Less than 20% will get jaundice (ALT levels may be over 10x ULN) 15-50% of patients infected will ultimately be unaffected and just clear the virus Serology HCV-antibodies (Anti-HCV): immunoassay that identifies a positive seroconversion of the HCV antibody in the serum ~50% will be unaffected by the virus and clear it normally HCV-RNA: presence in the serum indicates an active infection Threshold = 15 IU/mL A diagnosis of chronic HepC is when anti-HCV and HCV-RNA are present and detectable for 6+ months Prior to invitation of therapy, the patient must be asses for NS5A resistance (~15%) Treatment Options NS5A inhibitors (“-asvir”): assembly/replication Elbasvir Ledipasvir Daclatasvir Ombitasvir Pibrentasvir Velpatasvir AS5B inhibitors (“-buvir”): genome replication Sofosbuvir Dasabuvir NS3 inhibitors (“-previr”): polyprotein processing Glecaprevir Grazoprevir Simeprevir Paritaprevir Simplified HCV Treatment Eligibility: 18+ who have not been treated for HCV yet and do not have cirrhosis Exclusion criteria: HIV or HBsAg positive (co-infection), pregnancy, prior liver transplantation, hepatocellular carcinoma (known or suspected), cirrhosis (known or suspected) Options: Mavyret (glecaprevir 300 mg/pibrentasvir 120 mg), 8 weeks Epclusa (sofosbuvir 400 mg/velpatasvir 100 mg), 12 weeks Pediatric HCV management Eligibility: 3-17 years with genotype 1, 4, 5, or 6 HCV, OR 6-17 years with any genotype Treatment-naive or IFN-experienced without cirrhosis or ascites, hepatic encephalopathy, variceal hemorrhage, jaundice Options (weight based): Mavyret (glecaprevir/pibrentasvir), 8 weeks Can extend to 16 weeks if IFN experienced with genotype 3 Epclusa (sofosbuvir/velpatasvir), 12 weeks Harvoni (ledipasvir/sofosbuvir), 12 weeks Mavyret (glecaprevir + pibrentasvir): pan genotypic, once daily, ribavirin-free Can be given as short as 8 weeks of treatment naive, non-cirrhotic patients Must be given with food to increase absorption Contraindications: concurrent use of atazanavir or rifampin, atorvastatin, simvastatin, rosuvastatin > 10 mg Drug interactions: Moderate- H2RA, PPI, apixaban, edoxaban, rivaroxaban, ticagrelor, warfarin, enalapril, eplerenone, irbesartan, isradipine, Non-DHP CCBs, olmesartan, telmisartan, ezetimibe, fluvastatin, gemfibrozil, pitavastatin, pravastatin, rosuvastatin Contraindicated- dabigatran, aliskiren, atorvastatin, simvastatin, lovastatin Epclusa (sofosbuvir + velpatasvir): fixed dose once daily for 12 weeks Can be taken with or without food Contraindications: P-gp inducers, any CYP inducers, rosuvastatin > 10 mg (monitor other statins) Drug interactions: Moderate- antacids, H2RA, PPI, apixaban, dabigatran, edoxaban, rivaroxaban, ticagrelor, warfarin, diltiazem, atorvastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin Harvoni (ledipasvir + sofosbuvir): single tablet regimen for 12 weeks Can be given as short as 8 weeks if baseline HCV RNA < 6 million IU/mL Contraindications: concurrent use of p-gp inducers and CYP3A4 inducers, acid suppression therapy (if the patient must be on them, separate by 12 hours), rosuvastatin Therapeutic Monitoring During treatment: every 4 weeks (CBC, INR, hepatic function, GFR) At the end of treatment (usually at week 8 or 12): detects treatment resistance Pregnancy: identify pregnant patients prior to treatment Children: testing for children born to mother with HCV should be test at 18 months and 36 months to confirm clearance Hepatitis B 10 genotypes: A-C is most common in the US High risk: IVDU, multiple sex partners, surgery, MSM, sexual contact, needlesticks, household contact, occupational, dialysis, transfusion Pre-exposure prophylaxis: vaccination! Various schedules exist ranging from 2-4 doses Over 90% effective after the third dose Recommended for non vaccinated adults age 19-65, at risk 60+ year olds Post-vaccination serologic testing should be done in infants born to positive mothers, healthcare workers, public safety workers, chronic HD patients, HIV+, immunocompromised, sex partners of chronic HBV patients Non-occupational HBV exposure HBsAg-Positive Source Exposed person’s status Hep B vaccine HBIG Notes Completed vaccination course Yes, if no post-vaccination testing or level of anti-HBs is not 10+ No Vaccinate again if there was little or no response to the vaccine series (or unknown) Incomplete vaccine schedule Yes, complete regular schedule Yes, x1 Unvaccinated Yes, first dose now, complete at regular schedule Yes, x1 Risk of transmission is minimal if the source is not positive Hepatitis B specific Immune globulin (HBIG): provides passive anti-HBs and acute protection for 3-6 months HBV vaccine: three doses (1, 2, and 6 months), first dose should be administered within 12-24 hours after exposure, vaccine brands are interchangeable if necessary Diagnosing CHB: HBsAg + for at least 6 months Serum HBV DNA may range from undetectable to over 2 million ALT, AST, biopsy: may be normal or elevated ULN for ALT = 80-100 If the patient is under 2x ULN, consider age > 40, family history of cirrhosis, prior treatment, biopsy results Monitoring Treatment Response Sustained virologic response Less than 2000 IU/ML, HBeAg-, ALT normalized Evaluate at treatment start, every 3 months until undetectable, then 3-6 months afterwards Treatment options (for patients without HIV co-infection) Interferon-a (Intron, IFN-a) Injection Less resistance than other options MOA: increased phagocytic activity of macrophages, suppression of cell proliferation, inhibition of virus replication in infected cells Baseline ALT level in HBeAg+ can predict response BBW: neuropsychiatric, autoimmune, ischemic, infectious HBeAg+ = 12-24 weeks HBeAg- = 12+ months Can cause influenza-like illness, anorexia, fatigue, myelosuppression Pegylated Interferon-a-2a (Pegasys, pegIFN-a) Injection Less resistance than other options MOA: increased phagocytic activity of macrophages, suppression of cell proliferation, inhibition of virus replication in infected cells Baseline ALT level in HBeAg+ can predict response BBW: neuropsychiatric, autoimmune, ischemic, infectious Duration: 48 weeks Can cause influenza-like illness, anorexia, fatigue, myelosuppression Entecavir (Baraclude) Oral nucleoside analog MOA: inhibit reverse transcriptase inhibitor, causing chain termination Highest efficacy (over IFN products) Tenofovir disoproxil fumarate (Viread, TDF) Oral nucleotide analog MOA: inhibit reverse transcriptase inhibitor, causing chain termination Better safety in pregnancy, initiate in weeks 28-32, discontinue 0-3 months after delivery More effective in HBeAg- patients Highest efficacy (over IFN products) Tenofovir alafenamide (Vemlidy, TAF) Oral nucleotide analog MOA: inhibit reverse transcriptase inhibitor, causing chain termination More effective in HBeAg- patients Highest efficacy (over IFN products) When to treat? Patient is HBsAg+ and HBeAG+ and ALT > 2x ULN: treat when HBV DNA > 20,000 IU/mL Patient is HBsAg+ and HBeAG- and ALT > 2x ULN: treat when HBV DNA > 2,000 IU/mL TDF/TAF has better efficacy in these patients Children with ALT > 1.3x ULN IFN: given to children > 1 year Entecavir: given to children > 2 years Peg-IFN: given to children 5+ years TDF: children > 2 years (TAF not recommended due to lack of data) Combination therapy is not supported by the guideline Treatment prior to immunosuppressive therapy: screening should be done for all patients receiving immunosuppressive therapy (including prednisone 20 mg/day for over 4 weeks) Highest risk of reactivation with anti-CD20 (rituximab) and glucocorticoid use Treatment naive: tenofovir* (preferred) or entecavir Treatment experienced: tenofovir > entecavir (especially if prior lamivudine use) Continue treatment for at least 6 months post-withdrawal of immunosuppressive agents If the patient is on anti-Cd20 agents (rituximab), then continue for 12 months after withdrawal Hepatitis A Genotypes 1-3 are most common in the US Clinical presentation: acute anorexia, nausea, vomiting, malaise, fever, RUQ pain Jaundice or bilirubin levels > 3 or ALT > 200 Pre-exposure management: vaccine 2 dose series at time 0 and repeated no sooner than 6 months, very high efficacy Pre-exposure management: immune globulin Indicated for patients traveling to countries with intermediate-high risk of HAV, patients over 65, immunocompromised, chronic liver disease Administered in conjunction with HAV vaccine if travel starts within 2 weeks HAV Post-exposure prophylaxis Exposure identified within 14 days: household and sexual partners, persons sharing injectable medications/drugs, food handlers, multiple cases have been identified within the family Exposure identified after 14 days: symptomatic care, watchful waiting If the patient was previously unvaccinated or has unknown vaccination status Under 1 year or over 40: give immune globulin Between 1-40 years: give vaccine Do not give immune globulin with other live vaccines (wait 3 months for MMR and 5 months for varicella) The HAV vaccines can be interchanged if needed, protection is incurred within 4 weeks after the first dose (second dose is given 6-12 months after) Neutropenic Fever- Dr. Skirvin (November 6, 2023) Neutropenia: patients with an absolute neutrophil count (ANC) less than 1,500 cells/mm Severe neutropenia < 500 Profound neutropenia < 100 Common in oncology/hematology patients, HIV patients, immunosuppressed patients, congenital neutropenia, aplastic anemia Neutropenic fever: fever > 101 F (38.3 C) once OR fever > 100.4 F (38 C) for one hour, plus neutropenia ANC = WBC (cells/mm) * (% neutrophils (“segs”) + % bands) Convert WBC to thousands if needed (i.e. 1.2 = 1,200) Pathophysiology: stem cells in bone marrow are suppressed via radiation, chemotherapy, disease, infection Cell-mediated immunity is impaired because there are too few neutrophils to fight off the infection Opportunistic infections occur Diagnosis: History & Physical Clinical signs of infection Allergies Cultures Culture before antibiotics start, two sets of blood cultures Also culture urine, stool, and sputum, in addition to skin lesions CXR: look for pulmonary infiltrates Risk factors: impaired host defenses (surgical sites, IV lines, mucositis, radiation) and neutropenia Etiology of Infections ~60% of cultures are negative If the culture is positive: Gram positive is the most common infections (60-70%) Staph aureus, staph epidermidis, strep pneumo, enterococcus spp. Gram negatives are less common (30-40%) P. aeruginosa, Klebsiella pneumoniae, E. coli, Enterobacter, Citrobacter, Serratia, Acintobacter Initiating Antibiotic Therapy Majority of the patients who develop neutropenic fever have no identifiable site of infection and no positive culture results Recommendation is that patients should urgently receive antibiotics within 2 hours of presentation because infections can progress rapidly to death in these patients Target initial therapy to cover gram negatives (E. coli, klebsiella pneumoniae, and pseudomonas aeruginosa) and MSSA Use clinical judgment to determine if the patient is at risk for MRSA Viral coverage is not generally necessary unless the patient has severe mucositis- then add acyclovir for HSV Covering fungal pathogens can be done if the patient has thrush (use targeted therapy) or if the patient has had a fever for over 5-7 days after initiation of antibiotics Risk Assessment High risk: over 7 days of duration, profound neutropenia (less than 100), comorbid conditions (hypotension, pneumonia, new onset abdominal pain, neurologic changes), MASCC < 21 High risk patients should be hospitalized Low risk: less than 7 days of neutropenia expected, no or few comorbidities, MASCC > 21 Low risk patients can be treated outpatient Prognosis: ⅕ patients with neutropenic fever will have serious medical complications that correlate with the duration and severity of the neutropenia Initial Treatment Options Monotherapy Carbapenems (Meropenem or Imipenem) Ceftazidime or Cefepime Piperacillin/Tazobactam Antipsuedomonal penicillin + aminoglycoside Antipsuedomonal cephalosporin + aminoglycoside Antipsuedomonal cephalosporin + antipseudomonal penicillin Antipsuedomonal cephalosporin + aztreonam Good for patients with renal impairment Aminoglycoside + fluoroquinolone Good for patients with penicillin or cephalosporin allergy Oral therapy: When to Use Low risk patients can use oral therapy: no comorbidities, no other acute issues or interventions, does not require hospitalization Oral options Ciprofloxacin 750 mg PO q12h Augmentin 875 mg PO q12h Up to 50% of patients will fail antibiotics and require hospitalization and IV antibiotics Failure is defined as continued fever or acute signs of infection developing Vancomycin as Empiric Therapy Indicated for patients with a history of MRSA or patients with high suspicion and catheter-related signs and symptoms Re-evaluation of fever, ANC, culture results happens daily Afebrile: continue therapy until ANC > 500-1000 cells Febrile days 1-4 of ABX: continue current ABX or rotate to another ABX If the culture results show a resistant organism, adjust the antibiotic regimen as needed Most patients will continue to have fevers. If the patient has no signs of sepsis, continue the antibiotic course Dosing (Normal renal function) Antipseudomonal penicillin: Piperacillin/Tazobactam 3.375 g or 4.5 g IV q4h Ticarcillin/clavulanic acid 3.1 g IV q4h Cephalosporins: Ceftazidime or Cefepime 2 g IV q8h Cefoperazone 1-2 g IV q12h Imipenem/cilastatin 500 mg IV q6h Meropenem 1 g IV q8h Aztreonam 1-2 g IV q8h Levofloxacin 500-750 mg IV q24h Ciprofloxacin 400 mg IV q8h Antibiotic resistance MRSA Vancomycin, Linezolid, Daptomycin VRE Linezolid, Tedizolid, Daptomycin ESBL Carbapenems (Meropenem or Imipenem) KPC Polymyxin-colistin or tigecycline Severe penicillin allergy Treat with a combination that avoids beta-lactams Ciprofloxacin + clindamycin Aztreonam + vancomycin Cefepime General treatment measures- good handwashing, avoidance of invasive procedures, avoidance of fresh fruits and vegetables, plants, flowers, smoking Systemic Prophylaxis Bacterial: Ciprofloxacin 500-750 mg PO BID (limited data) Fungal: Fluconazole 400 mg PO QD Viral: seronegative patients should avoid other patients who are ill Colony stimulating factors (CSF) Continue filgrastim or peg-filgrastim if the patient has already been on it Not routinely recommended to start in adjunct to antibiotics in NF patients If the patient has declining clinical status or ANC < 100, start CSFs CSFs Filgrastim: bone pain, fever, rash, irritation at injection site Peg-filgrastim: bone pain, fever, rash, irritation at injection site Sargramostim: fever, edema, arthralgias, bone pain, lethargy, rash, pericarditis Biosimilars for CSFs are available Diarrhea Watch patient for foul smelling, watery stools and confirm with immunoassay Treatment: most patients should receive metronidazole PO, vancomycin PO can be used in severe cases, cases resistant to metronidazole, or patients with history of c. diff. If the patient does not have C. diff: loperamide Alternative: octreotide or tincture of opium Oral candidiasis (Thrush) Nystatin (5 mL PO QID) Clotrimazole troche (five times daily) Fluconazole (100-200 mg PO QD) Posaconazole (100 mg PO BID for one day, then QD) Systemic fungal infections Suspected either early on in therapy when the patient presents with thrush associated with neutropenia (topical) or after 5-7 days of antibiotic therapy with neutropenia and fever (systemic) Systemic infections are likely Aspergillus spp. Fungal serum diagnostics: Aspergillus galactomannan antigen testing and beta-1(1-3)-D-glucan assay Three treatment options: Liposomal Ampho B ADEs: LFT elevation, anemia, rash, allergic reaction, nephrotoxicity, hypokalemia, hypomagnesemia, fever, chills, infusion related reaction Premedicate the patient with acetaminophen, diphenhydramine, and corticosteroids Caspofungin or Micafungin First line! No renal dose adjustments Hepatic dose adjustments required ADEs: rash, fever, GI upset, edema (caspofungin), LFT elevation (micafungin), anemia (micafungin) Voriconazole First line! Do not use fluconazole, it is not broad enough for reliable coverage Alternative: itraconazole, posaconazole Prevention of Neutropenia with chemotherapy Dosage reduction of the chemotherapy Choose this if the goal of chemotherapy treatment is to reduce symptoms Reduce chemotherapy dose by 10-25% Addition of growth factors as a secondary prophylaxis measure Choose this if the goal of chemotherapy treatment is to cure the patient Maintains the dosage of chemotherapy Transplant Immunosuppression & Complications- Dr. Le and Dr. Joyal (November 13-15, 2023) Role of the Pharmacist Pre-transplant: selection meetings, pre-transport evaluation, extensive medication review, education, identifying barriers to transplant Peri-transplant: multidisciplinary team, daily rounds, IS management, medication education at time of discharge, assist with discharge planning Post-transplant: medication reconciliation, medication access, protocol adherence, drug information questions, post-transplant patient management meetings Reasons for transplant Kidneys = diabetes Liver = non-alcoholic steatohepatitis (NASH) Pancreas = diabetes Heart = cardiomyopathy Lung = idiopathic pulmonary fibrosis United Network for Organ Sharing (UNOs) is responsible for the allocation of organs in the US, and maintains the “waiting list” 11 total regions The immune system has 3 layers of defense: surface barriers (skin, acidic stomach), innate (present from birth, non memory, non-specific, response in hours), adaptive (specific memory, response time is days, includes cellular immunity (T cells) and humoral immunity (B cells)) Adaptive immune system is the focus of transplant immunosuppression T- cells can be activated by: Signal 1: recognition Signal 2: co-stimulation Signal 3: proliferation Goal of immunosuppressive agents Prevent rejection Preserve graft function Quality of life More rejection to less rejection Small bowel Lung Heart Pancreas Kidney Liver There are three categories of immunosuppressive agents: induction agents, maintenance agents, and rejection treatment agents Induction agents: decrease the rate of acute rejection T-cell depleting T-cell non-depleting Monoclonal antibodies Alemtuzumab (Campath) Basiliximab (Simulect) Polyclonal antibodies Equine anti-thymocyte globulin (ATGAM) Rabbit anti-thymocyte globulin (thymoglobulin) N/A Basiliximab (Simulect): T-cell non-depleting monoclonal antibody MOA: binds to CD25 on the surface of activated T cells preventing IL-2 mediated activation and T-cell proliferation (signal 3) Can be given via any line as a 30 minute infusion, no premedication necessary Well-tolerated, 30-40 day effect Used as an alternative for patients who are at low immunologic risk or in patients with known intolerance to other agents Can also be used for CNI holiday or delayed-initiation (not kidney transplants) Anti-thymocyte globulin (Horse and Rabbit): T-cell depleting polyclonal antibody MOA: inhibition of signal 1 Rabbit (rATG, Thymoglobulin) causes both T-cell depletion and has effects on b-cells and dendritic cells Weight based dosing, induction is 3-5 doses whereas rejection is 5-7 doses Central line administration preferred, the patient MUST be premedicated with steroids, diphenhydramine, and acetaminophen ADEs: leukopenia, thrombocytopenia, malignancy, infection, infusion related reactions, serum sickness If WBC 2-3 or platelets 50-75 = half the dose If WBC < 2 or platelets < 50 = hold the dose Infusion-related reactions: occur with the first or second infusion, usually fever, chills, rigor, dyspnea, hypo/hypertension, malaise, rash, headache. Consistent with cytokine release syndrome Serum sickness: 7-10 days after exposure, includes fever, myalgia, arthralgias, malaise, lymphadenopathy, urticaria, rash, renal dysfunction Lasts 2-3 months (up to one year) FDA approved for induction and rejection, most commonly used induction agents, cannot be used in patients with a rabbit allergy Alemtuzumab (Campath): T-cell depleting monoclonal antibody MOA: acts against the CD52 receptor and binds to T and B lymphocytes, macrophages, monocytes, and NK cells Given once at transplant Premedication with corticosteroids, diphenhydramine, and acetaminophen is required ADEs: leukopenia, malignancy, infection, infusion reactions Depletion of leukocytes may last up to 1 year Must be grandfathered into the Campath Distribution Program (then the drug is free) Choosing an induction agent Thymoglobulin or Campath: high risk (young, autoimmune diseases, steroid withdrawal) Simulect: preferred in low immunologic risk patients (sibling/parent donor, patients over 70 years, prior cancer or infection, prior organ transplant) Maintenance Immunosuppression: 5 classes Drug Class Available agents Calcineurin inhibitors Tacrolimus (Prograf, Astagraf XL, Envarsus XR) Cyclosporine (Neoral, Sandimmune) Mammalian target of rapamycin (mTOR) inhibitors Sirolimus (Rapamune) Everolimus (Zortress) Costimulation blockers Belatacept (Nulojix) Antiproliferatives Mycophenolate mofetil (Cellcept) Mycophenolic acid (Myfortic) Azathioprine (Imuran) Corticosteroids Methylprednisolone Prednisone Regimens consist of a primary agent + secondary agent +/- tertiary agent Primary: tacrolimus, cyclosporine, belatacept, sirolimus, everolimus Secondary: mycophenolate motil/sodium, azathioprine, everolimus, sirolimus Tertiary: corticosteroids Heart transplant = TAC + MMF + steroid Liver transplant = TAC + steroid +/- MMF Kidney transplant = TAC + MMF + steroid Lung transplant = TAC + MMF + steroid Calcineurin inhibitors: cyclosporine and tacrolimus Tacrolimus: binds to FK binding proteins Prograf = immediate release, Envarsus and Astagraf = delayed release, once daily Oral capsules, can be administered with or without food, as long as it is consistent Trough monitoring is required: correlated with efficacy and toxicity IR Tacrolimus = First line! Use Astagraf in a patient who tacrolimus was too low on 0.5 mg QD and too high on 1 mg QD Envarsus can improve symptoms of neurotoxicity (watch rapid metabolizers!) Drug interactions: CYP3A4 substrate, Astagraf cannot be given with alcohol CYP3A5*1/*1 = extensive metabolizers CYP3A5*3/*3 = poor metabolizers Neurotoxicity Tremor is the most common, 30-50% of patients 10 mg Prograf = 8 mg Envarsus Therapeutic Monitoring Organ 0-6 months 6-12 months Kidney 8-10 6-8 Pancreas 10-12 6-9 Liver 6-8 4-6 Lung 10-12 6-10 Heart 10-12 6-10 Cyclosporine (Neoral, Gengraf): binds to cyclophilin Modified has better pharmacokinetics-use this! Administered twice daily at least 12 hours apart, oral solution can be administered with juice Trough and peak levels are used for monitoring Target peak Target trough 0-2 months 1500 250-350 3-4 months 1300 150-250 4-6 months 1100 150-250 7-12 months 900 100-150 12+ months 800 100-150 Drug interactions: substrate of CYP3A4, inhibitor of P-gp and OATP1B1 IV CNIs: generally avoided due to significant toxicities (anaphylaxis, nephrotoxicity, neurotoxicity) Conversion IV:PO is NOT 1:1 (tacrolimus is 1:3 or 1:5 and cyclosporine is 1:3) Can be given either as a continuous IV over 24 hours or a 2-6 hour infusion BID SL Tacrolimus: when patients are NPO, unable to swallow, or those with severe nausea/vomiting Cut PO dose by 50% Use capsule powder (do not swallow, no food or drink after for 15-20 minutes) Adverse effects Tacrolimus: neurotoxicity, hyperkalemia, hypophosphatemia, hypomagnesemia, alopecia, nephrotoxicity, hypertension, hyperlipidemia, diabetes Cyclosporine: neurotoxicity (less than tacrolimus), hyperkalemia (less than tacrolimus), nephrotoxicity**, hypertension, hyperlipidemia, hirsutism, gingival hyperplasia, diabetes Nephrotoxicity = afferent arteriole Management: preserve renal function and reduce neurotoxicity Mammalian target of rapamycin (mTOR) inhibitors: Sirolimus and Everolimus MOA: inhibition of T cell response to cytokines, inhibits proliferation at the G1 to S phase Brand names: Everolimus (Zortress) and Sirolimus (Rapamune) Sirolimus Once daily, PO tablet or solution Trough monitoring- goal is 5-12 Weekly monitoring due to long half-life Everolimus Twice daily, PO tablet or suspension Trough monitoring- goal is 3-8 Monitoring every 3-5 days Interactions: substrate of CYP3A4 Black box warnings: hepatic artery thrombosis, renal artery thrombosis, bronchial anastomotic dehiscence Usually occur within the first 30 days of transplant Indications: patients who cannot tolerate the side effects of first line therapy, CAV prevention, add on as a fourth agent for refractory rejection, malignancy (skin cancer), viral infections, kidney preservation Not generally included in a standard regimen Management of mTOR related ADEs Pneumonitis = discontinue drug Angioedema = discontinue drug, common with ACEi Proteinuria = avoid use with increased baseline protein/SCr ratio, ACEi may be beneficial here Thrombosis = hepatic and renal arteries, ultrasound before and after initiation Impaired wound healing = avoid de novo use and conversion early in obese patients because the transplant wound will not heal (wait 30 days) Sirolimus causes mouth ulcers that may be related to poor wound healing (within first 2 weeks of initiation) Leukopenia/anemia = avoid in patients with low CBC prior to initiation, may supplement with G-CSF Rash/acne = topical steroid or acne treatment Hyperlipidemia/hypertriglyceridemia = initiate lipid lowering therapy to avoid pancreatitis Drug interactions of CNIs and MTORis: all are CYP3A4 substrates CYP3A4 inhibitors (decrease dose to account for increased exposure) Protease inhibitors or other HIV boosters (ritonavir/cobicistat) Paxlovid -azole antifungals (Vori, Posa, Itra, Keto, Fluc, and Clotrim) Macrolides (erythromycin and clarithromycin) Non-DHP CCBs (diltiazem and verapamil) Grapefruit CBD CYP3A4 Inducers (increase dose to account for decreased exposure) Antiepileptics (phenytoin, carbamazepine, phenobarbital, primidone) Rifamycins (rifampin, rifapentine) Nafcillin St. John’s Wort Additive nephrotoxicity: NSAIDs, aminoglycosides, foscarnet Additive marrow toxicity: Ganicyclovir, Bactrim, Valganciclovir Immunomodulation: echinacea, Vitamin C, Vitamin E Antiproliferatives: Mycophenolate mofetil/Mycophenoolate sodium, Azathioprine MPA inhibits the De novo pathway of purine biosynthesis, which the lymphocytes depend on for replication Mycophenolate mofetil (Cellcept): older product Twice daily, tablet, capsule, suspension, IV (1:1) Rapidly and readily absorbed No monitoring required ADEs: GI intolerance (nausea, vomiting, diarrhea, heartburn), marrow suppression (leukopenia, anemia) PREGNANCY CATEGORY D- REMs Drug interactions: aluminum, magnesium, calcium, phosphate, bile acid sequestrants, PPIs, cyclosporine Mycophenolate sodium (Myfortic): newer product Twice daily delayed release tablet No monitoring required ADEs: GI intolerance (nausea, vomiting, diarrhea, heartburn), marrow suppression (leukopenia, anemia PREGNANCY CATEGORY D- REMs Drug interactions: aluminum, magnesium, phosphate, bile acid sequestrants, PPIs, and cyclosporine 1000 mg Cellcept = 720 mg Myfortic MPA exposure is 30% higher with tacrolimus than with cyclosporine Tacrolimus levels will increase in patients with diarrhea from MPA (usually significant at > 4 episodes/day) Azathioprine (Imuran): alternative to mycophenolate Oral only- tablet Monitoring: thiopurine methyltransferase (TPMT) Lack of TPMT function can lead to high levels of thioguanine nucleotides (TGN), which cause life threatening myelosuppression ADEs: marrow suppression (thrombocytopenia, leukopenia, anemia*) Drug interactions: xanthine oxidase inhibitors Place in therapy is for intolerance to mycophenolate (diarrhea) or pregnancy Drug interaction management Decreased mycophenolate absorption Aluminum, magnesium, calcium, iron phosphate binders (sevelamer carbonate, lanthanum carbonate) Separate by 2-4 hours Interruption of enterohepatic recirculation (mycophenolate) Bile acid sequestrants = avoid Cyclosporine = monitor Sevelamer = separate by 2 hours Decreased mycophenolate absorption (pH dependent) PPIs = monitor Xanthine oxidase inhibition (azathioprine) Allopurinol = avoid, or decrease AZA dose by 67% Febuxostat = contraindicated Co-stimulation blocker: Belatacept (Nulojix) MOA: blocks signal 2 of the costimulation of T-cells No cytokine production, no cell division, undergoes apoptosis Given every 4 weeks during the maintenance phase Dosing is weight based, adjustment if BW fluctuates over 10% in either direction Dose must be divisible by 12.5, IV infusion over 30 minutes ADEs: anemia, diarrhea, constipation, UTIs, edema, hypertension, arthralgia, cough, dyspnea, headache Place in therapy: only approved in kidney transplant (showed preserved eGFR post transplant) Contraindicated in EBV negative patients due to increased risk of CNS post-transplant lymphoproliferative disorder Corticosteroids Exact MOA is not fully understood High dose (> 100 mg prednisone) = directly toxic to T cells Lower dose (< 100 mg prednisone) = nonspecific immunosuppression, decreased t-cell activation Doses vary between institutions (2.5-10 mg), highest doses will be seen at the time of transplant or as a treatment of acute rejection Drug interactions: CYP inducer, variable effects Place in therapy is often started then the patient is titrated off the drug ADEs: euphoria, buffalo hump, hypertension, thinning of the skin, muscle wasting, poor wound healing, easy bruising, avascular necrosis of femoral head, increased abdominal fat, moon face with red cheeks, cataracts, benign intracranial hypertension, osteoporosis, tendency to hyperglycemia, negative nitrogen balance, increased appetite, increased susceptibility to infection, obesity Timeline of rejections 6 months-1 year = acute cellular Greater than 6 months = antibody mediated Chronic = organ specific, mainly cardiothoracic Risk for rejection Sensitized patients Antibodies to the donor prior to transplant (can result from blood transfusions) Pregnancy (higher risk with multiple fathers) Multiple transplants Younger patients Stronger immune systems African american patients Altered kinetics of immunosuppression Higher immune response Non-specific markers for rejection Bump in SCr = kidney transplant rejection Bump in LFTs = liver transplant rejection HF symptoms, fluid overload = heart transplant rejection Shortness of breath = lung rejection Diagnosis of acute cellular rejection requires biopsy for confirmation of diagnosis, but this is very invasive Preventing acute cellular rejection can be helped by the optimal maintenance immunosuppressive regimen Induction therapies + CNIs + Cell cycle inhibitors (mTORs) + steroids Treatment of acute cellular rejection First line: high dose steroid pulse Prednisone or methylprednisolone Alternative: Thymoglobulin (rabbit ATG) Used for more severe rejections Antibody and cellular mediated rejection can occur independently and can coexist If coexisting rejections, utilize treatment options to treat both independently Treatment of antibody mediated rejection Options: High dose IVIG Targets B cells, plasma cells, antibodies MOA: induction of antibody-dependent cellular cytotoxicity via Fc receptor blockade, reduce anti-inflammatory cytokine, neutralization of microbial toxins, b-cell neutralization, t-cell neutralization, regulation of apoptosis SE: infusion reaction (headache)- premedicate with acetaminophen and diphenhydramine Non-O blood type: hemolytic anemia Rituximab (Rituxan) Targets B cells MOA: monoclonal antibody against CD20, which binds to the cell surface antigen and activates complement-dependent B-cell cytotoxicity Requires premedication with acetaminophen, diphenhydramine, and methylprednisolone SE: infusion reaction, HBV reactivation (black box warning- requires labs annually) Bortezomib (Velcade) Targets plasma cells MOA: proteasome inhibitor of 26S Can be given SQ or IVP SE: hepatic function Reduce dose to 750 mg if T bili < 1.5-3x ULN Eculizumab (Soliris) Targets complement MOA: Prevents CS binding IV infusion over 30 minutes, REMs required SE: infusion reactions, encapsulated bacterial infections (meningitis risk) All patients are required to have vaccinations for meningitis or prophylaxis with antibiotics for the duration of therapy Plasmapheresis: removal of plasma and antibodies Cannot be used alone Plasmapheresis and IVIG Non-adherence to medications is the main driver of rejection (both antibody and cellular) Immunosuppression plans must be custom to the patient Chronic rejection is usually less severe Kidneys: chronic allograft nephropathy Prevention: minimize CNI exposure, treat comorbid conditions (DM, HTN) Livers: Chronic active liver allograft AMR Prevention: avoid over weaning of immunosuppression Lungs: Bronchiolitis obliterans syndrome (BOS), Chronic lung allograft dysfunction (CLAD) Prevention: azithromycin, PPI/fundicoplation Heart: cardiac allograft vasculopathy Prevention: statin, aspirin 81 mg, mTOR Infectious Complications of Immunosuppression Overview PJP CMV Fungal infections Vaccinations Timeline of infections Less than 1 month: donor-derived, resistant candida (non-albicans), aspergillus colonization, wound infections, nosocomial bacteria Nosocomial and technical Month 1-6: cryptococcus, anastomotic complications, CMV, PJP, BK virus, C. diff, Nocardia spp. Activation of latent infections and opportunistic infections Month 6+: CAP, UTIs, Aspergillus spp., Mucor species, atypical molds Community acquired infections Pneumocystis jirovecii (PJP, PCP) Risk is related to time post-transplant (ie the amount of immunosuppression the patient is receiving) All organs will receive prophylaxis initially, then it depends on the organ transplanted (ex. Lung transplants are on lifelong PJP prevention) Preferred agent: TMP/SMX SE: hyperkalemia, leukopenia, false elevation in SCr Alternatives: Atovaquone: no renal dosing adjustments, improved side effect profile Use in true sulfa-allergy Dapsone: no renal dosing, risk of methemoglobinemia (G6PD), high risk for hematologic toxicity Cytomegalovirus (CMV): one of the most significant opportunistic infections in the transplant population Testing for CMV Serology: IgG Both the donor and recipient results are important, positive or negative D+/R-: highest risk, donor causes new infection D-/R+: CMV reactivation D+/R+: second highest risk, CMV reactivation D-/R-: lowest risk, community acquired Viremia: PCR Assay from recipients blood Disease: biopsy Small bowel, liver, and lung transplant recipients are at the highest risk Prevention of CMV: prophylaxis recommended for high risk transplant patients (D+/R-) for 200 days at the minimum CMV viral load monitoring required after discontinuation of therapy Presentation: flu-like symptoms (diarrhea*, fever, malaise, arthralgias, nausea, vomiting), hematologic changes (leukopenia*, atypical lymphocytosis, thrombocytopenia), rejection or chronic injury to allograft, specific organ involvement Treatment: Ganciclovir MOA: competitively inhibits the binding of deoxyguanosine triphosphate to DNA polymerase resulting in inhibition of viral DNA synthesis Induction for 2-3 weeks or until viral load undetectable, then maintenance for 1-3 months SE: hematologic (thrombocytopenia, neutropenia) Evaluate for resistance Valganciclovir Converted to ganciclovir in the body, pro-drug Same induction and maintenance durations as ganciclovir SE: hematologic (neutropenia, thrombocytopenia) Monitor for resistance Alternative Treatments Foscarnet: Second line MOA: pyrophosphate analog that is a noncompetitive inhibitor of viral RNA and DNA polymerases Induction for 2-3 weeks, then maintenance SE: extremely nephrotoxic** (must prehydrate and monitor for electrolyte abnormalities) Cidofovir: third line therapy MOA: same as foscarnet but relies on thymidine kinase to be activated within the body Must be given with probenecid SE: extremely nephrotoxic** Monitoring CMV Reduce immunosuppression- discontinue or reduce the dose of mycophenolate if possible Monitor CMV viral loads weekly Resistance is suspected if the viral load stabilizes or increases after 2+ weeks of therapy Renal dose adjustments are required for ganciclovir, valganciclovir, foscarnet, and cidofovir Prophylaxis for CMV Letermovir Can be given IV or PO Does not cover HSV and must be given with acyclovir CYP3A4 inhibitor- most effect seen in combination with cyclosporine Prophylaxis for patients who cannot tolerate valganciclovir SE: GI (abdominal pain, diarrhea, nausea, vomiting), peripheral edema Maribavir: not used MOA: inhibition of CMV enzyme UL97 which causes inhibition of phosphorylated proteins and DNA synthesis Oral tablets, twice daily Weak inhibitor of CYP3A4 and P-gp (watch tacrolimus!) Cannot cross the blood brain barrier and thus cannot be used for meningitis SE: dysgeusia (altered taste), diarrhea, nausea, vomiting, fatigue Treatment Algorithm for CMV Prophylaxis Valganciclovir If there are leukopenia concerns, either watchful waiting or letermovir Do not use Maribavir Treatment (Viremia) Use ganciclovir or valganciclovir first line Monitor response Potential role of letermovir in secondary prophylaxis Resistant Virus Treatment Consider maribavir depending on disease dissemination (no meningitis) Give low risk patients (D-/R-) HSV prophylaxis (acyclovir, famciclovir, or valacyclovir) Fungal Complications: commonly Aspergillus spp. Or Candida spp. Prophylaxis: Candida Nystatin is first line for oral candidiasis (thrush) Alternative is fluconazole Aspergillus Oral -azole antifungals, selection based on fungus of concern Initiation post-transplant, carefully monitor tacrolimus levels during initiation and discontinuation Posaconazole has the least interactions (only CYP3A4) Other Viruses Epstein Barr Virus Consider donor and recipient serology Implicated in post-transplant lymphoproliferative disease (PTLD) Treatment includes reduction in immunosuppression and R-CHOP BK Virus Can be detected in urine and blood Usually a URTI, then can become latent in the urogenital tract Shows up during immunosuppression as renal dysfunction without signs of infection COVID-19 Monoclonal antibodies are first line but concern for resistance Significant interaction with Paxlovid Vaccination in Solid Organ Transplant Live vaccines are contraindicated post-transplant Vaccines are usually avoided within the first 3 months post-transplant due to impaired immune response secondary to induction of immunosuppression Primary care management includes management of comorbid conditions such as HTN, hypercholesterolemia, neurotoxicity, nephrotoxicity, DM, osteoporosis, GI effects, Gout, drug interactions, skin cancer All of these conditions are side effects of immunosuppressive medications Post-transplant hypertension: high risk in post-transplant patients, especially with tacrolimus and steroids Treatment: CCB (usually DHP like amlodipine and nifedipine) or ACEi/ARB if the patient has proteinuria or DM ACEi/ARB cannot be given until 3-6 months post-transplant Second line Has nephroprotective effects, increase in SCr may mask rejection Benefit of use in: renal dysfunction, DM, HF, post-MI, high risk CAD Non-DHP CCBs have significant interactions and should be avoided Home blood pressure monitoring and blood pressure logs Post-transplant hyperlipidemia: high risk with CNI, steroids, and mTORs** Statins- watch interactions with cyclosporine Avoid: simvastatin, lovastatin, pitavastatin Maximum 10 mg atorvastatin Maximum 5 mg rosuvastatin Maximum 20-40 mg pravastatin Maximum 40-80 mg fluvastatin Lipid panel should be done yearly (or every 6 months for mTORs) New onset diabetes after transplant (NODAT): tacrolimus is toxic to pancreatic cells, maintenance steroids Consider insulin or SGLT-2 inhibitors/GLP-1s Monitor home blood glucose + blood sugar logs Risk factors: african american, hispanic, age over 40, male, family history, acute rejection history, deceased or male donor, polycystic kidneys NSAIDs & transplant: avoid NSAIDs in all solid organ transplant recipients given risk of nephrotoxicity regardless of time from transplant Potassium-binders & transplant: Sodium zirconium cyclosilicate (Lokelma)- separate administration by 2 hours Patiromer (Veltassa)- separate administration by 3 hours Sodium polystyrene sulfonate (Kayexalate)- separate administration by 3 hours Osteoporosis: long term use of steroids Watch decreased MMF absorption with calcium supplementation Monitor yearly Inflammatory conditions: short course prednisone, topical diclofenac gel CBD interaction (CYP3A4 and P-gp): tacrolimus, cyclosporine, sirolimus, everolimus Food interactions: caution with use of pomegranate and grapefruit, use clementines and cranberries in moderation Herbal supplements are a MAJOR no Non-melanoma skin cancer: 10% of transplant patients Immunosuppression can cause photosensitivity and skin cancer risk Wear at least SPF 30 sunscreen + yearly checks with a dermatologist HIV- Dr. Dionne (November 16-27, 2023) Most commonly diagnosed in children age > 15 (usually 15-24 years old) 14% of patients with HIv are not diagnosed, contributes to the spread Half of black men who MSM will be infected with HIV in their lifetime 25% of hispanic MSM 10% of white MSM HIV diagnoses is most common along the southeastern states of the US For males, MSM is the most common way to be infected with HIV, where women are more likely to be infected from heterosexual contact and IVDU HIV is more commonly diagnosed in black patients, then hispanic patients, and then white patients Diagnosis most commonly occurs from age 25-34 years Gap between patients who are diagnosed and those that actually receive care 13-24 years has the lowest percentage of patients who receive care after diagnosis Etiology HIV is a retrovirus (RNA virus), it uses reverse transcriptase to translate its RNA material to DNA HIV affects the immune system- primarily targeting the CD4 receptor of T-helper cells HIV can also infected other types of immune cells There are two types of HIV: HIV1 (most common in the US) and HIV 2 (less common, less virulent) HIV Life Cycle: HIV envelope protein binds to the CD4 and chemokine receptors on the cell surface Fusion: the viral core will insert itself into the cell Uncoating Reverse transcription of the viral genome (RNA to DNA) Nuclear import into the nucleus of the host Integration of the proviral DNA into the host genomic DNA Transcription of viral proteins (creates viral genomic RNA and viral proteins) The viral proteins are translated and assembled The viral RNA + proteins are packaged and the virus buds away from the cell for maturation Pathophysiology Infected CD4+ cells are destroyed- results in a decreased CD4+ count and increased susceptibility to opportunistic infections Causes a pro-inflammatory state: increased risk of CV, liver, kidney, bone, and neurologic disease Establishes a reservoir of virus that prevents cure Provirus resides in memory T cells and continues to replicate in protected sites (lymph nodes) Transmission occurs through mucocutaneous or parenteral exposure to HIV infected body fluids Sexual contact (higher risk for females or receptive partner in MSM) Needlestick injuries Perinatal transmission (antepartum through maternal circulation, during delivery, and postpartum through breastfeeding) Risk factors: condomless sexual contact with partners whos HIV status is unknown, uncircumcised males, sharing needles and syringes, surgery/blood transfusion in a developing country at any time, blood transfusion or clotting factor in the US between 1978-1985, history of STDs Socioeconomic factors: prevalence of HIV/AIDs within the community, undiagnosed STIs, poverty limits access to care and treatment, discrimination, stigma, homophobia, higher rates of incarceration, language barriers, immigration status Reducing transmission risk = condom use, treatment as prevention (undetectable = untransmittable), pre-exposure prophylaxis (PrEP) for high risk individuals, post-exposure prophylaxis (PEP) for high-risk individuals HIV Screening At least once for everyone age 13-64 years Patient with risk factors: every 3-6 months for MSM with multiple partners, each visit for STI treatment, annually for IVDU sharing equipment During each pregnancy Patients with tuberculosis Diagnosing HIV Enzyme-linked immunosorbent assay (ELISA) Detects antibodies and p24 antigen Highly sensitive after the eclipse period (10 days post exposure) HIV-1/HIV-2 differentiation assay Distinguishes HIV1 and HIV2 Rapid HIV tests OraQuick Advance, available over the counter HIV RNA Nucleic amplification test (NAAT) Can be qualitative (positive or negative) or quantitative (viral load) Detects the presence of HIV RNA in the serum, does not test for antibodies Will be positive 7-10 days post exposure Not reliable in detecting HIV2 Will detect HIV infection earlier than ELISA If both the ELISA and NAAT are positive, the HIV1 diagnosis is confirmed and no further testing is necessary False negatives Recent exposure- repeat testing is recommended 3 months after the initial or potential exposure Dilution of antibody concentrations due to receipt of large volume blood transfusions or plasmapheresis Infants False Positives Recent influenza vaccine Systemic lupus erythematosus and other autoimmune diseases Participation in HIV vaccine trial Liver disease Hemodialysis Infants HIV Infection Staging Less than 1 year of age 1-5 years of age Over 5 years of age Stage CD4 Cells/uL % CD4 cells/uL % CD4 cells/uL % 1 1500+ 34%+ 1000+ 30%+ 500+ 26%+ 2 750-1500 26-33% 500-1000 22-29% 200-500 14-25% 3 (AIDS) < 750 < 26% < 500 < 22% < 200 < 14% Acute HIV Infection: can occur 5 days-3 months after exposure ( within 2-4 weeks usually) 40-60% of patients will experience symptoms Flu-like presentation: fever, lethargy, myalgia, rash, headache, pharyngitis, adenopathy Abrupt onset, will last 3-14 days Diagnosis of HIV will usually be missed and antibody may not be detectable Clinical Latency: asymptomatic Virus is in the lymph nodes Massive viral production and destruction of T-cells 9 weeks to 7 years after initial exposure Stage 3 HIV (AIDS): usually develops after 7 years, lasts 11 years Plasma viremia begins to increase and CD4 count decreases further (below 200) Constitutional symptoms will develop (lymphadenopathy, malignancies, wasting syndrome, neurologic symptoms like dementia) AIDS-defining opportunistic infections will occur (PJP) Baseline labs required for patients with HIV CD4: Staging and progression or need for opportunistic infection treatment Viral load Genotypic resistance testing for initial ART selection Hepatitis B and C CBC, basic chemistry, LFTs, lipid panel, urinalysis Pregnancy test Immunization requirements Pneumococcal vaccine Meningococcal vaccine: booster every years Recombinant zoster vaccine: age 19+ Hepatitis B: all susceptible patients Hepatitis C: all at-risk patients HPV: 9-26 years Influenza: annually Tetanus and diphtheria toxoid: every 10 years Live vaccines are not recommended with CD4 < 200 Goals of antiretroviral therapy (ART): maximal and durable suppression of viral load, respiration of immunologic response, reduction of morbidity and mortality, improvement in QOL, prevent transmission Groups with increased urgency (start ART immediately) Pregnancy AIDS-defining conditions, including HIV associated dementia and AIDS-associated malignancies Acute opportunistic infections Low CD4 counts (under 200) HIV associated nephropathy acute/early infection HIV/HBV coinfection HIV/HCV coinfection Adherence is super important for efficacy of ART Determinant of degree and duration of viral suppression Poor adherence is associated with virologic failure and resistance Optimal suppression requires excellent adherence (over 95%) Suboptimal adherence is common in patients Entry Inhibitors: Attachment Inhibitors Fostemsavir (FTR, Rukobia) MOA: binds to gp120 on the virion Can be taken with or without food Avoid with CYP3A4 inducers SE: QTc prolongation Reserved for salvage therapy Entry Inhibitors: Post-attachment inhibitors Ibalizumab (IBA, Trogarzo) MOA: non competitively binds to CD4 Given every 2 weeks, IV Patients need to be monitored for at least 1 hour after initial dose (then 15 minutes for subsequent infusions) due to infusion reactions Reserved for salvage therapy CCR5 Inhibitor: Maraviroc (MVC, Selzentry) Dose adjust for administration with CYP3A4 inhibitor/inducer Requires tropism testing: cannot be used in CXCR4 or dial tropism virus, CXCR5 ONLY Generally reserved for salvage therapy Must be renally dose adjusted (CrCl < 30) Entry Inhibitors: Fusion inhibitors Enfuvirtide (ENF, T-20, Fuzeon) MOA: binds to gp41 on the virion Given SQ BID SE: injection site reaction, hypersensitivity reaction, bacterial pneumonia Reserved for salvage therapy Capsid Inhibitors Lencapavir (LEN, Sunlenca) MOA: binds to p24 on the capsid Given SQ every 6 months Moderate inhibitor of CYP3A4, avoid use with CYP3A4 inducers Reserved for salvage therapy Nucleoside Reverse Transcriptase Inhibitors (NRTIs) MOA: false nucleotides that cause chain termination SE: lactic acidosis (stavudine, didanosine, zidovudine), lipodystrophy (stavudine) Tenofovir alafenamide (TAF, Vemlidy) Newer formulation of tenofovir Given once daily, usually in combination with FTC Lower incidence of nephrotoxicity and reductions in bone mineral density compared to TDF No need for renal dose adjustment More weight gain compared with TDF Emtricitabine (FTC, Emtriva) Given once daily, orally Dose reduction when CrCl < 50 (or when CrCl < 30 as a single tablet regimen) Tenofovir disoproxil fumarate (TDF, Viread) Original formulation of tenofovir Given orally once daily SE: Causes nephrotoxicity, decreased bone mineral density Must motor urine protein, SCr Causes less weight gain compared to TAF Abacavir (ABC, Ziagen) Can be given orally either QD or BID REQUIRES HLA-B*5701 testing prior to initiation If present, ABC is contraindicated due to increased risk of hypersensitivity reaction Potential increase in risk for MI, unclear Lamivudine (3TC, Epivir) Given once daily, orally Renal dose adjustment when CrCl < 50 Stavudine (d4T, Zerit) Didanosine (ddl, Videx) Zidovudine (ZDV/AZT, Retrovir) Given orally BID Take with food to minimize GI upset Causes bone marrow suppression This is the only NRTI with an IV formulation- often used for prevention of maternal transfer during delivery Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Side effects: rash (stevens johnson syndrome), hepatotoxicity, CYP3A4 interactions Doravirine (DOR, Pifeltro): Second generation Taken orally once daily without regard to food Fewer CNS and metabolic effects compared to efavirenz No-cross resistance with other NNRTIs Fewer drug interactions Rilpivirine (RPV, Edurant): Second generation Orally once a day, take with food to increase absorption Requires an acidic environment for absorption (No PPIs or H2RAs) DO NOT START if the patient has CD4 < 200 or VL > 100,000 SE: worsened depression, QTc prolongation Etravirine (ETR, Intelence) Efavirenz (EFV, Sustiva): First generation Given orally once daily SE: dyslipidemia, psychological side effects (vivid dreams, worsened depression) Take without food to avoid the psychological side effects Multiple CYP interactions, its an inducer and an inhibitor Delavirdine (DLV, Rescriptor) Nevirapine (NVP, Viramune) Integrase Strand Transfer Inhibitors (INSTIs) MOA: prevention of integration of viral DNA into the host genome SE: weight gain (especially with dolutegravir and bictegravir) Concentrations of all INTIs is decreased when administered with polyvalent cations due to chelation (iron and magnesium) Cabotegravir (CAB) Can be given either orally once daily or IM monthly/every 2 months 7 day window for IM administration SE: CPK elevations, headache, insomnia, injection site reactions Bictegravir (BIC): second generation Given orally once daily Only available as a single tablet regimen (in combination with TAF/FTC) May cause benign increase in SCr SE: headache, insomnia May go away over time Dolutegravir (DTG, Tivicay): second generation Given orally once daily May cause benign increase in SCr SE: headache, insomnia May go away over time Elvitegravir (EVG): first generation Given orally once daily with food Only available in single tablet regimens MUST be given with a booster (cobicistat) SE: nausea, diarrhea Raltegravir (RAL, Isentress): first generation Given orally BID May cause CK elevations Protease Inhibitors (PI) MOA: inhibits maturation of the final viral product SE: hyperlipidemia, lipodystrophy, hepatotoxicity, GI intolerance, increased risk of bleeding, drug-drug interactions (CYP3A4) Cobicistat (Tybost): Booster Given once daily orally CYP3A4 interaction May cause a benign increase in SCr Darunavir/cobicistat (DRV/c, Prezcobix) Atazanavir/cobicistat (ATV/c, Evotaz) Darunavir (DRV, Prezista)* know this brand name! Given once daily orally Requires boosting with cobicistat May cause rash or liver toxicity Tipranavir (TPV, Aptivus) Atazanavir (ATV, Reyataz) Given once daily orally Must be boosted if given with tenofovir Causes hyperbilirubinemia (jaundice) Requires acidic environment for absorption Lopinavir/ritonavir (LPV/r, Kaletra) Fosamprenavir (FPV, Lexiva) Nelfinavir (NFV, Viracept) Indinavir (IDV, Crixivan) Ritonavir (RTV, Norvir): Booster Give once daily orally May cause resistance in nonadherence Only used as a booster (non-specific CYP inhibitor/inducer) Saquinavir (SQV, Invirase) Drug interactions with ARVs: many potential interactions, may be complex and hard to predict CYP-mediated: statins, rifampin, antifungals, anticoagulants (warfarin, DOACs), anticonvulsants, benzodiazepines, methadone, buprenorphine, corticosteroids (except beclomethasone) Non-CYP-mediated: metformin & dolutegravir, antacids (INSTIs- 2 hours before or 6 hours after antacids, Atazanavir/Rilpivirine- 2 hours before and after), H2RAs (atazanavir and rilpivirine, give together or 12 hours apart), PPIs (rilpivirine is contraindicated, ideally avoid atazanavir- max 20 mg omeprazole) Combination Tablets NRTI backbones Truvada: emtricitabine/tenofovir disoproxil fumarate Descovy: emtricitabine/tenofovir alafenamide Temyxis/Cimduo: lamivudine/tenofovir disoproxil fumarate Epzicom: lamivudine/abacavir Combivir: lamivudine/zidovudine Single Tablet regimens (STRs) Atripla: Efavirenz/Truvada Biktarvy: Bictegravir/Descovy Complera/Odefsey: Rilpivirine/Truvada or Descovy Delstrigo: doravirine/lamivudine/tenofovir disoproxil fumarate Stribild/Genvoya: Elvitegravir/cobicistat/Truvada or Descovy Symtuza: darunavir/cobicistat/descovy Triumeq: dolutegravir/lamivudine/abacavir Regimens recommended for most people- No Cabotegravir exposure Bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) First line, go-to therapy Dolutegravir (Tivicay) + (emtricitabine or lamivudine)/(tenofovir disoproxil fumarate or tenofovir alafenamide) Alternative to Biktarvy Dolutegravir/abacavir/lamivudine (Triumeq) Can only be used if HLA-B*5701 is not present Dolutegravir/lamivudine (Dovato) Can only be used if VL < 500,000, no HBV coinfection, and no resistance PI-based regimens Boosted darunavir + Truvada or Descovy or Temyxis/Cimduo Preferred regimen from this group based on evidence Boosted darunavir + Epzicom Boosted atazanavir + Truvada or Descovy or Temyxis/Cimduo NNRTI based regimens Delstrigo or Doravirine + Descovy Efavirenz + (FTC + 3TC) + (TDF or TAF) Complera or Odefsey Only if the CD4 > 200 and VL < 100,000 INSTI based regimens Stribild or Genvoya Raltegravir (Isentress) + (FTC or 3TC)/(TDF or TAF) Two-drug regimens Cabotegravir + rilpivirine (Cabenuva) Can start as oral therapy, then move to monthly or every two month injections Dolutegravir + rilpivirine (Juluca) Can only be used for patients virally suppressed for at least 6 months Can be used in significant renal insufficiency Darunavir + lamivudine Darunavir + raltegravir Only used if CD4 > 200 and VL < 100,000 Predictors of poor adherence: high pill burden, high cost, side effects, low health literacy, age-related challenges, psychosocial issues, substance abuse, stigma, difficulty taking medication Predictors of high adherence: once-daily regimens, belief in oneself, not living alone, dependent on significant other for support, history of OI or advanced HIV, belief in efficacy, belief that non-adherence will lead to viral resistance Improving adherence: support, reinforcement, simplified dosing regimens, reminders, ongoing patient education, trust in primary care provider, pharmacist involvement Viral Load monitoring Virologic suppression: confirmed HIV RNA below lower limit of detection (under 50 copies) Virologic failure: inability to achieve or maintain HIV RNA < 200 Partial viral suppression may be caused by suboptimal therapy regimens, adherence problems, PK problems Drug resistance is permenant Incomplete virologic response: 2 consecutive HIV RNA > 200 after 24 weeks on ART Virologic rebound: confirmed HIV RNA > 200 after virologic suppression Virologic blip: an isolated dete