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Infectious Diseases II I. HUMAN IMMUNODEFICIENCY VIRUS (HIV) A. Transmission of HIV 1. Sexual transmission a. Vaginal, anal, or oral sex b. Increases with increased number of sexual partners 2. Parenteral exposure to blood or blood products a. Persons who inject drugs; Increased...

Infectious Diseases II I. HUMAN IMMUNODEFICIENCY VIRUS (HIV) A. Transmission of HIV 1. Sexual transmission a. Vaginal, anal, or oral sex b. Increases with increased number of sexual partners 2. Parenteral exposure to blood or blood products a. Persons who inject drugs; Increased with increased needle sharing b. People with hemophilia and recipients of blood transfusions 3. Perinatal transmission a. Antepartum: Through maternal circulation b. During delivery c. Postpartum: Breastfeeding d. Zidovudine therapy decreases the risk of transmission from 23% to 3%–4% (less than 2% with combination therapy). The goal of the Centers for Disease Control and Prevention is to decrease transmissions to less than 1% through suppressive combination antiretroviral therapy (ART) administered throughout pregnancy. B. Diagnosis 1. Step 1 a. Fourth-generation HIV test b. Positive 2–3 weeks after being infected c. Negative tests require no further testing; positive tests proceed to step 2. d. Sensitivity and specificity: Greater than 99% e. Fourth-generation tests: Abbott Architect HIV Ag/Ab Combo Assay; Bio-Rad GS HIV Combo Ag/Ab EIA 2. Step 2 a. HIV test that differentiates HIV-1 from HIV-2 b. If positive, diagnosis is made c. If negative or indeterminate, proceed to step 3 d. Sensitivity and specificity: Greater than 99% e. Differentiation tests: Multispot HIV-1/HIV-2 Rapid Test 3. Step 3 a. HIV-1 nucleic acid amplification test (screening for HIV-1 RNA) b. If positive, diagnosis is made c. If negative, negative for HIV-1 d. HIV-1 NAT tests: APTIMA HIV-1 RNA Qualitative Assay; Procleix Ultrio 4. Rapid HIV testing a. Oral swab or fingerstick b. Results within 20 minutes c. Negative test result: HIV negative d. Positive test result: Repeat with a different manufacturer’s test. If positive, HIV positive (refer for appropriate care) e. If first test is positive and second test is negative, repeat with a different manufacturer’s test. If repeat test is positive, HIV positive; if negative, HIV negative f. FDA-approved tests: OraQuick Advance, Uni-Gold Recombigen, Chembio SURE CHECK, INSTI HIV, Determine HIV, Chembio DPP, Clearview Stat-Pak ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-250 Infectious Diseases II 5. 6. 7. 8. Test for HIV RNA (viral load) a. Detects HIV RNA in serum (tests for the virus, not for antibodies) b. Values expressed as copies of HIV RNA per milliliter or the log of copies of HIV RNA per milliliter c. Viral suppression, defined as HIV RNA below the level of detection of the assay (HIV RNA less than 20 copies/mL to 75 copies/mL), is the goal of treatment. d. While on treatment, changes greater than 3-fold (about 0.5 log) are statistically significant. Use of HIV RNA testing (viral load) a. Most important use of the viral load is to monitor the effectiveness of therapy after initiation of ART. b. Newly diagnosed HIV infection (for baseline value to follow) c. Every 3–6 months without therapy d. From 2 to 4 (no more than 8) weeks after starting or changing therapy (should detect a significant decrease) e. Every 3–4 months while on therapy (to check for increase—which would indicate therapy failure). May consider extension to every 6 months in patients on therapy and suppressed greater than 2 years with immune stability f. Whenever there is a clinical event or decrease in CD4 count CD4 T-cell count a. Measure of immune function, used to determine the urgency of ART, opportunistic infection prophylaxis, disease progression, and survival b. Changes greater than 30% in CD4 counts are considered clinically significant. c. CD4 counts decrease, on average, 50–80 cells/mm3 per year in untreated HIV-infected patients. d. With potent combination ART, CD4 counts increase, on average, 50–100 cells/mm3 per year. e. Monitor at diagnosis (baseline), after ART is started to guide discontinuation of opportunistic infection prophylaxis, every 12 months for those consistently on therapy and with CD4 counts between 300 and 500 cells/mm3 for at least 2 years, and optional if CD4 is greater than 500 cells/ mm3 in those virologically suppressed for at least 2 years. More frequent monitoring (every 3–6 months) may be needed based on clinical symptoms and viral load testing. Who should be screened for HIV? a. All patients 13–64 years of age at least once b. Adults and adolescents at high risk of HIV infection should be checked annually, including the following: persons who inject drugs and share needles/syringes, those who have sex with more than one partner, men who have sex with men, men or women who have sex for money or drugs, anyone who has had sex with someone who has HIV, people being treated for sexually transmitted infections, people diagnosed or treated for hepatitis or tuberculosis. c. Pregnant women – As early as possible and repeat testing in the third trimester ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-251 Infectious Diseases II 9. AIDS-defining conditions (Table 1) Table 1. AIDS-Defining Conditions Bacterial infections, multiple or recurrent (< 6 yr) Candidiasis: bronchi, trachea, or lungs Candidiasis: esophageal Cervical cancer: invasive (≥ 6 yr) Coccidioidomycosis: disseminated or extrapulmonary Cryptococcosis: extrapulmonary Cryptosporidiosis: chronic intestinal (> 1 mo in duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) Encephalopathy: HIV related Herpes simplex: chronic ulcer(s) (> 1 mo in duration); bronchitis, pneumonitis, or esophagitis Histoplasmosis: disseminated or extrapulmonary Isosporiasis: chronic intestinal (> 1 mo in duration) Kaposi sarcoma Lymphoma: Burkitt (or equivalent term) Lymphoma: immunoblastic (or equivalent term) Lymphoma: primary, of brain Mycobacterium avium complex or M. kansasii: disseminated or extrapulmonary M. tuberculosis: any site (pulmonary, disseminated, or extrapulmonary) Mycobacterium: other species or unidentified species; disseminated or extrapulmonary Pneumocystis jiroveci pneumonia Pneumonia: recurrent Progressive multifocal leukoencephalopathy Salmonella septicemia (recurrent) Toxoplasmosis of brain Wasting syndrome caused by HIV C. Prevention of HIV 1. Universal precautions (Table 2) a. Purpose is prevention of parenteral, mucous membrane, and non-intact skin exposures to bloodborne pathogens. Table 2. Universal Precautions Universal Precautions Apply to: Blood Bodily fluids containing visible blood Semen and vaginal secretions Tissue Cerebrospinal fluid Synovial fluid Pleural fluid Peritoneal fluid Pericardial fluid Amniotic fluid Universal Precautions Do Not Apply to: Feces Nasal secretions Sputum Sweat Tears Urine Vomitus Breast milk Saliva (precautions recommended for dentistry) b. General guidelines i. Take care when using and disposing of needles, scalpels, and other sharp instruments. ii. Use protective barriers (e.g., gloves, masks, and protective eyewear). iii. Wash hands and skin immediately if they are contaminated with body fluids to which universal precautions apply. 2. Nonpharmacologic prevention a. Latex condom b. Circumcision (males) 3. Pharmacologic prevention a. Pre-exposure prophylaxis (PrEP) i. Use in men who have sex with men and heterosexual women and men who recently tested HIV negative with one of the following: (a) An HIV-positive sexual partner ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-252 Infectious Diseases II (b) A recent bacterial sexually transmitted infection (c) A high number of sex partners (d) A history of inconsistent or no condom use (e) Commercial sex work ii. Use in persons who inject drugs who recently tested HIV negative with one of the following: (a) An HIV-positive injecting partner (b) Sharing injection equipment iii.  PrEP options (a) Tenofovir disoproxil fumarate 300 mg plus emtricitabine 200 mg orally daily (b) Tenofovir alafenamide 25 mg plus emtricitabine 200 mg orally daily (c)  Cabotegravir 600 mg every 2 months intramuscularly (optional oral lead-in before initiation) iv. On-demand PrEP (a) Tenofovir disoproxil fumarate 300 mg plus emtricitabine 200 mg, administered as 2-1-1 dosing: 2 doses 2–24 hours before sex, 1 dose 24 hours after the first dose, and 1 dose 48 hours after the first dose. (b) Option for men who have sex with men, who do not want daily PrEP dosing, have sex infrequently, and can anticipate when they will have sex (c) No FDA approval and not recommended by CDC at this time. v. Test every 90 days for HIV antibody (and if prophylaxis is discontinued). vi. Check renal function every 6 months with tenofovir. b. Treatment as prevention (TasP) i. Maintaining HIV RNA less than 200 copies/mL with ART prevents HIV transmission to sexual partners. ii. Other forms of prevention should be used during the first 6 months of treatment and until the HIV RNA is less than 200 copies/mL. iii. Adherence is crucial for TasP. c. Prevention of maternal-fetal transmission i. Pregnant women with HIV not receiving ART (a) All HIV-infected pregnant women should receive combination ART; initiate therapy as soon as possible, even in the first trimester. (b) Preferred regimens for HIV-infected pregnant women include a dual nucleoside reverse transcriptase inhibitor (NRTI) combination (abacavir/lamivudine, or tenofovir/emtricitabine or tenofovir/lamivudine) plus either a ritonavir-boosted protease inhibitor (PI) (atazanavir/ritonavir or darunavir/ritonavir) or an integrase strand transfer inhibitor (INSTI) (raltegravir or dolutegravir). (c) All women should have HIV antiretroviral resistance testing completed before starting therapy. (d) Continue combination regimen through intrapartum period. ii. Pregnant women with HIV receiving potent combination ART (a) Continue current combination regimens if already receiving therapy. (i) Specific regimen changes may be necessary including, but not limited to, replacing elvitegravir/cobicistat or more frequent dosing of darunavir. (ii) Risk-benefit of dolutegravir use in the first 12 weeks of pregnancy should be discussed with the patient. (b) Continue combination regimen through intrapartum period. iii. Pregnant women with HIV in labor (with or without therapy during pregnancy) (a) Intravenous zidovudine should be administered to HIV-infected women with an HIV RNA greater than 1000 copies/mL (or unknown HIV RNA) near delivery. Consideration can ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-253 Infectious Diseases II also be given to treating women with an HIV RNA of 50–1000 copies/mL. Intravenous zidovudine is not necessary for HIV-infected women with an HIV RNA of 50 copies/mL or less during late pregnancy who are near delivery and in whom there are no concerns about adherence to their ART regimen. (b) Continue combination ART during labor as able. iv. Infants born to mothers who are HIV positive (a) Low risk of perinatal HIV transmission: Zidovudine 4 mg/kg/dose every 12 hours for 4 weeks, initiated within 6–12 hours of delivery (b) Higher risk of perinatal transmission or presumed HIV exposure: Presumptive HIV therapy with zidovudine, lamivudine, and nevirapine OR zidovudine, lamivudine, and raltegravir. Presumptive therapy should continue for 6 weeks. d. Post-exposure prophylaxis (PEP) i. Use universal precautions. ii. Post-exposure prophylaxis can reduce HIV infection by about 80%. iii. Nonoccupational exposures (nPEP) (a) Treat if exposure of vagina, rectum, eye, mouth, mucous membrane, or non-intact skin with blood, semen, vaginal secretions, or breast milk of a person with a known HIV infection (b) Begin prophylaxis within 72 hours. Treatment should be administered for 4 weeks. (c) Preferred regimen: Raltegravir twice daily or dolutegravir daily plus tenofovir disoproxil fumarate/emtricitabine daily (d)  Alternative regimen: Darunavir/ritonavir daily plus tenofovir disoproxil fumarate/ emtricitabine daily iv. Occupational exposures (a) Needlesticks or cuts (1 in 300 risk) and mucous membrane exposure (1 in 1000 risk) (b) Begin treatment within hours; if HIV status of source patient is unknown, start treatment while status is being evaluated. Treatment should be administered for 4 weeks. (c) Preferred regimen: Raltegravir twice daily or raltegravir HD once daily or dolutegravir once daily plus tenofovir disoproxil fumarate/emtricitabine or lamivudine (d) Alternative regimens: (1) One of the following agents: Raltegravir, darunavir/ritonavir, etravirine, rilpivirine, atazanavir/ritonavir, or lopinavir/ritonavir plus one of the following combinations: tenofovir disoproxil fumarate/emtricitabine, tenofovir disoproxil fumarate/lamivudine, zidovudine/lamivudine, or zidovudine/emtricitabine (2) Elvitegravir, cobicistat, tenofovir disoproxil fumarate, emtricitabine (Stribild) D. Treatment of HIV 1. Reverse transcriptase inhibitors (RTIs) (nucleoside/nucleotide [NRTIs] and nonnucleoside [NNRTIs]) a. Reverse transcriptase: Enzyme needed to copy viral RNA to DNA b. See Tables 3 and 4 for RTI characteristics. 2. Protease inhibitors (PIs) a. Protease: Enzyme needed to cleave polyproteins into mature viral protein components b. See Table 5 for PI characteristics. 3. Integrase inhibitors (INSTIs) a. Integrase: Enzyme needed for integration of viral DNA into the host cellular genome b. See Table 6 for INSTI characteristics. 4. Entry and post-attachment inhibitors a. Block binding and/or entry of the virus into human cells b. See Table 7 for entry and post-attachment inhibitor characteristics. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-254 2-255 Drug interactions Bone marrow suppression, nausea, vomiting, headache, insomnia, asthenia, nail pigmentation, myalgia, lactic acidosis/hepatic steatosis Minimal toxicity Myelosuppressive agents Methadone, a tovaquone increases ZDV Metabolized to ZDV glucuronide (GZDV) Renal excretion of GZDV 7 1.1 60% 200 mg TID or 300 mg BIDb Zidovudine (AZT, Retrovir) Nucleoside 100-mg capsules, 300-mg tablets 50 mg/5 mL liquid 10 mg/mL injection Renally excreted unchanged (70%) 18–22 13–19 Lamivudine (Epivir) Nucleoside 150-, 300-mg tablets 10 mg/mL liquid Combivir: 150 mg 3TC/300 mg ZDV Epzicom: 300 mg 3TC/600 mg ABC Cimduo/Temixys: 3 00 mg 3TC/300 mg TDF Dovato (see Dolutegravir) Symfi (see Efavirenz) Trizivir (see Abacavir) Delstrigo (see Doravirine) 150 mg BID or 300 mg daily < 50 kg: 4 mg/kg BIDb 86% Diarrhea, nausea, headache, fewer effects on bone mineral density and renal function, more favorable effects on bone and kidneys than TDF Diarrhea, nausea, vomiting, headache, loss of bone mineral density, renal toxicity, more favorable effects on lipids than TAF Carbamazepine, oxcarbazepine, phenytoin, phenobarbital Rifampin, rifabutin, rifapentine St. John’s wort Eliminated primarily in urine and feces 150–180 0.5 Take with food 25 mg dailyc; 10 mg daily with cobicistat Tenofovir Alafenamide (Vemlidy) Nucleotide 25-mg tablets Descovy: 200 mg FTC/ 25 mg TAF Odefsey (see Rilpivirine) Genvoya (see Elvitegravir) Biktarvy (see Bictegravir) Symtuza (see Darunavir) Eliminated by renal filtration and active secretion > 60 40% Take with food 10–14 300 mg dailyc Tenofovir Disoproxil Fumarate (Viread) Nucleotide 300-mg tablets Truvada: 200 mg FTC/300 mg TDF Cimduo/Temixys (see Lamivudine) Atripla (see Efavirenz) Complera (see Rilpivirine) Stribild (see Elvitegravir) Delstrigo (see Doravirine) b Dosage adjustment in hepatic insufficiency. Dosage adjustment in renal insufficiency. c Dosage adjustment/avoid use in renal insufficiency: TDF < 50–70 mL/min; TAF < 30 mL/min. ABC = abacavir; AZT = azidothymidine (zidovudine); BID = twice daily; FTC = emtricitabine; RTI = reverse transcriptase inhibitor; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; 3TC = lamivudine; TID = three times daily; ZDV = zidovudine. a > 20 12–26 Adverse drug reactions 10 1.5 Renal excretion (86%) Metabolized by alcohol dehydrogenase and glucuronyltransferase Metabolites; renal Hypersensitivity reaction Minimal toxicity; skin hyperpigmentation (including fever, rash, nausea, vomiting, diarrhea, malaise, fatigue, respiratory symptoms – screen for HLAB*5701), increased risk of myocardial infarction ABC increases methadone clearance 93% 82% Oral bioavailability Serum half-life (hr) Intracellular half-life (hr) Elimination 200 mg daily or 240 mg liquid dailyb 300 mg BID or 600 mg dailya Emtricitabine (Emtriva) Nucleoside 200-mg capsules 10 mg/mL liquid Truvada: 200 mg FTC/300 mg TDF Atripla (see Efavirenz) Complera (see Rilpivirine) Stribild (see Elvitegravir) Genvoya (see Elvitegravir) Biktarvy (see Bictegravir) Symtuza (see Darunavir) Dosing RTI type Form Abacavir (Ziagen) Nucleoside 300-mg tablets 20 mg/mL liquid Trizivir: 300 mg ABC/150 mg 3TC/ 300 mg ZDV Triumeq: 600 mg ABC/ 50 mg DTG/ 300 mg 3TC Epzicom (see Lamivudine) Table 3. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors Infectious Diseases II ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-256 Induces CYP3A4 and CYP2B6 42% Avoid with high-fat meal 40–55 Metabolized by CYP2B6 and CYP3A4; 14%–34% excreted in urine, 16%–61% in feces Rash, CNS symptoms (insomnia, impaired concentration, nightmares, mania), elevated LFTs, hyperlipidemia 400–600 mg nightly Efavirenz (Sustiva) 50-, 200-mg capsules 600-mg tablets Atripla: 200 mg FTC/ 300 mg TDF/ ERV 600 mg Symfi: 600 mg EFV/300 mg 3TC/ 300 mg TDF Induces CYP3A4 Inhibits CYP2C9 and CYP2C19 Rash, nausea, hypersensitivity reaction 41 Metabolized by CYP3A4, CYP2C9, CYP2C19 Take with food 200 mg BID Etravirine (Intelence) 100-, 200-mg tablets Induces CYP3A4 Avoid strong CYP3A inducers and inhibitors 25–30 Metabolized by CYP3A4; 80% excreted in urine (< 5% unchanged), 10% in feces Rash, GI toxicity, elevated LFTs; hepatotoxicity 200 mg daily for 14 days, then 200 mg BID or 400 mg daily (XR)a,b > 90% Nevirapine (Viramune) 200-mg tablets 400-mg XR tablets 50 mg/5 mL suspension PPIs (contraindicated), histamine-2 blockers, antacids Avoid CYP3A inducers Rash, CNS symptoms (depression, insomnia, headache) – less than with EFV 50 Metabolized by CYP3A4 Take with food Rilpivirine (Edurant) 25-mg tablets Complera: 200 mg FTC/ 300 mg TDF/RPV 25 mg Odefsey: 200 mg FTC/25 mg TAF/RPV 25 mg Juluca: 25 mg RPV/50 mg DTG Cabenuva (see Cabotegravir) 25 mg daily b Dosage adjustment in hepatic insufficiency. Dosage adjustment in renal insufficiency. CNS = central nervous system; CYP = cytochrome P450; DOR = doravirine; EFV = efavirenz; ETR = etravirine; LFT = liver function test; NVP = nevirapine; PPI = proton pump inhibitor; RPV = rilpivirine; XR = extended release. a Drug interactions Adverse drug reactions Rash, nausea, diarrhea, abdominal pain, headache CNS symptoms (fatigue, dizziness, insomnia, abnormal dreams, somnolence) – less than with EFV Avoid CYP3A inducers 64% Take with or without food 15 Metabolized by CYP3A4, 6% excreted in urine Oral bioavailability Serum half-life (hr) Elimination 100 mg daily Doravirine (Pifeltro) 100-mg tablets Delstrigo: 300 mg 3TC/ 300 mg TDF/doravirine 100 mg Dosing Form Table 4. Nonnucleoside Reverse Transcriptase Inhibitors Infectious Diseases II ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-257 Darunavir (Prezista) Inhibits CYP3A4 Inhaled corticosteroids Food increases absorption and bioavailability; take with food 15 CYP3A4 Rash (sulfa), hepatotoxicity, endocrine disturbancesc 75-, 150-, 300-, 400-, 600-mg tablets Prezcobix: 800 mg/COBI 150-mg tablets Symtuza: 800 mg/COBI 150 mg/ FTC 200 mg/TAF 10 mg 800 mg with RTV 100 mg daily or 600 mg with RTV 100 mg BIDa DRV 800 mg + COBI 150 mg daily Lopinavir/Ritonavir (Kaletra) Ritonavir (Norvir) 100-mg tablets; 80 mg/mL liquid Inhibits CYP3A4, CYP2D6 Inhaled corticosteroids Take solution with food; take tablets without respect to food 56 CYP3A4 GI intolerance, fatigue, asthenia, pancreatitis, PR and QTc prolongation, endocrine disturbancesc Inhibits CYP3A4, CYP2D6 (potent) Induces glucuronyltransferases Inhaled corticosteroids 35 CYP3A4 > CYP2D6 > CYP2C9/10 GI intolerance, paresthesias (circumoral and extremities), taste disturbances, asthenia, endocrine disturbancesc 65%–75%; take with food 400/100 mg BID or 800/200 mg “Boosting dose” = 100–400 mg daily with food divided once or twice daily If taking efavirenz or nevirapine: 500 mg/125 mg BID 100/25-, 200/50-mg tablets; 80/20 mg/mL solution b Dosage adjustment in hepatic insufficiency. Dosage adjustment in renal insufficiency. c Endocrine disturbances include insulin resistance (type 2 diabetes in 8%–10%), peripheral fat loss and central fat accumulation (in 50%), and lipid abnormalities (in 70%). ATV = atazanavir; DRV = darunavir; GI = gastrointestinal; LPV/r = lopinavir/ritonavir; RTV = ritonavir. a Drug interactions Serum half-life (hr) Elimination Adverse drug reactions Oral bioavailability ATV 400 mg dailya,b or ATV 300 mg with RTV 100 mg daily or ATV 300 mg with COBI 150 mg daily ATV alone not recommended in antiretroviral-experienced patients If taking TDF but not EFV: ATV 300 mg + RTV 100 mg daily If taking EFV: ATV 400 mg + RTV 100 mg daily Food increases absorption and bioavailability; take with food 7 CYP3A4 Indirect hyperbilirubinemia rash, elevated transaminases, nephrolithiasis, prolonged PR interval and heart block, endocrine disturbancesc Inhibits CYP3A4, PPIs, histamine-2 blockers, antacids Inhaled corticosteroids Dosing Atazanavir (Reyataz) 100-, 150-, 200-, 300-mg capsules Evotaz: 300 mg/cobicistat (COBI) 150-mg tablets Form Table 5. Protease Inhibitors Infectious Diseases II ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-258 Inhibitors and inducers of UGT1A3, UGT1A9, BCRP, and P-glycoprotein. Avoid rifampin, rifapentine, certain anticonvulsants, St. John’s wort Divalent and trivalent cations Dofetilide Insomnia, headache, weight gain, hepatotoxicity Benign increases in creatinine (inhibits creatinine secretion) and bilirubin (blocks bilirubin clearance) 400 mg BID Isentress HD: 1200 mg daily Monitor closely if used with CYP3A inducers or inhibitors. Avoid rifampin, other rifamycins, certain anticonvulsants, St. John’s wort Divalent and trivalent cations Inhaled corticosteroids Dofetilide, eplerenone, ivabradine, ranolazine Metabolized by CYP3A and glucuronidation by UGT1A1/3 enzymes Cobicistat is metabolized by CYP3A and CYP2D6 Nausea, diarrhea Cobicistat: Benign increases in creatinine (inhibits creatinine secretion) and bilirubin (blocks bilirubin clearance) 5.6-11.5 (CAB)/13-28 (RPV) weeks Metabolized by hepatic glucuronidation by UGT1A1 30 mg orally daily for 1 month (optional); then 600 mg/900 mg IM once; then 400 mg/600 mg IM monthly or 600 mg/900 mg IM monthly for 2 months; then every other month N/A Injection site reactions, Nausea, diarrhea, rash, fever, fatigue, pain headache, pyrexia, creatine kinase elevation, insomnia, weight gain Benign increases in creatinine (inhibits creatinine secretion) and bilirubin (blocks bilirubin clearance) Inducers of UGT1A1: Inducers of UGT1A1: R ifampin, rifapentine, Rifampin, rifapentine, efavirenz, tipranavir/ efavirenz, tipranavir/ ritonavir, certain ritonavir, certain anticonvulsants anticonvulsants Divalent and trivalent cations Metabolized by hepatic glucuronidation by UGT1A1 Food increases absorption and Not established bioavailability Take with food 13 9 Stribild: Once dailya,b Genvoya: Once dailya,b Cabenuva: 400 mg CAB/ 600 mg RPV, 600 mg CAB/ 900 mg RPV extended release injectable suspension 25-, 100-, 400-mg tablets; Isentress HD: 600-mg tablets Stribild: EVG 150 mg/ c obicistat 150 mg/TDF 300 mg/FTC 200 mg Genvoya: Same as Stribild e xcept 10 mg of TAF instead of TDF Vocabria: 30 mg tablets Apretude: 600 mg injection Cabotegravir Raltegravir (Isentress) Elvitegravir ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course b Dosage adjustment in hepatic insufficiency. Dosage adjustment in renal insufficiency. BCRP = breast cancer resistance protein; BIC = bictegravir; CAB = cabotegravir; DTG = dolutegravir; EVG = elvitegravir; RAL = raltegravir; UGT = uridine diphosphate (UDP)-glucuronosyltransferase. a Watch CYP3A and UGT1A1 inducers and inhibitors. Avoid rifampin, other rifamycins, St. John’s wort, and certain anticonvulsants Dofetilide Divalent and trivalent cations Drug interactions Metabolized by CYP3A and glucuronidation by UGT1A1 Nausea, diarrhea, headache, weight gain Benign increases in c reatinine (inhibits creatinine secretion) and bilirubin (blocks bilirubin clearance) Metabolized by glucuronidation by UGT1A1/3 enzymes and by CYP3A 18 Serum half-life (hr) Elimination Adverse drug reactions 14 Take with or without food Oral bioavailability Take with or without food 50 mg once dailya,b Dosing 10-, 25-, 50-mg tablets Tivicay PD: 5-mg tablets for oral suspension Triumeq: 600 mg ABC/ 50 mg DTG/300 mg 3TC Dovato: 50 mg DTG/ 300 mg 3TC Juluca (see Rilpivirine) 50 mg once dailya Biktarvy: BIC 50 mg/TAF 25 mg/FTC 200 mg Dolutegravir (Tivicay) Form Bictegravir Table 6. Integrase Strand Transfer Inhibitors Infectious Diseases II 2-259 Hypersensitivity reactions, local injection site reactions (98%), pneumonia None Adverse drug reactions Drug interactions 150-, 300-mg tablets 150–600 mg BID (depending on concomitant drug interactions)a 23%–33% 14–18 Metabolized by CYP3A Abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, rash, upper respiratory tract infections, hepatotoxicity, orthostatic hypotension CYP3A substrate (watch CYP3A inducers and inhibitors) 200-mg vials 2000 mg IV × 1, followed by 800 mg IV every 2 wk N/A 64 Diarrhea, dizziness, nausea, rash, elevations in bilirubin, creatinine, glucose, and lipase, blood dyscrasias None Maraviroc (Selzentry) Entry inhibitor Binds to the CCR5 receptor of the CD4 T cell, preventing fusion and HIV entry Ibalizumab (Trogarzo) Post-attachment inhibitor Blocks HIV from binding to the domain 2 of CD4 and interfering with post-attachment steps required for HIV-1 entry CYP3A4 substrate (watch CYP3A4 inducers and inhibitors) 27% 11 Metabolized by esterases and CYP3A4 Nausea, diarrhea, abdominal pain, headache, fatigue, rash, sleep disturbances, elevations in LFTs and creatinine, may prolong QTc 600-mg tablets 600 mg BID Fostemsavir (Rukobia) Attachment inhibitor Converted to temsavir, which binds to the gp120 subunit of gp160, preventing the virus from interacting with CD4 receptors a Dosage adjustment in renal insufficiency. FTR = fostemsavir; gp = glycoprotein; IBA = ibalizumab; IV = intravenous(ly); MVC = maraviroc; N/A = not applicable; SC = subcutaneous(ly); T20 = enfuvirtide. N/A 3.8 Metabolized by hydrolysis Oral bioavailability Serum half-life (hr) Elimination Enfuvirtide (Fuzeon) Class Entry inhibitor Mechanism of action Attachment of gp120 to CD4 receptor and coreceptors CCR5 or CXCR4 results in exposure of the specific peptide sequence of gp41; enfuvirtide binds to this gp41 peptide sequence, preventing fusion Form 90-mg vials Dosing 90 mg SC BID Table 7. Entry Inhibitors Infectious Diseases II ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course Infectious Diseases II Patient Case 1. F.G. is a 27-year-old man who is HIV positive but asymptomatic. His CD4 count is 550 cells/mm3, and his viral load is 5000 copies/mL by reverse transcriptase polymerase chain reaction. Which is the best treatment for F.G.? A. ART should not be given because his CD4 count is still above 500 cells/mm3. B. Initiate emtricitabine/tenofovir only because his CD4 count is still above 500 cells/mm3. C. Initiate combination therapy of abacavir, lamivudine, and atazanavir/ritonavir. D. Initiate combination therapy of tenofovir, emtricitabine, and dolutegravir. 5. Treatment of the patient who is HIV positive a. Guidelines recommend HIV treatment for all infected patients, regardless of CD4 count (AI). b. Recommended initial regimens for most patients with HIV: The optimal ART for a treatment-naive patient consists of two NRTIs in combination with an INSTI. i.  Bictegravir/tenofovir alafenamide/emtricitabine ii. Dolutegravir/abacavir/lamivudine; only for patients who are HLA-B*5701 negative iii.  Dolutegravir plus tenofovir/emtricitabine iv. Dolutegravir plus lamivudine c. Recommended initial regimens in certain clinical situations: i. NNRTI-based regimens (a)  Doravirine/tenofovir disoproxil fumarate/lamivudine or doravirine plus tenofovir/ emtricitabine (b) Efavirenz/tenofovir/emtricitabine (c) Rilpivirine/tenofovir/emtricitabine; only for patients with viral load less than 100,000 copies/mL and CD4 count greater than 200 cells/mm3 ii. PI-based regimens (a) Atazanavir/ritonavir or atazanavir/cobicistat plus tenofovir/emtricitabine; if TDF, not recommended for CrCl less than 70 mL/minute/1.73 m2 (b) Darunavir/ritonavir or darunavir/cobicistat plus abacavir/lamivudine; only for patients who are HLA-B*5701 negative (c) Darunavir/ritonavir or darunavir/cobicistat plus tenofovir/emtricitabine; if TDF, not recommended for CrCl less than 70 mL/minute/1.73 m2 iii INSTI-based regimens: (a)  Elvitegravir/cobicistat/tenofovir/emtricitabine • Only for patients with pre-ART CrCl greater than 70 mL/minute/1.73 m 2 if using TDF or greater than 30 mL/minute/1.73 m 2 if using TAF (b)  Raltegravir plus tenofovir/emtricitabine iv. Regimens to consider when ABC, TAF and TDF cannot be used: (a) Dolutegravir plus lamivudine (b) Darunavir/ritonavir plus raltegravir (only if HIV RNA less than 100,000 copies/mL and CD4 greater than 200/mm3); (c) Darunavir/ritonavir plus lamivudine ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-260