Gastrointestinal Disorders PDF

Gastrointestinal Disorders 2. Diagnosis a. Clinical signs and symptoms include nausea, abdominal pain, jaundice, fever, malaise, or anorexia. Some patients may have mild asymptomatic disease. b. Recent possible exposures c. Laboratory data i. IgM antibody to HAV (anti-HAV) is...

Gastrointestinal Disorders 2. Diagnosis a. Clinical signs and symptoms include nausea, abdominal pain, jaundice, fever, malaise, or anorexia. Some patients may have mild asymptomatic disease. b. Recent possible exposures c. Laboratory data i. IgM antibody to HAV (anti-HAV) is detectable in the serum 5–10 days before the onset of symptoms. Once the infection clears, the IgM antibody is replaced by IgG antibodies during a 2- to 6-month period. These antibodies confer lifelong protective immunity against subsequent infection. ii. Elevation of aminotransferases d. Management of acute HAV infection is mainly supportive; avoid hepatotoxic medications, such as acetaminophen. 3. Preexposure prophylaxis a. Active (vaccination) or passive (immune globulin) prophylaxis can be used. b. Havrix (GlaxoSmithKline) and Vaqta (Merck) are the two available HAV vaccines; Twinrix is a combination HAV and HBV product (GlaxoSmithKline). c. Populations requiring preexposure prophylaxis with HAV vaccine i. All children older than 1 year ii. People experiencing homelessness iii.  International travelers iv. Men who have sex with men v. Injection or non-injection drug users vi. People with occupational risk of exposure vii. Patients with chronic liver disease or human immunodeficiency virus (HIV) infection viii. Pregnant women at risk for HAV infection or severe outcome from HAV infection ix. People who have close personal contact with international adoptee d. Populations requiring preexposure prophylaxis with HAV immune globulin i. Travelers to endemic countries ii. Children younger than 1 year (vaccine not approved for this age group) iii. Doses: 0.1 mL/kg for travel up to 1 month, 0.2 mL/kg for travel up to 2 months, 0.2 mL/kg every 2 months for travel longer than 2 months. Administer intramuscularly. 4. Postexposure prophylaxis a. Immune globulin can be given at a dose of 0.1 mL/kg intramuscularly within 2 weeks of exposure. HAV vaccine is recommended in patients 12 months to 40 years old who are otherwise healthy. Patients older than 40 should receive the vaccine with or without concurrent immune globulin administration. Patients 12 months and older who are immunocompromised or who have chronic liver disease should receive both the vaccine and immune globulin. b. Offer to those not previously vaccinated in the following situations: i. Close personal contact with a documented infected person ii. Staff or attendees of day care centers if one or more cases are recognized in children or employees or if cases are recognized in two or more households of attendees iii. Common source of exposures (a) If a food handler receives a diagnosis of HAV, vaccine or immune globulin should be administered to other food handlers at the same establishment. Administration of HAV vaccine or immune globulin to patrons typically is not indicated, but may be considered if: (1) The food handler was probably infectious, and he or she both directly handled uncooked or cooked food and had diarrhea or poor hygienic practices. (2) Patrons can be identified and treated in 2 weeks or less after exposure. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-153 Gastrointestinal Disorders (b) In settings where repeated exposures to HAV might have occurred, stronger consideration of HAV vaccine or immune globulin use could be warranted. In a common-source outbreak, postexposure prophylaxis should not be provided to exposed individuals after cases have begun to occur, because the 2-week period after exposure during which immune globulin or HAV vaccine is known to be effective will have been exceeded. C. HBV 1. Background a. HBV is a DNA virus; there are more than 350 million infected patients worldwide. b. Transmission routes i. Parenteral: intravenous drug abuse, needlestick, transfusion, ear or body piercing ii. Bodily fluids: saliva, semen, vaginal fluid iii. Sexual contact: heterosexual and homosexual iv. Perinatal: mother to child at birth c. Associated with both acute and chronic disease. Natural history of HBV is age dependent. Risk of developing chronic infection after an acute infection is 90% in neonates, 30% in children younger than 5 years, and 2%–6% in adults. d. Chronic infection with HBV increases the risk of hepatocellular carcinoma. e. Diagnosis i. Clinical signs and symptoms: nausea, vomiting, diarrhea, myalgia, fever, abdominal pain, jaundice (30% may have no symptoms) ii. Serologic diagnosis (Table 17) iii. Combinations of serologic markers must be reviewed to distinguish acute from chronic infections. iv. Eight different HBV genotypes (A–H) exist. Routine genotype testing is not endorsed by the guidelines. Table 17. HBV Serologies Serologic Marker Surface antigen Abbreviation HBsAg Core antigen HBcAg E antigen Anti–surface antigen antibody Anticore antigen antibody (IgM) Anticore antigen antibody (IgG) HBeAg Anti-HBs Anti-E antibody HBV DNA Anti-HBe HBV DNA IgM Anti-HBc Anti-HBc Comment First detectable serum antigen during acute infection; also present in chronic infection Present early after cell damage during acute infection; typically cannot measure this in the serum Denotes ongoing active viral replication Confers protective immunity; present after recovery from acute infection or after vaccination Present in acute infection Appears at onset of symptoms Denotes prior exposure to HBV Cannot use in isolation to distinguish acute from chronic infection May indicate peak replication has passed Marker of active HBV replication HBcAg = hepatitis B core antigen; HBeAg = hepatitis B early antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; Ig = immunoglobulin. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-154 Gastrointestinal Disorders (a) Most patients have hepatitis B envelope antigen (HBeAg)-positive disease. (b) HBeAg-negative disease: Mutation in the precore or core promoter regions. These variants are known as precore mutants; these mutations do not allow monitoring of loss of E antigen as a clinical marker of suppressed replication. Monitor reduction in HBV DNA; patients infected with these variants also tend to have lower serum HBV DNA and fluctuating liver function tests. (c) Centers for Disease Control and Prevention guidelines for screening for HBV infection indicate that the serologic assay for HBV surface antigen (HBsAg) should be the serologic screening test used for the following populations. Additional HBV tests are needed in combination with the HBsAg for select populations as listed below. (1) People born in geographic regions with HBsAg prevalence greater than 2% regardless of vaccination history (2) Men who have sex with men; also test for anti-HBc or anti-HBs (3) Past or current intravenous drug users; also test for anti-HBc or anti-HBs (4) Patients receiving cytotoxic chemotherapy or immunosuppressive therapy related to organ transplantation or rheumatologic or GI disorders. In addition, test for anti-HBc or anti-HBs. (5) U.S.-born people not vaccinated as infants whose parents were born in regions with HBV endemicity greater than 8% (6) People with elevated ALT and AST of unknown etiology (7) Donors of blood, plasma, organs, tissues, or semen. In addition, test for anti-HBc and HBV DNA. (8) Pregnant women (during each pregnancy, preferably in the first trimester) (9) Infants born to HBsAg-positive mothers (10) Household, needle sharing, or sex contacts of people known to be HBsAg positive. In addition, test for anti-HBc or anti-HBs. (11) People who are the sources of blood or bodily fluid for exposures that might require postexposure prophylaxis (12) People who are living with HIV. In addition, test for anti-HBc or anti-HBs. v. Clinical definitions (Table 18) Table 18. Clinical Definitions of HBV Chronic HBV Infection HBsAg positive > 6 mo Serum HBV DNA 20,000 IU/mL (105 copies/mL), lower values 2000–20,000 IU/ mL (104–105 copies/mL) are often observed in HBeAg-negative chronic HBV Persistent/intermittent elevation of AST and ALT Chronic hepatitis and moderate-severe necroinflammation on biopsy Inactive HBV Carrier State HBsAg positive > 6 mo HBeAg negative, anti-HBeAg positive Serum HBV DNA < 2000 IU/mL (104 copies/mL) Persistently normal AST and ALT; absence of significant hepatitis on biopsy ALT = alanine aminotransferase; AST = aspartate aminotransferase ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-155 Gastrointestinal Disorders 2. Treatment of chronic infection a. Treatment recommendations i. Patients who are HBeAg positive with elevated ALT concentrations and compensated liver disease should be observed for 3−6 months for spontaneous conversion from HBeAg positive to anti-HBe (or HBeAb positive) indicating seroconversion, before initiating treatment. Antiviral treatment should be considered in patients whose ALT remains greater than 2-fold the ULN and whose HBV DNA is greater than 20,000 IU/mL. ii. Patients who are HBeAg negative with positive anti-HBe, normal ALT, and HBV < 2000 IU/ mL should be monitored every 3 months for 1 year and then every 6–12 months if they remain in the inactive carrier state. b. Patients who meet the criteria for chronic infection should be treated. Choice of initial therapy is based on patient profile, prior treatments, contraindications to drug therapy, and medication and monitoring costs. c. Monitoring for efficacy should be based on the following responses: i. Biochemical: Reduction of liver function tests to within the normal range ii. Virologic: Reduction of HBV DNA to undetectable concentrations and loss of HBeAg if HBeAg positive (a) A primary nonresponse is considered a decrease in HBV DNA of less than 2 log/mL after at least 24 weeks of therapy. Patients who do not meet these criteria should receive an alternative treatment. (b) Response should be assessed by reductions in HBV DNA for HBeAg-negative patients. 3. Drug therapies a. Reverse transcriptase inhibitors i. In general, lamivudine and telbivudine are not preferred as first-line therapies because of high rates of resistance. ii. All reverse transcriptase inhibitors carry a black box warning for the development of lactic acidosis and severe hepatomegaly with steatosis. Monitor for worsening liver function tests, and periodically assess renal function. Female and obese patients are at higher risk. Reductions in bone mineral density (BMD) have been associated with long-term use. Assess baseline BMD in patients older than 12 years with a history of pathologic fracture or osteoporosis. iii. Tenofovir, disoproxil fumarate, and entecavir are preferred antivirals in HBV with decompensated cirrhosis, where they are safer than pegylated interferon and have higher potency and minimal risk of resistance compared with other antivirals. iv. Entecavir (Baraclude) (a) Indicated for HBeAg-negative and HBeAg-positive patients with persistently elevated AST or ALT or histologically active disease; effective in lamivudine-resistant YMDD mutants (b) Reduces HBV DNA by up to 6.86 log in HBeAg-positive, naive patients and by 5.2 log in HBeAg-negative patients or those with lamivudine resistance (c) Dose: 0.5 mg orally once daily for patients older than 16 years and nucleoside naive; 1 mg orally once daily for patients older than 16 years with HBV viremia while receiving lamivudine or in lamivudine-resistant HBV (d) Dose adjustments required for renal impairment (e) Toxicity: Similar to lamivudine with headache, cough, upper respiratory infection, abdominal pain; possibly fewer ALT flares. Rare lactic acidosis. Resistance reported as similar to 1% at 5 years. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-156 Gastrointestinal Disorders v. Tenofovir (Viread 300 mg, Vemlidy 25 mg) (a) Nucleotide analog, formulated as tenofovir disoproxil fumarate (Viread) or tenofovir alafenamide (Vemlidy), indicated for chronic HBV infection (b) Effective for lamivudine-resistant HBV (c) Dose adjustments of tenofovor disoproxil fumarate required for renal impairment. Tenofovir alafenamide is not recommended in patients with CrCl less than 15 mL/min, and for patients on hemodialysis, it should be dosed after dialysis. (d) Toxicity: Overall, well tolerated; headache, nausea, and nasopharyngitis most commonly reported; potential renal toxicity, so periodic monitoring of SCr recommended; potential ALT flares on withdrawal; rare lactic acidosis. Tenofovir alafenamide is associated with less renal and bone toxicity. b. Pegylated interferon i. Cytokine with antiviral, antiproliferative, and immunomodulatory effects ii. Best predictors of response to treatment are high pretreatment ALT, low-serum HBV DNA, presence of active inflammation on biopsy, and acquisition of infection; adult HBeAg-negative disease responds less favorably to interferon. iii. Dosing (a) Pegylated interferon is recommended over interferon alfa because of its reduced dosing frequency and improved tolerance. (b) Pegylated-α-2a (Pegasys): 180 mcg subcutaneously once weekly for 48 weeks (duration is the same for HBeAg-negative and HBeAg-positive disease) iv. If a response is obtained, it is usually long lasting (more than 4 years). vi. Treatment with interferon typically results in an increase in ALT 4–8 weeks into treatment. This response is expected; it should not be viewed as an adverse effect of therapy. vii. Adverse effects (a) Interferon is associated with many serious adverse effects, including bone marrow suppression. (1) Leukopenia: May use filgrastim (granulocyte colony-stimulating factor) for support. Requires frequent monitoring of complete blood cell count (every 1–3 months) (2) Thrombocytopenia: Minimal data with oprelvekin (interleukin-11). Not used because of many adverse effects including pulmonary hypertension (b) Predisposition to infections (c) CNS: depression, psychosis, anxiety, insomnia, seizures. Adverse CNS effects occur in 22%–31% of patients. (d) Flulike symptoms (tolerance usually develops after a few weeks) (e) Anorexia, alopecia, thyroid dysfunction, neuropathy (f) Exacerbation of underlying autoimmune disorders (i.e., thyroid). Thyroid-stimulating hormone testing recommended every 3 months (g) Ischemic or hemorrhagic cerebrovascular disorders (h) Serious hypersensitivity and rash formation (i) Manufacturers give recommendations for dose reductions in patients who develop bone marrow suppression and depression while on therapy. (j) Contraindicated in patients with current psychosis, a history of severe depression, neutropenia, thrombocytopenia, symptomatic heart disease, decompensated liver disease, and uncontrolled seizures; also use caution in patients with autoimmune disorders ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-157 Gastrointestinal Disorders vi. HBV Treatment is summarized in Table 19 Table 19. Summary of Treatment Recommendations for Chronic HBV Infection in Adults HBV Population HBeAg positive HBeAg negative Development of resistant HBV Preferred Treatment Options Entecavir and tenofovir are preferred oral agents; use of the other oral reverse transcriptase inhibitors is possible but not preferred PEG-IFNα Duration Minimum of 1 yr Comments Preferred if contraindications 48 wk Entecavir and tenofovir are preferred oral agents; use of the other oral reverse transcriptase inhibitors is possible but not preferred PEG-IFNα > 1 yr If contraindication or no response, use entecavir and tenofovir Preferred if contraindications Lamivudine, telbivudine, or entecavir resistance: Add or switch to tenofovir N/A Adefovir resistance: Add or switch to entecavir or no response to IFNα or no response to IFNα ≥ 1 yr If contraindication or no response, use entecavir and tenofovir Confirm resistance with genotypic testing; reinforce adherence to therapy Multidrug resistance: Combined tenofovir and entecavir N/A = not applicable; PEG-IFNα = pegylated interferon alfa. 4. Preventive strategies a. Vaccination (preexposure); indicated in the following groups: i. All infants, children, and adults age 19–59 years ii. Adults 60 years and older with hepatitis risk factors including: (a) Individuals at risk of infection by sexual exposure (sex partners or live with someone with hepatitis B; sexually active but not in a mutually monogamous relationship; have a sexually transmitted infection; men who have sex with men) (b) Individuals at risk of infection by percutaneous or mucosal exposure to blood (injection drug use; occupational risk of exposure to blood or blood-contaminated body fluids; patients receiving hemodialysis; patients with diabetes) (c) Others (international travelers to countries where hepatitis B is common; individuals with hepatitis C, chronic liver disease, or HIV infection; incarcerated individuals) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-158 Gastrointestinal Disorders b. Available HBV vaccines (dose schedules vary by age) i. Dose schedules (Table 20) Table 20. Dose Schedules for Hepatitis B Vaccinations Vaccinea Heplisav-B Engerix-B PreHevbrio (3-Antigen) Recombivax HB Twinrix (HAV and HBV) Intramuscular Doseb ≥ 18 yr: 0.5 mL Birth – 19 yr: 0.5 mL ≥ 20 yr: 1 mL Adults receiving hemodialysis: 2 mL >/= 18 yr: 1 mL Schedule Two doses (0 and 1 mo) Three doses (0, 1, and 6 mo) Birth – 19 yr: 0.5 mLc ≥ 20 yr: 1 mL Adults receiving hemodialysis: 1 mL of high-dose formulation (40 mcg) ≥ 18 yr: 1 mL Three doses (0, 1, and 6 mo) Four doses (0, 1, 2, and 6 mo) Three doses (0, 1, and 6 mo) Three doses (0, 1, and 6 mo) Three doses (0, 1, and 6 mo) All listed vaccines should be refrigerated (2°C–8°C). Do not freeze. All listed vaccines should be administered intramuscularly in the deltoid muscle for adults, adolescents, and children ≥ 1 yr whose deltoid is large enough for intramuscular injection. For children < 1 yr, the anterolateral aspect of the thigh should be used as the intramuscular injection site. c Ages 11–15 alternative dosing schedule: two intramuscular doses of 10 mcg/1 mL at 0 and 4–6 mo. HAV = hepatitis A virus. a b ii. Obtain titers 1–2 months after the third dose of the series for HCPs. iii. HBV vaccines are available as combination products with HAV (Twinrix), DTP/IPV (Pediarix), and Hib (Comvax). c. Postexposure prophylaxis i. Exposure can result in the need for HBV vaccine or immune globulin. ii. Doses of HBV immune globulin are 0.06 mL/kg intramuscularly and must be given within 7 days of exposure. iii. Patient populations requiring postexposure prophylaxis (a) Perinatal transmission (1) Children born to HBsAg-positive mothers should receive the first dose of the threedose vaccine series plus HBV immune globulin within 12 hours of birth. (2) Children born to mothers with unknown HBsAg status (but suspected) should receive the first dose of the three-dose vaccine series within 12 hours of birth; testing should be performed on the child, and if positive, HBV immune globulin should be administered within 1 week. (3) Infants weighing less than 2 kg at birth whose mothers are documented as HBsAg negative should receive the first dose of the vaccine series 1 month after birth or at hospital discharge, whichever comes first. (b) Sexual contact or household contact with an infected person: Should receive HBV immune globulin plus vaccine series if exposed person is previously unvaccinated (c) Sexual contact or household contact with an HBV carrier: Should receive vaccine series if exposed person was previously unvaccinated ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-159 Gastrointestinal Disorders (d) Postexposure recommendations for HCPs (Table 21) Table 21. Centers for Disease Control and Prevention Recommendations for Management of HBV Postexposure for HCPs HBV Status of HCP Documented responder Documented nonresponder after six doses Response unknown after one complete series Unvaccinated or incompletely vaccinated or vaccine refusers Postexposure Testing Source Patient HCP Testing (HBsAg) (anti-HBs) Postexposure Prophylaxis HBIG Vaccination Postvaccination Serologic Testing No action needed Positive or unknown Negative Positive or unknown Negative — HBIG × 2 separated by 1 mo — No action needed Initiate HBIG × 1 revaccination None <10 mIU/mL <10 mIU Any result Positive or unknown ≥10 mIU — HBIG × 1 Negative — None No action needed Complete vaccination Complete vaccination No Yes Yes Yes HBIG = hepatitis B immune globulin; HCP = health care provider. D. HCV 1. Background a. RNA virus: six genotypes (50 subtypes) i. Genotype 1 (subtypes 1a and 1b) accounts for 70%–75% of infections in the United States. ii. Genotypes 2 (subtypes 2a, 2b, and 2c) and 3 (3a and 3b) are less common in the United States. iii. Genotype helps determine therapy duration and likelihood of responding to therapy. b. Leading cause of liver disease and liver transplantation in the United States; also a common cause of hepatocellular carcinoma c. Viral replication occurs in the hepatocyte (virus is not directly cytopathic). d. Transmission is mainly bloodborne (transfusion, intravenous drug abuse). HCV risk factors include: i. HIV infection ii. Current or former injection drug use (including historical and one-time use) iii. Patients who ever received maintenance hemodialysis iv. Prior recipients of transfusions or organ transplants (received clotting factor concentrates produced before 1987, received a transfusion of blood or blood components before July 1992, received an organ transplant before July 1992, or notified that they received blood from a donor who later tested positive for HCV infection) v. Health care, emergency medical, and public safety personnel after needle sticks, sharps, or mucosal exposures to HCV-positive blood vi. Children born to mothers with HCV infection e. Associated with acute and chronic infection; after acute infection, most patients (60%–85%) develop chronic infection 2. Clinical features: About 30% of patients are asymptomatic. a. Acute infection: Symptoms present 4–12 weeks after exposure; most patients are asymptomatic and seldom progress to fulminant disease; those who develop symptoms have nonspecific findings such as malaise, weakness, anorexia, and jaundice. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-160 Gastrointestinal Disorders Chronic infection is defined as the presence of viral RNA in the serum for 6 months or more. i. It may be associated with the long-term development of end-stage liver disease, cirrhosis, hepatocellular carcinoma. ii. Progression to complications and end-stage liver disease can be accelerated by concurrent alcohol use and coinfection with HIV; younger female patients have slower progression. c. Extrahepatic manifestations: rheumatoid symptoms, glomerulonephritis, cryoglobulinemia 3. Diagnosis and monitoring a. Clinical signs and symptoms include nausea, abdominal pain, jaundice, fever, malaise, or anorexia. Many patients have asymptomatic disease. b. Once in a lifetime HCV testing is recommended for all individuals aged 18 years or older and for pregnant women with each pregnancy. c. In addition, one‑time HCV testing for patients with HCV risk factors, including: i. People with HIV ii. People who ever injected drugs and shared needles, syringes, or other drug preparation equipment, including those who injected once or a few times many years ago iii. People with select medical conditions, including those who ever received maintenance hemodialysis or those with persistently abnormal ALT levels iv. Prior recipients of transfusions or organ transplants, including clotting factor concentrates produced before 1987 or transfusion of blood or blood components or organ transplant before July 1992, or those notified that they received blood from a donor who later tested positive for HCV v. Health care, emergency medical, and public safety personnel after needle sticks, sharps, or mucosal exposures to HCV‑positive blood vi. Children born to mothers with HCV infection vii. Routine periodic testing for people with ongoing risk factors, including current injection drug users or those who ever received maintenance hemodialysis d. Laboratory i. Serum anti-HCV antibodies (99% sensitivity and specificity [enzyme immunoassays]) are used as an initial screening for HCV. The presence of anti-HCV antibody does not confer protective immunity from subsequent infection. (a) If serum anti-HCV antibodies are positive, confirmatory testing by a sensitive HCV RNA test is warranted. (b) Quantitative HCV RNA testing to document baseline viremia before initiating antiviral therapy (c) Sustained virologic response (SVR) is undetectable HCV RNA 12 weeks after completion of treatment; it is considered a virologic cure. iii. Liver biopsy, imaging, or noninvasive markers to evaluate liver fibrosis is recommended. iv. Genotyping: Genotype 1 is the most common genotype in the United States. Genotypes 2 and 3 are the other two most common genotypes in the United States. 4. Treatment a. Acute HCV infection i. Preexposure or postexposure prophylaxis is not recommended. ii. The same regimens used for chronic HCV are recommended for treatment. b. Chronic infection i. Therapy goal is to attain a SVR, defined as the absence of detectable HCV RNA 12 weeks after treatment. Obtaining undetectable concentrations at 12 weeks is considered a clinical cure. ii. With the availability of direct-acting antivirals (DAAs) therapies, treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be altered by treating HCV, transplantation, or other directed therapy. b. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-161 Gastrointestinal Disorders iii. DAAs carry a risk of reactivation of HBV infection. Patients receiving DAA therapy should be tested and monitored for HBV reactivation. c. Ribavirin in the treatment of HCV infection i. Oral nucleoside analog ii. Available as 200-mg tablets (Copegus) or capsules (Rebetol, Ribasphere; generic available) iii. Weight-based dosing of ribavirin, administered daily in two divided doses: for patients weighing less than 66 kg: 800 mg daily; 66–80 kg: 1000 mg daily; 81–105 kg: 1200 mg daily; greater than 105 kg: 1400 mg/day. Reduced dosing may be considered in patients with decompensated cirrhosis. iv. Significant adverse effect profile (a) Hemolytic anemia can occur in up to 10% of patients (usually within 1–2 weeks of initiating therapy); may worsen underlying cardiac disease; monitor complete blood cell count (CBC) at baseline, 2 weeks, 4 weeks, and periodically thereafter. In patients with no cardiac history, decrease the dose to 600 mg/day if hemoglobin drops to 10 g/dL or less, and discontinue when hemoglobin drops to 8.5 g/dL or less. In patients with a cardiac history, decrease the dose to 600 mg/day if hemoglobin drops more than 2 g/dL in any 4-week period during treatment. Discontinue if hemoglobin drops to less than 12 g/dL 4 weeks after dose reduction. Epoetin or darbepoetin can be used to stimulate red blood cell production, improve anemia, and sustain initial starting dose. It is also necessary to confirm that iron study results are normal and within range during treatment. (b) Teratogenicity: category X drug; requires a negative pregnancy test at baseline and every month up to 6 months after treatment, as well as the use of two forms of barrier contraception during treatment and for 6 months after treatment; applies to women taking the drug and female partners of male patients taking ribavirin (c) Other possible adverse events include pancreatitis, pulmonary dysfunction (dyspnea, pulmonary infiltrate, and pneumonitis), insomnia, irritability or depression (often called “riba rage”), and pruritus. d. NS5B/A polymerase inhibitors sofosbuvir (Sovaldi) and sofosbuvir/ledipasvir (Harvoni) i. Indications (a) Sofosbuvir: HCV genotypes 1–6, including those with hepatocellular carcinoma meeting Milan criteria and those with HCV/HIV coinfections (b) Sofosbuvir/ledipasvir: genotype 1, 4, 5, or 6 infection ii. Dosing: 400-mg tablet once daily with or without food iii. Adverse effects: fatigue, headache iv. Drug interactions (a) Avoid use with potent P-glycoprotein (P-gp) inducers. (b) Concentrations are significantly affected by anticonvulsants (carbamazepine, phenytoin, phenobarbital, and oxcarbazepine), rifabutin, rifampin, St. John’s wort, and tipranavir/ritonavir. (c) Avoid using with amiodarone because of symptomatic bradycardia. The mechanism of this interaction is not known. (d) Coadministration with acid-suppressive therapy may reduce DAA concentrations and is not recommended. (e) Coadministration with an HMG-CoA inhibitor may increase HMG-CoA inhibotor systemic concentrations and increase the risk of statin-related adverse effect. Coadministration is not recommended. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-162 Gastrointestinal Disorders e. NS5A/B inhibitor combination velpatasvir / sofosbuvir (Epclusa) i. Indication: Genotype 1–6 infection ii. Dosing: velpatasvir 100 mg / sofosbuvir 400 mg fixed-dose combination tablet once daily for 12 weeks. Weight-based ribavirin is added if decompensated cirrhosis is present with HCV genotypes 1–6. iii. Adverse effects: headache and fatigue iv. Drug interactions (a) Contraindicated with inducers of P-gp and moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine), which can decrease plasma concentrations of sofosbuvir and/or velpatasvir. (b) Avoid use of amiodarone and sofosbuvir because of symptomatic bradycardia. (c) Coadministration with acid-suppressive therapy may reduce DAA concentrations and is not recommended. (d) Coadministration with an HMG-CoA inhibitor may increase HMG-CoA inhibotor systemic concentrations and increase the risk of statin-related adverse effect. Coadministration is not recommended. f. NS3/4A and NS5A inhibitor combination glecaprevir and pibrentasvir (Mavyret) i. Indications (a) Genotype 1–6 infection with or without compensated cirrhosis (Child-Turcotte-Pugh A) (b) Recommended as an option for treatment-experienced patients depending on prior DAA treatment regimen. ii. Dosing: glecaprevir 100 mg / pibrentasvir 40mg fixed dose combination tablet, three tablets once daily with food for: (a) Eight weeks for genotype 1–6 treatment-naive patients without cirrhosis or compensated cirrhosis (except those with compensated cirrhosis who are coinfected with HIV). (b) 16 weeks for patients previously treated, depending on prior regimen iii. Adverse effects: headache, fatigue, nausea. NS3/4A protease inhibitors are associated with rare cases of worsening liver function or liver failure in patients with moderate to severe liver impairment and should be avoided in these patients. iv. Drug interactions: (a) Avoid use with P-gp or CYP3A inducers, because this can reduce the concentration of glecaprevir and pibrentasvir (carbamazepine, efavirnez, St. John’s wort). It is contraindicated with atazanavir or rifampin. (b) Coadministration with acid-suppressive therapy may reduce DAA concentrations and is not recommended. (c) Coadministration with an HMG-CoA inhibitor may increase HMG-CoA inhibotor systemic concentrations and increase the risk of statin-related adverse effect. Coadministration is not recommended. g. NS3/4A inhibitor Grazoprevir combined with NS5A inhibitor elbasvir (Zepatier) i. Indication: Geonotypes 1 or 4 infection with or without ribavirin ii. Dosing: Grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination tablet once daily for 12 or 16 weeks. (a) Testing for NS5A resistance-associated substitutions (RASs) is recommended. If RASs are present, another recommended regimen should be used. iii. Adverse effects (a) ALT elevations: Check ALT at baseline, 8 weeks of therapy, and 12 weeks of therapy if 16 week duration is indicated (contraindicated in Child-Pugh class B or C). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-163 Gastrointestinal Disorders (b) Headache, fatigue (c) NS3/4A protease inhibitors are associated with rare cases of worsening liver function or liver failure in patients with moderate to severe liver impairment and should be avoided in these patients. iv. Drug interactions (a) Contraindicated in combination with OATP1B1/3 inhibitors, strong CYP3A inducers, and efavirenz. (b) Coadministration with acid-suppressive therapy may reduce DAA concentrations and is not recommended. (c) Coadministration with an HMG-CoA inhibitor may increase HMG-CoA inhibotor systemic concentrations and increase the risk of statin-related adverse effect. Coadministration is not recommended. h. NS5A/B and NS3/4A inhibitor combination velpatasvir, sofosbuvir, and voxilaprevir (Vosevi) i. Indications (a) Genotypes 1–6 infection with or without compensated cirrhosis (Child-Turcotte-Pugh A) in patients who have been treated with an HCV regimen containing an NS5A inhibitor. (b) Recommended as an option for treatment-experienced patients depending on prior DAA treatment regimen. ii. Dosing: sofosbuvir 400 mg / velpatasvir 100 mg / voxilaprevir 100 mg fixed dose combination tablet once daily with food for 12 weeks iii. Adverse effects: headache, fatigue, diarrhea, nausea. NS3/4A protease inhibitors are associated with rare cases of worsening liver function or liver failure in patients with moderate to severe liver impairment and should be avoided in these patients. iv. Drug interactions: See velpatasvir / sofosbuvir (Epclusa) listing above. i. Effective and simplified treatment regimens are recommended in an effort to increase the number of health care providers who are able to prescribe curative HCV treatment and to increase the number of patients who are effectively treated for HCV. Simplified treatment regimens are not appropriate for patients who have received prior HCV treatment, have concurrent HIV or are HBsAg positive, are pregnant, have cirrhosis, prior liver transplant, or known or suspected hepatocellular carcinoma. Treatment recommendations for chronic HCV infection in treatment-naive adults are included in Table 22. Table 22. Simplified Treatment Algorithm for Treatment-Naive Adult Patients with HCV (irrespective of genotype unless noted) Patients without Cirrhosis Glecaprevir (300 mg)/pibrentasvir (120 mg) daily with food × 8 wk Sofosbuvir (400 mg)/velpatasvir (100 mg) daily × 12 wk Patients with Compensated Cirrhosis (Child-Pugh-Turcotte class A) Glecaprevir (300 mg)/pibrentasvir (120 mg) daily with food × 8 wk Sofosbuvir (400 mg)/velpatasvir (100 mg) daily × 12 wk for genotypes 1, 2, 4, 5, or 6. Genotype 3 requires baseline NS5A RAS testing. Sofosbuvir/velpatasvir can be used if Y93H is absent HCV = hepatitis C virus; RAS = resistance-associated substitution. j. Table 23 includes HCV genotype specific treatment recommendations. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-164