Pharmacologic Therapies in Gastrointestinal Diseases a, b Rena K. Fox, MD *, Thiruvengadam Muniraj, MD, PhD KEYWORDS Hepatitis C virus Direct acting antivirals Irritable bowel syndrome GERD Peptic ulcer disease KEY POINTS Treatment of hepatitis C virus has radically changed in recent years and most patients are now treatment candidates and have a high likelihood of permanent cure of the virus. First-line treatment of irritable bowel syndrome is lifestyle modification for patients with mild-moderate symptoms, and pharmacotherapy for patients with moderate to severe symptoms. Proton pump inhibitors (PPIs) are the mainstay of therapy in gastric and duodenal ulcers, and in gastroesophageal reflux disease, although long-term use of PPIs carries the risk of several side effects. PHARMACOTHERAPY FOR HEPATITIS C VIRUS In the United States, hepatitis C virus (HCV) is the leading case of liver-related deaths, hepatocellular carcinoma (HCC), and liver transplant.1 Until recently, treatment of HCV consisted of pegylated interferon plus ribavirin, a regimen that was complicated, high- ly toxic, poorly efficacious, and had multiple contraindications.1 Most patients were not treatment candidates, and in total only 5% to 6% of US patients with HCV were successfully treated in the interferon era.2 Clinical Benefit of Achieving Sustained Virologic Response The goal of HCV antiviral treatment is to achieve a sustained virologic response (SVR), defined as HCV RNA levels at less than the limit of detection in the blood at 12 or more weeks after completing antiviral treatment. There is compelling evidence that an SVR has clinically meaningful improvements in outcomes. Among patients with cirrhosis R.K. Fox has no disclosures. a Division of General Internal Medicine, Department of Medicine, University of California, San Francisco School of Medicine, 1545 Divisadero St, Ste 307, San Francisco, CA, USA; b Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, 333 Cedar Street, 1080 LMP, New Haven, CT 06520-8019, USA * Corresponding author. E-mail address: [email protected] Med Clin N Am 100 (2016) 827–850 http://dx.doi.org/10.1016/j.mcna.2016.03.009 medical.theclinics.com 0025-7125/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved. 828 Fox & Muniraj who achieved an SVR, compared with patients who did not achieve an SVR, those with an SVR had a significantly reduced risk of HCC, liver failure, death related to liver disease, and all-cause mortality.3,4 Direct-acting Antivirals HCV treatment has undergone radical changes since interferon. Novel treatments that target specific parts of the HCV lifecycle are called direct-acting antivirals (DAAs). Since late 2013, multiple DAAs have been introduced, such as sofosbuvir, simeprevir, ledipas- vir, ombitasvir, dasabuvir, parataprevir, and daclatasvir. These drugs are used in combi- nation with each other, or in combination with ribavirin. The new regimens are interferon free and all oral. The DAA regimens are generally short courses, usually 12 weeks in dura- tion, but in some situations are 8 weeks or 24 weeks. In clinical trials, the cure rates with the DAAs are generally more than 90% and reach 100% in some subgroups.5–16 In gen- eral, patients who are treatment naive achieve higher SVR rates, but, with DAA regimens, treatment-experienced patients are seen to still achieve SVR rates of more than 90%, although usually requiring at least a 12-week duration and sometimes longer, and/or often adding ribavirin, especially if there is also the presence of cirrhosis.9,12,13,15 In large observational real-world studies, SVR rates are also greater than 90%, similar to trial out- comes.17 The oral medicines have very mild and tolerable side effect profiles; when riba- virin is included in the regimen, there are higher side effect rates.8–10,14 Discontinuation rates in real-world studies have also seemed to be low, especially when ribavirin is not needed.17 Overall, these new interferon-free DAA regimens have dramatically changed HCV treatment, with most of the HCV population predicted to now be medically eligible, and to have a high likelihood of treatment success (Table 1). Principles for Patient Selection for Hepatitis C Virus Treatment All patients with chronic HCV who do not have medical contraindications are potential candidates for antiviral treatment. The natural history of untreated chronic HCV is var- iable; fibrosis progression is nonlinear, and it is estimated that 20% to 30% of patients with chronic HCV ultimately develop cirrhosis.1 The urgency for treatment should be highest for patients with cirrhosis and advanced fibrosis, and also patients with HCC awaiting liver transplant, extrahepatic manifestations of HCV, after transplant, and women planning to conceive a child in the near term.18,19 Table 1 HCV-specific targets and antiviral medications: US Food and Drug Administration (FDA) approved or in phase II or III trials as of 2015 NS3/4A Protease NS5B Polymerase Inhibitors NS5B Polymerase Inhibitors NS5A Inhibitors Nucleoside/Nucleotide Non–Nucleoside/Nucleotide Inhibitors Simeprevira Sofosbuvira Dasabuvira Ledipasvira Paritaprevira Mericitabine Beclabuvir Ombitasvira Grazoprevir ACH-3422 GS-9669 Daclatasvira ABT-493 MK/IDX-459 TMC-055 Elbasvir Sovaprevir MK-3682 MK-8876 Velpatasvir GS-9857 ABT-530 Danoprevir ACH-3102 Vedroprevir Samatasvir GSK-2336805 MK-8408 a Currently FDA approved. Pharmacologic Therapies of GI disorders 829 Evaluating a patient’s potential adherence to the prescribed regimen is crucial to the patient selection process. Providers should incorporate strategies for measuring and supporting adherence. Ongoing substance use, including drinking alcohol, using illicit drugs (including marijuana), or participating in opioid replacement programs should not be an exclusion for HCV treatment.18,19 Pretreatment Evaluation Before initiating antiviral therapy in a patient with chronic HCV, the information listed in Box 1 should be obtained.18,19 Principles of Regimen Selection The most important pretreatment considerations for selection of DAA regimen are (1) genotype and subtype; (2) the presence or absence of cirrhosis and, if cirrhosis, then a determination of Child-Turcotte-Pugh (CTP) class A, B, or C; and (3) any prior history of treatment experience (Table 2). Side Effects of Direct-acting Antiviral Regimens in Phase 3 Trials Side effects of current DAAs are common but generally mild.5–16 Periodic laboratory monitoring of levels of liver enzymes, bilirubin, and hemoglobin is recommended for patients receiving HCV antiviral therapy (Table 3).18,19 Box 1 HCV DAA pretreatment evaluation HCV genotype and subtype HCV RNA (quantitative viral load) ideally within 6 months before start of treatment Fibrosis assessment – may be done by 1 or more of the following: Liver biopsy Liver Fibrosis imaging such as transient elastography (FibroScan) Serum markers of fibrosis such as FibroSure, FibroTest, FIBROSpect Clinical calculators of fibrosis such APRI20,21 or FIB-422 Determination of the absence/presence of cirrhosis – may be done by 1 or more of the following: Physical exam findings (splenomegaly, spider angioma, other) Routine laboratory findings (thrombocytopenia, hypoalbuminemia, other) Abdominal imaging findings (nodular surface of liver, splenomegaly, other) Liver biopsy documentation of cirrhosis Non-invasive fibrosis assessment consistent with cirrhosis (e.g., APRI > 2.0, FIB-4 > 3.25, elastography > 1.25 kilopascals) If cirrhosis is detected, the CTP class should be determined If cirrhosis is detected, HCC should be excluded by imaging within the previous 6 months HCV treatment history and outcome Human immunodeficiency virus (HIV) status and, if HIV seropositive, current antiretroviral regimen and degree of viral suppression Documented use of 2 forms of birth control in patient and sex partners in whom a ribavirin- containing regimen is chosen. Abbreviations: APRI, AST to Platelet Ratio Index; FIB-4, Fibrosis-4 Calculator. 830 Fox & Muniraj Table 2 CTP classification of the severity of cirrhosis Class A Class B Class C Total points 5–6 7–9 10–15 Factor (points) 1 2 3 Total bilirubin (mmol/L) <34 34–50 >50 Serum albumin (g/L) >35 28–35 <28 Prothrombin time/ <1.7 1.71–2.30 >2.30 International Normalized Ratio Ascites None Mild Moderate–severe Hepatic None Grade I–II Grade III–IV encephalopathy (or suppressed (or refractory) with medication) Assessing Hepatitis C Virus Treatment Response Assessment of HCV RNA during and after therapy is critical to determining treatment response. The goal of treatment is to achieve an HCV RNA level less than the level of detection (ie, undetectable). Consider checking HCV RNA starting at week 2 or week 4, and every 2 weeks until the level becomes undetectable. End-of-treatment HCV RNA is recommended but optional. HCV RNA levels at 12 weeks after the completion of treatment need to be obtained to determine whether SVR was achieved (Box 2). Interpretation of Hepatitis C Virus RNA Results Several assays are available for quantifying HCV RNA levels, with different lower limits of quantification and ranges of detection. The US Food and Drug Administration (FDA) rec- ommends use of a sensitive, real-time, reverse-transcription polymerase chain reaction (RT-PCR) assay for monitoring HCV RNA levels during treatment with DAA agents. To assess treatment response, commercial assays that have a lower limit of HCV RNA quantification of less than or equal to 25 IU/mL are strongly recommended.