Lopinavir/ritonavir
The combination lopinavir/ritonavir is FDA-approved for the treatment of human immunodeficiency virus (HIV). More recently, it was utilized to treat MERS and SARS. There is 1 trial by Cao et al89 that randomized 199 hospitalized patients with severe COVID-19 to receive treatment to lopinavir/ritonavir (n = 99) or placebo (n = 100) for 14 days. GI adverse events were most common among those in the treatment group, and were the primary reason for medication discontinuation; of patients receiving lopinavir/ritonavir, there were 9.5% (9 of 99) with nausea, 6.3% (6 of 99) with vomiting, 4.2% (4 of 99) with diarrhea, 4.2% (4 of 99) with abdominal discomfort, 4.2% (4 of 99) with reported stomach ache, and 4.2% (4 of 99) with diarrhea. Additionally, there were 2 serious adverse events of acute gastritis, which both led to drug discontinuation. When lopinavir/ritonavir is used in patients with HIV, diarrhea is the most common GI adverse events (10%–30%), with greater prevalence among those receiving higher doses. Other GI adverse events in HIV are similar to Cao et al’s RCT, with nausea in 5%–15% and vomiting in 5%–10% of patients90 (Table 3 ).
Table 3 Gastrointestinal Treatment Adverse Effects of Currently Utilized COVID-19 Therapies
Medication type Medication name Adverse effects Major drug–drug interactions
Gastrointestinal Hepatic
Antimalarial ChloroquineHydroxychloroquine Nausea, vomiting, abdominal pain, and diarrhea reported; frequency not defined Likelihood score: D (possible rare cause of clinically apparent liver injury).Description: Rare elevations in aminotransferases. Most reactions are hypersensitivity with no known cross reactivity to hepatic injury. If this occurs, reasonable to switch between chloroquine therapies. Substrate for CYP2D6 and CYP3A4 substrateSame as above; also substrate for CYP3A5 and CYP2C8
Antiviral Remdesivir Not reported (limited data available) Likelihood score: Not scored.Description: Hepatotoxicity reported; frequency not yet known. Not a significant inducer/inhibitor of CYP enzymes
Lopinavir/ritonavir Nausea and vomiting: 5%–10% (higher in children: 20%)Abdominal pain: 1%–10%Diarrhea: 10%–30% + dose-dependentOther: dysguesia in adults <2%, children: 25%, increased serum amylase, lipase: 3%–8%. Likelihood score: D (possible, rare cause of clinically apparent liver injury).Description: Hepatotoxicity ranges from mild elevations in aminotransferases to acute liver failure.Recovery takes 1–2 mo.Re-challenging may lead to recurrence and should be avoided if possible. Substrate for: CYP3A4, CYP2D6P-gpInducer for: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT1A1Inhibitor for: CYP3A4
Favipiravir Nausea/vomiting: 5%–15%Diarrhea: 5%Limited data available Likelihood score: Not scoredDescription: 3% prevalence, but few data available. Inhibitor for: CYP2C8 and aldehyde oxidaseMetabolized by xanthine oxidase and aldehyde oxidase
The Cao et al89 RCT did not show a significant increase in hepatotoxicity in the treatment compared to the control group. However, in patients with HIV, there is a well-documented known risk of hepatotoxicity, with liver injury severity ranging from mild enzyme elevations to acute liver failure.91 Moderate-to-severe elevations in serum aminotransferases, defined as more than 5 times the ULN, are found in 3%–10%.91 Rates may be higher in patients with concurrent HIV and hepatitis C virus co-infection. In some cases, mild asymptomatic elevations are self-limited and can resolve with continuation of the medication, but re-challenging the medication can also lead to recurrence and, therefore, should be avoided when possible. Acute liver failure, although reported, is rare. Ritonavir has potent effects on cytochrome P450 and therefore affects drug levels of a large number of medications typically given in GI practices.