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Revista colombiana de Gastroenterología

versión impresa ISSN 0120-9957

Rev Col Gastroenterol vol.34 no.2 Bogotá abr./jun. 2019

https://doi.org/10.22516/25007440.252 

Review articles

Structured review of establishing and evaluating clinical relevance of drug interactions in hepatitis C virus treatment (Update 2015 - 2017)

Jaime Peláez A1 

Daniel Pino Marín1 

Priscilla Álvarez O1 

Juliana González C1 

Pedro Amariles1  * 

1Grupo de Promoción y Prevención Farmacéutica (P&PF), Universidad de Antioquia. Químico Farmacéutico. Departamento de farmacia, Universidad de Antioquia. Medellín, Colombia


Abstract

Objective:

This study-s objective is to establish and evaluate the clinical relevance of drug interactions during treatment of patients with hepatitis C.

Method:

A PubMed/MedLine search was conducted for articles published in English and Spanish from January 1, 2015 to March 30, 2017 using the terms Mesh: Hepatitis C AND drug interactions OR herb-drug interactions OR food-drug interactions, from studies conducted in humans. The clinical relevance of drug interactions was established and evaluated based on probability of occurrence and severity of interactions.

Results:

Of the 184 four articles identified, 92 were selected by title and abstract for full review. The full texts of two articles could not be accessed. Of the remaining articles, 57 describ ed relevant interactions. Of the 155 pairs of drugs that interact that were identified, 154 (99.4%) were pharmacokinetic, and one (0.6%) was pharmacodynamic. Thirty-four of the 155 pairs (21.9%) were assessed at level 1; 73 (47.1%) were assessed at level 2; 48 (31.0%) were assessed at level 3, none were assessed at level 4. In addition, 29 pairs of interacting drugs had no evidence of clinical relevance.

Conclusions:

More than 99% of clinically relevant drug interactions are pharmacokinetics and are associated with changes in metabolism and transport of drugs. Simeprevir and 3D (Paritaprevir/Ritonavir+ Ombitasvir+Dasabuvir) therapy had the greatest number of interactions.

Keywords: Drug interactions; hepatitis C; antivirals

Resumen

Objetivo:

establecer y evaluar la relevancia clínica de las interacciones medicamentosas en el tratamiento de pacientes con hepatitis C.

Método:

se realizó una búsqueda en PubMed/MedLine de artículos publicados en inglés y en español, desde el 1 de enero de 2015 hasta el 30 de marzo de 2017, utilizando los términos Mesh: Hepatitis C AND drug interactions OR herb-drug interactions OR food-drug interactions, de estudios realizados en humanos. La relevancia clínica de las interacciones medicamentosas se estableció y evaluó con base en la probabilidad de ocurrencia y la gravedad de la interacción.

Resultados:

se identificaron 184 artículos, de los cuales 92 se seleccionaron por el título y resumen para revisión completa, a 2 de ellos no fue posible acceder al texto completo. De estos, 57 aportaban interacciones, lo que permitió identificar 155 parejas de interacciones medicamentosas, de las cuales 154 (99,4 %) fueron farmacocinéticas y 1 (0,6 %) farmacodinámica. Por su parte, de las 155 parejas, 34 (21,9 %) se valoraron de nivel 1; 73 (47,1 %) de nivel 2; 48 (31,0 %) de nivel 3; y 0 (0,0 %) de nivel 4. Además, se identificaron 29 parejas agrupadas como interacciones con evidencia de ausencia de relevancia clínica.

Conclusiones:

más de 99 % de las interacciones medicamentosas de relevancia clínica son farmacocinéticas, asociadas con cambios en el metabolismo y el transporte de fármacos; el simeprevir y la terapia 3D (Paritaprevir/Ritonavir+ Ombitasvir+Dasabuvir) fueron los medicamentos con mayor número de interacciones.

Palabras clave: Interacciones medicamentosas; hepatitis C; antivirales

Introduction

Viral hepatitis is considered to be a public health problem worldwide. It has high morbidity and mortality rates, multiple virus serotypes, various transmission routes, and coinfections with human immunodeficiency virus (HIV). In addition, various drugs are used to treat complications and comorbidities, and access to diagnostic methods and effective and safe treatments is limited. 1,2,3 According to the World Health Organization (WHO), it is estimated that prevalence of hepatitis C virus (HCV) infections in the United States is 1.0%, or 7,000,000. Some authors have estimated that, globally, there are approximately 185 million people who have HCV. 4,5

HCV is characterized by two phases of infection. In the first asymptomatic acute phase, 15% to 45% of patients eliminate the virus spontaneously within 6 months and do not progress to the next phase. The other 55% to 85% of patients enter the chronic infection phase which involves the onset of complications such as liver fibrosis, cirrhosis and hepatocellular carcinoma. 3,4

In recent years, treatment for HCV has undergone considerable changes. In 2011, the first direct-acting antivirals (DAA) boceprevir and telaprevir (NS3/4A protease inhibitors) appeared. 4 They have increased sustained viral responses (SVR) from 60% to 75% in patients without prior treatment. 6 Since then, new DAAs such as nonstructural protein 5A (NS5A) inhibitors, NS5B nucleoside analogue inhibitors, polymerase inhibitors, and non-nucleoside NS5B polymerase inhibitors have been developed. They attack virus replication by inhibiting different proteins to achieve better SVR rates (> 90% to 95%), increased tolerability of treatment, less associated adverse events and less drug interactions. 3

Some of the new DAAs as well as other drugs that are widely used in clinical practice converge on metabolism through cytochrome P450 (CYP) isoenzymes and transporters such as glycoprotein-p (Gp-p), organic anionic transporter polypeptides (OATP), and breast cancer resistant protein (BCRP). 7 This makes it necessary to update previously systematized information on severity and probability of occurrence of drug interactions in patients with HCV genotype 1. 8,9

Method

We searched PubMed/MedLine for articles published in Spanish or English from January 1, 2015 to March 30, 2017 using the following Mesh terms: Hepatitis C AND drug interactions OR herb-drug interactions OR food-drug interactions.

Inclusion Criteria

We considered systematic reviews, metaanalyses, multicenter studies, randomized controlled clinical trials, quasi-experimental studies (non-randomized), observational studies, guidelines, letters and case reports as long as they were human studies in Spanish or English and there was access to the full text. Articles about drug interactions between drugs used to treat HCV and other drugs were considered and, in some cases, references used in those articles were added to increase context and document results.

Exclusion Criteria

We excluded articles about in-vitro and/or animal studies, articles about experimental drugs, and those that did not address drug interactions related to treatment of HCV.

Review Methods

The articles included were independently selected by three researchers. Titles and abstracts of all the articles identified were reviewed to decide upon eligibility. The three authors together analyzed articles selected and decided about inclusion or exclusion of each article by consensus.

Outcome Measures and Assessment of Clinical Relevance of Interactions

Clinical relevance of drug interactions was defined using the severity and probability of occurrence of the interaction. (9) Three categories of severity were considered:

  • Severe: The interaction may harm or injure the patient. The consequence of a negative clinical outcome of pharmacotherapy might cause patient death, risk to life, hospitalization, permanent or significant disability, congenital anomalies, or malformations at birth. In addition, there may be other effects that, in medical judgment, could compromise the integrity of a patient and require surgical intervention to avoid death, hospitalization or congenital anomalies.

  • Moderate: The interaction requires monitoring of the patient. The consequence of a negative clinical outcome of pharmacotherapy could modify, change or interruption pharmacotherapy or require the use of additional drugs to treat a problem related to drugs or to prolongation of hospitalization.

  • Mild: The interaction does not harm the patient. The consequence of a negative result from the drug does not require modification, change or withdrawal of the pharmacotherapy and does not require the use of new drugs to treat a drug-related problem or prolongation of hospitalization.

Three categories of probability of interaction occurrence were established on the basis of the type of study documenting the interaction.

  • Defined: interaction documented in metaanalyses, systemic reviews, randomized clinical trials or non-randomized clinical trials.

  • Likely: interaction documented in analytical studies or by three or more clinical cases.

  • Possible: interaction documented by less than three clinical cases.

From the possible combinations of severity and probability of occurrence, the interactions can be grouped into 4 categories:

  • Level 1 (very high risk) results from a combination of serious and defined, or serious and probable. Simultaneous use of drugs is considered to be absolutely contraindicated.

  • Level 2 (high risk) results from a combination of serious and possible, moderate and defined, or moderate and probable. Concomitant use of drugs requires dose adjustment from the dosage schedule and assessment of signs and symptoms of effectiveness and safety of pharmacotherapy, ideally quantitatively.

  • Level 3 (medium risk) results from a combination of moderate and possible, mild and defined, or mild and probable. Simultaneous use of drugs requires dosage adjustment or assessment of signs and symptoms of effectiveness and safety of treatment, ideally quantitatively.

  • Level 4 (low risk) results from the combination of mild and possible. The interaction is of little clinical relevance.

  • Evidence of absence of interaction results from safe combinations of drugs that do not change the magnitude and effect of the drugs involved.

Information Collection Form

A form for collection and tabulation of data about drug-drug interactions related to treatment of HCV was designed on Excel 2016 for Windows®. It had the following structure: pharmacological group of the concomitant drug; interaction class (drug-drug, phytotherapeutic drug, drug-food, drug-disease); pair of interacting drugs; level, severity and probability of occurrence of the interaction; bibliography; interaction mechanism (pharmacokinetics or pharmacodynamics); details of the mechanism of interaction; observations; and recommendations.

Results

The search terms Hepatitis C AND drug interactions OR herb-drug interactions OR food-drug interactions identified 184 articles, of which 90 met the inclusion criteria. Of these, 57 reported new HCV treatment drug interactions and met the inclusion criteria (Figure 1). One hundred eighty-four pairs of interacting drugs were identified, of which 155 contributed new interactions or updates to the previous review (Table 1): 34 (21.9%) were level 1, 73 (47.1%) were level 2, and 48 (31.0%) were level 3. Of the new interactions, 140 (90.3%) were pairs of drug-to-drug interactions, five (3.2%) were phytotherapeutic drugs, eight (5.2%) were medicines with special conditions, and two (1.3%) were medicines with food. Of the 155 pairs, 154 reported interactions of the pharmacokinetic mechanism, especially enzymatic inhibition (70; 45.2%), enzymatic induction (25; 16.1%), changes in bioavailability (56; 36.2%) and excretion inhibition (3; 1.9%).

Figure 1 General scheme of structured review of clinical relevance of drug interactions in the treatment of patients infected with HCV. 

Table 1 Overall results from 155 pairs of clinically relevant drug interactions 

ASV: asunaprevir; DNV: danoprevir; DSB: dasabuvir; EBR: elbasvir; FDV: faldaprevir; GZR: grazoprevir; IFN: interferon; LDV: ledipasvir; OMB: ombitasvir; PTV: paritaprevir; RTV: ritonavir; RBV: ribavirin; VEL: velpatasvir.

In one of these three cases of excretion inhibition, it was shown that exposure to daclatasvir (DCV) increases up to two times in patients with severe renal impairment but remains within the range of therapeutic safety and does not require adjustments. 7,10 Simeprevir (SIM) exposure increases 62% which requires monitoring and dose adjustment. 11,12,13 Sofosbuvir (SOF) is contraindicated in patients with creatinine clearance over 30 mL/min by increased plasma SOF levels and circulating inactive metabolite GS-331007. 4,6,7,10,11,14-20

Only one case (0.6%), that of DCV and the amiodarone antiarrhythmic, was an interaction using a pharmacodynamic mechanism. It resulted in asymptomatic severe bradycardia. 21

Table 2 shows levels of clinical relevance. One hundred eight interactions (69.7%) were assessed with a higher risk of generating problems of effectiveness and safety of DAA drugs. Of these, 53 (34.2%) were due to enzymatic inhibition, 17 (11.0%) were due to enzymatic induction (Table 3) and 34 (21.9%) were due to changes in bioavailability (Table 4). Twenty-nine pairs of drugs were identified with evidence of absence of clinically relevant interactions. Of these, eight were related to ASV, six to LDV, three to DCV, three to OMB, two to DSB, two to SIM, two to SOF, two to PTV/RTV, and one to SOF/LDV (Table 5).

Table 2 Enzyme inhibition drug interactions related to HCV drugs 

AUC: area under the curve; ALT: alanine transaminase; ARV: antiretroviral; ATV: atazanavir; CCB: calcium channel blocker; c: cobicistat; CCR5: type 5 receptor chemokine; Cmax: maximum concentration; Cmin: minimum concentration; PC: plasma concentration; CsA: cyclosporine; CYP: cytochrome P450; CYP2C8: cytochrome P450 2C8; CYP3a4: cytochrome P450 3A4; DRV: darunavir; EE: ethinylestradiol; GFB: gemfibrozil; Gp-p: glycoprotein p; IP: protease inhibitor; NNRTI: Non-nucleoside reverse-transcriptase inhibitors; KCZ: ketoconazole; LPV: lopinavir; MDL: midazolam; MVC: maraviroc; NG: norgestrel; NGMN: norelgestromin; NOR: norethindrone; RFP: rifampicin; SRL: sirolimus; TAC: tacrolimus; t1/2: average life time; TDF: tenofovir disoproxil fumarate; 3D: PTV/RTV/OMB + DSB.

Table 3 Drug interactions induced by enzymes related to HCV drugs 

CBZ: carbamazepine; EFZ: efavirenz.

Table 4 Drug interactions due to changes in bioavailability related to HCV drugs 

AVA: atorvastatin; DIG: digoxin; FMT: famotidine; GCR: glycyrrhizin; PPI: proton pump inhibitor; NRTI: nucleoside analogue reverse transcriptase inhibitor. OMZ: omeprazole; PRA: pravastatin; RAL: raltegravir; RFB: rifabutin; RVS: rosuvastatin; GFR: glomerular filtration rate; UGT: Glucuronosyltransferase; 2D: PTV/RTV.

Table 5 Drugs with evidence of absence of clinically relevant interactions 

ARA II: angiotensin II receptor antagonist; SSRI: selective serotonin reuptake inhibitor; CNS: central nervous system.

Discussion

Some HCV patients may have comorbidities that compromise their health status, among them HIV and hepatitis B virus (HBV) stand out for the similarity of their routes of infection. Other common comorbidities include dyslipidemia, arterial hypertension, diabetes, and arthritis typical of the passage of age. 28,61 The emergence of new DAAs means that health professionals should be attentive to possible drug interactions, since DAAs’ pharmacokinetic profiles involve isoenzymes, transporters and mechanisms that are shared with other medicines. This can contribute to development of drug-related problems thereby increasing the risk of adverse events. Consequently, continuous review of clinically relevant interactions with DAA related to HCV treatment is important for avoiding risks that alter the safety and effectiveness of treatment. 62

This review identified 155 pairs of interactions: thirty-four (21.9%) were level 1, seventy-three (47.1%) were level 2, and forty-eight (31.0%) were level 3. One hundred fifty-four (99.4%) of these were pharmacokinetic, a finding similar to those of other reviews which have found that more than 90.0% of reported drug interactions were pharmacokinetic. Similarly, the most common mechanisms were enzyme inhibition and enzyme induction. This is a strong indication that clinicians should evaluate concomitant pharmacotherapy in cases where drugs used can affect enzymatic activity of the CYP450 complex. 37 Assessment of clinical relevance is based on severity and probability of an interaction occurring. 9 This method is one of the strengths of this review with respect to similar reviews since it allows identification of levels of drug interaction severity which can be used to discriminate among pharmacological choices. 10,59,63 In addition, 29 pairs of drugs with evidence of absence of clinically relevant interaction were identified.

Compared to our previous review of drug interactions in HCV patients,8 there are 27 additional pairs of drug interactions that are the result of the development and marketing of new DAAs. IN that earlier review, pharmacokinetic drug interactions accounted for 93.7% of these pairs. Enzyme inhibition accounted for 64.0%, enzyme induction accounted for 27.3%, changes in bioavailability accounted for 2.4%, pharmacodynamic interactions accounted for 6.3%. Drug interactions identified by the enzyme inhibition mechanism decreased by 12 in this new review while drug interactions identified by the enzyme induction mechanism decreased by 10. These were attributed to different DAAs since boceprevir and telaprevir have fallen out of use. On the other hand, drug interactions identified by changes in bioavailability increased 33.8% because the pharmacokinetic profiles of the new DAAs include carriers such as OATP, Gp-p and BCRP. 7,29,36,50,53,64 Pharmacodynamic interactions decreased 5.7% because of the greater number of interactions with RBV associated with mitochondrial toxicity, lactic acidosis and hematological toxicity identified during concomitant use with NRTI, telaprevir, boceprevir and IFN in the previous review. 8

The 3D therapy composed of PTV/RTV, OMB + DSB presented 34 drug interactions. Of these, 24 (70.6%) were due to enzymatic inhibition, six (17.6%) were due to induction, and four (11.8%) were due to changes in bioavailability. These interactions were mainly due to the drugs’ pharmacokinetic profiles since the drugs that make up 3D therapy are substrates and inhibitors of Gp-p and BCRP. In addition, PTV is an OATP substrate. PTV is a substrate of CYP3A4 while OMB is metabolized by hydrolysis, DSB is metabolized by CYP2C8 and, to a lesser extent, by CYP3A4. For its part, RTV is used as a pharmacokinetic enhancer of PTV. 29,36

Although SOF is a prodrug that does not inhibit or induce the CYP450 complex or transporters, it is also a substrate of Gp-p and BCRP. This is metabolized in hepatocytes into a pharmacologically active nucleoside (GS-461203 triphosphate analog) and in greater proportion (> 78%) to the circulating inactive metabolite (GS-331007). 50,53 Due to its pharmacokinetic profile, few clinically relevant interactions with the SOF are expected, although it is recommended that concomitant use with strong Gp-p inducers such as RFP and some natural products such as St. John’s wort be avoided. On the other hand, SOF can be safely administered with immunosuppressants. 50 In combination with LDV, SOF can be used safely with most ARVs although there is some risk of hyperbilirubinemia when administered with ATV. 37

The results of this review suggest that clinically relevant interactions with DAAs can be related to multiple mechanisms. Among them, interactions between DAAs with certain morbidities of clinical interest such as cirrhosis, renal failure and inflammatory infectious processes are evident. 32,65 Liver and kidney damage alters the metabolism and excretion of drugs and their metabolites. This can lead to accumulation of the metabolites in the bloodstream and to possible unwanted toxic effects. Therefore, it is important to constantly monitor therapy and promote rational use of drugs to ensure the best possible health outcomes.

Conclusions

According to the results obtained, more than 99% of the drug interactions of clinical relevance in HCV patients receiving pharmacological therapy are pharmacokinetic and are associated with either induction or inhibition of liver metabolism and changes in the bioavailability of drugs due to inhibition and/or induction of Gp-p, OATP and BCRP. Clinically relevant interactions may occur frequently in polymedicated patients who receive concomitant therapy for treatment of other associated diseases when they are also receiving SIM or therapies such as 2D and 3D enhanced with RTV. Plasma concentrations of concomitant drugs can be altered in HCV patients being treated with these drugs and drugs for other associated diseases. This situation is more likely in cases where DAAs are administered simultaneously with ARVs, tuberculosis treatments, lipid lowering agents, antiarrhythmic agents, immunosuppressants and anticonvulsants. We recommend looking for the most appropriate therapeutic alternative for each patient’s health condition to guarantee effectiveness and safety.

Limitations

The main limitation of this study was its restricttion to the PubMed/MedLine database. However, this effect was lessened because the review was complemented by a search for bibliographic references found in the 90 articles reviewed.

Acknowledgements

This review was conducted with the advice of professors Daniel Pino, Pedro Amariles and other members of the Pharmaceutical Promotion and Prevention (P&PF) research group of the Faculty of Pharmaceutical and Food Sciences of the University of Antioquia to whom we would like to express our deepest thanks for making the study possible and for guiding each of our steps in this process. In addition, thank you for the time spent and for your patience and dedication to making this review successful

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Funding Source Strategy for sustainability 2018-2019, Research Development Committee (CODI) of the University of Antioquia

Received: May 16, 2018; Accepted: July 29, 2018

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