Chronic Hepatitis C Virus (HCV) Infection: Treatment Considerations
March 18, 2021Chronic Hepatitis C Virus (HCV) Infection:Treatment Considerationsfrom the Department of Veterans Affairs HIV, Hepatitis,and Related Conditions Program in the Office of SpecialtyCare ServicesUpdated: March 18, 2021Please send questions or comments about this document to Dr. Timothy Morgan atTimothy.Morgan@va.gov, Dr. Helen Yee at Helen.Yee@va.gov, or the National Viral HepatitisProgram at VHAHHRC@va.gov.ContentsI.II.III.What's New and Updates/Changes . 4Summary Tables . 4Introduction . 10Limitations . 10Grading the Evidence. 11Clinical Benefit of Achieving SVR (i.e., cure) . 11Principles of Patient Identification, Evaluation, and Treatment . 12Principles for Patient Selection for HCV Treatment . 13Patient Adherence . 14Patient Identification . 15Pre-treatment Evaluation . 15Definitions of Treatment Candidates. 15Treatment Response. 15Definitions of treatment response. 16Interpretation of resistance-associated substitutions (RAS) . 16IV.Chronic HCV Genotype 1 Infection. 18Treatments for Genotype 1-Infected Patients. 26Genotype 1-Infected Patients Who Have Failed DAA-Based Therapy.26Summary of Pivotal Trials in Genotype 1-Infected Patients .30V.Chronic HCV Genotype 2 Infection. 35Treatment of Chronic HCV Genotype 2 . 37VI.Chronic HCV Genotype 3 Infection. 39Treatment of Chronic HCV Genotype 3 . 41Genotype 3-Infected Patients Who Have Failed NS5A-Based Therapy. 43VII.Chronic HCV Genotype 4 Infection. 45VA HCV Treatment Considerations1
March 18, 2021Treatment of Chronic HCV Genotype 4 . 46VIII.Identifying Treatment Candidates Based on Liver Disease Stage. 48Liver Disease Stage. 50Diagnosis of Advanced Fibrosis and Compensated Cirrhosis . 50Serum Markers. 50Radiological Studies . 50Imaging Tools for Hepatic Fibrosis Assessment. 50Liver Biopsy . 50IX.Laboratory Monitoring . 51Use and Interpretation of HCV RNA Results . 52X.Adverse Events . 52Reporting unexpected or serious adverse events . 52Elbasvir/grazoprevir ribavirin. 53Glecaprevir/pibrentasvir. 53Ledipasvir/sofosbuvir. 53Sofosbuvir/velpatasvir . 53Sofosbuvir/velpatasvir/voxilaprevir. 54XI.Proper Use. 54Drug-Drug Interactions . 54Storage and Stability . 55Missed Doses . 55XII.Groups with Special Considerations for Therapy . 56Acute HCV . 56Mental Health Disorders. 57Substance or Alcohol Use Disorders . 57HCV Reinfection After Successful HCV Treatment. 57HCV and Harm Reduction Services . 58HIV/HCV Coinfection. 58Selecting Patients for Treatment . 59HIV/HCV Coinfection Clinical Trials. 59HIV/HCV Drug-Drug Interactions . 60Laboratory Monitoring. 61Modification of Drug Use in Patients with Renal or Hepatic Impairment . 62Hepatocellular Carcinoma . 65Pre-Liver and Pre-Renal Transplant Patients . 65Post-Liver or Post-Renal Transplant Patients . 66Treatment in Post-Liver or Post-Renal Transplant Patients. 69Extra-Hepatic Manifestations of HCV . 71Pregnancy and Lactation. 71XIII.XIV.XV.Panel Members . 72Resources . 73Appendices. 74Appendix A: Drug-Drug Interaction Tables. 74VA HCV Treatment Considerations2
March 18, 2021Appendix B: HCV Resistance Genotyping . 84Ordering the Test(s) . 84Appendix C: Sample Resistance Test Reports. 87Appendix D: Recommendations for Hepatitis B Viral Infection Testing and Monitoring. 88Table IndexSummary Table 1: DAA Regimens and Dosages . 5Summary Table 2: Treatment Considerations and Choice of Regimen for HCV-infected Patients includingHIV/HCV-Coinfection . 6Table 3. Grading System . 11Table 4. Considerations for Selecting Chronic HCV-Infected Patients for Treatment. 14Table 5. Pre-Treatment Evaluation. 15Table 6. Pre-Treatment NS5A RAS Testing for Select Regimens . 17Table 7. Treatment Regimens for GT1. 18Table 8. Treatment Regimens and SVR Rates in Treatment-Naïve Patients . 20Table 9. Genotype 1: Treatment Regimens and SVR Rates in Treatment-Experienced Patients. 22Table 10. Genotype 1 Subtypes: Treatment Regimens and SVR Rates in Treatment-Experienced NS5ANaïve Patients based on Subtype. 24Table 11. Treatment regimens for GT2. 35Table 12. Genotype 2: Treatment Regimens and SVR Rates . 36Table 13. Treatment regimens for GT3. 39Table 14. Genotype 3: Treatment Regimens and SVR Rates . 40Table 15. Treatment Regimens for GT4. 45Table 16. Diagnosis of Advanced Fibrosis and Compensated Cirrhosis. 49Table 17. Modification of Drug Use in Patients with Renal Insufficiency. 62Table 18. Modification of Drug Use in Patients with Hepatic Impairment. 62Table 19. HCV Treatment Recommendations after Liver or Renal Transplant . 67Table 20. Treatment in Post-Liver Transplant Patients . 68Table 21. Treatment of Patients with Extra-Hepatic Manifestations of HCV . 71Table 22. Drug-Drug Interactions with HCV Antiviral Agents . 74Table 23. Drug-Drug Interactions with HIV Antiretrovirals . 81Figure IndexFigure 1. Re-Treatment Options for HCV Genotype 1 NS5A-Naïve and NS5A-Experienced Patients . 25Figure 2. Sample Specimen Shipment Manifest . 86Figure 3. Sample Test Report for HCV NS5A Resistance. 87VA HCV Treatment Considerations3
March 18, 2021AbbreviationsThe following is a list of abbreviations used throughout this document.CrCL creatinine clearanceCTP Child-Turcotte-PughDAA direct-acting antiviralDDI drug-drug interactionEBR elbasvirGLE glecaprevirGT genotypeGZR grazoprevirHCC hepatocellular carcinomaLDV ledipasvirLLOQ lower limit of quantificationPEG-IFN/IFN peginterferon/interferonPI protease inhibitorPIB pibrentasvirPrOD paritaprevir/ritonavir/ombitasvir/dasabuvir (Viekira )RAS resistance-associated substitutionsRBV ribavirinRTV or r ritonavirSMV simeprevir (Olysio )SOF sofosbuvirVEL velpatasvirVOX voxilaprevirI. What's New and Updates/ChangesThis revision (March 18, 2021) incorporates universal HCV testing for adults aged 18-79 years, andrepeated testing for patients with ongoing risk exposure. The treatment section has been updated toinclude 8 weeks of glecaprevir/pibrentasvir (Mavyret ) in all HCV genotypes who are treatment-naïvewith compensated cirrhosis (CTP A) without a history of decompensation; 12 weeks can be consideredfor patients with poor prognostic factors. Treatment has been updated to include SOF-based therapy inpatients with chronic kidney disease, including those on hemodialysis. Patients with acute HCV infectioncan be treated with DAAs upon initial diagnosis (based on detectable HCV RNA) without awaitingspontaneous resolution if appropriate. Selection for HCV treatment should include patients who becomereinfected with HCV after initially achieving sustained virologic response. Treatment regimens for posttransplant patients have been updated (Table 19. HCV Treatment Recommendations after Liver or RenalTransplant).Prior revisions incorporated drug-drug interactions tables to provide clinicians with guidance on theconcomitant use of HCV drugs and other drugs, including HIV antiretroviral agents (Table 22. Drug-DrugInteractions with HCV Antiviral Agents1-5and Table 23. Drug-Drug Interactions with HIV Antiretrovirals15,10). The Panel continues to recommend that HIV/HCV-coinfected patients receive the same HCVantiviral regimens as HCV-infected patients without HIV unless ledipasvir/sofosbuvir is being considered,in which case a 12-week regimen should be used (instead of an 8-week regimen). HBV testing andmonitoring recommendations should continue to be performed prior to starting HCV DAA (Appendix D:Recommendations for Hepatitis B Viral Infection Testing and Monitoring).II. Summary TablesThis document supplements the Veterans Affairs (VA) Pharmacy Benefits Management (PBM) Criteria ForUse documents for HCV antivirals (available at: PBM Criteria For Use Documents). Information in thisdocument may be used to support individualized treatment decisions based on the existing PBM CriteriaVA HCV Treatment Considerations4
March 18, 2021For Use documents. The following treatment considerations are based on available medical evidence andrepresent the consensus of an expert panel of VA HCV clinicians. This document provides an algorithmicapproach to assist in clinical decision making on HCV treatment considerations based on specific patientcharacteristics including prior treatment history and presence or absence of cirrhosis. The practitionershould interpret these treatment considerations in the clinical context of the individual patient. Thecontent of this document will be revised periodically as new information becomes available; updatedinformation is available at VA Viral Hepatitis Website. For considerations regarding patient selection forhepatitis C antiviral therapy, refer to Table 4. Considerations for Selecting Chronic HCV-Infected Patientsfor Treatment.Summary Table 1: DAA Regimens and Dosages1-7DAA doses should not be used in reduced doses or restarted if discontinued. RBV may be dose adjusted as indicated.Drug NameOral DosePangenotypic RegimensGLE/PIB (100/40 mg, Mavyret )3 tablets daily with foodSOF/VEL (400/100 mg, Epclusa )1 tablet dailySOF/VEL/VOX (400/100/100 mg, Vosevi )1 tablet daily with foodNon-pangenotypic Regimens (for HCV GT1 and GT4)EBR/GZR (50/100 mg, Zepatier )1 tablet dailyLDV/SOF (90/400 mg, Harvoni )1 tablet dailyOtherRBV (200 mg, Various brands)Non-Cirrhotic or CTP A 75 kg: 1,000 mg orally daily (in 2 divided doses) with food 75 kg: 1,200 mg orally daily (in 2 divided doses) with foodCTP B or C receiving LDV/SOFRBV 600 mg/day and increase by 200 mg/day every 2 weeks astoleratedCTP B or C receiving SOF/VEL 75 kg: 1,000 mg orally daily (in 2 divided doses) with food 75 kg: 1,200 mg orally daily (in 2 divided doses) with food; start atlower RBV doses as clinically indicated (e.g., baseline Hgb)Renal ImpairmentCrCl 30-50 mL/min: 200 mg daily alternating with 400mg dailyCrCl 30 mL/min, including hemodialysis: 200 mg dailyBaseline Hgb 12 mg/dLNo dose adjustment needed unless CrCl 50 mL/min or if CTP B and CBaseline Hgb 10 mg/dL in patients without cardiac diseaseReduce dose by at least 50%. If advanced cirrhosis (CTP B and C) orrenal impairment, initiate with lower dose and increase as tolerated.Discontinue RBV if Hgb 8.5 g/dL.CTP Score CalculatorVA HCV Treatment Considerations5
March 18, 2021Summary Table 2: Treatment Considerations and Choice of Regimen for HCVinfected Patients including HIV/HCV-CoinfectionUpdated March 18, 2021. Within each genotype/treatment history/cirrhosis status category, regimens are listed inalphabetical order; this ordering does not imply any preference for a particular regimen unless otherwise indicated.Providers should consider the most clinically appropriate option based on patient individual characteristics. Refer toSummary Table n-cirrhoticGT1NaïveCirrhotic,CTP AGT1NaïveCirrhotic,CTP B, CTreatment Option(s)Alternative Option(s)(in alphabetical order)Pangenotypic regimens GLE/PIB x 8 weeks SOF/VEL x 12 weeksNon-pangenotypic regimen EBR/GZRo If GT1b: 12 weeks LDV/SOFo If HCV RNA is 6 million IU/mL and HCVinfected (without HIV): 8 weeksa,bo If HCV RNA is 6 million IU/mL, HIV/HCV-coinfected, or African American: 12 weeksPangenotypic regimens GLE/PIB x 8 weeks; consider 12 weeks inpatients with poor prognostic factors SOF/VEL x 12 weeksNon-pangenotypic regimens EBR/GZRo If GT1b: 12 weeks LDV/SOF x 12 weekso Consider adding RBV; refer to Table 8for SVR rates(in alphabetical order) EBR/GZRo If GT1a, test for NS5A RASprior to treatmentdo If GT1a without baselineNS5A RAS: 12 weekso If GT1a with baseline NS5ARASc: add RBV; 16 weeksPangenotypic regimen SOF/VEL RBV x 12 weeks; start at lower RBVdoses as clinically indicated (e.g., baseline Hgb)Non-pangenotypic regimen LDV/SOF RBV (600 mg/day and increase by200 mg/day every 2 weeks as tolerated) x 12weeksPangenotypic regimen SOF/VEL x 24 weeksVA HCV Treatment Considerations EBR/GZRo If GT1a, test for NS5A RASprior to treatmentdo If GT1a without baselineNS5A RAS: 12 weekso If GT1a with baseline NS5ARASc: add RBV; 16 weeksNon-pangenotypic regimen LDV/SOF x 24 weeks6
March 18, e;see Figure 1)CirrhosisStatusNon-cirrhoticor Cirrhotic,CTP ATreatment Option(s)Alternative Option(s)(in alphabetical order)If NS3/4A PI-naive and SOF-experienced GLE/PIBo If non-cirrhotic: 8 weekso If CTP A: 12 weeks SOF/VEL x 12 weeks if GT1b SOF/VEL/VOX x 12 weeks if GT1a(in alphabetical order)If NS3/4A PI-experienced and SOF-naive GLE/PIB x 12 weeks SOF/VEL x 12 weeksGT1Experienced(NS5Aexperienced;see Figure 1)GT1Experienced(NS5A-naïve;see Figure 1)GT1Experienced(NS5Aexperienced;see Figure 1)Non-cirrhoticor Cirrhotic,CTP ACirrhotic,CTPB, CCirrhotic,CTPB, C SOF/VEL/VOX x 12 weeksIf failed an NS5A inhibitor without NS3/4A PI(e.g., LDV/SOF): GLE/PIB x 16 weeks SOF/VEL RBV x 12 weeks; start at lower RBVdoses as clinically indicated (e.g., baselineHgb)If failed PEG-IFN/RBV NS3/4A PI: LDV/SOF RBV x 12 weeks; RBV 600 mg/dayand increase by 200 mg/day every 2 weeks astolerated SOF/VEL RBV x 24 weeks; start at lower RBVdoses as clinically indicated (e.g., baseline Hgb)NOT FDA approved for 24 weeksGT2NaïveNon-cirrhoticor Cirrhotic,CTP A GLE/PIB x 8 weeks; consider 12 weeks inpatients with poor prognostic factors SOF/VEL x 12 weeksGT2NaïveCirrhotic,CTPB, C SOF/VEL RBV x 12 weeks; start at lower RBVdoses as clinically indicated (e.g., baseline Hgb)GT2ExperiencedNon-cirrhoticor Cirrhotic,CTP A GLE/PIBo If non-cirrhotic: 8 weekso If CTP A: 12 weeks SOF/VEL x 12 weeks(PEG-IFN/RBV SOFexperiencedand NS5Anaïve)VA HCV Treatment Considerations SOF/VEL x 24 weeksIf failed PEG-IFN/RBV NS3/4A PI: LDV/SOF x 24 weeks SOF/VEL x 24 weeks7
March 18, isStatusNon-cirrhoticor Cirrhotic,CTP ACirrhotic,CTP B, CTreatment Option(s)Alternative Option(s)(in alphabetical order)(in alphabetical order) SOF/VEL/VOX x 12 weeks SOF/VEL RBV; start at lower RBV dosesasclinically indicated (e.g., baseline Hgb)o If NS5A-naïve: 12 weekso If NS5A-experienced: 24 weeks; NOT FDAapproved for 24 weeksNon-cirrhotic GLE/PIB x 8 weeks; consider 12 weeks inpatients with poor prognostic factors SOF/VEL x 12 weeksCirrhotic, GLE/PIB x 8 weeks; consider 12 weeks inCTP Apatients with poor prognostic factors SOF/VEL x 12 weekso Test for NS5A RASe; add RBV if Y93H RASpresentCirrhotic, SOF/VEL RBV x 12 weeks; start at lower RBVCTP B, Cdoses as clinically indicated (e.g., baseline Hgb)Non-cirrhotic SOF/VEL/VOX x 12 weeksor Cirrhotic,o If CTP A: Consider adding RBV (no supportingCTP Adata)Cirrhotic, SOF/VEL RBV; start at lower RBV doses asCTP B, Cclinically indicated (e.g., baseline Hgb)o If NS5A-naïve: 12 weekso If NS5A-experienced: 24 weeks; NOT FDAapproved for 24 weeksNonPangenotypic regimenscirrhotic GLE/PIB x 8 weeks; consider 12 weeks inorpatients with poor prognostic factorsCirrhotic, SOF/VEL x 12 weeksCTP ANon-pangenotypic regimens EBR/GZR x 12 weeks LDV/SOF x 12 weeksCirrhotic, LDV/SOF RBV (600 mg/day and increaseCTP B, Cas tolerated) x 12 weeks SOF/VEL RBV x 12 weeks; start at lowerRBVdoses as clinically indicatedVA HCV Treatment ConsiderationsIf NS5A-naïve: SOF/VEL x 24 weeks SOF/VEL x 24 weeksIf NS5A-naïve: SOF/VEL x 24 weeks LDV/SOF x 24 weeks SOF/VEL x 24 weeks8
March 18, ncedand iencedCirrhosisStatusTreatment Option(s)Alternative Option(s)(in alphabetical order)(in alphabetical order)Non-cirrhoticor Cirrhotic,CTP A GLE/PIBo If NS3/4A PI-naïve and non-cirrhotic: 8 weekso If NS3/4A PI-experienced or CTP A: 12 weeks SOF/VEL x 12 weeksNon-cirrhoticor Cirrhotic,CTP ACirrhotic,CTP B, C SOF/VEL/VOX x 12 weeks SOF/VEL RBV; start at lower RBV doses asclinically indicated (e.g., baseline Hgb)o If NS5A-naïve: 12 weekso If NS5A-experienced: 24 weeks; NOT FDAapproved for 24 weeksIf NS5A-naïve: SOF/VEL x 24 weeksa 12-weekregimen should be used in HIV/HCV-infected patients.should be given to 12 weeks of treatment in African Americans and those with quantifiable ( LLOQ)HCV RNA at week 4 on treatment.8c It is unclear whether the 1-fold shift in EBR concentrations observed in vitro with the M28V mutation reducesefficacy.9 May consider the addition of RBV and extending treatment to 16 weeks if clinically appropriate.d Testing of HCV RAS for patients can be performed through the VHA Public Health Reference Laboratory (emailV21PHRL@va.gov) or a commercial laboratory (see Section XV, Appendix B).b ConsiderationCTP Score CalculatorVA HCV Treatment Considerations9
March 18, 2021III. IntroductionKey Points Successful antiviral treatment of chronic HCV infection decreases the risk of disease progressionand death. Treatment of Veterans with HCV should be based on evidence-based guidelines such as those inthis document. Evaluation of patients prior to initiation of treatment is essential (see Table 5).The goal of hepatitis C antiviral treatment is to achieve a sustained virologic response (SVR), defined asHCV RNA level below the limit of quantification in the blood 12 or more weeks after completing antiviraltreatment. Achieving an SVR is synonymous with curing hepatitis C for the majority of patients. Achievingan SVR decreases the risk of disease progression to cirrhosis, liver cancer, liver failure, and death.Although the timing of treatment for individual patients may depend on the stage of liver disease andpatients' readiness for treatment, Veterans Health Administration (VHA) expects to treat all Veteranswith chronic HCV infection who wish to be treated and are suitable for treatment. Furthermore, VHA willuse the optimal drug treatments available, after analysis of efficacy/effectiveness, safety, and costs.Providing appropriate treatment to Veterans requires time, expertise, care coordination (e.g., PrimaryCare, Mental Health, Pharmacy, Social Work), and adequate resources, including but not limited tofunding.The following treatment considerations summarize the current best practices in the treatment of chronicHCV infection within VHA. These considerations are based on review of published data and abstracts,American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America(IDSA) Recommendations for Testing, Managing, and Treating Hepatitis C (www.hcvguidelines.org),publicly available summaries from reviews by the United States Food and Drug Administration (FDA), andinput from VHA thought leaders involved in the care of Veterans with HCV infection.LimitationsThere are limitations in the design of some clinical trials of direct-acting antiviral (DAA) agents in thetreatment of hepatitis C. These limitations include: 1) small number of patients with cirrhosis, especiallyadvanced cirrhosis; 2) lack of head-to-head trials of DAA regimens; 3) exclusion of patients with chronichepatitis B virus (HBV) infection, cancer, hepatocellular carcinoma (HCC), decompensated cirrhosis,severe psychiatric, cardiac, pulmonary comorbidities, and alcohol or substance use. The committeeweighed the strengths, weaknesses, and gaps in the evidence to make decisions based on existing andsometimes suboptimal data from studies with potential biases or uncertain generalizability. Some of thelimitations of studies are noted in the "Comments" column in the treatment consideration tables. Thecontent in this document will be updated as new data become available.VA HCV Treatment Considerations10
March 18, 2021Grading the EvidenceTreatment considerations were developed using weighting and grading of the quality of evidenceaccording to recommendations from the Centers for Disease Control and Prevention, the NationalInstitutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of AmericanGuidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents withHIV (Table 3).10 Each panel member participated in the preparation and review of the draftconsiderations and the committee approved the consensus statements reflected in the final document.The final considerations were reviewed and endorsed by the HIV, Hepatitis, and Related ConditionsProgram in the Office of Specialty Care Services. Additional resources pertaining to the care of the HCVinfected patient are available at the Viral Hepatitis and Liver Disease Home (va.gov)(www.hepatitis.va.gov).Table 3. Grading SystemStrength of RecommendationA: Strong recommendation for the statementB: Moderate recommendation for thestatementC: Optional recommendation for the statementQuality of Evidence for RecommendationI:On
Prior revisions incorporated drug-drug interactions tables to provide clinicians with guidance on the concomitant use of HCV drugs and other drugs, including HIV antiretroviral agents (Table 22. Drug-Drug Interactions with HCV Antiviral Agents1-5and Table 23. Drug-Drug Interactions with HIV Antiretrovirals1-5,10).
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Hepatitis C 2 What is hepatitis C? Hepatitis C is a disease caused by a virus that infects the liver. This virus, called the hepatitis C virus or HCV for short, is just one of the hepatitis viruses. The other common hepatitis viruses are A and B, which differ somewhat from hepatitis C in the way they are spread and treated.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) can cause acute and chronic hepatitis and potentially lead to the development of cirrhosis, liver cancer and death. In the EU/EFTA, an estimated 4.7 million people have a chronic hepatitis B virus infection, and 3.9 million people have chronic
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Federal Bureau of Prisons Evaluation and Management of Chronic HCV Infection Clinical Practice Guidelines July 2015 2 b. Clinical Conditions: HCV testing is recommended for all inmates with the following clinical conditions, regardless of sentencing status: A reported history of HCV i
Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV) that affects the liver. The virus causes both acute and chronic infections. An estimated 257 million people/3.5% of the global population are living with chronic hepatitis B
Hepatitis B (HBV) and hepatitis C virus (HCV) infections are global health problems and remain as the most common infectious diseases worldwide. Latest data from World Health Organisation (WHO) 2015 reported that 71 million people living with HCV worldwide, of whom 399,000 die each year.1
Academic writing is cautious, because many things are uncertain. When we put forward an argument, point of view or claim, we know that it can probably be contested and that not everybody would necessarily agree with it. We use words and phrases that express lack of certainty, such as: Appears to Tends to Seems to May indicate Might In some .
