Wedemeyer, HeinerYurdaydin, CihanHardtke, SvenjaCaruntu, Florin AlexandruCurescu, Manuela G.Yalcin, KendalAkarca, Ulus S.Erhardt, AndreasLueth, StefanPapatheodoridis, George V.Keskin, OnurPort, KerstinRadu, MonicaCelen, Mustafa K.Idilman, RamazanWeber, KristinaStift, JudithWittkop, UlrikeHeidrich, BenjaminZeuzem, Stefan2022-11-282022-11-282019-03Wedemeyer, H. vd. (2019). ''Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial''. Lancet infectious diseases, 19(3), 275-286.1473-30991474-4457https://doi.org/10.1016/S1473-3099(18)30663-7https://www.sciencedirect.com/science/article/pii/S1473309918306637http://hdl.handle.net/11452/29598Abstract Background Hepatitis D is the most severe form of chronic viral hepatitis. Treatment guidelines recommend 1 year of peginterferon alfa, which is effective in 25-30% of patients only. Whether prolonged therapy with peginterferon alfa-2a for 96 weeks and combination therapy with tenofovir disoproxil fumarate (TDF) would increase hepatitis D virus (HDV) RNA suppression is unknown. We aimed to explore whether prolonged treatment of HDV with 96 weeks of peginterferon would increase HDV RNA response rates and reduces post-treatment relapses. Methods We did two parallel, investigator-initiated, multicentre, double-blind randomised, controlled trials at 14 study sites in Germany, Greece, Romania, and Turkey. Patients with chronic HDV infection and compensated liver disease who were aged 18 years or older were eligible for inclusion. All patients were HBsAg positive for at least 7 months, anti-HDV positive for at least 3 months, and HDV-RNA positive at the local laboratory at the screening visit. Patients were ineligible if alanine aminotransferase levels were higher than ten times above the upper limit of normal and if platelet counts were lower than 90 000 per mu L, or if they had received interferon therapy or treatment with a nucleoside and nucleotide analogue within the preceding 6 months. Patients were randomly assigned by blinded stratified block randomisation (1:1) to receive 180 mu g of peginterferon alfa-2a weekly plus either TDF (300 mg once daily) or placebo for 96 weeks. The primary endpoint was the percentage of patients with undetectable HDV RNA at the end of treatment assessed by intention to treat. The trials are registered as NCT00932971 and NCT01088659. Findings Between June 24, 2009, and Feb 28, 2011, we randomly assigned 59 HDV RNA-positive patients to receive peginterferon alfa-2a plus TDF and 61 to receive peginterferon alfa-2a plus placebo, including 48 (40%) patients with cirrhosis to the two treatment groups (23 in the peginterferon alfa-2a plus TDF group and 25 in the peginterferon alfa-2a plus placebo group). The primary endpoint was achieved in 28 (48%) of 59 patients in the peginterferon alfa-2a plus TDF group and in 20 (33%) of 61 patients in the peginterferon alfa-2a plus placebo group (odds ratio 1.84, 95% CI 0.86-3.91, p=0.12). We recorded 944 adverse events (459 in the peginterferon alfa-2a plus TDF group and 485 in the peginterferon alfa-2a plus placebo group). The most common adverse events were haematological, behavioural (eg, fatigue), musculoskeletal, influenza-like syndromes, and psychiatric complaints. Interpretation Addition of TDF resulted in no significant improvement in HDV RNA response rates at the end of treatment. These findings highlight that alternative treatment options are needed for hepatitis D.eninfo:eu-repo/semantics/closedAccessDelta virus-replicationTherapyInterferonInfectionAdolescentAdultAgedAged, 80 and overAlanine transaminaseAntiviral agentsDouble-blind methodDrug therapyCombinationDrug-related side effects and adverse reactionsEuropeHepatitis DHepatitis delta virusHumansInterferon-alphaMaleMiddle agedPlacebosPlatelet countPolyethylene glycolsRecombinant proteinsRecurrenceRNA, viralTenofovirTreatment outcomeYoung adultArticle0004599195000372-s2.0-8506202140527528619330833068Infectious diseasesHepatitis Delta Virus; Chronic Hepatitis D; Hepatitis BAlanine aminotransferaseAlbuminAspartate aminotransferaseBilirubinCreatinineGamma glutamyltransferaseHepatitis B surface antigenHepatitis B(e) antigenPeginterferon alpha2aTenofovir disoproxilVirus DNAVirus loadXerostomiaAdolescentAdverse drug reactionAdverse eventAgedBloodClinical trialCombination drug therapyDelta agent hepatitisVirus RNAEuropeGeneticsHepatitis delta virusMiddle agedPathologyProceduresRecurrent diseaseTreatment outcomeVery elderlyYoung adultAlanine aminotransferaseAlpha interferonAntivirus agentMacrogolPlaceboRecombinant proteinTenofovirAbdominal painAdultAlanine aminotransferase blood levelAlbumin blood levelAlopeciaAnemiaAntiviral therapyArticleAspartate aminotransferase blood levelAstheniaBilirubin blood levelBody weight lossBreast diseaseChronic hepatitisClinical outcomeCombination drug therapyWeight lossBreast diseaseChronic hepatitisClinical outcomeCombination drug therapyCompensated liver cirrhosisConnective tissue diseaseControlled studyCoughingCreatinine blood levelDecreased appetiteDelta agent hepatitisDiarrheaDizzinessDouble blind procedureDrug efficacyDrug safetyDyspepsiaEndocrine diseaseEpistaxisEye diseaseFatigueFemaleFeverFlu like syndromeFollow upGamma glutamyl transferase blood levelGastrointestinal diseaseGenital system diseaseGermanyGreeceHeadacheHematologic diseaseHepatobiliary diseaseHumanImmunopathologyInfectionInfestationIntention to treat analysisLeukopeniaLong term careLymphatic system diseaseMajor clinical studyMaleMediastinum diseaseMental diseaseMetabolic disorderMulticenter studyMusculoskeletal diseaseNauseaNeurologic diseaseNeutropeniaNutritional disorderOropharynx painPhase 2 clinical trialPlatelet countPriority journalProthrombin timePruritusRandomized controlled trialRespiratory tract diseaseRomaniaSide effectSkin diseaseTurkey (republic)