Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide ...clinical trials aiming to ‘cure’ HBV. Agreement among the conference participants was reached on some key points. ‘Functional’ but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV ‘functional cure’, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
Human papillomaviruses (HPV) replicate their DNA in the suprabasal layer of the infected mucosa or skin. In order to create a suitable environment for vegetative viral DNA replication HPV delay ...differentiation and sustain keratinocyte proliferation that can lead to hyperplasia. The mechanism underlying cell growth stimulation is not well characterized. Here, we show that the E6 oncoprotein of the βHPV type 8 (HPV8), which infects the cutaneous skin and is associated with skin cancer in Epidermodysplasia verruciformis patients and immunosuppressed organ transplant recipients, binds to the protein tyrosine phosphatase H1 (PTPH1), which resulted in increased protein expression and phosphatase activity of PTPH1. Suppression of PTPH1 in immortalized keratinocytes reduced cell proliferation as well as the level of epidermal growth factor receptor (EGFR). Furthermore, we report that HPV8E6 expressing keratinocytes have increased level of active, GTP-bound Ras. This effect was independent of PTPH1. Therefore, HPV8E6-mediated targeting of PTPH1 might result in higher level of EGFR and enhanced keratinocyte proliferation. The HPV8E6-mediated stimulation of Ras may be an additional step to induce cell growth. Our results provide novel insights into the mechanism how βHPVE6 proteins support proliferation of infected keratinocytes, thus creating an environment with increased risk of development of skin cancer particularly upon UV-induced DNA mutations.
Das niedersächsische Nordhorn war historisch lange eine Hochburg der Kommunistischen Partei Deutschlands (KPD) sowie später der Deutschen Kommunistischen Partei (DKP), bis in die 1990er-Jahre hinein ...konnten sie hier lokalpolitische Ämter erringen. Von welchen Kontextbedingungen hing der lokale Erfolg der Nordhorner DKP ab? Wie fügte sich die Partei historisch in die Protestgeschichte ein und welches sind die zentralen Charakteristika der örtlichen gegenkulturellen Szene? Diesen Fragen geht die vorliegende FoDEx-Studie nach. Sie skizziert die zentralen Charakteristika und langfristigen Entwicklungstendenzen der linksradikalen bzw. linken Szene vor Ort und setzt diese in Bezug zum stadtpolitischen Erbe der Textilindustrie Nordhorns und der andauernden materialistischen Konfliktlinie. In einer mehrschrittigen Analyse werden wichtige Resonanz- und Verständigungsräume ebenso beleuchtet wie das individuelle Akteurshandeln vor Ort.
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic hepatitis B virus (HBV) treatment ...endpoints to guide clinical trials aiming to “cure” HBV. Agreement among the conference participants was reached on some key points. “Functional” but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post‐treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg‐positive or negative chronic hepatitis, who are treatment‐naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV “functional cure”, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
Abstract
Chronic hepatitis B, a major cause of liver disease and cancer, affects >250 million people worldwide. Currently there is no cure, only suppressive therapies. Efforts to develop finite ...curative hepatitis B virus (HBV) therapies are underway, consisting of combinations of multiple novel agents with or without nucleos(t)ide reverse-transcriptase inhibitors. The HBV Forum convened a webinar in July 2021, along with subsequent working group discussions to address how and when to stop finite therapy for demonstration of sustained off-treatment efficacy and safety responses. Participants included leading experts in academia, clinical practice, pharmaceutical companies, patient representatives, and regulatory agencies. This Viewpoints article outlines areas of consensus within our multistakeholder group for stopping finite therapies in chronic hepatitis B investigational studies, including trial design, patient selection, outcomes, biomarkers, predefined stopping criteria, predefined retreatment criteria, duration of investigational therapies, and follow-up after stopping therapy. Future research of unmet needs are discussed.
This Viewpoints article summarizes how hepatitis B virus biomarkers may inform stopping treatment and predict off-treatment responses in clinical trials with novel therapies. It provides expert consensus on strategies for stopping therapy and criteria for retreatment given off-treatment adverse events.
Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under AASLD and EASL in June 2022 with the primary goal of achieving consensus on chronic hepatitis ...B virus (HBV) and hepatitis delta virus (HDV) (HDV) treatment endpoints to guide clinical trials aiming to “cure” HBV and HDV. Conference participants reached agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is “functional” cure, defined as sustained HBsAg loss and HBV DNA less than lower limit of quantification (LLOQ) 24 weeks off-treatment. An alternate endpoint would be “partial cure” defined as sustained HBsAg level <100 IU/mL and HBV DNA <LLOQ 24 weeks off-treatment. Clinical trials should initially focus on patients with HBeAg-positive or negative chronic hepatitis B, who are treatment-naїve or virally suppressed on nucleos(t)ide analogues. Hepatitis flares may occur during curative therapy and should be promptly investigated and outcomes reported. HBsAg loss would be the preferred endpoint for chronic hepatitis D, but HDV RNA <LLOQ 24 weeks off-treatment is a suitable alternate primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA <LLOQ assessed at on-treatment week 48. An alternate endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase (ALT) level. Suitable candidates for phase II/III trials would be treatment-naїve or -experienced patients with quantifiable HDV RNA. Novel biomarkers (HBcrAg, HBV RNA) remain exploratory while nucleos(t)ide analogues and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs.
WHO-prequalified antiretrovirals (ARVs) are widely used in HIV treatment programmes of Member States. For each prequalified medicine, a detailed WHO Public Assessment Reports (WHOPAR) is available on ...the WHO Prequalification website. As part of a WHO quality monitoring study, the documents supplied with 107 samples of selected ARVs in five African countries were compared with the product information shown in the WHOPAR (for prequalified products) or publicly available information for the innovator product (for non-prequalified products). Deviations, some of them potentially impacting on patient safety, were found for most of the samples. It is recommended that regulators, procurers, health professionals and patients make more use of the WHOPARs to verify that the product information supplied with prequalified medicines conforms to that accepted by WHO.
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