Daclatasvir

證據等級: L5

預測適應症: 10 個

Daclatasvir: From Hepatitis C to Hepatitis B Virus Infection

One-Sentence Summary

Daclatasvir (BMS-790052) is a pangenotypic NS5A replication complex inhibitor, approved in multiple countries for the treatment of chronic Hepatitis C virus (HCV) infection in combination with other direct-acting antivirals. The TxGNN model predicts it may be effective for Hepatitis B Virus (HBV) Infection with a confidence score of 99.80%, making it the top-ranked repurposing candidate. However, this prediction is supported by only 1 partially relevant clinical trial (n=23) and a handful of observational studies — with the majority of available evidence reflecting HBV reactivation events during Daclatasvir therapy, not antiviral suppression of HBV.

Quick Overview

Item	Content
Original Indication	Chronic Hepatitis C virus (HCV) infection
Predicted New Indication	Hepatitis B Virus Infection
TxGNN Prediction Score	99.80%
Evidence Level	L4
Saudi Arabia Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Daclatasvir binds directly to the NS5A replication complex of HCV, disrupting viral RNA replication, assembly, and virion release. It is active across all HCV genotypes and has demonstrated sustained virologic response (SVR) rates exceeding 90% in combination regimens with sofosbuvir or asunaprevir. Its potent antiviral activity against a hepatotropic RNA virus forms the basis for the TxGNN knowledge graph placing it in proximity to other hepatitis viral infections — including HBV.

The mechanistic connection to HBV is, however, extremely tenuous. HBV is a partially double-stranded DNA virus (Hepadnaviridae) that replicates via reverse transcription of a pregenomic RNA (pgRNA) intermediate. It does not encode an NS5A homologous protein. One computational study (PMID 36838792) used in silico virtual screening to identify Daclatasvir as a potential binder to the ε stem-loop of HBV pgRNA — a cis-acting element required for polymerase binding and pgRNA packaging — but this remains entirely speculative with no wet-lab or in vivo validation.

The clinical evidence available paints a more cautionary picture. Rather than suppressing HBV, Daclatasvir-based DAA therapy in HBV/HCV co-infected patients has been repeatedly associated with HBV reactivation (PMID 27329484, 26297529, 29194858). The leading hypothesis is that rapid HCV clearance removes the immunosuppressive competition HCV exerted on HBV, allowing dormant HBV to resurge. This mechanistic inverse — Daclatasvir indirectly unmasking HBV rather than suppressing it — fundamentally undermines the repurposing rationale. The TxGNN high score most likely reflects disease ontology proximity (both are hepatotropic viral infections in the same MeSH neighbourhood) rather than true pharmacological activity against HBV.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02555943	Phase 2/3	Completed	23	The only trial directly enrolling HCV/HBV co-infected patients. Study purpose was to determine HBV reactivation incidence during anti-HCV DAA treatment — not to evaluate Daclatasvir's efficacy against HBV. Sample size far too small to draw conclusions on direct anti-HBV activity.
NCT02098616	N/A	Completed	25	Pilot HCV elimination trial evaluating DCV/ASV/BMS-791325 ± ribavirin for 4–8 weeks in genotype 1a HCV without cirrhosis. No HBV-specific design.
NCT03687229	N/A	Unknown	60	Mechanistic study on miRNA-122 and insulin resistance in chronic HCV patients receiving DAAs. No HBV relevance.
NCT03572140	N/A	Unknown	297	Safety and resistance-associated variant assessment for sofosbuvir/daclatasvir in chronic HCV GT-4. No HBV design.
NCT02565888	Phase 1	Completed	16	Drug-drug interaction study between Daclatasvir and antiretrovirals (atazanavir/ritonavir or cobicistat) in healthy volunteers. PK study; no antiviral efficacy assessment.
NCT01012895	Phase 2	Completed	215	Safety, PK, and pharmacodynamics of BMS-790052 + BMS-650032 in HCV genotype 1 null responders to standard of care. HCV-only population.
NCT03612973	N/A	Completed	80	Assessment of liver fibrosis, lipid profile, and insulin resistance in chronic HCV patients on DAA therapy. No HBV design.
NCT00546715	Phase 1/2	Completed	95	Early single ascending dose study of daclatasvir in chronic HCV genotype 1 patients; safety and tolerability focus. No HBV relevance.
NCT02640157	Phase 3	Completed	506	Active-controlled comparison of ABT-493/ABT-530 versus SOF+DCV in HCV genotype 3. No HBV patients enrolled.
NCT02095860	Phase 1	Completed	24	Crossover PK study assessing food effect on DCV/ASV/BMS-791325 fixed-dose combination in healthy subjects. No disease-relevance to HBV.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
29194858	2018	Cohort	J Viral Hepatitis	Among 25 HBV co-infected patients receiving interferon-free DAA therapy (including asunaprevir + daclatasvir), HBV reactivation occurred in a subset. Confirms Daclatasvir does not suppress HBV replication and may unmask dormant infection.
27329484	2016	Case Report	Clin J Gastroenterol	An 83-year-old woman developed acute hepatitis B after daclatasvir + asunaprevir therapy cleared her HCV. HBV reactivation directly following Daclatasvir use demonstrates absence of anti-HBV activity.
26297529	2016	Case Report	Hepatol Res	HBV reactivation (anti-HBe hepatitis) emerged in an HBV/HCV co-infected patient during interferon-free daclatasvir + asunaprevir therapy, requiring tenofovir rescue.
31722032	2020	Cohort	Trans R Soc Trop Med Hyg	SOF/DCV-based therapy in Egyptian HCV and HCV/HBV co-infected patients confirmed high SVR rates for HCV component; did not evaluate direct antiviral activity of Daclatasvir against HBV.
36838792	2023	In silico	Molecules	Virtual screening study identifying potential small molecule binders to the HBV pgRNA ε stem-loop (novel therapeutic target). Daclatasvir appeared as a candidate binder — entirely computational, no experimental validation.
28555436	2017	Cohort	Indian J Gastroenterol	HBV co-infection was associated with higher HCC recurrence rates after DAA therapy in HCV patients; highlights clinical importance of HBV monitoring during DAA treatment.
27311286	2016	Review	Rinsho Byori	Review of viral hepatitis therapy including DAA-era HCV treatment; discusses HBV reactivation as a recognised complication of interferon-free DAA regimens.
26904396	2016	Review	Acta Pharm Sin B	Review of HCV DAA targets (NS3/4A, NS5A, NS5B); explicitly distinguishes HCV as curable with DAAs while noting HBV and HIV require entirely different treatment approaches.
30369001	2019	Cohort	Transpl Infect Dis	SOF+DCV achieved high HCV SVR rates in kidney transplant recipients; good tolerability profile. No HBV data; included for drug safety characterisation.
35248212	2022	Cohort	Lancet Gastroenterol Hepatol	SOF-VEL-VOX re-treatment in patients with prior daclatasvir failure in Rwanda; relevant to understanding limitations and resistance patterns of NS5A inhibitors. No HBV data.

Saudi Arabia Market Information

Daclatasvir is currently not approved or marketed in Saudi Arabia. No product registrations or authorisation numbers are on file with the regulatory authority. Any clinical use within Saudi Arabia would require individual patient compassionate access or import exemption procedures.

Safety Considerations

Please refer to the package insert for safety information.

Note for HBV co-infected patients: Multiple published case reports and cohort data document HBV reactivation during Daclatasvir-containing DAA regimens (PMID 27329484, 26297529, 29194858). Screening for HBsAg and anti-HBc prior to initiating any DAA therapy and appropriate HBV prophylaxis or monitoring are strongly recommended per current international guidelines.

Conclusion and Next Steps

Decision: Hold

Rationale: The mechanistic basis for Daclatasvir repurposing in HBV is critically weak — HBV lacks any NS5A homolog, replicates via reverse transcriptase rather than RNA-dependent RNA polymerase, and the available clinical evidence specifically documents that Daclatasvir does not suppress HBV replication. On the contrary, DAA-mediated HCV clearance can trigger HBV reactivation, representing a net safety concern rather than a therapeutic opportunity.

To proceed, the following would be required:

Wet-lab antiviral activity data: In vitro HBV inhibition assays (HepG2.2.15, HBV-transfected cells) to experimentally verify or refute the in silico binding prediction (PMID 36838792)
Mechanism validation: Biophysical binding confirmation of Daclatasvir to HBV pgRNA ε stem-loop (EMSA, ITC, or NMR)
MOA characterisation: Formal Daclatasvir mechanism-of-action data from DrugBank to assess cross-target potential (currently unavailable)
Safety label review: Full SFDA prescribing information for contraindications and warnings (currently unavailable)
Regulatory baseline: Given zero Saudi Arabia market authorisations, any clinical development would require full dossier submission from scratch
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.