Glecaprevir
| Evidence Level: L4 | Predicted Indications: 10 |
Table of Contents
Glecaprevir: From Chronic Hepatitis C to HIV Infectious Disease
One-Sentence Summary
Glecaprevir is an HCV NS3/4A protease inhibitor, originally used (in a fixed-dose combination with pibrentasvir) to treat chronic hepatitis C virus infection. The TxGNN model predicts it may be effective for HIV infectious disease, but the 6 clinical trials and 20 publications linked to this prediction all concern HCV treatment (including in people who also have HIV), not HIV treatment itself. The prediction is best regarded as an unsupported model signal.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic hepatitis C virus infection (from the knowledge graph; no approved indication text is available in the New Zealand licence record) |
| Predicted New Indication | HIV infectious disease |
| TxGNN Prediction Score | 99.87% |
| Evidence Level | L4 |
| New Zealand Market Status | Cancelled only |
| Number of Authorizations | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known information, glecaprevir is an HCV NS3/4A serine protease inhibitor, used together with the NS5A inhibitor pibrentasvir, and its efficacy in chronic hepatitis C is well established.
The mechanistic link to HIV is weak. HIV protease is an aspartic protease that is structurally and mechanistically distinct from the HCV NS3/4A serine protease, and glecaprevir has no established anti-HIV activity. The high TxGNN score most likely reflects network proximity to antiviral drugs and the frequent HCV/HIV co-infection, rather than a true therapeutic signal.
The trials and publications show that glecaprevir/pibrentasvir cures HCV in people who also have HIV. That is an HCV indication in an HIV population, not evidence of treating HIV.
The other predictions are weaker still. Hepatitis B, hepatitis A, hepatitis E, feline and simian immunodeficiency viruses, and a genetic neurodevelopmental disorder have no plausible protease-based rationale. Omsk hemorrhagic fever and Kyasanur forest disease involve flaviviruses with a distantly related NS3 protease, but this is speculative and unvalidated.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02738138 | Phase 3 | Completed | 153 | EXPEDITION-2: efficacy and safety in HCV genotype 1-6 with HIV-1 co-infection; HCV endpoint only |
| NCT03222583 | Phase 3 | Completed | 546 | Placebo-controlled study in non-cirrhotic Asian adults with HCV, with or without HIV co-infection; HCV outcomes |
| NCT03235349 | Phase 3 | Completed | 160 | Asian adults with HCV and compensated cirrhosis, with or without HIV; HCV SVR endpoint |
| NCT02634008 | Phase 3 | Completed | 83 | Pilot of DAA regimens in recently acquired HCV, with or without HIV; endpoint is HCV cure |
| NCT04042740 | Phase 2 | Completed | 45 | PURGE-C: 4-week glecaprevir/pibrentasvir in acute HCV, with or without HIV-1 co-infection |
| NCT03823911 | Phase 4 | Completed | 87 | Cardiovascular risk after HCV eradication in HCV mono-infected and HIV co-infected people; context only |
| NCT07040319 | Phase 1/2 | Recruiting | 30 | Pharmacokinetics and safety of glecaprevir/pibrentasvir started in pregnancy, with or without HIV |
None of these trials tests anti-HIV efficacy.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37671831 | 2023 | Cohort | J Antimicrob Chemother | Real-world response to glecaprevir/pibrentasvir in HIV/HCV-coinfected patients (HCV cure rates) |
| 39697370 | 2024 | Cohort | Clin Exp Hepatol | Effectiveness and safety of glecaprevir/pibrentasvir in HIV/HCV patients on bictegravir/emtricitabine/tenofovir alafenamide |
| 31504702 | 2020 | Pharmacology study | J Infect Dis | Drug-drug interactions of glecaprevir/pibrentasvir with HIV antiretrovirals |
| 41297677 | 2026 | Single-arm Phase IIIb | J Hepatol | 8-week glecaprevir/pibrentasvir in acute HCV |
| 32754824 | 2020 | Cohort | Adv Ther | Real-world 8-week regimen in treatment-naïve patients with compensated cirrhosis |
| 31284039 | 2019 | Systematic review/meta-analysis | Int J Antimicrob Agents | 13 studies, 3,082 patients with HCV; pooled SVR12 about 97.8% |
| 30499343 | 2019 | Review | Future Microbiol | Overview of glecaprevir/pibrentasvir for chronic HCV |
| 29595065 | 2018 | Review | Expert Opin Pharmacother | Protease inhibitor therapy for HCV; notes HIV/HCV co-infection frequency |
| 38293756 | 2024 | Systematic review/meta-analysis | Liver Int | DAA efficacy and safety in children and adolescents with HCV |
| 30090878 | 2018 | Review | Drugs Today | Glecaprevir/pibrentasvir in adults with chronic HCV |
All of this literature concerns HCV; none shows anti-HIV activity.
New Zealand Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 2552019 | Maviret | Tab 100 mg with pibrentasvir 40 mg | Not recorded (licence status: cancelled) |
Safety Considerations
- Drug Interactions: 57 interactions are recorded. Major-level interactions include rosuvastatin, simvastatin and edoxaban. Moderate-level interactions include dexamethasone, esomeprazole, omeprazole, cobicistat, deferasirox, apixaban, betrixaban, lusutrombopag, metreleptin, naldemedine, revefenacin, griseofulvin and troglitazone. Minor-level interactions include fidaxomicin, naloxegol, prucalopride and indacaterol.
- Antiretroviral interactions: Interactions with HIV antiretrovirals are clinically relevant when treating people with HIV/HCV co-infection.
- HBV reactivation: Hepatitis B reactivation during HCV direct-acting antiviral therapy is a safety consideration, as noted in the hepatitis B-related prediction.
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The high TxGNN score is not backed by any evidence of anti-HIV activity. Every linked trial and publication addresses HCV, including in people with HIV co-infection. There is no plausible mechanistic link between an HCV NS3/4A protease inhibitor and HIV protease. The only New Zealand licence is cancelled, and the other nine predictions are L5 or weaker, with no supporting evidence.
To proceed, the following is needed:
- Mechanism of action data for glecaprevir
- Package insert warnings and contraindications from Medsafe (needed before any safety screening)
- In vitro evidence of anti-HIV activity, as a minimum, before any clinical development
- Clarification of the cancelled licence status and any current New Zealand availability of glecaprevir/pibrentasvir
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.