TS2022

Clinical and Public Health Needs

LA therapy is convenient and could prevent HBV reactivation stemming from poor adherence.

  • Current HBV therapies are effective, but adherence drops off with daily long-term therapies. Clinical scenarios for LA HBV treatment.

Clinical

Jordan Feld (University Health Network) reviewed clinical scenarios for LA HBV treatment.

  • During pregnancy for PMTCT.
    • Oral medications can be challenging during pregnancy; a one-time LA dose would be beneficial.
  • In the setting of immunosuppression.
    • HBV reactivation is a life-threatening complication of immunomodulatory therapies (i.e., cancer chemotherapy and biologics).
    • Avoiding daily HBV therapy where missed doses could have severe consequences would be helpful.
  • Rural/remote areas.
    • LAIs are particularly suited to high burden areas where care is intermittent or unavailable (i.e., SSA and many parts of Asia).
    • LAIs, even with current therapies, would be a significant benefit.
    • HBV cure.
    • Delivering a stable backbone without interruption is important to achieve cure with a purely antiviral approach (backbone of current NRTIs is likely).
    • If immunomodulatory therapies are added, need to ensure the safety of no interruptions.
  • Pediatrics.
    • Children are not always willing or able to take pills.
  • HIV-HBV co-infection.
    • Including HBV-active drugs in a LA HIV approach could control both conditions at the same time.
  • Other potential areas exist.

Public health considerations

  • An estimated 257 million people are living with chronic HBV worldwide – large market from a pharmaceutical perspective.
  • Most new cases occur in infants at birth (MTCT).
  • Birth dose HBV vaccination is a practical and effective PMTCT approach, but only 39% of infants born to HBV+ mothers received a birth dose vaccine in 2015.
  • This number may be hard to raise due to the number of children born in non-traditional settings.
  • Giving a LA agent during pregnancy could prevent some of these MTCT events – global health level.

Discussion Highlights

Chari Cohen from Hep B Foundation (represents patient/community voice).

  • Daily pills can be stigmatizing or empowering - depends on the individual.
  • Systemic access and discrimination are a concern for any non-curative treatment in RLS.Any treatment needs to lead to surface antigen negative status to be widely accepted – cannot get employment without seronegativity.
  • It will be a challenge to deliver LA medications during pregnancy (due to access to care)

U=U campaign for HBV could be powerful in addressing discrimination/stigma.

LA HBV in pregnancy: in RLS, home deliveries are really the issue limiting the current PMTCT strategy.

  • Many pregnant women attend at least one ANC visit (even if they deliver at home).
  • Could implement a system – confirm HBV viremia via POC test and administer a LAI in the same ANC visit (would need to establish safety and same benefit as birth dose vaccination).
  • As an add on, there is a need to train and license midwives to administer HBV birth dose vaccination at home deliveries.

Review of Existing LA HBV Efforts

TAF implants Marc Baum (Oak Crest Institute)

  • TAF is one of few drugs potent enough to theoretically enable drug delivery up to 6mo from an implant.
  • Overview of technologies being studied.
  • Toxicity of Northwestern implant is possibly due to a combination of factors – mechanical, polyurethane material, fumaric acid plus TAF and wound healing.

 

 

 

 

TFV ProTides – Benson Edagwa (UNMC)

  • Single IM injection of a novel TFV prodrug formulation (NM1TFV) suppresses HBV replication for up to 4mo in HBV-infected, humanized mice.
    • NM1TFV gets distribution in lymph nodes and hepatocytes without specific organ targeting.
    • Prodrug formulations are well-tolerated (preliminary toxicology and injection site examination).
  • Nanoformulated TAF (control) administered at the equivalent IM dose had a minimal effect on HBV replication.
    • Changing from oral to parenteral route of administration affects TAF biodistribution and delivery into the liver.

TFV prodrug bolus approach – Arnab Chatterjee (Calibr)

  • Finding the right form of TAF and the right way to deliver it is key.
  • Observed different release rates and differences in conversion to TFV-DP among oil-based vs aqueous suspensions of TAF – better results seen with free-base form compared to heavy fumarate.
  • IM bolus of TAF (aqueous suspension) in dogs sustained good drug levels in PBMCs (TFV and metabolites) over 80 days.
    • Good shelf stability for LMICs (potentially up to 6 months).
    • Bolus approach allows ISR to resolve vs continual release strategies – still have work to do with histopathology.

Discussion Highlights

Are treatment and prevention targets for intracellular TFV-DP the same for HIV and HBV?

  • PK targets for HBV treatment may be higher than HIV.
    • Small study of patients with HIV-HBV coinfection: TFV levels were consistent with four doses/week and suppressed HIV, but not HBV.
    • HBV is replicated exclusively in the liver. Without oral delivery, the advantage of first pass metabolism is eliminated –need to target the tissue.
  • There are no strategies for targeting the liver with parenteral therapy.
    • TFV ProTides have high drug levels in lymphocytes and liver tissue – enough to suppress HBV in mice, but do not specifically target the liver. Therapeutic concentration may have to do with the lipophilicity of the formulation.
    • Rodney Ho also has evidence that TFV is taken up in lymphocytes and liver.
  • Combining HIV prevention with a TFV product and HBV prevention in pregnancy would be useful.
    • Meg Doherty (WHO): There is great public use for this work. There are many places where birth dosing is not happening – LA TFV for HBV and LA PrEP would be a nice correlate. How long from this stage to human to reality?

Need to engage industry to accelerate development.

  • 257 million people represents a huge potential market for a LA formulation – large enough to offset small profits on an individual basis.
  • This group can engage in consciousness raising with the pharmaceutical and biotech industry.

This is an ongoing discussion......