 |
|
|
| |
HDV-RNA decline less than 1 log after 6 months of BLV 2 mg monotherapy could define poor-response and lead to therapeutic decision.
|
| |
| |
Real-World HDV Response to Bulevirtide Suggests Stopping Rule for Monotherapy
EASL Congress 2023, June 21-24, Vienna
Mark Mascolini
People coinfected with hepatitis D and B virus (HDV and HBV) who lowered their HDV RNA less than 1 log (10-fold) after 6 months of bulevirtide monotherapy rarely had an encouraging virologic response after 18 months and so should be managed with another strategy [1]. That proposal came from analysis of 57 HDV/HBV-coinfected people in France. Similar analysis of 46 coinfected people treated with bulevirtide plus pegylated interferon-α2a (PEG-IFN) did not yield enough data to support a bulevirtide stopping rule.
European drug regulators offered conditional approval of bulevirtide at a subcutaneous dose of 2 mg once daily for people with chronic HDV infection, but the US FDA has yet to give this HDV entry inhibitor a green light. Because factors that predict poor early response to bulevirtide remain poorly defined, French investigators addressed that question by tapping data from the French Early Access Program for bulevirtide, which ran from September 2019 to September 2020.
The researchers focused on people with (1) compensated cirrhosis or severe (F3) fibrosis or (2) F2 fibrosis with alanine aminotransferase (ALT) persistently above 2 times the upper limit of normal for at least 6 months. Individual clinicians picked the treatment regimen for early-access participants and modified doses when deemed necessary.
The analysis had two goals: (1) evaluate virologic response after 12 months of therapy according to virologic response at month 3 in 57 people using bulevirtide monotherapy (2 mg subcutaneously daily) and 46 using both bulevirtide and PEG-IFN, and (2) evaluate virologic response after 18 months of treatment according to virologic response at month 6 in 37 people using bulevirtide monotherapy and 21 using bulevirtide with PEG-IFN.
The month-12 assessment involved 57 people using bulevirtide monotherapy and 46 combining bulevirtide with PEG-IFN. Those two groups averaged 42.1 and 41.5 years in age, 73.7% and 65.2% were men, ALT averaged 95.3 and 126.3 IU/L, median HDV RNA stood at 6.15 and 6.2 log10 IU/mL, and 12.7% and 9.8% were HBeAg-positive (indicating active HBV replication).
Overall on-treatment response rates (undetectable HDV RNA) were 36% (19 of 53) at month 12 and 32% (11 of 34) at month 18 with bulevirtide monotherapy. Response rates with bulevirtide plus PEG-IFN were 78% (35 of 45) at month 12 and 60% (12 of 20) at month 18.
Among people taking only bulevirtide at the 2-mg daily dose, 21 had less than a 1-log (10-fold) drop in viral load at month 3. In this group16.7% (3 of 18) had less than a 1-log viral load decline at month 12 (and none had attained a normal ALT); 27.8% (5 of 18) had a viral load drop of 1 to 2 log (10- to 100-fold) (and 3 of 5 had reached a normal ALT); and 55.5% (10 of 18) had a viral load decrease more than 2 log (and 5 of 9 reached a normal ALT).
When researchers analyzed the impact of month-6 virologic response on month-18 response in people taking bulevirtide monotherapy, participant numbers were smaller and thus less revealing. The best month-18 response came in the 7 people with an HDV RNA drop between 1 and 2 log (10- and 100-fold) at month 6: 71% of that group (5 of 7) had more than a 2-log HDV RNA decline at month 18, compared with 29% (2 of 7) whose HDV load fell 1 to 2 log at month 18. Among 7 people getting bulevirtide monotherapy with less than a 1-log viral load dip at month 6, no one reached more than a 2-log fall at month 18, 43% (3 of 7) saw their HDV RNA fall between 1 and 2 log, and 57% (4 of 7) did not attain even a 1-log drop by month 18.
Among people taking bulevirtide with PEG-IFN, HDV RNA response at month 3 did not predict virologic response at month 12. But there were only 4 people who had less than a 1-log drop in HDV RNA by month 3 and only 5 people who had less than a 2-log HDV RNA decline. Because of these tiny samples, the French team could propose no bulevirtide stopping rule for people starting bulevirtide plus PEG-IFN.
Among people taking 2 mg of bulevirtide monotherapy daily, virologic response rates were reasonable in those with less than a 1-log HDV RNA drop at month 3 (55%) or a drop between 1 and 2 log at month 6 (71%). This bulevirtide monotherapy analysis allowed the researchers to identify a group of poor responders who had only a slim chance of improving their virologic response if continuing this treatment: People with less than a 1-log fall in HDV RNA at month 6 did not have an acceptable virologic response at month 18.
The French team proposed that trials should evaluate other strategies for these poor responders, perhaps including adding PEG-IFN, stopping treatment entirely in people without severe disease, switching to another therapy, or continuing bulevirtide guided by biochemical response.
Reference
1. de Lédinghen V, Bardou-Jacquet E, Metivier S, et al. HDV-RNA decline less than 1 log after 6 months of BLV 2 mg monotherapy could define poor-response and lead to therapeutic decision. Data from real-life cohort. EASL Congress 2023, June 21-24, Vienna. Abstract OS-066.
|
| |
|
|
|
|
|
