 |
|
|
| |
Bulevirtide, with or without peg- interferon, in HDV infected patients in a real-life setting. two-year results from the French multicenter early access program
|
| |
| |
Two Thirds With HDV/HBV Have 2-Year RNA Response to Bulevirtide Monotherapy
AASLD-The Liver Meeting, November 4-8, 2022, Washington, DC
Mark Mascolini
Two thirds of people in the French bulevirtide open-access program had a virologic response (undetectable HDV RNA or more than 100-fold drop) after 2 years of bulevirtide monotherapy, while 52% had a virologic response plus normal alanine aminotransferase (ALT) [1]. A pretreatment HDV RNA above 6.5 log10 IU/mL and cirrhosis may predict failure to attain a virologic response.
Hepatitis delta virus (HDV), which requires hepatitis B surface antigen (HBsAg) to enter cells, is the most severe form of viral hepatitis. People with HDV/HBV have cirrhosis within 5 years and hepatocellular carcinoma within 10 years, according to French researchers who conducted this multicenter, real-world, early-access study of bulevirtide. European drug regulators gave bulevirtide conditional approval for people with compensated chronic cirrhosis at a dose of 2 mg daily by subcutaneous injection.
The French early-access program for bulevirtide ran from September 2019 to September 2020. To be eligible for the protocol, people with HDV/HBV infection needed (1) compensated cirrhosis or severe (F3) fibrosis, or (2) F2 fibrosis with ALT more than 2 times the upper limit of normal for at least 6 months. At their clinician's discretion, early-access protocol participants could receive bulevirtide once daily alone or bulevirtide plus once-weekly PEG-IFNα-2a.
Seventy participants got bulevirtide monotherapy for 12 months. After that, with their clinician's advice, they could continue bulevirtide to month 24 or stop the drug and continue follow-up until month 24. Sixty-nine participants received bulevirtide plus PEG-IFN for 12 months then at their clinician's discretion could (1) continue that regimen, (2) switch to bulevirtide monotherapy, or (3) stop treatment and continue follow-up to month 24.
The primary endpoint was undetectable HDV RNA or at least a 2-log10 (100-fold) drop in viral load and normal ALT.
The bulevirtide monotherapy group and bulevirtide/PEG-IFN group were similar in average age (42 and 40 years), proportion of men (71.4% and 65.2%), average body mass index (25.9 and 25.1 kg/m2), proportion with cirrhosis (62.9% and 60.9%), median HDV RNA (6.52 log10 in both groups), and current nucleos(t)ide use (80% and 73.9%). The monotherapy group had a lower average ALT (94 vs 124 IU/L), a higher proportion born in Europe (67% vs 52%), a higher proportion with a pretreatment undetectable HBV DNA (70.8% vs 63.5%), and a higher proportion with HIV infection (18.6% vs 8.7%).
After 24 months 52% of all participants had a combined virologic response and normal ALT, with little difference between people who took bulevirtide with or without PEG-IFN. At the same point 68% getting bulevirtide monotherapy, 71% getting bulevirtide plus PEG-IFN, and 75% getting bulevirtide plus PEG-IFN followed by bulevirtide alone had an undetectable viral load or at least a 2-log10 drop in viral load from the baseline value. Proportions in each treatment arm who had normal ALT at week 24 were 56% in the bulevirtide monotherapy group, 59% in the bulevirtide/PEG-IFN group, and 63% in the group that started with bulevirtide/PEG-IFN then switched to bulevirtide alone. The researchers calculated all these virologic results as on-treatment responses.
In multivariate analysis involving participants taking bulevirtide with PEG-IFN, only one factor independently predicted undetectable HDV RNA at month 24-more than a 2-log10 drop in viral load at month 3 (hazard ratio [HR] 2.68, 95% confidence interval [CI] 1.31 TO 5.48, P = 0.007). The same variable predicted both a virologic response and normal ALT at month 24 (HR 2.75, 95% CI 1.33 to 5.72, P = 0.007). And in people taking bulevirtide monotherapy, multivariate analysis identified only that factor as a predictor of undetectable HDV RNA at month 18 (HR 5.84, 95% CI 1.11 to 30.7, P = 0.04).
In univariate analysis at month 18, other variables predicted undetectable HDV RNA at month 18: Higher baseline viral load lowered chances of virologic response about 55%, and using PEG-IFN with bulevirtide boosted chances of virologic response 2.7-fold.
Subanalysis at month 18 involving 34 people receiving bulevirtide monotherapy suggested that baseline cirrhosis and HDV RNA above 6.5 log10 predicted a lower chance of virologic response (undetectable HDV RNA or at least a 2-log10 drop from baseline viral load): Fourteen of those 34 people did not have cirrhosis and 6 of those 14 had a pretreatment viral load below 6.5 log10. All 6 of these people had a virologic response at month 18. In contrast, 20 of these 34 people had cirrhosis going into the study, and 14 of these people had a pretreatment viral load above 6.5 log10. Only 4 of 10 people with both cirrhosis and a viral load above 6.5 log10 when treatment began had a virologic response at month 18. The same type of analysis involving 52 people who took bulevirtide with PEG-IFN yielded similar evidence that starting treatment with cirrhosis and a viral load above 6.5 log10 dims chances of virologic response.
Among the 70 people getting bulevirtide monotherapy, 20 (29%) stopped treatment before or at month 12. The most frequent reasons for stopping were lack of virologic response in 4 people, loss to follow-up in 3, and other reasons in 4 (homelessness, prison, adherence, and COVID lockdown). Among 69 people receiving bulevirtide plus PEG-IFN, 26 (38%) stopped treatment before or at week 12. The most frequent reasons for stopping in this group were PEG-IFN side effects in 7, loss to follow-up in 5, and similar "other" reasons in 4.
The most frequent adverse events in the 69 people receiving bulevirtide plus PEG-IFN were 22 cases of asthenia (weakness), 15 cases of neutropenia (low level of neutrophils, an infection-fighting white blood cell), 10 cases of flu-like symptoms, 9 cases of headache, and 9 cases of psychiatric disorders. The most frequent adverse events among 70 people treated with bulevirtide monotherapy were asthenia in 8 and headache in 3.
In the United States the FDA has not given bulevirtide a go-ahead, citing concerns about making and delivering the drug [2]. But the FDA did not ask the sponsor for new studies to assess efficacy and safety of bulevirtide. No other medications have been licensed to treat HDV infection.
References
1. De Ledinghen V, Hermabessiere P, Metivier S, et al. Bulevirtide, with or without peg- interferon, in HDV infected patients in a real-life setting. two-year results from the French multicenter early access program. AASLD-The Liver Meeting, November 4-8, 2022, Washington, DC. Abstract 28.
2. Gilead. Gilead receives complete response letter from U.S. FDA for bulevirtide for the treatment of adults with hepatitis delta virus. October 27, 2022.
https://www.gilead.com/news-and-press/company-statements/gilead-receives-complete-response-letter-from-us-fda-for-bulevirtide-for-the-treatment-of-adults-with-hepatitis-delta-virus
|
| |
|
|
|
|
|
