LNF-based regimens for CHD achieved the primary efficacy endpoints in the phase III D-LIVR trial.Individuals with chronic hepatitis D (CHD) may benefit from lonafarnib boosted with ritonavir (LNF/RTV) alone or in combination with peg-interferon-alfa (PEG), findings from the phase III D-LIVR trial have shown.
“In this trial, LNF-based therapies achieved the primary efficacy endpoints, are universally favoured over placebo across endpoints, and delivered numerically greater treatment effects after off-treatment follow-up,” said Dr Saeed Sadiq Hamid from Aga Khan University, Karachi, Pakistan, at EASL 2026.
At week 48 on treatment, the LNF/RTV groups had more composite responders (ie, participants who achieved ALT normalization and ≥2 log10 reduction in HDV RNA vs baseline) than the placebo group (with PEG: 19.2 percent vs 1.9 percent; p<0.0001; without PEG: 10.1 percent vs 1.9 percent; p<0.01).
Similar patterns were observed when evaluating the individual components of the primary endpoint, such as the proportions of biochemical (24.7 percent [LNF/RTV] and 34.4 percent [LNF/RTV + PEG] vs 7.7 percent [placebo]) and virologic responders (14.6 percent and 32 percent vs 3.8 percent). [EASL 2026, abstract OS-075]
The better treatment effects with LNF/RTV were sustained after 24 weeks of off-treatment follow-up in the composite (26.4 percent [with PEG] and 14.2 percent [without PEG] vs 0 percent [placebo]; p<0.0001 for both comparisons), biochemical (38.2 percent and 26.4 percent vs 5.1 percent), and virologic responder groups (34.5 percent and 21.6 percent vs 2.6 percent).
Durable and new responses
Among week 48 composite responders, the durability rates with LNF/RTV, with or without PEG, were 41.7 percent and 44.4 percent, respectively; with placebo, there were none after a 24-week follow-up period without treatment.
The proportions of new responders in the LNF/RTV alone and with PEG groups were 10 percent and 22.8 percent, respectively. Again, there were none in the placebo group.
“[New responders are] patients who did not achieve composite virologic and biochemical response at the end of the 48-week treatment period [but did so] during the off-treatment follow-up period,” Hamid said. “[These suggest that] on-treatment response to LNF was durable and new treatment response emerged after 24 weeks of off-treatment follow-up.”
ALT normalization
Approximately 94 percent of the overall cohort began the study with an ALT above the upper limit of normal, Hamid noted.
At 48 weeks on treatment, more patients on LNF/RTV than on placebo achieved ALT normalization (with PEG: 34.4 percent vs 7.7 percent; p<0.0001; without PEG: 24.7 percent vs 7.7 percent; p=0.0003). This was sustained at the 24-week post-treatment follow-up (38.2 percent and 26.4 percent vs 5.1 percent).
Looking at histological response among patients who did not achieve virological response, the proportions of participants with normalized ALT at week 48 were 55.6 percent and 75 percent in the respective LNF/RTV and LNF/RTV + PEG groups.
“In the absence of a full virologic response, resolution of inflammation drives histological improvement, likely reflecting a reduction in the infection of new hepatocytes,” said Hamid.
Improved histology
Among participants with liver biopsies at baseline and at week 48 (n=229), more patients on the LNF/RTV-based regimens had a histological response at 48 weeks on treatment (53 percent [with PEG] and 32.7 percent [without PEG] vs 26.7 percent [placebo]).
According to Hamid, histological response was defined as a ≥2-point improvement in the Histologic Activity Index (HAI) score and no worsening of fibrosis on the Ishak score, as determined by blinded assessment of paired liver biopsies. “The effect is above the background histology benefits all patients experienced due to background HBV [nucleotide analogue (NA)] therapy, as most patients started NA therapy within 1 year of study start.”
Safety, tolerability
The most common adverse events were gastrointestinal (72.1 percent), and most were mild or moderate. These usually occurred within the first 30 days of treatment and were managed with temporary dose reduction and/or supportive medication.
“The safety profile of LNF/RTV with or without PEG is predictable, manageable, and clinically acceptable,” Hamid said.
A serious unmet need
Hepatitis delta virus (HDV) occurs alongside hepatitis B virus (HBV) infection, and HBV has no curative treatment, Hamid emphasized. “HBV patients who are HVD+ have a 2.2-fold higher risk of liver-related complications. However, HDV prevalence is likely underestimated as routine HDV screening is not widely implemented even among HBV patients.”
Moreover, treatment for HDV remains limited; standard care is off-label use of PEG, while bulevirtide has limited availability. “LNF remains the only oral HDV treatment option in development. Thus, there continues to be a critical need for novel therapeutics that target distinct steps in the HDV cycle,” Hamid continued.
In D-LIVR, 407 CHD patients (mean age 42.7 years, 69.3 percent men, 23.3 percent Asian) were randomized 7:5:2:2 to LNF/RTV (lonafarnib 50 mg BID + ritonavir 100 mg BID), LNF/RTV + SC PEG 180 mg QW, PEG, or placebo for 48 weeks. A quarter (26.5 percent) of participants had cirrhosis at baseline. The mean liver stiffness was 12.1 kPa, the mean HDV RNA level was 4.9 log10 IU/mL, and the mean ALT level was 100.3 U/L.
Takeaways
Apart from achieving the primary efficacy endpoints, LNF-based therapies normalized ALT, a biomarker of inflammation and a key driver and prerequisite for histologic improvement, noted Hamid.
“Furthermore, LNF-based therapies produced histological benefit, with combination therapy achieving significant improvement in modified Ishak HAI at 48 weeks above background HBV treatment. It also promoted inflammation-related histologic benefit even in the absence of full virologic response,” he continued.
“Taken together, these results support LNF/RTV-based regimens as clinically impactful therapies with the potential to alter the trajectory of HDV [treatment]. LNF is a first-in-class oral HDV therapy with a unique mechanism of action that may form the basis of future combination therapies,” Hamid concluded.