Combination therapy for hepatitis B makes the grade in real world

A 48-week course of combination therapy with pegylated interferon (Peg-IFN) and tenofovir disoproxil fumarate (TDF) appears to induce functional cure in patients with chronic hepatitis B (CHB), leading to a remarkable reduction in viral surface antigen levels (HBsAg) in the blood, according to real-world data.

Significantly more patients treated with the combination than with TDF monotherapy achieved HBsAg seroclearance, with a steep decline in HBsAg at week 24 being associated with a greater likelihood of achieving seroclearance at week 72, the investigators noted.

The study included a cohort of 330 Chinese patients with CHB; 104 of them received the Peg-IFN–TDF combination for 48 weeks, 106 Peg-IFN alone for 48 weeks, and 120 TDF alone for 144 weeks. Their average age was 30 years, 70 percent of the patients were male, and 78.5 percent were positive for the e antigen (HBeAg).

At week 72, the cumulative HBsAg loss was 11.5 percent with the combination and 5.7 percent with Peg-IFN; none of the patients on TDF met this endpoint. The difference between the first two treatments was not statistically significant (p=0.143), but both showed superiority to TDF (p=0.000 and p=0.010, respectively). [Clin Ther 2021;43:572-581.E3]

A higher number of patients in the combination and Peg-IFN groups had serum HBsAg of <100 IU/mL relative to the TDF group (32.7 percent vs 23.6 percent vs 9.2 percent; p<0.001). However, virologic response (87.4 percent, 86.5 percent, and 84.3 percent, respectively) and HBeAg seroconversion (24.3 percent, 21.2 percent, and 14.4 percent, respectively) rates were similar across the treatment groups.

At week 12, a decrease of >1 log₁₀ IU/mL in HBsAg predicted HBsAg loss at week 72 quite well (area under the receiver operating characteristic curve [AUC], 0.772). But a reduction of >1.5 log₁₀ IU/mL at week 24 predicted seroclearance with better accuracy (AUC, 0.846).

Thus, patients on Peg-IFN plus TDF should be encouraged to complete their treatment after achieving the milestone reduction at week 12 or 24, according to the investigators.

In terms of safety, adverse events (AEs) occurred with similar frequency in the combination and Peg-IFN groups but significantly less so in the TDF group (p<0.001). The most common AEs were those previously reported with Peg-IFN, including pyrexia, fatigue, neutropoenia, and alopecia. None of the patients had serious AEs.

“A durable serum HBsAg loss that usually follows the loss of serum HBV DNA marks HBV functional cure in chronic HBV infection,” the investigators pointed out. “Many clinical studies are refocusing on a combination strategy to improve [the chances of] achieving HBsAg loss.”

While combining Peg-IFN with less potent nucleot/side analogue (NA) inhibitors (eg, lamivudine or adefovir) flopped for improving HBsAg loss rates over Peg-IFN monotherapy, using more potent NAs (eg, entecavir or tenofovir) did the job, they added. [N Engl J Med 2005;352:2682-2695; Antivir Ther 2009;14:1165-1174; Lancet 2005;365:123-129; Infect Drug Resist 2018;11:2001-2009; Viral Hepat 2019;26:109-117; Hepatol Res 2018;48:451-458]

“This study adds new data that indicate a greater HBsAg seroclearance after 48 weeks of Peg-IFN combination with TDF versus TDF monotherapy,” the investigators said.

“The statistical analyses in this study may be underpowered by relatively small patient population size, which was further confounded by the fact that all patients were recruited in a single research centre. To further validate these findings, large-scale prospective and multicentre studies are warranted,” they added.