Sequential combination therapies for HBeAg-positive chronic hepatitis B: the search continues

Abstract

Total eradication of the hepatitis B virus (HBV) is still elusive, as even if HBsAg is lost, covalently closed circular DNA (cccDNA) often persists in the hepatocytes. The currently available drugs for treatment of chronic hepatitis B (CHB) are not able to give sustained off-treatment HBsAg loss (functional cure) in most of the patients, which is the ultimate goal of therapy of CHB and is closest to eradication. In the absence of functional cure, Hepatitis B e antigen (HBeAg) seroconversion and undetectable HBV DNA are taken as end-points of antiviral therapy in HBeAg-positive CHB. At present, monotherapy with potent nucleot(s)ide analogues (NAs) (directly inhibit HBV DNA polymerase) or pegylated interferon alpha (Peg-IFN) (immune modulator) is recommended as the first-line therapy for HBeAg-positive CHB. Long-term potent NA treatment has excellent viral suppression (more than 95% at 5 years) [1], but relapse is common after stopping NAs. Therefore, prolongation of potent NAs therapy over long period maintains the initially high virological remission rates. The rationale for Peg-IFN use is to induce immunological control with a finite duration of therapy [2]. However, the response to Peg-IFN treatment is highly variable and it has more side effects as compared to NAs. Among HBeAg-positive CHB patients, Peg-IFN therapy leads to higher HBeAg seroconversion and HBsAg seroclearance rates as compared to NAs, but the sustained virologic response rates at 6 months following 12 months of Peg-IFNa therapy are ~ 20–30% [3]. Baseline predictors for good response to Peg-IFN treatment include lower HBV DNA levels (< 7 log10 IU/ml) and higher ALT levels (2–3 times ULN) [1]. Many investigational agents are in pipeline with varied mechanisms of actions including interference with specific steps in HBV replication or acting as host cellular targeting agents or as immune modulators. However, these drugs are currently not approved for clinical use. Therefore, novel therapeutic concepts involving the currently approved therapies, such as combination of agents with differential mechanisms of actions on HBV (e.g., NAs plus Peg-IFN) are being explored to achieve higher rates of HBsAg loss. The combination of NAs and Peg-IFN has been studied in CHB patients. The approaches to combination therapy include: simultaneous administration of Peg-IFN and NA or sequential administration of Peg-IFN and NA (either starting with NA for a variable period, followed by ‘switch to’ or ‘add-on’ Peg-IFN; or starting with Peg-IFN followed by addition of NA). At present, the optimal combination therapy to obtain the best treatment outcomes remains undefined due to differences in study designs and case–control selection. There is no robust evidence that a simultaneous combination of Peg-IFN and NA is superior compared to Peg-IFN or NA alone in treatment naïve patients. The main theoretical advantage of this approach is the possible synergy of the different mechanisms of the 2 drugs and simplicity of the regime. In one recent randomized-controlled trial, HBsAg loss rates at 72 weeks were superior in the Peg-IFN and tenofovir (TDF)-treated patients as compared to patients receiving Peg-IFN alone or TDF alone (9% vs. 3% vs. 0%), but the overall rates were low and mainly in genotype A patients [4]. Because high viral loads lead to blunting of immune responses to HBV, viral load reduction by NAs leads to increased immune responses against HBV, which then followed by immune modulation by addition of Peg-IFN results in increase in r HBV virus-specific cytotoxic T-cell activity [5]. In CHB patients on NA treatment, Peg-IFN can be used as a ‘switch to’ or ‘add-on’ strategy. Studies have shown higher HBeAg seroconversion rates using ‘switch to’ or ‘add-on’ strategies [6, 7]. * Manoj Kumar [email protected]; [email protected]