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Alqahtani et al. Hepatoma Res 2020;6:58 I http://dx.doi.org/10.20517/2394-5079.2020.49 Page 11 of 18

have a chronic HBV infection globally, of whom 60-70 million have an HDV coinfection, which is almost
twice as much as the previous estimate [144] . HDV does not integrate into the genome of hepatocytes, making
a direct oncogenic mechanism unlikely. However, preliminary data have indicated the potential indirect
oncogenic effects of this virus. HDV can modify several key signaling pathways with a known role in
cirrhosis and hepatocarcinogenesis, including the activation of the TGF-β, NF-κB, and JAK-STAT signaling
pathways [145-147] .

Studies comparing HCC incidence between HBV/HDV coinfected and HBV mono-infected patients
provide better insights on the oncogenic impact of HDV. A critical Eurohep study demonstrated that HBV/
HDV-positive cirrhotic patients followed for a median of 6.6 years had a twofold increase in mortality risk
compared to patients with HBV-related cirrhosis [148] . Moreover, the estimated risk for HCC was 13% among
cirrhotic HBV/HDV patients compared to 2%-4% for cirrhotic patients with an HBV mono-infection,
corresponding to a threefold increase in HCC risk for coinfected patients [148] . Also, a large Swedish
retrospective cohort study demonstrated a significantly higher risk of HCC for patients with acute (RR = 6.1,
95%CI: 2.8-11.7) or chronic (RR = 3.9, 95%CI: 1.6-7.2) HDV [149] . Similarly, an American study, including
2,175 HBV patients, found a 2.9-fold increase in the incidence of HCC in individuals with an HBV/HDV
coinfection (OR = 2.1, 95%CI: 1.1-3.9) [150] .

Cohort studies evaluating the HCC incidence among patients with HDV yielded variable results. Among
299 HDV infected patients who were included in a single-center Italian study (diagnosed between 1987
and 2006), 46 HCC cases were reported, accounting for an annual rate of 2.8% [151] . Interestingly, the
authors of this analysis later identified high serum levels of HDV RNA as a predictor of cirrhosis and liver
cancer in HDV patients [152] . In a large cohort study which included 1,576 HDV patients, the annual HCC
incidence was slightly lower at 1.9% [153] . The results obtained in other cohort studies with a fewer patients
were inconsistent and reported an annual HCC incidence among HDV patients of 3%-13% [154-156] . Finally,
a recent study addressed the HDV-associated mortality in HIV/HBV coinfected patients. HDV infection
appeared to be strongly associated with overall death (HR = 2.33, 95%CI: 1.41-3.84), liver-related death (HR
= 7.71, 95%CI: 3.13-18.97), and HCC occurrence (HR = 9.3, 95%CI: 3.03-28.61) [157] .

Very recently, a meta-analysis pooling data from 93 studies compared the HCC risk in patients with HBV/
HDV and HBV alone (68 case-control studies with 22,862 patients and 25 cohort studies with 75,427
[5]
patients) was published . Patients with HBV/HDV had a significantly higher HCC risk than patients with
an HBV mono-infection (pooled OR = 1.28, 95%CI: 1.05-1.57). Of note, this association was particularly
[5]
pronounced in studies with HIV-infected patients (pooled OR = 7.13, 95%CI: 2.83-17.92) .

In summary, though most studies evaluating the incidence of HCC in HDV-infected patients have
provided low-level evidence, data support an association between HDV and the development of HCC.
Similar to what was described for HBV and HCV, the objective of antiviral treatment in patients with a
chronic HDV infection is to eliminate HDV and HBV and, as such, prevent the long-term detrimental
effects of hepatitis D on the liver. Unfortunately, the treatment options for patients with HDV are limited,
and HDV elimination is not commonly achieved. In fact, 1-year of interferon-α (IFN-α) only induces
a sustained HDV clearance in 10%-20% of patients [158] . More recently, several studies have evaluated the
use of pegylated IFN-α in HDV patients. While response rates in these trials were higher than what was
seen with classical IFN-α, sustained clearance of HDV RNA proved feasible in only about a quarter of
patients [159-161] . Data on the impact of IFN-α treatment on the natural history of hepatitis D are scarce. In an
extended follow-up of 36 chronic HDV patients treated with one year of IFN-α found that some patients
experienced regression of their advanced stage fibrosis, indicating a positive effect on the natural HDV
disease course [162] . Less favorable data come from the HIDIT trial in which pegylated IFN-α was used
to treat chronic HDV. In this trial, 58% of patients who were shown to be HDV RNA negative 6 months