Opisthorchis viverrini, commonly known as the Southeast Asian liver fluke, is a parasite that belongs to the family Opisthorchiidae [1]. It is endemic in Southeast Asia and is estimated to cause opisthorchiasis in more than 10 million people in just Thailand and Laos alone [2]. The impact of liver fluke infection on daily living can be significant. A study by Sayasone et al. found that individuals infected with a higher burden of adult worms report significant gastrointestinal symptoms such as right upper quadrant pain and abdominal discomfort [3]. In addition, chronic infection with Opisthorchis viverrini is a leading cause of bile duct cancer in Southeast Asia [4]. Despite the significant number of deaths (1200–1800/year) and disability-adjusted life years (DALYs) due to opisthorchiasis and Opisthorchis viverrini-associated cholangiocarcinoma (150–235 × 10³ DALYs) [5], opisthorchiasis remains a neglected tropical disease [6].

The development of cholangiocarcinoma associated with Opisthorchis viverrini infection also brings about a large socioeconomic burden on regions where the fluke is endemic. According to Muller et al., the financial impact of opisthorchiasis and cholangiocarcinoma in Thailand is estimated to be USD 120 million annually in healthcare costs and lost wages [7]. As opisthorchiasis is most prevalent in people of lower socioeconomic status, the financial impact on their families is even more significant. Despite the implementation of the Universal Health Coverage scheme to subsidize treatments for this group of patients, accessibility to care and affordability of treatment are unmet needs. Without attention and intervention, if status quo prevails, the socioeconomic gap in endemic regions is likely to widen and negatively impact these societies in future [8]. Therefore, prompt, effective, and efficient implementation of transmission controlling measures is necessary to reduce the global burden of Opisthorchis viverrini. Here we will highlight advancements in treatment of Opisthorchis viverrini infection and its associated cholangiocarcinoma.

2. Treatment

2.1. Eradication of Parasites

The treatment of hepatobiliary opisthorchiasis involves the use of anthelmintic drugs, such as praziquantel and tribendimidine. The first-line treatment for Opisthorchis viverrini infection is praziquantel with a dosage of 25 mg/kg three times a day for 2 to 3 consecutive days as recommended by the World Health Organization. Alternatively, a single dose of 40 mg/kg praziquantel can be used. All cases of confirmed Opisthorchis viverrini infection and suspected cases in endemic regions should be treated regardless of whether they are symptomatic to reduce potentially severe complications such as recurrent pyogenic cholangitis and cholangiocarcinogenesis [9]. Alternatively, tribendimidine is suggested to be at least as efficacious as praziquantel in the treatment of Opisthorchis viverrini infections [10,11,12]. In a randomized controlled trial involving more than 600 patients, tribendimidine was shown to have a cure rate slightly lower than praziquantel of 94% compared to 97%, but it has a similar egg reduction rate of 99.9% to praziquantel. Tribendimidine is also associated with fewer adverse events and may serve as a valuable alternative to praziquantel [11].

2.2. Treatment of Co-Infection (Helicobacter pylori)

Opisthorchis viverrini infections lead to hepatobiliary manifestations, including advanced periductal fibrosis (APF), which is correlated with the risk of cholangiocarcinoma. The existing literature proposes that a carcinogenic bacterium, Helicobacter pylori (H. pylori), also contributes to the development of cholangiocarcinoma by enhancing the severity of hepatobiliary abnormalities [13]. A study by Hang et al. found that even after completion of therapy with praziquantel, patients with co-infection by H. pylori, especially cagA-positive strain, continued to have persistent APF [14]. Hence, this suggests the need for concurrent H. pylori treatment for better outcomes.

2.3. Treatment of Symptoms

Patients infected by Opisthorchis viverrini often present with hepatobiliary symptoms and should be treated. Cholecystectomy is indicated in patients with isolated cholecystitis; early laparoscopic cholecystectomy is associated with better patient outcomes [15,16] and is considered gold standard treatment. Further, decompression of the biliary tract and drainage of the abdominal cavity via percutaneous transhepatic biliary drainage (PTBD) is required in patients presenting with cholangitis to prevent biliary peritonitis in the postoperative period [17]. ERCP is also another useful modality to treat choledocholithiasis associated with Opisthorchis viverrini infection via endoscopic sphincterotomy [18]. Although endoscopic extraction of worms has led to rapid resolution of symptoms in other parasitic infections such as biliary ascariasis, endoscopic extraction of adult Opisthorchis viverrini flukes has been not reported to date [19].

2.4. Treatment of Opisthorchis viverrini-Associated Cholangiocarcinoma

The treatment of Opisthorchis viverrini-associated cholangiocarcinoma depends on the anatomic subtype, which includes intrahepatic, perihilar and distal extrahepatic cholangiocarcinoma [20]. Early-stage tumours are amenable to surgical resection or liver transplantation, whereas palliative chemotherapy is the mainstay of treatment for advanced-stage disease. Several targeted and immune-directed therapies are currently in development and have shown promising results in phase II trials [21].

2.4.1. Surgical Resection

Prior to liver resection, staging laparoscopy is recommended to evaluate for any occult peritoneal metastases. If present, these patients should be spared an unnecessary laparotomy due to unresectable disease [22]. Liver resection for intrahepatic cholangiocarcinoma is potentially curative if margin negative (R0) resection can be achieved [21]. On the other hand, surgical resection with a positive resection margin (R1) is associated with a decrease in the 5-year survival from 32.2% to 13.1% and a drop in median recurrence-free survival from 12.4 months to 7.4 months [23]. In perihilar cholangiocarcinoma, liver resection with negative margin is associated with a 5-year survival of 67.1% [24]. In addition, patients with locally advanced Bismuth type IV perihilar cholangiocarcinoma, which has traditionally been categorized as unresectable, have improved 5-year survival of 32.8% from 1.5% post-resection [25]. A new modification of the 8th American Joint Committee on Cancer (AJCC) staging system, the Khon Kaen University (KKU) staging system for perihilar cholangiocarcinoma, has been proposed recently. It uses growth patterns, histological grading, and lymph node and distant metastases to prognosticate the overall survival, and a prospective study is underway to evaluate its effectiveness as a prognostic tool [26]. Pancreaticoduodenectomy is the treatment of choice for surgically resectable distal cholangiocarcinoma. Prognostic factors post-pancreaticoduodenectomy of distal cholangiocarcinoma include size of tumour, lymph node status, growth patterns and resection margin status [27,28]. Achieving a negative margin resection has been found to significantly increase overall survival from 9 months to 48 months [29].

2.4.2. Liver Transplantation

Liver transplantation for intrahepatic cholangiocarcinoma has been a subject of controversy due to the high incidence of recurrence after transplantation and the scarcity of donor organs. However, recent studies have found that liver transplantation can yield better outcomes in a selected group of patients with smaller tumours and favourable tumour biology [30]. For example, a study by McMillan et al. saw that patients who underwent liver transplantation had an overall survival of 100%, 71% and 57% at 1, 3 and 5 years [31]. In perihilar cholangiocarcinoma, neoadjuvant chemotherapy followed by liver transplantation has been found to provide a survival benefit with overall survival at 2-years at 65–70% and 5-year recurrence-free survival at 47–68% [32]. Elevated carbohydrate antigen 19–9 (CA 19–9) and portal vein encasement are identified as predictors of recurrence post-transplant [33].

2.4.3. Locoregional Therapy

Locoregional therapies such as thermal ablation, transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), chemotherapy hepatic arterial infusion (HAI), and external beam radiotherapy (EBRT) can be used to treat unresectable liver-only intrahepatic cholangiocarcinoma [34]. A pooled analysis conducted by Edeline et al. found the overall survival of patients who underwent locoregional therapies for intrahepatic cholangiocarcinomas to be 30.2 months for thermal ablation, 15.9 months for TACE, 14.1 months for SIRT, 21.3 months for HAI and 18.9 months for EBRT. Overall survival was also found to be higher in patients who were treated with systemic chemotherapy before TACE, SIRT, or HAI [35].

2.4.4. Systemic Therapy

Systemic therapies used to treat cholangiocarcinoma include adjuvant therapy post-surgical resection and palliative chemotherapy. A randomised controlled multicentre phase III trial (BILCAP study) showed that the use of capecitabine as adjuvant therapy had an overall improved survival of 53 months as compared to 36 months in the observation group [36]. Based on these findings, the American Society of Clinical Oncology (ASCO) clinical practice guideline recommends the use of adjuvant capecitabine chemotherapy for a duration of 6 months post-resection. In addition, patients with positive resection margins may be offered chemoradiotherapy [37]. In patients with advanced-stage disease, palliative chemotherapy options are available. The Advanced Biliary Cancer-02 (ABC-02) phase III trial involving 410 patients showed that a cisplatin plus gemcitabine regime conferred a longer survival period of 11.7 months as compared to 8.1 months when gemcitabine was used alone, without the addition of substantial toxicity [38]. The ABC-06 phase III clinical trial conducted showed that the use of folinic acid, fluorouracil, and oxaliplatin chemotherapy regime as second-line treatment in patients who became unresponsive to the first-line cisplatin-plus-gemcitabine regime resulted in an improvement in survival from 5.3 months to 6.2 months [39]. Numerous studies on targeted therapy for Opisthorchis viverrini-associated cholangiocarcinoma are in progress. Loilome et al. identified PRKARIA (a regulatory substrate of protein kinase A) and MARCKS (a substrate of protein kinase C) as genes which are involved in cholangiocarcinogenesis and metastases [40,41,42]. These findings subsequently led to the investigation of the roles of other protein kinases in cholangiocarcinogenesis. One such study noted the overexpression of epidermal growth factor receptor (EGFR) in patients with Opisthorchis viverrini-associated cholangiocarcinoma and also found that cholangiocarcinoma cells from these tissues showed inhibited cell growth and metastatic potential after treatment with nimotuzumab [43]. Another study investigated the use of a highly selective pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor, buparlisib, to target the PI3K/RAC serine/threonine-protein kinase (Akt) pathway, which has been implicated in the development of Opisthorchis viverrini-associated cholangiocarcinoma [44]. The in vivo study on mice models led to a reduction in tumour size without substantial signs of toxicity, suggesting that buparlisib is a possible therapeutic agent [45]. More work needs to be carried out to develop specific inhibitors for targeted treatment of Opisthorchis viverrini-associated cholangiocarcinoma [46].