Date Published: March 13, 2019
Publisher: Public Library of Science
Author(s): Chau Le Ngoc, Thanh Tran Thi Thanh, Phuong Tran Thi Lan, Trinh Nguyen Mai, Trang Nguyen Hoa, Ngoc Nghiem My, Tan Le Van, Hung Le Manh, Phuong Le Thanh, Chau Nguyen Van Vinh, Guy Thwaites, Graham Cooke, Gabrielle M. Heilek, Cecilia Shikuma, Thuy Le, Stephen Baker, Motiur Rahman, Yury E. Khudyakov.
The highest burden of disease from hepatitis C virus (HCV) is found in Southeast Asia, but our understanding of the epidemiology of infection in many heavily burdened countries is still limited. In particular, there is relatively little data on acute HCV infection, the outcome of which can be influenced by both viral and host genetics which differ within the region. We studied HCV genotype and IL28B gene polymorphism in a cohort of acute HCV-infected patients in Southern Vietnam alongside two other cohorts of chronic HCV-infected patients to better understand the epidemiology of HCV infection locally and inform the development of programs for therapy with the increasing availability of directly acting antiviral therapy (DAAs).
We analysed plasma samples from patients with acute and chronic HCV infection, including chronic HCV mono-infection and chronic Human Immunodeficiency Virus (HIV)-HCV coinfection, who enrolled in four epidemiological or clinical research studies. HCV infection was confirmed with RNA testing. The 5’ UTR, core and NSB5 regions of HCV RNA positive samples were sequenced, and the genotype and subtype of the viral strains were determined. Host DNA from all HCV positive patients and age- and sex-matched non-HCV-infected control individuals were analysed for IL28B single nucleotide polymorphism (SNP) (rs12979860 and rs8099917). Geolocation of the patients were mapped using QGIS.
355 HCV antibody positive patients were analysed; 54.6% (194/355) and 46.4% (161/355) were acute and chronic infections, respectively. 50.4% (81/161) and 49.6.4% (80/161) of chronic infections had HCV mono-infection and HIV-HCV coinfection, respectively. 88.7% (315/355) and 10.1% (36/355) of the patients were from southern and central regions of Vietnam, respectively. 92.4% (328/355) of patients were HCV RNA positive, including 86.1% (167/194) acute and 100% (161/161) chronic infections. Genotype could be determined in 98.4% (322/328) patients. Genotypes 1 (56.5%; 182/322) and 6 (33.9%; 109/322) predominated. Genotype 1 including genotype 1a was significantly higher in HIV-HCV coinfected patients compared to acute HCV patients [43.8% (35/80) versus 20.5% (33/167)], (p = <0.001), while genotype 6 was significantly higher in chronic HCV mono-infected patients [(44.4% (36/81) versus 20.0% (16/80)] (p = < 0.004) compared to HIV-HCV coinfected patients. The prevalence of IL28B SNP (rs12979860) homozygous CC was 86.46% (83/96) in control individuals and was significantly higher in acutely-infected compared to chronically-infected patients [93.2 (82/88) versus 76.1% (35/46)] (p = < 0.005). HCV genotype 6 is highly prevalent in Vietnam and the high prevalence in treatment naïve chronic HCV patients may results from poor spontaneous clearance of acute HCV infection with genotype 6.
Hepatitis C virus (HCV) infection is a major public health threat, and the Global Health Sector Strategy (GHSS) on viral hepatitis 2016–2021 calls for the elimination of viral hepatitis, reducing new infections by 90% and mortality by 65% by 2030 . The World Health Organization (WHO) estimates that approximately 71 million people are suffering from chronic HCV infection globally, and annually 700,000 people die from HCV-related complications, including liver cirrhosis and hepatocellular carcinoma (HCC) . African continent have highest HCV disease burden followed by Asia (2.8% and 2.7% seroprevalence respectively) . One fifth of the global HCV burden (14/71 million) is in Western Pacific Region which includes Vietnam . HCV transmission results from direct exposure to contaminated blood and is associated with injectable drug use (IDU), iatrogenic exposure (blood transfusion, surgical and dental procedures, dialysis, acupuncture, needle stick injury, and use of unsterilized needles), body piercing and less frequently, through vertical transmission and high risk sexual behavior [3, 4]. Acute HCV infection is infrequently diagnosed as the majority of acutely infected individuals are asymptomatic . After acute infection, approximately 75–85% of patients do not clear the virus by six months and develop chronic HCV infection . Progression to chronic HCV infection depends on several factors, including the age at the time of infection, gender, ethnicity, host genetic factors, immune status, development of jaundice during acute infection and viral genotype and subtype . It is estimated that chronic HCV infection accounts for 20% of HCC globally . HCV related HCC is more prevalent in countries where HCC prevalence is low (Western Europe and North America) or intermediate (Japan, Italy and Spain) [7–10].
HCV pathogenesis depends on host and viral factors including host genetics, the genotype and subtypes of the infecting viral strain . The prevalence of HCV genotype among IDUs, dialysis and multi-transfusion and HIV patients have been reported earlier; however, data on HCV genotype among the general population and especially in acute HCV infection are lacking in Vietnam [22, 35–42]. By collating data from four hospital based studies in Vietnam to identify the prevalence HCV genotype and to examine the geographic distribution of genotypes, we identified a high genetic diversity in HCV, illustrating a polyphyletic nature of the HCV epidemic in Vietnam. Genotype 1 was predominant, with nearly half of the acute and chronic HCV mono-infection and three fourth of the HIV-HCV coinfection groups. This is consistent with earlier studies in Vietnam, one of which documented a high (60.0%) prevalence of genotype 1 in IDUs . HIV-HCV coinfected patients had the highest prevalence of subtype 1a (43.8% compared to 20.5% in acute and 25.9% in HCV monoinfected patients. Subtype 1a has been shown to be common in male with high risk behaviors in Europe and America, e.g. IDUs, men who have sex with men (MSM), and is more commonly transmitted through IDU [36, 43–45]. It is likely that HCV subtype 1a is being efficiently circulated through IDU as a shared risk behavior for both HIV and HCV transmission. In HIV-infected individuals, spontaneous clearance of acute HCV infection is rare; therefore it is likely that most of the HIV-HCV coinfection patients in our study were infected with HCV genotype 1, which was not subsequently cleared . Subtype 1b was predominant in acutely infected patients in our study (28.9%; 93/328). Subtype 1b is also the predominant subtype in Vietnam’s neighboring countries, accounting for 66% of HCV infection in China, 64.4% in Japan, and 66% in South Korea [46–48], and is also a major subtype in Europe . HCV subtype 1b has been shown in the 1990s to be associated with blood transfusion and unsafe medical injections . It might be possible that genotype 1b has introduced to Vietnam from neighboring countries and subsequently spread in the country via transfusion or unsafe medical practices or population movement.