Current challenges and possible solutions to improve access to care and treatment for hepatitis C infection in Vietnam: a systematic review

We searched PubMed-, MEDLINE- and Embase®-indexed articles for English-Vietnamese languages articles in June 2016, according to the PRISMA guidelines (Fig. 1) [13].

Databases were searched using a combination of the following MeSH terms and keywords, including (Hepatitis C virus OR HCV) AND Vietnam AND (Prevalence OR Epidemiology OR Surve* OR Seroprevalence) (OR hepatitis C). No date restriction was used although included articles/data were restricted to original research articles relating to hepatitis C infection and HCV in Vietnam only, and on those published in either English or Vietnamese. We further searched the clinical trials registry http:/ClinicalTrial.gov for treatment trials currently underway or completed in Vietnam using the search term “Hepatitis C” AND “Vietnam”.

After performing the literature searches, one author (AB) extracted and screened the titles and abstracts before selecting and reviewing the full-text articles. The following data were extracted from each article: first author’s name, publication year, country of origin, date of study, type of patient group, and additional details of epidemiology, seroprevalence, HCV RNA positivity figures, treatment availability etc.

A total of 99 abstracts for manuscripts published between September 1990 and June 2016 were identified. Of these, 42 contained information relevant for our review and full texts were retrieved [11, 14‐60] (Table 1 and Fig. 1). The majority of publications (73.8%, 31/42) assessed the prevalence of HCV infection specifically in high-risk groups, including HIV infected patients, injecting drug users (IDU), community sex workers (CSW), men that have sex with men (MSM) and renal haemodialysis patients [11, 17, 21‐23, 25, 26, 28, 29, 31, 32, 34, 36, 37, 39, 41‐47, 51‐53, 55‐60] (Table 1). Online search for Vietnamese articles retrieved one research publication and four Standard Operating Procedures (SOPs); only the Vietnamese research paper retrieved from a Vietnamese journal was included in this analysis [38].

Twenty one percent (9/42) of the publications reported data from Ho Chi Minh City (HCMC) or from the southern Vietnam region (Table 1), while 52.3% (22/42) reported studies conducted in the north of the country, principally in Hanoi and surrounding provinces [18, 22, 27, 32, 36, 47, 49, 52, 53] (Table 1). Eight of forty two retrieved publications characterized the diversity of HCV genotypes in Vietnam [14, 16, 21, 33, 34, 48, 50, 51] (Table 1). Two manuscripts were reviews assessing risk factors associated with HCV acquisition in Vietnam [11, 24]. One article, retrieved from a Vietnamese website assessed the prevalence of HCV in the Vietnamese ethnic minority [38].

Nine clinical trials were found registered with ClinicalTrials.com (see Table 2). Five out of nine were completed but no results have been published to-date, two are completed with results available, one is active but no recruiting, while one is actively recruiting (Fig. 1). Only the two clinical trials that had published results were included in the review, the remaining seven studies have been excluded.

In Vietnam, the background prevalence of HCV infection in the general population, at least historically, appears to vary depending on the region studied. In 1994 it was estimated that the seroprevalence in individuals without liver disease was 9% (43/491; 95% CI, 6.4%–11.5%) and 4% (18/511; 95% CI, 2.3%–5.6%) in HCMC and Hanoi, respectively [53] (Fig. 2). By 1998 it was estimated that in HCMC, the HCV seroprevalence in patients with underlying liver disease was 23% (69/289; 95% CI, 18.1%–27.8%) and in this population, HCV RNA was detectable in blood of 61% (42/69; 95% CI, 49.4%–72.5%) of the individuals [47]. This same study reported an HCV seroprevalence in healthy individuals in Da Lat (in the Southern Highlands) of 1% (9/890; 95% CI, 0.9%–1.0%); HCV RNA was detected in 44% (4/9) of these individuals [47]. Four years later in 2002, HCV RNA detection in HCMC was estimated to be 2% (2/100; 95% CI, 1.3%–5.3%) in apparently healthy individuals and 33% (45/234; 95% CI, 27.0%–39.0%) in patients with liver disease [15]. In Binh Thuan province (212 km northeast of HCMC) HCV seroprevalence in the general population between 2005 and 2007 was estimated to be 3.3% (17/509; 95% CI, 1.7%–4.8%); the male population exhibited a higher burden of seropositive samples (3.3%) than women (1.8%), and HCV RNA was detected in 52.9% (9/17) of the identified anti-HCV positive individuals (Fig. 2) [30]. Furthermore, one article was retrieved from a Vietnamese journal. The original manuscript was in Vietnamese and only the abstract was translated in English. The manuscript assessed the seroprevalence of HCV in the Vietnamese ethnic minority in the north of Vietnam and the detected seroprevalence in 1305 individuals was 1.22% (95% CI, 0.6%–1.7%) in 2011 [38].

The majority of the remaining publications evaluated HCV prevalence in specific high-risk groups (Table 1). These data estimated that 89% (1255/1434; 95% CI, 87.3%–90.6%) of IDU in Nguyen province (Northern Vietnam) were HCV RNA positive between 2005 and 2007 and 35% (502/1434; 95% CI, 32.5%-37.4) were HIV/HCV co-infected [29]. Similar figures were reported in Hai Phong province (northern Vietnam) in 2014 (Fig. 2), where the prevalence of HCV in HIV-infected individual was 89.4% (93/104; 95% CI, 82.1%–96.6%). This study also reported that the majority of HCV cases presented with clinical features of advanced liver fibrosis and cirrhosis [26].

Between 2005 and 2012, several studies were conducted around Vietnam (including HCMC, Hanoi, Hai Phong Province, Da Nang, Khanh Hoa Province and Can Tho), which aimed to determine HCV seroprevalence in patients undergoing renal haemodialysis or receiving multiple blood transfusions [23, 37]. These six hospital-based studies found an apparent iatrogenic HCV seroprevalence of 26% (n = 153/575; 95% CI, 22.4%–29.5%) and was similar at all sites assessed.

In 2010, a study estimated the prevalence of HCV infection in MSM in the south of Vietnam (Can Tho and HCMC) and in the north of Vietnam (Hai Phong Province and Hanoi) [25]. The overall seroprevalence of infection in 1588 male participants was 28.4% (95% CI, 26.1%–30.6%) [25]; 29% of the individuals were co-infected with HIV and more northerly regions observed a higher HCV and HCV/HIV co-infection prevalence [25]. A single publication from 1997 assessed the frequency of HCV infection in patients with chronic hepatitis in HCMC, and concluded that HCV was the underlying etiology in 19–27% of chronic hepatitis cases [19]. However, no indication of the sample size used to derive this estimate was provided.

A study conducted in four major conurbations in Vietnam – Hanoi, Hai Phong Province, Da Nang, Khanh Hoa Province and Can Tho, identified HCV genotypes 1, 6, 3 and 2 in 59.9% (n = 169), 37.9% (n = 107), 1.8% (n = 5) and 0.4% (n = 1) of samples collected from mixed healthy and high-risk populations, respectively [37]. While genotype 1 was the most prevalent HCV genotype in all four areas, the genotype distribution ranged from 47% in Khanh Hoa Province to 81% in Da Nang [37]. These four genotypes (1–3, 6, and) were identified in dialysis and multi-transfused individuals with nine recognized subtypes (1a, 1b, 2a, 3a, 3b, 6a, 6e, 6 h, 6 l) [39]. A further study similarly identified HCV genotype 1 as the predominant virus circulating in MSM in Hanoi, Hai Phong Province, HCMC and Can Tho [25]. Additionally, plasma samples from 97 HCV infected individuals were molecularly characterized between 2003 and 2010 in HCMC. The RNA sequences obtained from these samples suggested that genotypes 1b and 2a were imported from East Asia, 1a from the United States, 2i, 2j and 2 m imported from France [33, 58]. They also identified an additional 4 subtypes of genotype 6 (6a, 6ax, 6xb and 6xc) with no obvious international link [34].

Of the nine trials registered on ClinicalTrials.gov , only two had published results available at time of review [61, 62]. Both studies were sponsored by Debiopharm International SA and neither the source country information nor the locations where trial participant recruitment was performed within the country have been specified. Both studies were multicenter international trials to assess the treatment responses (SVR to single agent or combination treatment) to the synthetic cyclosporine-like agent, Alisporivir, a novel host-targeting antiviral (HTA) agent [61, 62].

In addition to assessing the burden of HCV disease, further data is required regarding HCV genotype, viral mutations and viral loads in HCV infected patients in order to assess how to implement the recent HCV treatment guidance, and to estimate the cost-benefit of an integrated HCV control program.

While currently available data are limited, they imply a broad genetic diversity within circulating HCV strains in all parts of the country [33, 34, 37, 39, 58]. More detailed phylogenetic approaches have proposed that the HCV population has been influenced by the international turmoil of the past, with importation of genotypes that are more typically associated with North America, Europe and other parts of Asia [34]. This genetic variation can also be observed in high-risk groups, meaning that the formation of a local treatment policy may be more complex than in other locations. For example, the distribution of HCV genotype in haemodialysis patients is variable according to the geographical region, this may be due to a lack of infection control and or point source outbreaks [37]. This genotype distribution is in contrast to other countries in Asia, such as China, where hemodialysis patients are predominantly affected by genotype 2 HCV [71, 72]. An improved understanding of the genotype distribution and frequency of viral treatment mutations among Vietnamese patients will facilitate the development of appropriate local guidelines.

Early diagnosis and access to treatment are essential components for an effective HCV control program in Vietnam. As in most LMICs, current treatment for HCV infection in Vietnam is limited to interferon-based (IFN-gamma and pegylated-IFN) therapy [10]. More recently, some patients have been treated with newer DAA agents at the Hospital for Tropical Diseases (HTD) in HCMC, where more than 18,000 patients with viral hepatitis are assessed each year. Further clinical treatment studies have received funding and are planned to commence in the near future [73].

The more widespread introduction of the DAAs is hindered by a lack of data regarding HCV genotype distribution and viral treatment mutations [74]. This lack of data is especially problematic for the early detection of treatment resistance mutations, which occurred previously with hepatitis B treatment and HCV treatment in Japan and North America [75‐77]. Furthermore, the efficacy of DAAs against some of the less common genotypes, such as genotype 6 which was frequently identified in previously studies, is not well established [78].

Other barriers to increasing the utilization of HCV treatment in resource-limited settings such as Vietnam include high costs, a perceived complexity in treatment regimes and bureaucratic support for importation, licensing and distribution of medicines for which specific clinical trial data in the local populations is lacking. Vietnam is a rapidly developing country, whose GDP per-capita has increased from $1095 to $1684 from 2004 until 2014 [79]. However, the per capita income remains low (~ $1024) [80] with limited annual spending on healthcare (according to WHO, approximately $264 in 2006) [80]. A large proportion of people in Vietnam do not invest in health insurance and even those who do may not have full coverage to expensive treatment courses: pegylated-interferon courses are reimbursed at 30% ($10,000–18,000 for a 48 week treatmentcourse), and this partial reimbursement is based on doctor opinion only, with no allowance given for those in high-risk populations such as haemodialysis patients [81, 82].

While the treatment of HCV infection requires prescription from a medical practitioner, a further concern is the non-completion of treatment courses due to high costs and changes in family/patient financial circumstances. Some patients may also travel to other countries in the region where medications, which may be substandard, might be more affordable. Incomplete or inadequate treatment courses are likely to lead to increased rates of viral resistance, which has been previously widely observed in hepatitis B treatment programs in Vietnam [83, 84]. Further, PEG + INF + RBV remains (as 2016) the first line of therapy for chronic patients in many part of Asia, Vietnam included [85].

The majority of the studies included here had small sample sizes and concentrated on groups of individuals at known high-risk of acquiring HCV infection thus risking an overestimation bias. Given the heterogeneity of the study populations sampled, in addition to the broad time period and diverse geographic locations described, more accurate meta-analysis is not currently feasible. Thus, a considerable knowledge gap remains regarding the likely true burden of chronic HCV infection in the general, healthy adult Vietnamese population.