Viral hepatitis is a serious worldwide health problem that recently has acquired major awareness and relevance, given the enactment of the World Health Organization (WHO) elimination strategies [1]. The global disease burden in 2015 was ∼500 million people infected with hepatitis B and C viruses, of which ∼400,000 succumb due to clinical complications, such as liver cirrhosis (LC) and hepatocellular carcinoma (HCC) [1]. There is currently no vaccine against HCV. While 25% of acutely infected people can achieve spontaneous viral clearance, most of them become chronically infected, a condition that affects 71 million people [1], who are predisposed during their lifetime to develop LC and HCC [2,3]. For these reasons, the WHO’s “Global Health Sector Strategy on Viral Hepatitis 2016–2021” aims to reduce mortality and incidence by 65% and 90%, respectively, by 2030 [4]. This goal is promising due to the advent of the highly effective direct-acting antivirals (DAAs). However, there are several caveats which concern the implementation of elimination strategies against HCV infection. Mainly, the approach may not be the same for all regions due to epidemiological differences in the prevalence of HCV positivity, active infection, rates of advanced disease, and hepatitis C-related mortality [5]. Across the WHO’s regions, chronic infection prevalence is highest in the Eastern Mediterranean and European areas with 2.3% and 1.5%, respectively, whereas the Region of the Americas documents 1.0% [1]. Furthermore, the HCV (family Flaviviridae, genus Hepacivirus) is a positive-sense, single-stranded RNA divided into seven genotypes (GTs), each with multiple subtypes (a, b, c, and so forth) showing regional distribution [6,7]. HCV GTs1–3 are worldwide; GT4 circulates in both the Middle East and Africa, whereas GT5 prevails mainly in Africa; GT6 prevails in Asia; GT7 is very uncommon and has been reported only in people with epidemiological links to central Africa [8,9].

Since the introduction of the new pan-genotypic DAAs, pharmaceutical companies have promoted among the medical community the no need for pre-treatment genotyping [10]. However, during the active infection stage, some HCV genotypes indirectly exert more liver damage than others. HCC may occur even after a sustained viral response has been achieved [11]. Furthermore, naturally occurring or drug resistance-associated substitutions (RAS) in the NS3, NS5A, NS5B viral protein regions have been documented [12]. Therefore, molecular analysis is still relevant for evolutionary purposes, detecting nucleotide genetic variations, and epidemiological transmission linkage [13].

Ideally, all eligible patients should have access to antiviral therapy with DAAs. However, among the developing countries of Latin America, including Mexico, the accessibility of these highly effective drugs is still an important limitation for most patients, which may increase the mortality of HCV-related liver disease [14]. In Mexico, the HCV prevalence rates of 1.2% and 1.4% among the general population were reported by us in previous systematic reviews, respectively [15,16]. However, higher rates of 2.0% and 1.5% correspondingly have been documented in North and South Mexico [17]. These differences may relate to specific high-risk groups and their putative transmission routes or factors related to diagnostic sensitivity and pro-active screening. Notably, they represent flag alarms that need to be acted upon by designing elimination strategies. This reality and the lack of a real national consensus plan to fight against viral hepatitis may hinder any intended elimination strategy [18]. Therefore, as part of a joint effort between hepatitis research groups, we aimed to provide an updated comprehensive review of the epidemiological data of incidence, prevalence, genotype distribution, and risk factors of HCV infection in Mexico to work towards building a national elimination strategy.

This study presents a comprehensive update of HCV infection epidemiology in Mexico for more than a decade (2008–2019), including incidence, prevalence, genotype distribution, and risk factors of transmission. These data are relevant to address the need for a national elimination strategy against HCV among targeted populations based on current evidence.

The national states with the highest incidence of HCV infection outside of Ciudad de Mexico (Mexico City) were Baja California Norte, Chihuahua, Tamaulipas, and Sonora located on the Mexico-United States border. Next were Jalisco and Sinaloa on the West Coast, Veracruz on the East Coast, and adjacent to Mexico City are Estado de Mexico and Puebla. The high incidence of HCV infection among the four northern states may be related to the migration dynamics in several border cities, especially Tijuana, Ciudad Juarez, Nogales, Matamoros, and Mexicali have a high rate of people crossing in both directions [65]. These cities are also hotspots for drug trafficking and illicit drug injection (‘picaderos’) with cocaine, heroin, and amphetamines [66,67].

Likewise, the metropolitan cities within the non-border states are densely populated, highly attractive to international tourism. Unfortunately, they are also exposed to drug trafficking and injection and non-injection drug abuse. This fact agrees with the finding of several studies reporting HCV prevalence related to prison inmates and injection drug users among these States [40–44,64]. In contrast, the remaining 22 States lacked significant research on HCV’s epidemiology in several risk groups. Therefore, besides considering that sub-registration may be more common than expected, further studies are required in each State based on prediction modeling of new cases to establish tailored prevention strategies in specific risk groups.

Furthermore, HCV infection continues affecting male and female adults between the ages of 40 and 60, as reported previously [68]. However, HCV infection incidence increased during the study period in men with an M/F ratio of 1.73:1 in 2019. It peaked at an incidence rate of 5.22 cases per 105 inhabitants, similar to women at least one decade earlier. This fact places men at risk for chronic liver disease at relatively earlier stages of life. Despite an overall significant decrease in women, the incidence rate increased by age groups and up to >60, presenting the highest rate. This finding agrees with earlier studies that attributed iatrogenic HCV acquisition by contaminated blood products (blood transfusion before 1993) or obstetric surgeries [15,69,70]. Therefore, because the infection rate’s tendency has not declined during the study period, strategies of screening measures and early detection of liver disease by gender and age groups are warranted [71].

Next are the results of the systematic review/meta-analysis of the prevalence data among LR-Gs (overall WMP = 1.48%) and HR-Gs (overall WMP = 37.06%). Firstly, there was a notable contrast between the lowest PP of the LR-Gs and the highest PP in HR-Gs (0.64% in blood donors vs. 84.25% among drug users). Overall, blood donors were the most studied group, whereas, in the HR-Gs, prison inmates, injection drug abusers, and dialyzed patients were the most affected subgroups.

Among the LR-Gs, blood donors revealed a WMP of 0.774%, similar to data previously reported in the reviews 1999–2008 (<1%) [15,16], suggesting that the transmission of HCV in this group continues at a steady rate. Interestingly, unlike the previous reviews, a high WMP prevalence (2.57%) was found in hospital out-patients who are asymptomatic individuals compared to blood donors and those belonging to the general population (1.35%). This increased WMP rate may be related to the incremented incidence mentioned above, revealing that these subgroups may reflect HCV infection’s real situation among the Mexican population due to the selection bias among blood donors. Additionally, this group of hospital out-patients attending medical clinics called our attention due to the coincidence with the age group where more HCV infection (50–64 years) occurred.

Among the HR-Gs, the broader range of WMP from 0.67% in the people with risk of STIs to 39.6% in prison inmates was notable. In conjunction, prison inmates and drug abusers had the highest prevalence reflecting the situation explained before among the states with the highest incidences since drug trafficking, drug abuse, and incarceration go hand in hand [64,72]. Besides drug traffic control, more needle/syringe exchange programs, which are confronted locally and globally with significant challenges, are urgently needed throughout Mexico to reduce HCV harm and other blood-borne pathogens among people who inject drugs (PWID) [73,74]. Lastly, studies conducted in dialyzed patients, sex workers, and HIV patients were found in a lesser proportion, despite that these groups are highly exposed to co-infections with HCV and hepatitis B [75].

In the past, it was acknowledged that distinct HCV GTs have different clinical outcomes [76]. In this study, 15 studies analyzed the distribution and frequency of the HCV GTs. As in previous studies, HCV GT1 continued predominantly in blood donors, patients with a history of surgery, and tattoos [77]. However, in this study, one crucial difference was the emergence of GT3 in the North and Center-West region associated with HCV transmission utilizing injection drug abuse [56,78]. Additionally, two novel GT4 and GT5 considered non-endemic were reported in the East/Center/West regions of Mexico [56] and both are known to prevail mainly in the Eastern Hemisphere. Likewise, changes in the distribution of prominent HCV subtypes and the emergence of new subtypes was observed. Such is the case of the appearance of first-reported Mexican strains of GT2 subtypes j, k, and r, which have been detected abroad [79]. The appearance of these GTs may result from higher temporal or permanent human migration combined with the use of more sensitive DNA sequencing methods rather than LIPA. However, a direct relationship between a specific GT and a risk group was not found. Therefore, the lessons learned by molecular epidemiology studies show that the introduction of novel non-endemic GTs or subtypes is occurring. Further studies are necessary to decipher whether they are undergoing evolutionary changes that may lead to RAS despite the over announced promise of a pan-genotypic antiviral treatment and future elimination of HCV,

Regarding risk factors associated with HCV infection, in the present study, despite the decreasing trend of incidence in women and fewer reports of transfusions before 1994, the rate of women diagnosed at age 60–64 years remains high. Likewise, the number of new cases in the younger groups was lower, which could be related to new blood security measures after 1994. However, tattooing and piercing in this group may cause a higher incidence shortly, as described in the revision of RFs. On the other hand, in the HR-G of incarcerated people, the increment of HCV infection may be related to the clustering of risky behavior factors such as unsafe sexual practices, injection drug abuse, tattooing, and piercing before imprisonment or within the prison. Therefore, prevention measures considering proactive screening are urgently needed in these groups exposed to HCV infection and other blood-borne transmissible agents.

Several limitations and strengths were noted in this study. Firstly, a high heterogeneity attributed to study groups’ inherent diversity, study design, diagnostic techniques, sample size, and sampling methods was tackled by using WMP to compare frequencies. On the other hand, the increased amount of studies reporting GTs and RFs may be due to worldwide awareness of HCV infection. Nonetheless, the road to HCV elimination in Mexico requires further epidemiological research protocols improving the systematization of study designs, serological and molecular diagnostics, and registry of HCV transmission risk factors.

The study also revealed that the degree of liver damage was not accessed nor reported in most studies. However, it is known that the burden of HCV infection on liver health has changed over the years. In Mexico, liver cirrhosis (LC) is the fourth leading cause of death [80], and one decade ago, alcoholic liver disease (ALD) was the first etiology of LC [81]. Currently, HCV infection ranks almost equally with ALD as the leading cause of morbidity in liver-diseased patients, as shown in a retrospective national multicenter study reporting a mean prevalence of 36.2% of HCV among this group [80]. Knowing this data, it seems evident that caring for patients with an active infection will increase soon. However, more importantly, patients who achieve viral clearance therapeutically will require consecutive follow-ups to monitor post-infection liver disease [82]. Additionally, genetic factors and nutrition-driven metabolic abnormalities play an essential role in managing HCV infection that requires medical and nutritional supervision [83,84].

On revising HCV infection epidemiological data, it was noted that incidence data is not broken down by acute or chronic infection. Furthermore, the national registry of mortality due to LC or HCC revealed the lack of data regarding if any hepatotropic viruses were involved [85]. Therefore, it is not clear the fraction of deaths attributed to HCV. On the other hand, despite that in Mexico, hepatitis virus-related HCC incidence is considered the lowest worldwide [86,87], a rise in HCC in patients who achieved sustained viral response with DAAs has been alerted, indicating that post-infection monitoring is necessary [11]. Therefore, better death registries are warranted [1]. In conjunction, these limitations may constitute a drawback to obtain a complete scope of the impact of HCV infection in Mexico and to estimate the cost-benefits of how many lives are saved due to prevention and elimination strategies. Such an information gap can be reduced if research studies and surveys combined with institutional public health actions develop robust epidemiological registries and databases.

Additionally, the data presented herein justifies the need to renew medical training programs at all educational levels and clinical practice guidelines so that physicians and specialists achieve better diagnostic and management skills for HCV infection [88]. These actions should go along with a national campaign supported by the governmental health authorities to guarantee antiviral drugs and treatment to all eligible HCV-infected patients [89]. Moreover, acquisition of HCV infection, like any other blood-borne infectious diseases, is often linked to low socio-economic conditions, unsafe and iatrogenic circumstances, poor accessibility to social healthcare that makes people vulnerable. Therefore, the major pharmaceutical companies’ marketing policies need to consider these prevailing limitations that low and middle-income countries have to achieve the goal of HCV elimination in Latin America and beyond [5,14,18,90,91].

Building a national elimination strategy will require supporting harm reduction measures, implementing screening test programs in first contact hospital services for individuals within specific gender/age groups, those exposed to parenteral transmission, and those within the high-risk groups. Additionally, research in molecular epidemiology and continuing education courses for physicians and specialists is significantly essential. The development of integrative algorithms for clinical practice guidelines are needed to detect HCV infection in patients with obvious risk factors effectively, those with suspicion of occult hepatitis C infection [92] and those with other co-morbidities such as type 2 diabetes [93], rheumatic arthritis [94], or kidney disease. The use of big data technologies to build robust epidemiological databases is also warranted. Finally, government health authorities, the pharmaceutical industry, healthcare professionals, and NGOs need to construct an alliance to guarantee that all eligible HCV-infected patients receive opportunely antiviral medications.

This systematic review/meta-analysis reveals that HCV transmission continues and has increased over the last decade among both LR-Gs and HR-Gs. Novel GTs and subtypes have emerged as well as risky behavioral routes of transmission. A national elimination strategy will require preventive pro-active screening in designated risk groups, further research in molecular epidemiology, medical training, robust epidemiological databases, and antiviral treatment available to all eligible HCV-infected patients.

Conceptualization: SR, AP, GS-L; Methodology: MAM-R, MC-C, FS-J, AP, AJ-B, SL-M,SR; Acquisition of data: MAM-R, MC-C, DM-M, SL-M, SR; Formal analysis and investigation: VS-M, GS-L, FS-J, SL-M, AJ-B, AP, SR; Writing – original draft preparation: VS-M, GS-L, SL-M; Writing – review, critical feedback, and editing: VS-M, GS-L, SR, AP. All authors approved the final version of the manuscript for publication and agreed to be accountable for all aspects of the work.

This study was partly supported by the National Science and Technology Council of Mexico (CONACYT-Mexico) to AP [PN-2017-01-5254].

The authors have no conflicts of interest to declare.