Early years of hepatitis C virus infection
The history of the hepatitis C virus (HCV) is a strong example of a bench-to-bedside approach illustrating how basic scientific knowledge is applied to patient care.
Following the discovery of hepatitis B virus (HBV) in 1965, and hepatitis A virus (HAV) in 1973, a clinical entity known as post-transfusion non-A non-B (NANB) hepatitis became more evident. This was regardless of the banning of commercial blood donations systems, and the implementation of HAV and HBV blood testing in 1975[3,4]. Furthermore in 1989, after years of intensive research, a scientific breakthrough discovered another virus consisting of a single positive strand of RNA, the HCV, classified in the Flaviridae family. HCV was determined to be the causing agent of the post-transfusion NANB hepatitis[4,5].
In 1992, following the cloning of HCV, an evolving series of sensitive and specific anti-HCV antibody immunoassays were developed which allowed for the mandatory testing of blood collections in the United States. Subsequently, third-generation immunoassays and RNA-HCV nucleic acid amplification tests improved the diagnostics of HCV for blood transfusion safety. During the 90’s, the HCV genotypes and subtypes, as well as their heterogeneous geographic distribution became apparent through basic research and molecular epidemiology. Additionally in the United States, blood transfusions, injection drug use (IDU) and several medical procedures were identified as high-risk factors.
During the 90’s but before 2011, the first antivirals to be marketed were standard interferon, followed by pegylated-interferon which was later combined with ribavirin. Unfortunately, these antivirals achieved a low-level of sustained viral response (SVR) among patients with HCV genotype 1 compared to other genotypes. However after 2011, the first and second generation direct-acting antivirals based on targeting the specific molecules of the HCV life cycle have proven more efficient regardless of genotype reaching an SVR in more than 90% or 95% of the patients who receive treatment.
In recent years, DNA sequencing and bioinformatics of HCV strains worldwide have allowed the evolutionary analysis and molecular tracing of the HCV epidemic across countries, mainly focusing on genotype 1a and 1b. These studies have documented the prevalence of HCV in Japan since 1920, in Europe since 1940 and the United States since 1960[11,12]. Further studies have confirmed that the introduction of HCV in the United States may have occurred even earlier (in the 1950’s) and is related to the use of contaminated blood obtained from commercial blood donors and the return of World War II soldiers. These reasons, along with the fact that hepatitis C is a stealthy virus causing injury to the liver in a silent manner, people who were born from 1945-1965 are currently in the target population of the “baby boomers” screening campaign for HCV in the United States.
Transmission of HCV infection in Latin America
Mexico’s geographic location serves as a common pathway of intracontinental migration between the United States and other countries of LA. Thus, HCV could have spread from the United States to this region. However in LA, awareness of an NANB hepatitis did not intensify until the late 1970s and early 1980s. During this period, the United States veterans returning from Vietnam, as well as the migration of Latin Americans to their homeland as retirees or by multiple processes of deportation and migration between countries became a major social-demographic phenomenon.
The first HCV epidemic outbreak was associated with the emergence of HIV in the mid-1980s, at a time where the presence of paid blood donors was a common situation. This parenteral route of transmission may have been the primary source of dispersion in Central and South America since IDU, during those decades, was very rare in LA. Furthermore, even though in the United States mandatory screening of blood-borne viruses had been implemented in 1992, it was not fully established in Mexico and LA until 1996[18,19]. This information indicates that even before 2000, blood donations contaminated with HCV were still a relevant risk factor. Moreover, an additional route of HCV infection in the LA may have been the indiscriminate use of caesarean births and other medical procedures that took place during the same period. Brazil and Mexico are the two countries with the highest rates of cesarean sections within the Americas. This could explain why Mexico has a female-to-male ratio of 2:1 of HCV infection.
Although partial reports were stating the frequency of HCV in countries of LA during the 1990s, it was not until after 2000 that HCV-related liver cirrhosis began to rise. In Mexico, this disease entity represents over 12 deaths per 100000 inhabitants and the estimated number of people infected with HCV may range from 1.5 to 2 million[24-26], and at least ten million in LA[26-28]. In this region the route of transmission of HCV may have been similar as it was in Mexico, taking into account that as of 2000 the use of IDU, as well as tattooing and piercing, had increased from that year forward.
HCV TREATMENT IN LATIN AMERICA
HCV infection can only be prevented by evading or eradicating the virus. To achieve eradication, treatment with highly effective drugs to all who are infected is required. Currently with the introduction of the new, but very costly, direct-acting antivirals (DAAs) an enormous feeling of success is felt. This elation may be comprehensible for the developed countries, but it may not be true for many developing countries worldwide[29-32], including those in LA[33-37].
However, there are two sides to this story. On one hand, the feasibility of eradicating HCV is closer than ever due to new treatments; yet, on the other hand, neither the authorities nor the physicians, recognize that many infected patients are the result of an iatrogenic spread of HCV. More than 95% of patients infected with viral hepatitis belong to a lower social class in their respective countries, and they can not afford to pay the current market prices of these new antiviral drugs.
Additionally, a significant challenge for the eradication of HCV is that there is more than one genotype of the human virus. There are seven genotypes and multiple subtypes, which have infected populations with heterogeneous genetic makeups worldwide. This point indicates that research data on HCV needs to be population-based, especially in LA. Further studies are required to identify the genotypes that circulate[41,42], the main risk factors[17,20,21] and the immunogenetic background of the population[43-45].
To date, less than 2% of the people infected with HCV have been treated with the standard pegylated-interferon/ribavirin therapy. The new DAAs, such as boceprevir, telaprevir, simeprevir, and sofosbuvir have been slowly licensed in a limited number of countries in LA. Moreover, HCV treatments are based on the United States and European guidelines which provide evidence of the SVR obtained in clinical trials carried out in populations other than LA.
Thus, under these circumstances who will have access to treatment in Latin America? A substantial body of literature has documented the multiple barriers to health care in HCV-infected patients[46-49]. Although crucial, they are not within the scope of this editorial. Alternatively, we address several issues regarding the health authorities, the medical community, and the pharmaceutical industry. These are key players involved in the prevention, diagnosis, and treatment of this disease.
The health officials have not considered viral hepatitis to be a severe health problem, which in turn has manifested ignorance or reluctance towards a state program of detection or treatment of this disease. Consequently, there are a limited number of up-to-date population-based epidemiological studies of viral hepatitis in most LA countries[35,36] sponsored by the government. The few that do exist are accomplished by the attention and personal interest of researchers, rather than the concern of the health authorities. This lack of concern from the health authorities translates into key factors and information being overlooked. Some of these factors include; lack of precision of who and how many people are infected, primary risk factors involved, transition in genotypes and co-morbidities (obesity, diabetes, alcoholism, co-infection with HVB and HIV). Furthermore, these epidemiological studies need to be documented in the population of LA because most clinicians assume that the same SVR achieved in Caucasians will replicate in people from this region.
In LA, including Mexico, most medical societies involved in the study of the liver have a limited number of members with a solid scientific career, based on their poor scientific productivity in indexed and high impact factor journals in their dedicated fields[52,53]. These society members are hosted by the pharmaceutical companies to attend international forums. In turn, they are the only speakers that echo their experience at the liver meetings to their fellows but do not contribute with scientific data or share their clinical experience. This circumstance has led to the situation that some members only intend to be their society’s President (or Chairperson) without the actual contribution of new knowledge in their field of expertise. Moreover, it is precisely these “leaders of the field” who take part, on multiple occasions, as representatives of the health authority, sometimes playing a dual role as clinician and politician.
Therefore, when the support of the medical community is required to establish health policies that have an impact on vulnerable social groups, the members are left without a voice, and vote, on these issues. Consequently, the decisions are made in an unipersonal manner. Furthermore, if the clinician-politician now has a position within the health institutions or the government, he/she may now have a conflict of interest with his/her private practice.
Unfortunately, the lack of an official standpoint in many educational or health institutions to promote a high standard of scientific and academic quality is a serious weakness. This challenge, paired together with a high level of corruption and preferential treatment that prevails among some government authorities, makes it tough to provide treatment for this virus. This situation has created elitist groups of treating physicians being sponsored by the pharmaceutical industry. These doctors may be knowledgeable, however, in some cases, this information does not necessarily apply to their respective countries or communities.
Furthermore, many of these physicians focus on his/her private practice and have negligible interest in understanding the reality of the disease in their community or country of origin. A reminder of the Hippocratic Oath is “We as doctors should seek the best benefit for the patients, including those who do not have access to treatment“.
Likewise, in the majority of LA countries, there are no specialists in hepatology. Patients living with liver diseases are treated mainly by a gastroenterologist or internist. However, with the introduction of the new effective antivirals, and the possibility of the pharmaceutical industry involvement, medical specialists from different fields now claim the liver-diseased patient. Thus, a specialty or subspecialty in hepatology supported by academic institutions should be established as soon as possible.
The pharmaceutical industry has declared a responsibility to eradicate HCV by creating agreements based on the economy of each country for the marketing of the antiviral drugs. In general, the standard procedure for the pricing of these drugs is to achieve a full refund of the R and D investment in the developed countries, intermediate reimbursement in the middle-income countries, and the possibility to offer a generic product at a lower and accessible cost for the low-income countries (defined as a win-win situation).
Unfortunately, there are still some well-known challenges to overcome in many developing countries, such as corruption and slow bureaucracy to introduce these drugs. Additionally, the lack of precise epidemiological information about HCV infection is an ongoing difficulty.
Another obstacle is performing the diagnostic tests. Each patient should be evaluated before treatment because not all patients that are positive for anti-HCV antibodies have detectable viral loads or have a similar grade of liver damage. Thus, a pretreatment algorithm including initial and follow-up viral loads, genotyping and identification of possible resistance mutations, and staging of liver damage (fibrosis/cirrhosis) should be considered. A conservative estimate of the costs of these tests may exceed up to $2000 to $4000 United States dollars before paying at least $10000 to $80000 United States dollars for a three-month period of treatment. If the patient is a potential non-responder or present with advanced liver damage, this cost may rise even higher.
Considering these conditions several options have been proposed, such as the establishment of non-profit societies that aid in the funding of these high costs for the poor. This creates a risky situation, given the lack of transparency and poor attitudes of some key players previously mentioned, there is a chance that these “non-profit” organizations may end up as personal or family businesses, or in the hand of small groups who are in power.
Nevertheless, with the justification of “supporting updated scientific medical education”, the pharmaceutical companies focus mainly on the treating physicians (clinicians) by selecting medical “leaders”, doctors who have influence among the medical groups or societies, or are representatives of health institutions. Whereas, the few scholars or scientists who are knowledgeable in the field of viral hepatitis are not considered under the argument that they are not clinicians or do not treat patients.
This situation leads to the lost opportunity to be supported by the pharmaceutical industry. Thus, in the absence of proposals and sanitary laws, the pharmaceutical industry is interested in selling their drug; but the academic or research sector in the developing countries do not fall within their scope.
HCV infection imposes a large challenge in the world, and it certainly will be eradicated faster in some regions than others. In low- and medium-income countries of LA the health problem of HCV may not depend entirely on money, other nations with fewer resources are proactively establishing public-private partnerships to lower the cost of the DDAs (e.g., Egypt). Hopefully, these strategies will close the gap between the number of patients who are infected (diagnosed) versus those who are treated.
The advancement of scientific knowledge and its impact on health are correlated with the progressive changes in the attitude and behavior of key players and others responsible. The increase in knowledge should benefit all people irrespective of their socio-economic status. To achieve such impact, and to reach all those who need an efficient antiviral therapy, this change in attitude needs to become a reality.
Where and how to start to face this critical situation in Latin America? One recommendation is that both politicians and authorities must consider viral hepatitis as a health problem in their respective region, and establish support strategies to investigate the burden of HCV infection. It is no longer safe to assume that any health issue can be resolved without recognizing the magnitude of the situation.
In the medical communities, a good start would be to establish a partnership between the academic sector, researchers, and physicians, instead of independently acting on their own. This collaborative shift could strengthen the figure of the MD/PhD in each medical society. This may be achieved if alongside, the academic institutions in LA make every effort towards higher standards of education and professionalism. This would greatly strengthen the quality of the medical associations with academic leaders that contribute with knowledge publishable in indexed international journals. In countries such as Spain and Brasil, the use of the h-index (Hirsch-index) has been considered to grant membership to their respective National Academy of Medicine.
Another important change would be to educate the younger generations that the purpose of belonging to a medical society is not only to be their president or chairperson. As mentioned above, the ultimate goals are to provide prestige and effectiveness by contributing to new knowledge about their country or city in matters of health. The higher income groups require treatments, however, so does the general population. If we reconsider and always remember the Hippocratic Oath, this will help to reflect and advance the field quickly to achieve these goals.
To conclude, the disclosure of the clinicians (speakers), in regards to their sponsorship by the pharmaceutical industry, should be regulated by law and enforced by an ethical practice. Likewise, academics, scientists, medical practitioners and the pharmaceutical companies should equally engage and commit to solving the problem of HCV infection in this region of the world. Moreover, grants given by the pharmaceutical industry in LA to support research in liver disease would be extremely beneficial. These are recommendations that need to be heavily considered by all key players.