Keywords
hepatitis C virus - chronic hepatitis C - prevalence - access to treatment - resource-limited
countries - direct-acting antivirals
Hepatitis C virus (HCV) infection is prevalent in every country where it has been
sought making it a global health problem with an estimated prevalence of over 184
million people worldwide.[1] However, the prevalence rates of infection are highly heterogeneous with a disproportionate
burden of infection in countries with limited health care resources. In addition to
heterogeneity in the prevalence of infection there is also heterogeneity in the distribution
of viral genotypes; in most developed countries genotypes 1 and 3 dominate whereas
genotypes 4, 5, and 6 are more common in countries with limited healthcare resources.[2]
Over the past 15 years HCV genotype 1 has been regarded as the most difficult to treat,
requiring 48 weeks of pegylated interferon and ribavirin (PegIFN/RBV) and achieving
sustained virological response (SVR) rates of only 45%. However, the development of
new direct-acting antivirals (DAAs) which are frequently targeted at genotype 1 have
made this genotype easier to treat. New IFN-free DAA combinations have also significantly
improved SVR rates in HCV genotype 2 and 4 infected patients. However, results are
still unsatisfactory in genotype 3 and data in genotypes 5 and 6 are limited.
There are important differences in the dominant routes of transmission between geographical
regions with intravenous drug use being the most common route of transmission in Europe,
North America, and Australasia and iatrogenic transmission being more important in
most resource-limited settings.[3] Preventive strategies are essential to the control of the HCV epidemic, but the
variation in routes of transmission will require a tailored approach to infection
control according to the local population needs. The priority in resource-limited
countries will be control of transmission in health care facilities whereas the priority
in affluent countries will be the interruption of transmission among people who inject
drugs (PWID).
Although there is significant variation between countries in the routes of transmission,
prevalence and burden of disease there is consistency in resource-limited settings
for the poor access to treatment.
Prevalence and Burden of Disease
Prevalence and Burden of Disease
Chronic viral hepatitis infections impose a tremendous health burden globally both
in terms of mortality and in terms of disability adjusted life years lost. The Global
Burden of Disease Study separates morbidity and mortality due to cirrhosis from that
due to liver cancer although both of these outcomes may be caused by chronic viral
hepatitis.[4] One of the consequences of bundling diseases in this way is that cirrhosis (ranked
at number 12) and liver cancer (ranked at number 16) lie outside of the top 10 causes
of global mortality.[4] As a result the burden of disease imposed by viral hepatitis lies outside the international
health agenda. When the Millennium Development Goals were set they defined the “major
infectious diseases” as human immunodeficiency virus (HIV), tuberculosis, and malaria,
which subsequently received the lion's share of health care resources and research
funding.[5] If mortality and morbidity from cirrhosis and liver cancer were combined then viral
hepatitis would sit comfortably within the top 10, above tuberculosis and malaria,
and would be more difficult for international health authorities to ignore.[6]
Based on systematic reviews and mathematical modeling research the prevalence of HCV
in 2005 was 2.8% globally representing over 184 million people. This figure had increased
for estimates in 1990, which placed the global prevalence at 2.3% or 122 million.[1] Only ∼ 12% of these infected people live in countries which are sufficiently affluent
to be able to provide access to reliable health care resources for treatment of HCV
([Table1]).[1]
Table 1
Regional estimates of HCV prevalence adapted from Mohd Hanafiah et al.[1]
|
Region
|
Total population in 2005 (millions)
|
Prevalence
(%)
(95% uncertainty interval)
|
Estimated number infected
(millions)
|
|
High-income Asia-Pacific
|
180
|
1.4 (1.2–1.5)
|
2.4
|
|
Central Asia
|
77
|
3.8 (3.0–4.5)
|
2.9
|
|
East Asia
|
1,351
|
3.7 (3.1–4.5)
|
50
|
|
South Asia
|
1,520
|
3.3 (2.6–4.4)
|
50
|
|
Southeast Asia
|
57.7
|
2.0 (1.7–2.3)
|
11
|
|
Australasia
|
24
|
2.7 (2.2– .2)
|
0.6
|
|
Caribbean
|
42
|
2.1 (1.6–2.6)
|
0.7
|
|
Central Europe
|
119
|
2.4 (2.0–2.8)
|
2.9
|
|
Eastern Europe
|
212
|
2.9 (2.3–3.5)
|
6.2
|
|
Western Europe
|
409
|
2.4 (2.2–2.7)
|
10
|
|
Andean Latin America
|
50
|
2.0 (1.4–2.7)
|
1
|
|
Central Latin America
|
216
|
1.6 (1.3–1.9)
|
3.4
|
|
Southern Latin America
|
58
|
1.6 (1.1–2.2)
|
0.9
|
|
Tropical Latin America
|
193
|
1.2 (1.0–1.4)
|
2.3
|
|
North Africa / Middle East
|
420
|
3.6 (3.2–4.1)
|
15
|
|
High-Income North America
|
337
|
1.3 (1.1–1.6)
|
4.4
|
|
Oceana
|
8
|
2.6 (2.1–3.1)
|
0.2
|
|
Central Sub-Saharan Africa
|
87
|
2.1 (1.6–3.1)
|
1.9
|
|
East Sub-Saharan Africa
|
317
|
2.0 (1.6–2.4)
|
6.1
|
|
South Sub-Saharan Africa
|
68
|
2.1 (1.7–2.5)
|
1.4
|
|
West Sub-Saharan Africa
|
303
|
2.8 (2.4–3.3)
|
8.4
|
|
World
|
6,500
|
2.8 (2.6–3.1)
|
184
|
Asia
Estimates of the prevalence of chronic hepatitis C infection in Asian countries are
undermined by deficiencies of data or by data generated from unrepresentative populations
such as blood donors. At least 14 countries in the Western Pacific and Southeast Asian
regions have no reliable data on HCV prevalence, which inevitably means that official
prevalence statistics are an underestimate of the true value. Nevertheless, the World
Health Organization (WHO) statistics indicate that there are 62 million individuals
with chronic HCV in the Western Pacific region and 32 million in the Southeast Asian
region, meaning that the majority of infected individuals globally are located in
Asia.[7]
[8]
[9]
Prevalence estimates are invariably generated according to country with published
values ranging from 0.08% in Hong Kong to 6.0% in Vietnam.[10] Many of the published studies rely on prevalence rates in blood donors rather than
community-based surveys. Although the numbers studied are often very large, blood-donor
studies can give an underestimate of population HCV prevalence where the service is
based on volunteer donation and prescreening or an overestimate where paid donors
are used. A recent systematic review by Nguyen et al summarizes the data available
and the populations studied for the Asian region.[10]
Viral genotype distribution is heterogeneous in most parts of Asia. In Japan over
85% of infections is genotype 1b. Genotype 1b also dominates in China, Hong Kong,
Taiwan, Indonesia, and Vietnam. Genotype 2 is not a frequent genotype in any country,
but is found in China, Taiwan, Singapore, and the Philippines. Genotype 3 is the dominant
genotype in South Asian countries such as India, Pakistan, and Bangladesh, but also
in Thailand. Genotypes 4 and 5 are rarely found in Asia, but genotype 6, which is
unique to this region, is found in Cambodia, Laos, Myanmar, Thailand, and Vietnam
accounting for more than one third of HCV infections.[10]
[11] Treatment response rates for HCV genotype 6 are not well documented. A recent study
by Thu Thuy and colleagues found that PegIFN/RBV therapy gave a 60% SVR after 24-weeks
treatment and 71% SVR after 48-weeks treatment.[12] IFN-based treatment response rates in Asia are generally higher than those seen
in Europe and North America due to the higher frequency of favorable IL-28B genotypes
in Asian populations.
Middle East and North Africa
North Africa is recognized as one of the highest prevalence regions for HCV globally
with an average 3.6% of adults infected with HCV. However, within this region Egypt
stands out as the country with the highest prevalence, recently estimated at 14.7%
in subjects aged 15 to 59 years with lower prevalence in urban areas (10.3%) compared
with rural areas (18%).[13] The rapid emergence of the epidemic in Egypt was originally fueled by the mass treatment
of schistosomiasis using the injectable drug tartar emetic during the 1960s.[14] As the population who were initially infected have now aged and died, the prevalence
rate in Egypt has fallen. Furthermore, there is a profound age cohort effect with
much higher prevalence rates in the population over 50 years. Furthermore, the HCV
epidemic in Egypt faces significant geographical disparities, the prevalence being
highest in the Nile Delta (17.5%) and lower in Cairo, Alexandria, or Suez (9.5%) and
in Frontier Governates (3.8%).[13] However, as the morbidity and mortality from HCV infection depend on the duration
of infection, the burden of cirrhosis and hepatocellular carcinoma (HCC) in Egypt
is still rising and is expected to produce more than 200,000 deaths from cirrhosis
or HCC over the next decade.[15]
Eastern Europe
The prevalence of HCV in Western European countries is moderately well documented
and averages out in adult populations at 2.4% with a range from 0.1% in Ireland to
4.5% in Italy.[16] In Eastern Europe, documentation of HCV epidemiology is not as well covered, but
on the whole the prevalence rates are a little higher at an average of 2.9%. Lowest
estimates of prevalence come from the former Yugoslavian countries at an average of
0.2% in adult populations. Uzbekistan has the highest prevalence at 13%. In Poland
seroprevalence of HCV is 1.4 to 1.7% and in Russia 4.5% of the population are HCV
infected. HCV genotypes 1 and 3 dominate across the majority of the European regions.[16]
[17] However, several studies have recently reported an increase in the prevalence of
HCV genotype 4 infections in Western and Southern European countries such as Greece,
Spain, Italy, and France where prevalence rates have been estimated between 10 to
24% in some areas[18]
[19]
[20]
[21]
Latin America
Very little published data have emerged from Latin America with the majority of studies
emerging from the more developed nations: Argentina, Brazil, Mexico, Peru, and Venezuela.
Prevalence rates range from 1.5 to 2.9% in the adult populations. Overall, it is estimated
that 6.8 to 8.9 million people in Latin America have chronic HCV infection. HCV genotype
1 is dominant throughout Latin America with approximately equal prevalence of genotypes
1a and 1b.[22]
Sub-Saharan Africa
Population estimates for the prevalence of chronic HCV infection in sub-Saharan Africa
range from 0.1% in South Africa to 13.4% in Cameroon. According to WHO statistics,
the average prevalence rate in Africa is 5.3%, but this is distorted by the North
African countries such as Egypt with a large population and a high prevalence rate.
As with other global regions, data on prevalence rates are frequently generated from
blood-donor populations, which results in some degree of uncertainty. In addition,
there is a general paucity in the number of HCV prevalence studies from the region
with no data from Cape Verde, Chad, Namibia, Sierra Leone, Swaziland, and Western
Sahara.[23]
[24]
The distribution of HCV genotypes in Africa is, to some extent, clustered according
to geographical location and is also characterized by a considerable HCV subtype diversity.
Specific genotypes and subtypes are several centuries old and originated in West Africa
(genotype 2)[25] or Central Africa (genotypes 1 and 4).[26] In West Africa, genotypes 1 to 3 dominate, whereas in Central Africa genotype 4
is dominant.[27] Southern Africa, including South Africa, Tanzania, and Zambia, is the only region
of the world where genotype 5 is the dominant genotype. There is limited experience
in the treatment of patients infected with HCV genotype 5; however, trials suggest
that 48 weeks of PegIFN/RBV therapy can achieve SVR rates between 50 and 70%.[28]
HIV–HCV Coinfection
Of the 34 million HIV-infected individuals worldwide, 4 to 5 million (5–15%) are estimated
to be coinfected with HCV. The prevalence of HIV–HCV coinfection considerably varies
within regions and populations, drug users and men who have sex with men being the
two main at-risk groups. Globally, intravenous drug use represents the main mode of
HCV transmission in HIV individuals. In Eastern Europe and Asia, the HCV infection
rate has been reported to be up to 70 to 90% in HIV-infected patients who are mainly
drug users.[29]
[30] Almost 70% of PWID worldwide are infected with HCV.[31] In contrast, in central Europe, where HIV sexual transmission dominates, the rate
of coinfection with HCV is lower estimated between 10 to 15%.[32] In Sub-Saharan Africa, the number of PWID is limited and HIV transmission is mainly
heterosexual associated with a lower rate (under 5%) of HIV–HCV coinfection.[33] However, there is a wide variation according the Sub-Saharan African regions and
populations (e.g., prisoners), and some studies have reported a high rate of HIV–HCV
coinfection over 10%.[34]
[35] In addition, injecting drug use has emerged as a recent concern and is a silent
hidden epidemic in several Sub-Saharan African capitals such as Dakar or Dar-Es Salam.[36]
[37]
HIV infection significantly accelerates the progression of HCV-related liver disease
and increases the risk of liver complications. In Western countries, coinfection has
become a major cause of morbidity and mortality since the introduction of highly active
antiretroviral therapy, and the incidence of cirrhosis and its complications, including
HCC, has increased greatly over recent years.[38] HCC is now responsible for a quarter of liver-related deaths in HIV patients.[39] Owing to considerable improvements in the management and treatment of HIV/AIDS in
resource-limited countries, these regions are likely to face the same alarming mortality
rates, with chronic hepatitis becoming a significant clinical problem. Thus, harm
reduction services and access to screening and treatment in HIV individuals are critical.
Transmission and Prevention
Transmission and Prevention
HCV is transmitted parenterally, requiring close contact with infected blood. The
major routes for HCV transmission have been well documented[3] although it is possible that rare causes of transmission have yet to be confirmed.
Prior to the identification of HCV blood transfusion was one of the main routes of
infection worldwide. Other major routes of transmission include intravenous drug use,
medical injections, surgical and dental procedures, and intranasal cocaine. Mother-to-child
(vertical) transmission of HCV is well recognized though fortunately not common (4–7%).
Sexual transmission of HCV is extremely rare among heterosexual couples, but is well
recognized among men who have sex with men particularly when sexual activity is traumatic
and in HIV-infected individuals.[3]
Recognition of HCV as the main cause of posttransfusion hepatitis allowed the development
of enzyme-linked immunosorbent assay- (ELISA-) based tests for screening donor blood
supplies. Current ELISA tests are highly sensitive and specific and have made a significant
impact on the safety of transfusion medicine. HCV antibody screening reduced the risk
of HCV transmission from 7.7% to 1 in 276,000 donations in the United States by 2002.[40] However, during the early phase of infection HCV antibodies are not present allowing
a window period when the donors HCV status cannot be accurately assessed serologically.
This resulted in the development and deployment of nucleic acid testing for HCV RNA
in serum. In the United States, this has further reduced the risk of transmitting
HCV by transfusion to 1 in 1.9 million donations. There is a stark contrast between
transfusion safety in North America and Europe compared with resource-limited settings.
Routine testing for transfusion transmissible infections is not conducted at all in
39 countries worldwide. In other countries, the testing of donors for HIV, HBV, and
HCV is patchy with priority mostly given to HIV. Where testing is performed there
is widespread use of rapid test assays with poor quality control leading to a lack
of sensitivity. Nucleic acid testing is extremely uncommon in low- and middle-income
countries where the skills and financial resources are not readily available. Even
in Egypt, where the size of the HCV epidemic has been acknowledged by the government,
only 20% of the blood supply is subjected to nucleic acid testing. Ensuring the safety
of blood and blood products is a vital part of the fight to prevent transmission of
HCV and should be given priority by global health authorities.
Transmission of HCV through medical or dental procedures has been documented in virtually
all countries. WHO estimates that 2 million new HCV infections each year result from
unsafe injections.[41] Initial reports highlighted the high risk of HCV transmission in hemodialysis patients
and subsequently transmission was associated with the use of multidose drug vials,
surgery, dental procedures, obstetric care, and gastrointestinal endoscopy. Education
of clinicians coupled with the implementation of strict infection control measures
has reduced this route of transmission substantially in industrialized countries.
Single use hypodermics and drug vials combined with more effective sterilization techniques
have helped to ensure that iatrogenic transmission of infection is now a rare event.
However, lapses in clinical hygiene procedures are linked to outbreaks of infection
reinforcing the need for continued vigilance.
In resource-limited countries iatrogenic transmission has played an important role
both in the initiation of HCV epidemics and also in the perpetuation of incident infections.
The best example of this was the public health campaign in Egypt to eradicate schistosomiasis
using reusable syringes to inject tartar emetic.[14] However, other mass treatment or vaccination campaigns have also led to a rapid
spread of HCV exemplified by a malaria treatment program in Cameroon[42] and the Democratic Republic of Congo.[26] Tracing HCV infection to medical or dental procedures is particularly difficult
as the majority of new infections are asymptomatic. However, a case-control study
in acute hepatitis in Egypt revealed a significantly higher risk of recent attendance
at medical facilities, sutures, hypodermic infection or dental work in subjects with
acute HCV compared with those with acute hepatitis A virus infections.[43] Studies in Eastern Europe[44] and Pakistan[45] also confirm the importance of poor infection control measures in medical and dental
practice as a source of ongoing HCV transmission.
In Western countries, vigilant infection control is now widely accepted as part of
normal clinical practice and iatrogenically mediated outbreaks of infection are treated
as scandalous. For iatrogenic transmission to be terminated globally, there will need
to be a large-scale investment in education and awareness campaigns that ensures a
similar attitudinal change among medical practitioners which results in better protection
for their patients. An additional strategy, advocated by patient groups, is to educate
the general public about the dangers associated with reuse of medical instruments,
which would empower patients to make their own decisions about infection risk when
engaging with medical services.
Access and Barriers to Treatment in Resource-Limited Countries
Access and Barriers to Treatment in Resource-Limited Countries
The majority of HCV-infected individuals are living in low- or middle-income countries
where screening and access to care and treatment are rarely available, and public
funding for health care is very limited. Lack of screening, expensive diagnostics,
the high cost of the drugs, and the lack of human and technical resources combined
with political inertia are the main barriers to access to treatment in resource-poor
countries.[46]
Screening and Surveillance
Chronic viral hepatitis infections are invariably asymptomatic until the late stages
of cirrhosis or HCC develop. Identifying cases for treatment therefore relies on awareness
of the potential of being infected coupled to diagnostic testing or dependent on screening
programs. According to the World Hepatitis Alliance/WHO study conducted in 2010 nearly
two-thirds of the world population lives in countries where HCV testing is not accessible.[47] To date, it is estimated that up to 90% of HCV infected individuals worldwide are
unaware of their HCV-positive status.[48]
[49] Identifying and testing at-risk populations for HCV infection in each country represent
a critical step in the control of the global burden. Currently, there are no formal
recommendations from WHO on population-based screening for HCV. Although population
screening is a logical step in public health management of the disease, there have
been few pilot studies and no health economic analysis in resource-limited settings.
Furthermore, screening may reinforce stigmatization of marginalized populations living
in countries where screening is sometimes assimilated to social control. Screening
may also create ethical dilemmas where false-positive test results cause unnecessary
psychological distress and false-negative results allow the disease to progress in
infected patients as well as increasing the risk of further transmission. To minimize
these risks, there is an urgent need for affordable point-of-care tests for HCV including
rapid assessment of HCV antibody and viral load.
To ascertain accurate estimates on the prevalence of HCV infection and the burden
of disease imposed by the virus it is vital to establish surveillance systems designed
to capture data relevant to chronic infection. According to the Global Policy Report
on Prevention and control of viral hepatitis[50] from the WHO, 82.5% of member-state countries have a hepatitis surveillance system,
but a substantially smaller proportion had surveillance systems that are appropriate
for HCV. Furthermore, the WHO report is based on responses from only 65% of member-state
countries, and many of those listed as nonresponders are located in high-prevalence
regions of the world.
Drug Costs and Availability
The World Hepatitis Alliance/WHO study reported that 41% of the world's population
lives in countries where no public funding is available for viral hepatitis B/C treatment
with a particular gap in access to HCV antiviral drugs.[47] Even in countries where appropriate antiviral drugs are licensed and appear on the
essential medicines list, there is limited access to treatment. One of the most important
barriers to treatment access is the high cost of anti-HCV drugs. PegIFN/RBV treatment
still costs approximately €15,000 to €25,000 for a 48-week course in Europe, without
taking into account the additional biological and medical costs. DAAs are even more
expensive (∼ €20,000–40,000 per year for telaprevir and boceprevir). Prices of second-generation
DAAs are expected to be much higher. As an example, sofosbuvir, which provides excellent
results in association or not with IFN has been recently licensed in the United States
at US $70,000 for a 12-week course of treatment—US $1,000/pill. Other IFN-free regimens
provide excellent results in HCV monoinfected patients as well as HIV coinfected individuals
reaching almost 100% of SVR and are also expected to be highly expensive. Yet, the
simplicity, efficiency, and tolerance of such new drugs are particularly adapted to
resource-limited settings and must be urgently considered accessible at lower price
in developing countries.
Some low- or middle-income countries have succeeded in negotiating PegIFN/RBV therapy
costs with or without the support of international health agencies. A biosimilar of
PegIFN (Reiferon Retard, RHEIN-MINAPHARM, Cairo, Egypt) has been developed and commercialized
at low prices in Egypt with clinical outcomes similar to proprietary branded PegIFN.
The Egyptian hepatitis C program has negotiated a price of $2000 for a course of treatment
and has been able to provide treatment for more than 200,000 individuals since 2008.[51] With the support of the Global Fund, the Georgian government has recently started
to cover PegIFN/RBV therapy for HIV–HCV coinfected subjects.[52]
Treatment coverage should be improved not only in resource-limited countries, but
also in developed countries where less than 20% of HCV-infected patients receive antiviral
therapy. Decreasing the cost of the drugs is urgent for developing countries as well
as developed countries, which will not be able to cover all the HCV-treatment-related
expenses. This goal is feasible, but will require the support of pharmaceutical companies,
international health agencies and donors, governments, and nongovernmental organizations,
and the commitment of scientists and physicians.
The HIV/AIDS epidemic has demonstrated that barriers to treatment can be overcome,
and lessons from HIV/AIDS must be applied to fighting viral hepatitis. Until the mid-2000s,
antiretroviral therapy (ART) cost more than $10,000 per patient per year, and treatment
was not considered cost effective.[53] Today, following the strong pressure on policy-makers and drug companies by society,
this cost has fallen to less than $100 per person per year. As a result, the number
of individuals receiving ART in developing countries has increased considerably from
200,000 in 2000 to 8 million to date. Only 0.1% of African individuals with HIV received
ART in 2000, compared with 54% in 2011.[54]
The example set in response to the HIV/AIDS epidemic, allows governments to challenge
pharmaceutical companies and empowers international health agencies to achieve widespread
access to medications that could now be applied to the HCV epidemic. In 2001, following
the Pretoria trial in South Africa against pharmaceutical companies, strong pressure
from nongovernmental organizations and civil society led to the Doha Declaration on
Trade-Related Aspects of Intellectual Property Rights allowing compulsory licenses
for medicines “to protect public health and promote access to medicines for all.”[55] Based on this declaration, each country can now declare a disease as an urgent public
health issue in its own territory and produce generic drugs to fight the disease.
Using this declaration, numerous countries have improved access to ART, but have also
opened access to other treatments. As an example, India has declared liver cancer
as an urgent public health issue and now produces sorafenib at a generic price (€150/month
Soranib, Cipla Company, Mumbai, India) much lower than the €4,000 monthly cost in
Western countries.
Moreover, antiviral drugs are often extremely cheap to make. According to Hill et
al, the cost of production of sofosbuvir and simeprevir for a 12-week treatment course
is estimated, respectively, between $US68 to $US136 and $US130 to $US326.[56] Thus, the final selling prices of these drugs are incredibly disproportionate. From
a public health perspective, pharmaceutical companies and world trade organizations
should have a moral obligation to reduce this unacceptable gap.
There are other alternatives to open access to treatment in poor countries. For example,
the creation of a medicines patent pool, which aims at pharmaceutical companies that
can register their products in a common health impact fund and sell the drugs at lower
prices in resource-poor countries. The fund proposes to assess the impact on population
health and provide incentives to firms in exchange.[57] Following the significant increase in ART coverage associated with a great improvement
in the survival of HIV/AIDS patients living in developing countries, HIV/AIDS donors
(e.g., The Global Fund to Fight AIDS, Tuberculosis and Malaria [GF] and the Presidents
Emergency Plan for Aids Relief [PEPFAR]) should urgently consider access to viral
hepatitis treatment for those patients who will now die from end-stage liver disease
as observed in developed countries.
Skills and Training
Although PegIFN/RBV therapy has been demonstrated to be feasible in resource-limited
countries with similar SVR rates and side effects than those observed in developed
countries,[58] IFN-based therapy is difficult to implement in developing countries because of numerous
constrains: the conditions of IFN storage, the management of side effects that require
strong medical support, expensive hematopoietic growth factors or blood transfusions
in countries where the blood safety is poor, and finally the necessity to regularly
assess HCV viral load and full blood count with limited local laboratory capacities.
In addition, in many countries such as in Africa and the Middle East, the benefits
to be treated with PegIFN/RBV therapy is low as the majority of individuals are nonresponders
to IFN therapy being infected with genotypes 1 or 4, and being IL28B non-CC carriers.
The shortage of health care workers and facilities and the lack of diagnostic tools
create another major barrier to access to treatment in resource-limited countries.
The number of liver specialists in low- and middle-income countries is very limited
and these countries have often very few diagnostic tools for assessing accurately
the severity of the liver disease. Thus, transfer of knowledge, capacities, and diagnostic
tools from developed countries to developing countries is urgently needed. The recent
innovative tools (e.g., portable ultrasound, transient elastography…), which have
dramatically improved the management of viral hepatitis-infected patients in developed
countries, should now benefit the resource-poor countries.
Low-Cost Diagnostics
Accurate measurement of HCV viral load is taken for granted in industrialized countries,
but is inaccessible and expensive in resource-limited settings. Viral-load measurement
costs between $75 and $200 per test and is generally provided in tertiary centers
where sophisticated laboratory equipment is available to run patent-protected kits
sold by European and American diagnostics companies. The availability of robust, reliable,
reproducible, and cheap viral load assays is a major barrier to the expansion of HCV
treatment programs. A small number of companies (Epistem, www.epistem.co.uk; Alere, www.alere.com; Cepheid, www.cepheid.com) are now developing point-of-care devices that might surmount this barrier in the
near future. One potential impact of the new DAA is the ability to simplify viral
monitoring during therapy. It is entirely feasible that a single qualitative HCV RNA
assay prior to treatment and a second qualitative HCV RNA assay 12 weeks after the
end of treatment will suffice for the management of the majority of patients and would
impose less demands and expenses on diagnostics services. It is also feasible to perform
HCV core antigen detection by enzyme immunoassay at baseline and 12 weeks after the
end of therapy because core antigen has been shown to be an accurate surrogate marker
of viral replication.[59] A commercial HCV core antigen assay is available, easy to perform, and cheaper than
HCV RNA assays, but with slightly less sensitivity for low viral loads.
Guidelines and Strategies
Very few developing countries have set up national strategies on HCV infection and
when available, these guidelines are often incomplete.[47] At the international level, WHO has set up only recently a group of international
experts to design HCV guidelines; in July 2012, WHO announced a framework for global
action for the prevention and control of viral hepatitis.[60] In 2014 the first WHO HCV guidelines should be published. These guidelines may have
an impact at the national level and should help governments to support access to screening
and treatment for HCV infection in the future.
Political Inertia
Beyond the preventive and therapeutic measures, successful control of a disease at
a global level requires strong political will and societal mobilization. However,
since its discovery, HCV infection has not raised the same level of attention that
has been deployed to fight HIV/AIDS, malaria, tuberculosis, or even polio in the 1950s.
Indeed, HCV infection is a silent disease without obvious visible scars that does
not mobilize the political actors. And to date, HCV infection does not receive any
significant funding in resource-poor countries. Even in the United States, although
HCV causes more deaths and infects four times more individuals than HIV, appropriations
for HCV are less than 2% of resources for research and for medical care related to
HIV.[61]
Despite the importance of liver diseases attributable to viral hepatitis infections
([Fig. 1]), major contributors to global health developments such as The UK Department for
International Development and The Gates Foundation do not prioritize viral hepatitis
research or program development. The Global Fund, which provides drugs for the treatment
of HIV, tuberculosis, and malaria, has, until recently, been unable to provide medication
for viral hepatitis. The Global Fund recently supported the purchase of PegIFN in
Georgia for HIV coinfected patients but HCV monoinfected patients remain disadvantaged.
In the absence of a strong patient lobby, it is unclear what political levers are
required to rectify this alarming situation.
Fig. 1 Putting the mortality from chronic viral hepatitis into context. HBV, hepatitis B
virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human papillomavirus;
SARS, severe acute respiratory syndrome; vCJD, variant Creutzfeldt-Jakob disease.
Prospects for Treatment in the Future
Prospects for Treatment in the Future
All oral DAA with high efficacy and low incidence of side effects promise to change
the management of HCV globally. There should no longer be a need for extensive training
and skills for the treatment of HCV once we are able to dispense with the side-effect
burden imposed by PegIFN/RBV therapy. Furthermore, these drugs will be available for
use in patients whom we now consider to be ineligible for treatment, including those
who have advanced liver disease or who are intolerant of the IFN-related side effects.
The high efficacy rates and the broad genotypic coverage of some of the new drugs
will allow treatment regimens to be simplified and obviate the need for sophisticated
molecular diagnostics.
From a global health perspective and in the absence of a vaccine, improving access
to HCV treatment in low- and middle-income countries has become urgent. By decreasing
the pool of transmitters, antiviral therapy also represents an important measure of
prevention. To date, with the advent of very highly effective drugs HCV cure has become
feasible and global eradication of HCV a new objective.[62]
[63]
[64] This goal can be achieved, as HCV has no natural nonhuman reservoir, the virus is
not integrated in the host genome and is not transmitted by air or food. As a result,
transmission can be controlled even in the absence of vaccine with the use of effective
antiviral drugs and preventive measures adapted to each country and population.
Three important issues now remain to be addressed for the potential of the new drugs
to be realized on a global scale. First, the cost of the new drugs needs to be negotiated
to a level that is affordable in resource-limited settings. Second, we need substantial
investment in public health research and infrastructure to provide effective means
of screening and surveillance for HCV. Third, but most importantly, we need to overcome
the political inertia that blocks access to the research funding, health service resources,
and financial investment required to tackle the HCV epidemic effectively.
Conclusion
HCV infection is a leading cause of morbidity and mortality worldwide. The vast majority
of HCV-infected individuals are living in resource-limited countries where screening,
care, and treatment are rarely accessible. HCV infection has been facing a therapeutic
and technologic revolution. For the first time in HCV history, innovative diagnostic
tools and highly effective and well-tolerated drugs make an HCV cure and eradication
a realistic goal. From public health and health equity perspectives, it is now urgent
to overcome the numerous barriers to care and treatment for HCV infection in low-
and middle-income countries. Low-cost drugs and diagnostic tools are urgently needed
to set up better screening and surveillance, implement treatment programs, and design
guidelines adapted to the local settings and populations. To be successful, this new
HCV era will require a stronger political commitment at international and national
levels involving the support of drug companies, patients' groups, and the scientific
community.
