3. Hepatitis C

Jenny Bischoff, Christoph Boesecke and Jan-Christian Wasmuth

Epidemiology

Hepatitis C is a disease with significant global impact. According to the World Health Organization there are 71 million people chronically infected with the hepatitis C virus (HCV), corresponding to 3% of the world’s population (WHO 2019). In Europe and the United States, HCV is the most common chronic liver disease and responsible for the majority of liver transplants.

Prevalence and genotype distribution vary considerably among different regions (WHO 2019; Polaris Observatory 2017) . The prevalence is highest in the Eastern Mediterranean Region (15 million, 2.3%) and the WHO European Region (14 million, 1.5%). In North America and north and western Europe lower prevalence rates around 1% are estimated. Certain groups are preferentially affected with the highest risk factor in most cases being injection drug use. But patients undergoing hemodialysis and persons who received blood transfusions before 1991 are also at high risk.

It is estimated that there had been 1.75 million (Incidence rate 23,7 per 100000) new HCV infections in 2015 globally (WHO 2019). But as acute infections remain asymptomatic in most cases, it is difficult to determine the actual number of new HCV infections. In addition, it is not generally possible to determine the duration of infection upon diagnosis. In 2017 an estimated 19% (13.1 million) of those infected globally were aware of their infection with only 5 million being referred to antiviral treatment by the end of 2017 (WHO 2019). Nevertheless, it had been assumed that the number of new infections has considerably decreased over the past decades. In the US, it is estimated that the number of new cases of HCV infection has decreased from approximately 230,000 per year in the 1980s to about 20,000 cases per year in the early 2000s (Wasley 2008)but began to increase again steadily with an estimated 30,500 cases in 2014 up to 44,700 cases in 2017 (CDC 2019).

Overall, epidemiology of HCV is rapidly changing due to a scale up in screening and prevention measures and high cure rates in the era of interferon free direct acting antiviral (DAA) treatment. Highly effective and well tolerated treatment options are now available even for those with advanced liver disease(European Association for the Study of the Liver. Electronic address 2018; Ghany 2019). The implementation of a routinely screening of donated blood for bloodborne viruses in the early 1990s and changes in injection practices as well as needle exchange and opioid substitution programs have already led to a significant reduction of transfusion associated HCV infections and infections in people who inject drugs (PWID). But a substantial increase can be observed in some regions especially in those being younger of age without reported injecting drug use, mainly driven by an increase in acute HCV infections and reinfections in HIV positive men who have sex with men (MSM) (Boesecke 2012; Boesecke 2015).And, since the introduction of a pre-exposure prophylaxis (PrEP) for HIV, increasing numbers of acute HCV infections in HIV negative MSM are documented as well(Hoornenborg 2019; Boerekamps 2018).

Transmission

Parenteral exposure to HCV is the most efficient means of transmission. The majority of patients infected with HCV in Europe and the US acquired the disease through intravenous drug use. While infection via transfusion of blood products has become rare since routine testing of the blood supply for HCV began in the early 1990s other routes of transmission have been acknowledged. Routes of transmission vary in specific regions and subgroups in the world.

Possible routes of transmission are:

• Injection drug use
• Nosocomial/Unsafe medical procedures and injections
• Blood transfusion and organ transplantation
• Having been in jail more than three days
• Sex with a person who injects drugs/Men who have sex with men
• Heterosexual and household contacts
• Perinatal

Injection drug use

Injection drug use has been the most commonly identified source of acute HCV infection. It is estimated that most newly acquired infections occur in individuals who have injected illicit drugs. The seroprevalence of anti-HCV antibodies in groups of PWID may be up to 70% with considerable variation depending on factors such as region, risk behaviour, socioeconomic status etc. underscoring the efficiency of transmission via direct blood contact (Sutton 2008). HCV infection has also been associated with a history of injecting recreational drugs such as methamphetamine in a sexual context or intranasal cocaine use, presumably due to blood on shared straws or other sniffing paraphernalia. This may explain partly the recent increase in cases of acute HCV in HIV positive MSM (Schmidt 2011, Boesecke 2015). Both WHO and CDC now recognise sex as an HCV transmission route.

Nosocomial/Unsafe medical procedures and injections

Unsafe medical procedures: Until 2000 about 40% of new HCV infections globally were acquired through unsafe medical injections reusing unsterilized devices. Largest numbers of unsafe injections and procedures were reported in the eastern Mediterranean Region and South East Asia. Since 2000 great efforts have been made resulting in a substantial risk reduction in many regions (WHO 2017).

Haemodialysis: Patients who participate in haemodialysis programmes are at increased risk for HCV. The prevalence of HCV antibodies in such patients reaches 15%, although it has declined in recent years (Fissell 2004). A number of risk factors have been identified for HCV infection among dialysis patients. These include blood transfusions, duration of hemodialysis, HCV prevalence in the dialysis unit, and type of dialysis. The risk is higher with in-hospital haemodialysis as opposed to peritoneal dialysis.

Needle-stick injuries: There is some risk of HCV transmission for healthcare workers after unintentional needle stick injury or exposure to other sharp objects. The incidence of seroconversion after exposure to an HCV positive source is generally estimated to be less than 2% (Service 2001). However, data are divergent and figures ranging from 0 to 10% can be found. Exposure of HCV to intact skin has not been associated with HCV transmission.

Blood transfusion

Historically, blood transfusion or use of other blood products was a major risk factor for transmission of HCV. In some historic cohorts 10% or more of patients who received blood transfusions were infected with hepatitis C (Alter 1989). However, blood donor screening for HCV since the early 1990s has nearly eliminated this transmission route. Blood donors are screened for anti-HCV antibodies and HCV RNA – at least in high-income countries. The risk is now estimated to be between 1:500,000 and 1:1,000,000 units (Pomper 2003).

Before screening was introduced, over 90% of patients in cohorts of multiply transfused patients such as hemophiliacs, were infected with HCV (Francois 1993). Since the use of recombinant clotting factors, new cases of HCV have become uncommon in these patients.

Organ transplantation

Transplant recipients who receive organs from HCV positive donors have a high risk of acquiring HCV infection. Transmission rates in different cohorts vary from 30 to 80% (Pereira 1991; Roth 1994). Therefore, most transplant organisations have developed strategies for screening and selective utilisation of organs from HCV positive donors. The introduction of second generation DAAs in 2014 offered a high possibility of cure for HCV even in those patients being referred to as difficult- to -treat due to end-stage kidney or liver disease and in patients awaiting transplantation. Thus, DAA treatment can be offered before or after solid organ transplantation with beneficial effects on liver function and post-transplant survival (European Association for the Study of the Liver. Electronic address and European Association for the Study of the 2018). In the US the willingness of transplant recipients to accept an organ of an anti-HCV + donor as well as the use of anti-HCV (+) organs for transplantation increased in the last few years. Short term data concerning allograft survival seems to be promising in the era of DAA treatment (Wang 2020).

People in prison

Prevalence and incidence rates for HCV are higher for people in prison comparing to the general population. Main risk factors for the transmission of HCV in prison are injecting drug use associated with needle and syringe sharing as well as unprotected sex and unsafe tattooing (Mason 2019; Falla 2018). Opioid substitution programs as well as needle exchange programs and a scale up of screening for HCV and subsequent DAA treatment before release constitute a high possibility to reduce transmission of HCV rapidly in this well-defined subgroup (Dalgic 2019).

Men who have sex with men

In the last two decades sexual transmission of HCV in men who have sex with men, especially in those being HIV positive has come into focus. Whereas HCV transmission by sexual contact is uncommon between heterosexual couples, there is no doubt that sexual transmission of hepatitis C is possible particularly where sexual practices associated with traumas are combined with stimulants such as methamphetamine, mephendrone or crystal meth being injected in a sexual context. Outbreaks of cases of acute HCV in several cities in Europe and the United States among MSM have focused attention on sexual transmission of HCV (Boesecke 2015; Boesecke 2012). As there is evidence that HCV can be transmitted sexually, condoms might reduce this risk. Anal sex without condoms, fisting, having many sex partners in a short time period, a concomitant sexually transmitted disease including HIV and use of recreational drugs have been identified as risk factors (Danta 2007; Schmidt 2011; Vanhommerig 2015). Mucosal damage might also be a prerequisite for HCV transmission. According to these observations, the seroprevalence of HCV in MSM ranges from about 4 to 8%, which is higher than the HCV prevalence reported for general populations in European countries. Furthermore, since the introduction of PrEP an increase of acute HCV infections in HIV negative MSM has been described, emphasizing the need for further prevention strategies and behavioral interventions.

Men who have sex with men

Common household contacts do not pose a risk of HCV transmission.

The exact risk of HCV transmission in monogamous heterosexual relationships has been difficult to determine. It appears that the risk in long-term partnerships is very low. In prospective cohorts of monogamous, heterosexual couples, there was a long-term transmission risk of 0.01% or lower (Vandelli 2004). Factors that may increase the risk of HCV infection include greater numbers of sex partners, history of sexually transmitted diseases, sexual practices associated with higher risk of trauma and bleeding and not using a condom (Tohme 2010). Whether underlying HIV infection increases the risk of heterosexual HCV transmission to an uninfected partner is unclear. Very often it is difficult to rule out the possibility that transmission results from risk factors other than sexual exposure.

Nevertheless, patients with acute or chronic HCV should be advised that transmission through sexual contact is possible, although the risk is extremely low in heterosexual relationships. It is likely that the use of condoms will lower the risk of sexual transmission further. In most countries, there are no firm recommendations to use barrier precautions in stable monogamous heterosexual partnerships. The transmission risk in MSM as discussed in the section above, is considerably higher and – as for risk of other sexually transmitted diseases – safer sex practices and counselling regarding the risk of injecting recreational drugs are advised for this group.

Perinatal transmission

The risk of perinatal transmission of HCV in HCV RNA positive mothers is estimated to be 5% or less (Ohto 1994). In mothers coinfected with HCV and HIV this risk correlates with immunosuppression and has been described in up to 20%. To date, there are no specific recommendations for prevention of perinatal transmission (Pembrey 2005). Caesarean section has not been shown to reduce the transmission risk. There is no evidence that breastfeeding is a risk for infection among infants born to women with HCV. Early diagnosis of infection in new-borns requires HCV RNA testing since HCV antibodies are passively transferred from the mother.

Other rare transmission routes

Procedures involved in traditional medicine (e.g., scarification, cupping), tattooing, and body piercing bear the potential of transmitting HCV (Haley 2001). Possible transmissions through these procedures are very likely due to unsterile equipment (Tohme 2012).  However, in most instances it is not clear if the risk is due to the procedure itself, or whether there are possible contacts with persons involved who are HCV positive. In addition, transmission via these routes is so rare that persons with exposure are not at increased risk for acquiring HCV.

Clinical manifestations

The spectrum of clinical manifestations of HCV infection varies in acute versus chronic disease. Acute HCV is most often asymptomatic (Vogel 2009) and leads to chronic infection in about 75% of cases. The manifestations of chronic HCV range from an asymptomatic state to cirrhosis and hepatocellular carcinoma. HCV is usually slowly progressive. Thus, it may not result in clinically apparent liver disease in many patients if the infection is acquired later in life. Approximately 20 to 30% of chronically infected individuals develop cirrhosis over a period of 20 to 30 years (WHO 2016).

Acute HCV

After inoculation of HCV, there is a variable incubation period. HCV RNA in blood (or liver) can be detected by PCR within several days to eight weeks. Aminotransferases become elevated approximately 6–12 weeks after exposure (range 1–26 weeks). The elevation of aminotransferases varies considerably among individuals but tends to be more than 10–30 times the upper limit of normal (typically around 800 U/L). HCV antibodies can be found first around 8 weeks after exposure although in some patients it may take several months by ELISA testing.

However, the majority of newly infected patients will be asymptomatic and have a clinically non-apparent or mild course. Jaundice as a clinical feature of acute hepatitis C will be present in less than 25% of infected patients. Therefore, acute hepatitis C will not be noticed in most patients (Vogel et al. 2009). Periodic screening for infection may be warranted in certain groups of patients who are at high risk for infection, e.g., HIV positive MSM. If acute HCV is suspected HCV-RNA testing by PCR is recommended as HCV antibodies might not be present yet; particularly in HIV coinfected individuals HCV seroconversion can be delayed.

Other symptoms that may occur are similar to those in other forms of acute viral hepatitis, including malaise, nausea, and right upper quadrant pain. In patients who experience such symptoms of acute hepatitis, the illness typically lasts for 2–12 weeks. Along with clinical resolution of symptoms, aminotransferase levels will normalise in about 40% of patients. Loss of HCV RNA, which indicates cure from hepatitis C, occurs in fewer than 20% of patients regardless of normalisation of aminotransferases. Implementation of highly efficacious DAA treatment led to several changes in management and treatment of acute HCV with varying recommendations in international guidelines (European Association for the Study of the Liver [EASL] 2018; Ghany 2019; EACS 2019). Early treatment initiation 4 weeks after diagnosis after spontaneous clearance has been ruled out as recommended by EACS has been shown to be beneficial for patients’ outcome, to reduce transmission and to be cost effective.

Fulminant hepatic failure due to acute HCV infection is very rare. It may be more common in patients with underlying chronic hepatitis B virus infection (Chu 1999).

Chronic HCV

The risk of chronic HCV infection is high. 75–100% of patients remain HCV RNA positive after acute hepatitis C (Alter 1999, Vogel 2009). Most of these will have persistently elevated liver enzymes in further follow-up. HCV is defined as chronic after viral persistence for more than six months after presumed infection. Once chronic infection is established, there is a very low rate of spontaneous clearance.

It is unclear why HCV results in chronic infection in most cases. Genetic diversity of the virus and its rapid mutation rate may allow HCV to escape immune recognition. Host factors may also be involved in the ability to spontaneously clear the virus. Factors that have been associated with successful HCV clearance are HCV-specific CD4 T cell and NK cell responses, high titres of neutralising antibodies against HCV structural proteins, IL28B gene polymorphisms and specific HLA-DRB1 and -DQB1 alleles (Lauer 2001, Thomas 2009, Rauch 2010). HCV infection during childhood appears to be associated with a lower risk of chronic infection, approximately 50 to 60% (Vogt 1999). Finally, there seem to be ethnic differences with lower risk of chronicity in certain populations, which may in part be explained by different distribution of host genotypes such as IL28B (Ge 2009).

Most patients with chronic infection are asymptomatic or have only mild non-specific symptoms as long as liver cirrhosis is not present (Merican 1993, Lauer 2001). The most frequent complaint is fatigue. Less common manifestations are nausea, weakness, myalgia, arthralgia, and weight loss. HCV has also been associated with cognitive impairment. All of these symptoms are non-specific and do not reflect disease activity or severity (Merican 1993). Very often symptoms may be caused by underlying diseases (e.g., depression), and it can be difficult to distinguish between different diseases. Fatigue as the most common symptom may be present in many other situations (including healthy control groups within clinical studies). HCV is rarely incapacitating.

Aminotransferase levels can vary considerably over the natural history of chronic HCV. Most patients have only slight elevations of transaminases. Up to one third of patients have normal serum ALT (Martinot-Peignoux 2001, Puoti 2002). About 25% of patients have serum ALT concentration of between 2 and 5 times above the upper limit of normal. Elevations of 10 times the upper limit of normal are very rarely seen.

There is a poor correlation between concentrations of aminotransferases and liver histology. Even patients with normal serum ALT show histologic evidence of chronic inflammation in the majority of cases (Mathurin 1998). The degree of injury is typically minimal or mild in these patients. Accordingly, normalisation of aminotransferases after interferon therapy does not necessarily reflect histologic improvement.

Extrahepatic manifestations

Around 30 to 40% of patients with chronic HCV have an extrahepatic manifestation of HCV (Zignego 2008). There are a wide variety of extrahepatic manifestations described as being associated with HCV:

• Hematologic manifestations (essential mixed cryoglobulinaemia, lymphoma)
• Autoimmune disorders (thyroiditis, presence of various autoantibodies)
• Renal disease (membranoproliferative glomerulonephritis)
• Dermatologic disease (porphyria cutanea tarda, lichen planus)
• Diabetes mellitus

For further details, refer to Chapter 13.

Natural history

The risk of developing cirrhosis within 20 years is estimated to be around 10 to 20%, with some studies showing estimates up to 50% (Poynard 1997, Wiese 2000, Sangiovanni 2006, de Ledinghen 2007). Due to the long course of HCV, the exact risk is very difficult to determine, and figures are divergent for different studies and populations. In fact, chronic HCV is not necessarily progressive in all affected patients. In several cohorts it has been shown that a substantial number of patients will not develop cirrhosis over a given time. It is estimated that about 30% of patients will not develop cirrhosis for at least 50 years (Poynard 1997).

Therefore, studies with short observation periods fail to show HCV increases mortality. In addition, survival is generally not impaired until cirrhosis has developed. On the other hand, there is no doubt that patients with chronic HCV have a high risk of cirrhosis, decompensation, and hepatocellular carcinoma in long-term follow-up. For example, in a cohort of patients with posttransfusion HCV evaluated more than 20 years after transfusion, 23% had chronic active hepatitis, 51% cirrhosis, and 5% hepatocellular carcinoma (Tong 1995). It is not completely understood why there are such differences in disease progression. An influence of host and viral factors has to be assumed, particularly other liver comorbidities such as high alcohol consumption and/or non-alcoholic fatty liver disease.

Cirrhosis and hepatic decompensation

Complications of HCV occur almost exclusively in patients who have developed cirrhosis. Interestingly, non-liver related mortality is higher in cirrhotic patients as well. However, cirrhosis may be very difficult to diagnose clinically, as most cirrhotic patients will be asymptomatic as long as hepatic decompensation does not occur. Findings that can be associated with cirrhosis are hepatomegaly and/or splenomegaly on physical examination, elevated serum bilirubin concentration, hyperalbuminaemia, or low platelets. Other clinical findings associated with chronic liver disease may be found such as spider angioma, caput medusae, palmar erythema, testicular atrophy, or gynecomastia. Most of these findings are found in less than half of cirrhotic patients, and therefore none is sufficient to establish a diagnosis of cirrhosis. Therefore, regular screening for liver fibrosis/cirrhosis, e.g. with transient elastography, is recommended by current guidelines (Ghany et al. 2019).

Hepatic decompensation can occur in several forms. Most common is ascites, followed by variceal bleeding, encephalopathy and jaundice. As mentioned earlier, hepatic decompensation will develop only in cirrhotic patients. However, not all patients with cirrhosis actually show signs of decompensation over time. The risk for decompensation is estimated to be close to 5% per year in cirrhotics (Poynard, Bedossa, and Opolon 1997). Once decompensation has developed the 5-year survival rate is roughly 50% (Planas 2004). For this group of patients, liver transplantation is the only effective therapy. Nevertheless, DAA treatment seems to have a clinically relevant impact on disease progression, development of hepatocellular carcinoma (HCC) and liver transplantation (Park 2019; Belli 2018).

HCC develops mostly in patients with cirrhosis. The risk for HCC has been estimated to be less than 3% per year once cirrhosis has developed (Di Bisceglie 1997; Fattovich 1997). However, HCV-associated HCC has significant impact on survival (see chapter 18).

Elevated concentrations of α-fetoprotein (AFP) do not necessarily indicate HCC. AFP may be mildly elevated in chronic HCV infection (i.e., 10 to 100 ng/mL) and are higher in patients with considerable fibrotic activity in the liver. Levels above 400 ng/mL as well as a continuous rise in AFP over time are suggestive of HCC.

Disease progression

Chronic HCV has different courses among individuals. It is not completely understood why there are differences in disease progression. Several factors have been identified that may be associated with such differences. However, other factors not yet identified may also be important.

Age and gender: Acquisition of HCV infection after the age of 40 to 55 may be associated with a more rapid progression of liver injury, as well as male gender (Svirtlih 2007). Children appear to have a lower risk of disease progression (Pawlowska 2015). In one cohort, for example, of 77 patients with chronic HCV, 60% of HCV-RNA positive patients had abnormal ALT and 5% had developed cirrhosis after 2–3 decades of observation (Cesaro 2010).

Ethnic background: Disease progression appears to be slower and changes in liver histology less severe in African-Americans (Sterling 2004).

HCV-specific cellular immune response: The severity of liver injury is influenced by the cellular immune response to HCV-specific targets. Inflammatory responses are regulated by complex mechanisms and probably depend on genetic determinants such as HLA expression and chemokines such as interferon-gamma-inducible protein-10 (IP-10) (Hraber 2007, Larrubia 2008).

Alcohol intake: Alcohol increases HCV replication, enhances the progression of chronic HCV, and accelerates liver injury (Gitto 2009). Even moderate amounts of alcohol appear to increase the risk of fibrosis. Accordingly, in alcoholic patients with cirrhosis and liver failure a high prevalence of anti-HCV antibodies has been described. Alcohol intake should be avoided in all patients with chronic HCV. A safe level of alcohol intake has not been established.

Daily use of marijuana: Daily use of marijuana has been associated with more rapid fibrosis progression, possibly through stimulation of endogenous hepatic cannabinoid receptors.

Other host factors: Genetic polymorphisms of certain genes might influence the fibrosis progression rate (Jonsson 2008). For example, transforming growth factor B1 (TGF B1) phenotype or PNPLA3 (adiponutrin) are correlated with fibrosis stage (Zimmer 2011). Patients with moderate to severe steatosis (e.g. non-alcoholic fatty liver disease/non-alcoholic steatohepatitis) are at higher risk for developing hepatic fibrosis.

Viral coinfection: Progression of HCV is clearly accelerated in HIV positive patients (see section on coinfection). Acute hepatitis B (HBV) in a patient with chronic HCV may be more severe. Chronic HBV may be associated with decreased HCV replication as opposed to HCV-monoinfected patients, although HCV usually predominates. Nevertheless, liver damage is usually worse and progression faster in patients with dual HBV/HCV infections. Around one third of patients coinfected with HBV and HCV lack markers of HBV infection (i.e., HBsAg) although HBV DNA is detectable.

Geography and environmental factors: There are some obvious geographic differences (Lim 2008). For example, hepatocellular carcinoma is observed more often in Japan than in the United States. The reason for this is not clear.

Use of steroids: It is well known that use of steroids increases HCV viral load, while the effect on aminotransferases is variable. They tend to decrease in most patients, although increases in transaminases and bilirubin have also been described (Romero-Gutierrez 2014). Reducing dosage of corticosteroids returns HCV viral load to baseline. However, the clinical consequences of corticosteroid use are largely unknown. It seems reasonable to assume that short-term use of corticosteroids is not associated with significant changes in long-term prognosis.

Viral factors: The influence of viral factors on disease progression is unclear. Overall, there seems to be no significant role of different genotypes and viral quasispecies on fibrosis progression or outcome. However, coinfection with several genotypes may have a worse outcome as compared to monoinfection (Lin 2014).

It is very difficult to predict the individual course of HCV due to the many factors influencing disease progression. Today, assessment of liver fibrosis by non-invasive techniques such as transient elastography (FibroScan®) or by the more traditional liver biopsy is the best predictor of disease progression (Gebo 2002, Caviglia 2014). The grade of inflammation and stage of fibrosis are useful in predicting further clinical course. In patients with severe inflammation or bridging fibrosis virtually all will develop cirrhosis within ten years. In contrast, patients with mild inflammation and no fibrosis have an annual progression risk to cirrhosis of around 1%.

Several predictive models of disease progression that include clinical parameters (e.g., hepatic decompensation) and laboratory parameters (e.g., bilirubin, INR) have been evaluated, but none of these models is routinely used in the clinic at present. In patients with cirrhosis, the MELD score (Model for End-Stage Liver Disease) and the Child score (Table 1) are used to stage disease and to describe the prognosis (see Chapters 19 & 20). The MELD Score is used especially to estimate relative disease severity and likely survival of patients awaiting liver transplant. It is calculated as: MELD Score = 10 x (0.957 x ln(creatinine)) + (0.378 x ln(bilirubin)) + (1.12 x ln(INR)) + 6.43. An online calculator and further information can be found at the website of the United Network for Organ Sharing (UNOS) (http://www.unos.org).

However, the best way to slow liver fibrosis and the risk for hepatic decompensation in cirrhotics is successful HCV treatment (van der Meer 2012, Anderson 2013). The new directly acting antivirals (DAAs) with their high efficacy and very favourable safety profiles are already largely contributing contribute to lowering the disease burden caused by chronic HCV infection.

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