The incubation period of hepatitis C ranges from 14-180 days, after which one of the following clinical scenarios can be observed:

Acute hepatitis C, which is frequently asymptomatic. Less than a third of patients develops non-specific symptoms such as fever, fatigue, malaise, upper abdominal pain, nausea, vomiting, and myalgia. Jaundice and dark urine may be noted. Acute hepatitis C is self-limiting, and symptoms subside after up to three months. In 50-80% of cases, though, acute hepatitic C leads to chronic infection, with the majority of patients remaining unaware of this development [1].

Chronic hepatitis C, as indicated by persistent viremia after 12-24 weeks of infection. The vast majority of individuals who acquire HCV develop a persistent infection where chronic fatigue is the principal symptom. Additional symptoms are non-specific and may comprise hepatomegaly, upper abdominal pain, nausea, vomiting and loss of appetite [2]. The systemic nature of the disease is reflected in extrahepatic manifestations, which may include immune-related disorders such as cryoglobulinemia, B-cell lymphoma, Sicca syndrome, myalgia, and arthralgia, as well as inflammatory-related conditions like diabetes mellitus type 2, membranoproliferative glomerulonephritis, polyarthritis, and fibromyalgia [3].
Jaundice, ascites, variceal bleeding, and encephalopathy with cognitive deficiencies, which are suggestive of liver disease, are not usually observed until the progression to cirrhosis [4]. Cirrhosis may develop decades after the initial infection and predisposes to the development of hepatocellular carcinoma [5]. Liver cancer may be associated with non-specific symptoms as described above, and with malaise, weight loss, and gastrointestinal complaints.

Fulminant hepatitis C. A rapid progression of acute hepatitis to fulminant hepatic failure is observed in a very few cases. It is associated with a rapid deterioration of liver function due to massive hepatic necrosis, leading to encephalopathy and multiorgan failure.

The diagnosis of hepatitis C based solely on clinical criteria is difficult, especially in mildly symptomatic chronic carriers. For this reason, a detailed patient history is mandatory during the workup, as physicians can assess risk factors - risky sexual intercourse, intravenous drug abuse or even recent tattooing - as well as the onset and progression of symptoms. When a clinical suspicion of viral hepatitis is supported by data obtained during the anamnesis and physical examination, an extensive laboratory workup is necessary. Complete blood count and biochemical profile are drawn, comprised of serum electrolytes, liver function tests, bilirubin, albumin, and alkaline phosphatase levels, and renal parameters. In case of hepatitis C, liver enzymes may be elevated up to 10 times the normal values, and these findings warrant testing for viral hepatitis.

Serological testing for anti-HCV IgM and IgG antibodies is the basis of the diagnosis of both acute and chronic infections with HCV. However, the presence of antibodies is no proof of an active infection and may possibly be explained by a previous, yet overcome infection with HCV, and seroconversion may not occur until two months after the exposure to HCV. Thus, the effective and early confirmation of hepatitis C requires the detection of viral RNA in serum. Molecular biological studies are also preferred in the immunocompromised, who may not be able to produce detectable amounts of antibodies and who make up a considerable share of hepatitis C patients.

Co-infections with HCV, hepatitis B virus and human immunodeficiency virus are not rare occurrences, since these pathogens are transmitted via similar routes [6] [7]. Accordingly, the confirmation of hepatitis C should prompt testing for infections with the other agents. Furthermore, the diagnosis of hepatitis C requires a thorough assessment of the advancement of liver disease. Most reliable results are obtained by the histological examination of tissue samples obtained by biopsy, with diagnostic imaging playing a greater role in gaining an overview and during follow-ups.

The development of drugs with direct antiviral activity have made hepatitis C a curable condition. The respective pharmaceuticals are well tolerated, and response rates exceed 90%. The precise treatment regimen will depend on the HCV genotype and subtype, the severity of liver disease, and the results of prior therapy, if carried out. When available, interferon-free regimens are preferred over those based on the application of peginterferon α-2a and peginterferon α-2b. Patients infected with HCV genotypes 1, 4, 5, or 6 may be provided sofosbuvir and ledipasvir, while sofosbuvir and ribavirin may be indicated if HCV genotypes 2 or 3 are detected [2] [8]. There are other compounds that are approved for hepatitis C treatment, namely simeprevir, daclatasvir, paritaprevir, ombitasvir, and dasabuvir, and the interested reader is referred to the treatment recommendations published by the European Association for the Study of the Liver: Here, guidelines are provided for the management of a number of special cases [8].

A sustained virologic response is achieved when HCV RNA is no longer detectable in the patient's serum, and the respective tests are carried out 12 and 24 weeks after the end of treatment; patients are considered to be cured if retesting after 48 weeks Still, the elimination of the causative agent does not imply the complete regression of fibrosis or cirrhosis. These conditions may improve in the absence of HCV, but patients with advanced-stage hepatitis C remain at risk of portal hypertension, hepatic failure, and hepatocellular carcinoma. Accordingly, they should be offered regular follow-ups to facilitate the early detection of a possible deterioration or malignant degeneration [8].

End-stage liver disease is an indication for liver transplantation, regardless of the provision of antiviral therapy. The preventive elimination of HCV is highly recommended, though, to prevent liver graft infection after transplantation [8].

Spontaneous clearance of HCV occurs within 6 months of infection in up to 45% of infected individuals, without treatment being provided [9]. Still, this process does not result in long-term immunity and those belonging to certain risk groups may re-contract the disease. Similarly, the elimination of HCV by means of antiviral therapy does not protect from new infections.

The prognosis of patients who receive anti-HCV therapy primarily depends on the severity of liver disease at the time of diagnosis. Fibrosis, cirrhosis, and carcinoma development are largely irreversible and often associated with a poor outcome. Fulminant hepatitis C has long since been associated with the highest mortality rates, but progress in therapy considerably improved the prognosis of affected individuals [10]. On the other hand, patients who are diagnosed and treated before the onset of irreversible liver damage have a good prognosis [11] [12].

HCV is a single strained RNA virus with pronounced genetic variability. To date, 7 genotypes and 67 subtypes have been defined [2] [9]:

• Genotype 1 accounts for almost half of HCV infections worldwide. It is particularly common in developed countries.
• Genotype 3 is the second most common variant of HCV. It accounts for about a third of all cases and is mainly detected in South Asia, Europe, and the Americas.
• Genotypes 2 and 6 account for greater shares of infections in East Asia, while genotype 4 is mainly found in Africa and the Middle East.
• Genotype 5 has been related to some infections in Southern Africa, and genotype 7 has been defined after being isolated from a patient originating from the Democratic Republic of Congo [13].

HCV is transmitted through blood and blood products, and via the sexual route. Accordingly, intravenous drug abuse and needle-sharing, as well as unprotected sexual activity are considered risk factors for hepatitis C. In both settings, concomitant immunodeficiency significantly increases the risk of HCV transmission. Those who receive infected blood products, undergo invasive procedures, receive piercings or tattoos in facilities with inadequate infection control practices may also contract the disease, but iatrogenic hepatitis C has become less frequent. Vertical transmission, on the other hand, is the principal mode of virus acquisition in children. Children born to affected mothers thus form another risk group. The risk of vertical HCV transmission has been estimated at <10% in the absence of the human immunodeficiency virus but may rise to 25% in case of co-infections.

Hepatitis C is a major public health concern, and it has been estimated that there are about 160 million persons with serological evidence of current or past HCV infection [8]. Each year, up to 700,000 patients die from this disease. Prevalence rates are highest in lower and middle-income countries, in Sub-Saharan Africa and Eastern Europe, where insufficient safety measures contributed to the iatrogenic spread of hepatitis C [9]. Still, the primary reason for the high number of cases on a global scale is the insidious nature of the infection, as up to 85% of infected individuals develop a stable chronic infection that tends to go unnoticed [14].

Acute HCV infections rapidly trigger an innate immune response. However, HCV alters the host defense and innate immunity through a variety of complementary mechanisms, thereby facilitating chronic infection. Neutralizing antibodies against HCV are produced from the second month after infection, but it has not yet been clarified whether these antibodies suffice for viral clearance. On the other hand, weak, delayed, or transient CD4+ and CD8+ T-cell responses have been identified as causes of persistent infection. The inhibition of T-cell response might be mediated by the infection of dendritic cells, or by the direct inhibition of T-cell differentiation and maturation, but further research is required to confirm these hypotheses. Those patients who can overcome the infection show year-long sustained, vigorous, and HCV-specific T-cell responses [5].

Initially, the very high cost of direct antivirals severely limited the access to curative treatment, but substantial price reductions have opened up the opportunity for appropriate management even in resource-limited settings. Unfortunately, though, the majority of hepatitis C patient develops chronic liver disease and remains unaware of the infection. Comprehensive screenings may be required to unveil millions of cases of subclinical hepatitis C, which is a prerequisite to reach the ambitious goal of globally eliminating the disease within the next decades. To date, the costs of HCV diagnostics may exceed those of curative therapies, and further research is required to facilitate the development of specific, sensitive, and affordable tools that may close that gap [14].

On an individual scale, the correct and consistent use of condoms and the avoidance of exposure to blood and blood products are the best options to prevent infection with HCV. Those at risk should regularly be tested, e.g., medical personnel, health-care workers, tattooists, sex workers, and immunodeficient patients.

Hepatitis C is a sexually transmissible disease and major public health concern. According to estimates, there are >150 million people infected with HCV. While acute symptoms may develop, the disease usually follows a chronic course. Chronic hepatitis C may be associated with constitutional symptoms, gastrointestinal complaints, and immune disorders, among others. The absence of liver-specific symptoms contributes to long delays in diagnosis, where the majority of patients remains unaware of the infection until decades after the acquisition of HCV. During that time, they may infect others, and they are likely to develop fibrosis and cirrhosis. Cirrhosis, in turn, is a major risk factor for hepatocellular carcinoma.

The introduction of drugs with direct antiviral activity as well as recent price reductions put a cure within reach of many patients who did not yet develop irreversible liver damage. The latter may require liver transplantation, but even those patients will benefit from pangenotypic anti-HCV therapy. Current challenges thus consist in raising awareness, increasing detection rates, and providing effective treatment to the highest possible number of patients. This way, hepatitis C may eventually be eradicated on a global scale.

Hepatitis C is a major public health concern. It is a sexually transmissible disease, but hepatitis C virus may also be acquired when exposed to blood or blood products, when needles are shared by intravenous drug users, or when children are born to infected mothers. Symptoms of acute infection are not usually developed and don't suggest liver disease. Patients with acute hepatitis C may claim fever, fatigue, malaise, upper abdominal pain, nausea, vomiting, and myalgia. These symptoms typically subside after several weeks, and the patients assume to be cured of whatever disease they had contracted. In fact, however, the infection persists. Over the course of decades, chronic hepatitis C may manifest in distinct constitutional symptoms, gastrointestinal complaints, and immune disorders. Symptoms suggestive of liver disease may not be developed until irreversible damage occurs, until the patient suffers from liver fibrosis, cirrhosis, or even cancer. What's more, while unaware of the infection, patients may infect others.

The causes of symptoms consistent with acute or chronic hepatitis C should thus be clarified. What's more, good outcomes are linked to an early diagnosis and timely initiation of treatment. Those who prevent an infection in the first place have the best prognosis, though: The acquisition of hepatitis C virus can be avoided by the consistent use of condoms and the responsible handling of potentially infective materials.

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