Hepatitis C: Symptoms, Transmission, and Treatment

What is hepatitis C?

Hepatitis is a term that means inflammation of the liver. Many conditions can cause hepatitis, including medications, toxins, excessive alcohol use, autoimmune diseases, and various types of infections, including viral hepatitis, which is among the most common causes.

Hepatitis C is a specific type of viral hepatitis caused by HCV (hepatitis C virus).

Although they have similar names, are caused by viruses, and affect the liver, hepatitis A, B, C, D, and E are different diseases caused by different viruses, with distinct modes of transmission and clinical courses.

Hepatitis C infection usually occurs in two phases: acute infection and chronic infection.

Acute infection refers to the first six months after acquiring the virus and is asymptomatic in most patients. During this period, the immune system may be able to eliminate the virus completely.

About 15% to 45% of infected people spontaneously clear HCV within the first six months. In the remaining cases, the virus persists and the infection becomes chronic.

Chronic hepatitis C can remain silent until advanced stages. Liver damage develops slowly, and in some cases symptoms do not appear until decades after infection. This explains why many people infected with HCV do not know they have the disease.

Without treatment, about 15% to 30% of people with chronic hepatitis C may develop liver cirrhosis over approximately 20 years.

According to the World Health Organization, approximately 47 million people worldwide are currently living with chronic HCV infection, with around 900,000 new infections occurring each year.

How is hepatitis C transmitted?

The main route of hepatitis C transmission is exposure to infected blood.

Until the late 1980s, the hepatitis C virus had not yet been identified. Therefore, donated blood was not tested for this virus. For many years, hepatitis C was known as non-A, non-B hepatitis. Doctors knew there was a form of hepatitis different from the already recognized hepatitis A and hepatitis B, but its cause was still unknown.

As a result, many people acquired the infection through blood transfusions without either patients or doctors being aware of the risk. After HCV was discovered in 1989, systematic screening of donated blood made transfusion-related transmission extremely rare in countries with adequate blood safety programs.

Consequently, many cases of transfusion-acquired hepatitis C diagnosed today are the result of transfusions received decades ago.

Today, sharing needles, syringes, or other equipment used to inject drugs is one of the main routes of HCV transmission in many countries.

Hepatitis C can also be transmitted sexually, although this occurs much less easily than with hepatitis B, HIV, and many other sexually transmitted infections. Among stable, monogamous heterosexual couples, the risk is very low, but it increases when there is exposure to blood, multiple sexual partners, other sexually transmitted infections, HIV infection, or sexual practices that cause trauma or bleeding.

Because direct contact with blood is the main route of transmission, people with hepatitis C should not share objects that may contain small amounts of blood, such as razors, toothbrushes, nail clippers, or manicure tools.

Less common routes of transmission include organ transplantation from infected donors, hemodialysis, occupational exposure to blood, and tattoos or piercings performed with contaminated equipment.

Mother-to-child transmission during pregnancy or childbirth can also occur. Among pregnant women with detectable HCV RNA, the risk of transmission to the baby is approximately 6% to 7% and is higher in women who are also infected with HIV, particularly when HIV is not well controlled. Cesarean delivery does not reduce the risk of HCV transmission, and there is no evidence that the virus is transmitted through breast milk.

Breastfeeding can continue as long as the nipples are not cracked or bleeding.

Hepatitis C is not transmitted through everyday contact. Hugging, shaking hands, coughing, sneezing, food, water, sharing glasses or utensils, and ordinary kissing do not transmit HCV.

How can hepatitis C be prevented?

There is no vaccine against hepatitis C. The main preventive measure is to avoid contact with infected blood.

Preventive measures include not sharing needles, syringes, or other equipment used to inject drugs; not sharing razors, toothbrushes, nail clippers, manicure tools, or other objects that may come into contact with blood; and ensuring that sterile or single-use equipment is used for tattoos, piercings, and other procedures that puncture the skin.

People with hepatitis C who are not immune to hepatitis A and B should discuss vaccination against these two viruses with a healthcare professional. These vaccines do not protect against HCV, but they prevent other infections that could worsen pre-existing liver disease.

What are the symptoms of hepatitis C?

Acute hepatitis C

As mentioned above, acute hepatitis C is usually asymptomatic. Approximately 80% of infected people have no clinical manifestations.

When symptoms do occur, they usually appear between two and 12 weeks after infection.

Symptoms of acute hepatitis C include feeling unwell, fever, nausea and vomiting, jaundice (yellowing of the skin and eyes), itching, fatigue, dark urine, and abdominal pain in the area of the liver, below the ribs on the right side.

Symptoms are usually mild and nonspecific, which is why many cases of acute hepatitis C go unnoticed.

Blood tests may show elevated liver enzymes, particularly AST and ALT, as well as increased bilirubin levels.

It is important to remember that the absence of symptoms does not mean that the virus has been eliminated. Most patients who go on to develop chronic hepatitis C did not have clinical symptoms during the acute phase.

Chronic hepatitis C

The main risk associated with hepatitis C arises when the infection becomes chronic. After acquiring the virus, whether or not symptoms occur, about 15% to 45% of patients spontaneously clear HCV within the first six months. In the remaining cases, the infection persists.

A patient is considered to have a chronic infection when HCV remains present in the body six months after infection.

Chronic hepatitis C usually progresses silently for many years. Some patients experience only nonspecific symptoms, such as fatigue, feeling unwell, or mild abdominal discomfort, while others remain completely asymptomatic until signs of advanced liver disease appear.

Without treatment, about 15% to 30% of patients with chronic hepatitis C may develop liver cirrhosis over approximately 20 years. Patients with cirrhosis also have an increased risk of hepatocellular carcinoma, the most common type of primary liver cancer.

When cirrhosis and liver failure develop, symptoms may include:

• Jaundice.
• Ascites.
• Dark urine.
• Pale stools.
• Itching.
• Collateral circulation, with blood vessels becoming more visible through the skin, especially over the abdomen and trunk.
• Swelling of the legs.
• Weight loss.
• Loss of appetite.
• Mental confusion in cases of hepatic encephalopathy.

It is not entirely clear why some patients with chronic hepatitis C develop fibrosis and cirrhosis more rapidly, while others remain for decades with little liver damage.

However, several factors are known to favor faster disease progression, including:

• Excessive alcohol consumption.
• Infection acquired at an older age.
• HIV coinfection.
• Hepatitis B virus coinfection.
• Diabetes mellitus.
• Fatty liver disease.
• Obesity.

Other complications

In addition to cirrhosis and hepatocellular carcinoma, patients with chronic hepatitis C have an increased risk of developing the following complications:

• Cryoglobulinemia.
• Glomerulonephritis.
• Thyroiditis.
• Porphyria cutanea tarda.
• Lichen planus.
• Diabetes mellitus.
• Some types of B-cell lymphoma.

How is hepatitis C diagnosed?

Because hepatitis C can remain asymptomatic for many years, diagnosis should not depend on the development of symptoms or abnormalities in liver enzymes.

Recommendations for hepatitis C testing vary according to local epidemiology and national health policies. The World Health Organization recommends offering HCV antibody testing in all settings to adults and adolescents who belong to populations disproportionately affected by HCV infection or who have a history of exposure or behaviors associated with increased risk.

WHO also recommends testing adults, adolescents, and children when there is clinical suspicion of chronic viral hepatitis.

In settings where the prevalence of HCV antibodies in the general population is 2% or higher, WHO recommends offering hepatitis C testing to all adults and adolescents. Some countries also recommend testing specific age groups in which hepatitis C prevalence is higher than in the general population.

WHO does not currently make a specific universal recommendation to test every pregnant woman for hepatitis C. Screening policies during pregnancy depend on local epidemiology and national recommendations. Some countries, including the United States, recommend hepatitis C screening during every pregnancy.

People with ongoing or repeated risk of HCV exposure should be tested periodically. Examples include people who share equipment used to inject drugs, patients receiving hemodialysis, and others who are frequently exposed to blood.

People with unexplained elevations in liver enzymes and those who received blood transfusions or blood products before systematic HCV screening of donated blood was introduced in their country should also be evaluated.

Diagnosis of hepatitis C begins with testing for antibodies against the virus, known as anti-HCV antibodies. This can be done using a rapid test or a laboratory immunoassay.

If the anti-HCV test is negative, infection is unlikely, except when exposure to the virus occurred recently or in certain cases of immunodeficiency.

If the anti-HCV test is positive, it is necessary to determine whether there is an active infection. This is done by directly detecting HCV RNA using a molecular test, usually a PCR-based test.

Therefore, a positive anti-HCV result does not necessarily mean that the person still has hepatitis C. HCV antibodies usually remain positive for life, even after spontaneous clearance of the virus or successful treatment.

In simplified terms:

• Negative anti-HCV: there is no evidence of previous exposure to the virus, provided the exposure was not recent.
• Positive anti-HCV + detectable HCV RNA: there is an active HCV infection.
• Positive anti-HCV + undetectable HCV RNA: there is no evidence of active infection at that time. This can occur after spontaneous clearance of the virus or after successful treatment.

HCV RNA testing can also quantify the amount of virus circulating in the blood, known as the viral load.

A patient with detectable HCV RNA more than six months after infection is considered to have chronic hepatitis C.

How soon after infection can hepatitis C tests detect the virus?

After recent exposure to HCV, antibody testing may still be negative during the first few weeks. This happens because the body needs time to produce detectable levels of antibodies.

HCV RNA can be detected earlier, usually within the first or second week after exposure. Anti-HCV antibodies, on the other hand, usually become detectable between one and three months after exposure.

When there is a known HCV exposure, such as a needlestick injury involving a potentially contaminated needle, an initial evaluation is performed to determine whether there was already evidence of infection before the incident.

When follow-up is indicated, HCV RNA is usually tested again three to six weeks after exposure. A final anti-HCV test is generally performed four to six months later, with HCV RNA testing if antibodies become positive or if there is another clinical indication.

The testing schedule may vary depending on the type of exposure and the status of the source person.

There is currently no post-exposure prophylaxis for hepatitis C comparable to the PEP used for HIV. If a new HCV infection is confirmed, some current guidelines recommend starting antiviral treatment without waiting six months to see whether spontaneous clearance occurs.

Is HCV genotype testing still necessary?

There are different genetic variants of HCV, known as genotypes. For many years, identifying the genotype responsible for the infection was essential for choosing the appropriate medications and determining treatment duration.

With the introduction of pangenotypic direct-acting antivirals, which are effective against different HCV genotypes, this information has lost much of its practical importance.

Today, pangenotypic regimens allow most patients to be treated without prior genotype testing. However, genotyping may still be necessary in certain situations, depending on the available treatment, previous therapies, the presence of cirrhosis, and local guidelines.

The choice of treatment now depends mainly on the degree of liver damage, whether cirrhosis is present and how severe it is, previous treatments, potential drug interactions, and specific clinical circumstances.

How is liver fibrosis assessed?

All patients with chronic hepatitis C should be evaluated for the degree of liver fibrosis.

Liver biopsy, which for many years was the standard method, has largely been replaced by noninvasive methods such as liver elastography (FibroScan), which measures liver stiffness using ultrasound waves and allows fibrosis to be estimated quickly and noninvasively, and blood-based scores such as FIB-4 and APRI, which use simple laboratory parameters to indirectly estimate the degree of liver fibrosis.

The APRI (AST to Platelet Ratio Index) is calculated using two basic blood test results: the AST level and platelet count. It helps indirectly estimate the degree of liver fibrosis because AST tends to rise with liver injury, while platelet counts often fall as fibrosis and portal hypertension progress.

Like other indirect markers, APRI should not be interpreted in isolation because AST levels and platelet counts can be altered for reasons unrelated to liver fibrosis.

APRI does not completely replace methods such as elastography, but it is useful as an initial tool because it is simple, inexpensive, and available in virtually any healthcare setting.

Cutoff values may vary according to the protocol being used. Under WHO criteria, an APRI below 1 is associated with a low probability of cirrhosis. A result of 1 or higher warrants closer evaluation, while values of 2 or higher have greater specificity for cirrhosis.

A liver biopsy is now mainly reserved for situations in which hepatitis C must be distinguished from other liver diseases or when noninvasive methods do not provide enough information.

When a liver biopsy is still indicated, one of the most commonly used systems for grading and standardizing the results is the METAVIR scoring system. The degree of inflammation, or disease activity, is classified from A0 to A3, while the degree of fibrosis is classified from F0 to F4.

METAVIR scoring system:

• A0: no activity.
• A1: mild activity.
• A2: moderate activity.
• A3: severe activity.
• F0: no fibrosis.
• F1: portal fibrosis without septa.
• F2: portal fibrosis with few septa.
• F3: numerous septa without cirrhosis.
• F4: cirrhosis.

Assessing the degree of fibrosis is important not only for treatment decisions but also for determining which patients will need continued follow-up even after hepatitis C has been cured.

Can hepatitis C be cured? How is it treated?

Until a few years ago, the goal of hepatitis C treatment was to prevent the infection from progressing to cirrhosis and liver failure. Because many patients did not progress to these complications and the available medications caused a high rate of adverse effects, not everyone infected with HCV was considered a candidate for treatment.

The introduction of direct-acting antivirals (DAAs) revolutionized the treatment of hepatitis C.

These medications are taken orally for a relatively short period, cause far fewer side effects than older interferon-based regimens, and cure more than 95% of patients.

WHO currently recommends treatment with pangenotypic direct-acting antivirals for all adults, adolescents, and children aged 3 years and older with chronic hepatitis C.

In confirmed acute HCV infection, some current guidelines also recommend starting treatment once active infection has been established, rather than waiting six months to see whether spontaneous viral clearance occurs.

Treatment during pregnancy is a special situation. WHO currently does not provide a universal recommendation for the use of direct-acting antivirals during pregnancy because safety and efficacy data remain more limited than in the general population. Management should follow local recommendations and be assessed on an individual basis.

Another major advance was the introduction of pangenotypic regimens, which are effective against different HCV genotypes. As a result, treatment has become simpler and genotype testing is no longer necessary in most situations.

The choice of medication depends mainly on the degree of liver damage, the presence and severity of cirrhosis, previous treatments, associated medical conditions, and potential interactions with other medications used by the patient.

Treatment with direct-acting antivirals

The medications available and the treatment protocols covered by healthcare systems vary between countries. However, WHO currently recommends several pangenotypic regimens that allow most patients with hepatitis C to be treated without prior genotype testing.

Some of the main regimens used in adults, adolescents, and children aged 3 years and older include:

• Sofosbuvir/velpatasvir for 12 weeks.
• Sofosbuvir/daclatasvir for 12 weeks in patients without cirrhosis, with treatment duration adjusted in certain situations.
• Glecaprevir/pibrentasvir for 8 weeks in many patients without cirrhosis and in selected patients with compensated cirrhosis.

The exact treatment duration and choice of regimen depend on the presence of cirrhosis, previous treatment, the child’s age and weight when applicable, potential drug interactions, and national or local recommendations.

Patients with decompensated cirrhosis require more specialized assessment. In these cases, sofosbuvir/velpatasvir-based regimens may be used, with treatment duration and the possible addition of other medications depending on the clinical situation. Regimens containing protease inhibitors, such as glecaprevir or voxilaprevir, should not be used in patients with decompensated cirrhosis.

Specific regimens are also available for patients who were not cured by previous treatment. One of the main retreatment options for selected patients without decompensated cirrhosis is the combination of sofosbuvir/velpatasvir/voxilaprevir.

Although direct-acting antivirals are generally well tolerated, they can interact with other medications. For this reason, all prescription drugs, over-the-counter medications, supplements, and herbal products should be reviewed before treatment begins.

The goal of treatment is to eliminate HCV from the bloodstream. Hepatitis C is considered cured when HCV RNA remains undetectable at least 12 weeks after treatment has ended. This result is known as a sustained virologic response (SVR).

What happens after hepatitis C is cured?

Successful treatment eliminates the current HCV infection but does not produce immunity against the virus. Therefore, a person who has been cured can become infected with hepatitis C again after a new exposure.

Anti-HCV antibodies also usually remain positive after successful treatment. For this reason, when reinfection is suspected, the appropriate test is HCV RNA rather than simply repeating the anti-HCV antibody test.

Patients without significant liver fibrosis and without other important risk factors may no longer require hepatitis C-specific follow-up once sustained virologic response has been confirmed.

Patients with cirrhosis, however, must continue to be monitored even after the virus has been eliminated. Successful treatment substantially reduces the risk of liver cancer but does not eliminate it completely. For this reason, WHO recommends continued surveillance for hepatocellular carcinoma every six months in patients with cirrhosis.

For patients with advanced F3 fibrosis without cirrhosis, whether continued liver cancer surveillance is recommended may vary according to professional society guidelines, national recommendations, and the patient’s individual risk.

Some important points

• The only treatments scientifically proven to eliminate HCV are appropriate antiviral medications. Be cautious with so-called natural treatments because, in addition to not eliminating the virus, some herbs and supplements can be toxic to the liver.
• There is no diet that can cure hepatitis C. In general, a balanced diet, maintaining a healthy weight, and avoiding alcohol are recommended. Patients with cirrhosis or other liver complications may require specific nutritional advice.
• Physical activity does not act directly against HCV, but it is recommended according to the patient’s clinical condition because of its benefits for body weight, insulin resistance, fatty liver disease, and cardiovascular health.
• Unlike hepatitis A and B, there is no vaccine against hepatitis C.

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