Hepatitis C virus: Prevention, screening, and interpretation of assays

GROUPS AT HIGH RISK OF HCV

Groups at risk of HCV infection can be classified as being at high, intermediate, or low risk. The American Association for the Study of Liver Diseases² rates the level of evidence for screening in all of the following risk groups as class I (ie, there is evidence or general agreement that it is beneficial, useful, and effective) and level B (ie, the data are derived from non-randomized studies).

Intravenous drug abusers

Intravenous drug abuse is the strongest independent risk factor for HCV infection.^30–33 It has been the main route of HCV infection over the past decades and currently accounts for 60% of HCV transmission in the United States.^7,10,34–37

Hemophilia patients treated with clotting factor concentrates produced before 1987

HCV seroprevalence is very high in patients with hemophilia who received infusions of plasma-derived clotting factor concentrates before 1987.³⁸ In these patients, the HCV genotypes are predominantly 1 and 3, and to a lesser extent genotype 2.^39,40 These genotypes likely reflect the prior exposures of the plasma donors.⁴¹ (See discussion of HCV genotypes below.) Individuals receiving clotting factor concentrates prepared from plasma pools were at high risk of HCV infection until effective procedures to inactivate viruses were introduced in 1985 (factor VIII) and 1987 (factor IX).⁴²

People infected with HIV

About 25% of people infected with human immunodeficiency virus (HIV) in the Western world also have chronic HCV infection.⁴³ Progression of liver disease is accelerated in HIV-HCV coinfection, and the risk of cirrhosis is twice as high.⁴⁴

However, about 6% of HIV-positive patients fail to develop HCV antibodies when infected. Thus, HCV RNA should be assessed in HIV patients with unexplained liver disease who are negative for anti-HCV.⁴⁵

The distribution of HCV genotypes in HIV-infected patients reflects the route of transmission. Genotype 1b accounts for 66% of posttransfusion HCV infections, while genotypes 1a and 3a are more common in intravenous drug users.

GROUPS AT INTERMEDIATE RISK OF HCV

Recipients of blood transfusions before 1992

Before 1992, blood transfusions carried a risk of HCV infection of up to 7% with each unit transfused. Prospective studies of transfusion recipients in the United States found that rates of posttransfusion hepatitis in the 1960s exceeded 20%,³⁶ since most patients received multiple units of blood.

In the mid-1970s, before HCV had been identified, available diagnostic tests indicated that 90% of cases of posttransfusion hepatitis were not caused by hepatitis A or hepatitis B viruses. By this time, the move to all-volunteer blood donors instead of paid donors had reduced the risk of posttransfusion hepatitis to 10%.^22,37,46

Although non-A, non-B hepatitis was first recognized because of its association with blood transfusion, population-based sentinel surveillance showed that it accounted for 15% to 20% of cases of community-acquired viral hepatitis in the United States.³⁵ The advent of molecular cloning in 1988 indicated that non-A, non-B hepatitis was primarily caused by HCV.^47–52

Screening of blood has reduced the rate of posttransfusion hepatitis C by a factor of about 10,000, to a current rate of 1 per million transfusions.⁵³ The few cases that still occur are due to newly infected people donating blood before they have developed antibodies to the virus, which can take up to 8 weeks.⁵⁴

Recipients of solid-organ transplants before 1992

Before organ donors were screened for HCV, recipients of solid-organ transplants from infected donors had a high risk of acquiring HCV infection. Transmission rates in different cohorts ranged from 30% to 80%.⁵⁵ In an attempt to improve the safety of organ transplantation, many transplant centers now screen donors for anti-HCV and test for HCV RNA for verification.

A related problem is pre-existing HCV infection in transplant recipients. Izopet et al⁵⁶ reported that, in renal transplant recipients with preexisting HCV infection, the HCV RNA titer rose about 10 times (1 log) higher after transplantation, owing to the immunosuppressive drugs that transplant recipients must take. Although this higher viral load does not affect the progression of fibrosis in all patients, the effect of immunosuppressive therapy on liver disease results in a worse outcome for some, and it reduces survival beginning in the second decade after kidney transplantation.⁵⁶

Additionally, treatment of HCV infection in transplant recipients may pose a challenge, as those receiving immunosuppressive therapy with tacrolimus (Prograf) or cyclosporine (Sandimmune) may develop some degree of renal insufficiency, complicating the use of ribavirin (Rebetol) and subjecting patients to a higher risk of severe anemia. Furthermore, interferon therapy increases the risk of renal allograft rejection and, accordingly, is not often used in renal transplant recipients.

Patients with unexplained elevated aminotransferase levels

HCV infection affects an estimated 1.8% of the general population, but the rate is much higher in people with ALT levels over 40 U/L. Most patients with chronic hepatitis C have no symptoms or only mild symptoms and minimally elevated levels of ALT and aspartate aminotransferase (AST)—ie, two to five times higher than the upper limit of normal.

The first step in the workup of aminotransferase elevations is to confirm the abnormality by repeating the blood test. If an elevation is confirmed, further investigation is warranted. A directed history and physical examination is important and may disclose risk factors, raising clinical suspicion of a particular disease.

Some caveats: The proportion of patients with HCV viremia who have abnormally high aminotransferase levels ranges between only 54% and 66%.^57–59 In patients with risk factors for HCV infection and abnormal liver enzyme levels, HCV infection is probable but not certain. Also, liver enzyme tests do not reveal the extent of hepatic injury or reflect the true status of hepatic function.⁶⁰

Infants born to infected mothers

Children born to HCV-positive women should be tested for anti-HCV no sooner than age 12 months, when passively transferred maternal anti-HCV declines below detectable levels. If earlier diagnosis of HCV infection is desired, a real-time polymerase chain reaction (PCR) test for HCV RNA can be done at or after the infant's first “well-child” visit at age 1 to 2 months.

If positive for either anti-HCV or HCV RNA, children should be evaluated for liver disease, and those with persistently elevated ALT levels should be referred to a specialist for medical management.^2,5