Hepatitis C Infection

Background

In the United States, an estimated 2.7-3.9 million people are living with chronic hepatitis C virus (HCV) infection and about 12,000 deaths per year are attributable to HCV. Among HIV-infected patients, liver disease owing to hepatitis C virus (HCV) infection has become a leading cause of death, as antiretroviral therapy (ART) has reduced AIDS-related mortality, but the sequelae of chronic HCV have increased. HCV is common among persons with HIV infection in the United States. It is estimated that 30-40% of the HIV-infected population in the United States is coinfected with HCV, but the prevalence varies with risk factor for transmission. Among HIV-infected injection drug users and hemophiliacs, 70-95% may be coinfected with HCV; among HIV-infected men who have sex with men (MSM), 1-12% are coinfected with HCV

HCV is a single-stranded RNA virus that is transmitted mainly through blood exposure, and, less commonly, through perinatal or sexual exposure. HCV is more likely than HIV to be transmitted via a bloodborne route; there is an approximately 10-fold greater risk of HCV transmission after needlestick exposure compared with the risk of HIV transmission, and the concentrations of HCV in a given volume of blood are greater than those of HIV. Perinatal transmission of HIV is more likely among women who are coinfected with HIV and HCV than among women with HIV infection alone; similarly, perinatal transmission of HCV is more likely in coinfected women than in those with HCV monoinfection. Breast-feeding is not known to transmit HCV, although HIV-infected women are advised against breast-feeding because of the risk of transmitting HIV.

Although sexual transmission of HCV is not efficient, 10% of acutely infected HCV persons report no risk factor other than sexual contact with an HCV-infected partner. Many centers have reported an increase in acute HCV in MSM, and rates of sexual transmission of HCV appear to be higher in in MSM than in the general population, especially among persons who are coinfected with HIV.

The natural history of HCV infection is variable. Approximately 20% of monoinfected patients ultimately develop cirrhosis, whereas approximately 80% of patients develop some degree of fibrosis (without progression to cirrhosis); patients without cirrhosis typically remain asymptomatic. HCV can affect organ systems outside the liver, such as dermatological and renal systems, but its effects most commonly are limited to the liver. Coinfection with HIV adversely impacts the natural history of HCV infection. HIV/HCV-coinfected patients have lower rates of spontaneous HCV clearance, higher HCV viral loads, lower rates of successful HCV treatment, faster progression to cirrhosis, and greater risk of developing liver decompensation, end-stage liver disease, and hepatocellular carcinoma (HCC). On the other hand, HCV coinfection does not appear to increase HIV- and AIDS-related complications or the success of HIV antiretroviral (ARV) treatment.

Newly available directly acting anti-HCV drugs, when used in conjunction with standard HCV therapy, appear to substantially enhance the likelihood of successfully treating HCV in challenging subgroups of coinfected persons; these and additional new drugs that are in advanced stages of development offer the hope of greatly improved therapies for HCV.

Acute HCV Infection

Persons with acute HCV infection typically are asymptomatic or have only mild symptoms. Patients who do present with new onset of jaundice, weakness, anorexia, abdominal pain, or malaise without a known cause should be tested for acute HCV infection. Symptoms usually subside after several weeks. Patients who present after a potential exposure, such as a needlestick injury, should be tested for acute infection whether or not they are symptomatic. Overall, approximately 15-30% of patients acutely infected with HCV will clear the virus spontaneously, and 70-85% of patients will develop chronic infection. However, there are few prospective studies on the natural history of acute HCV infection with preexisting HIV infection. Because it is difficult to establish the precise timing of HCV infection, prospective natural history studies are difficult to perform.

Chronic HCV Infection

For the majority of HCV patients, other than laboratory abnormalities, there are no clinical manifestations of infection until the late stages of cirrhosis. Cirrhosis develops in approximately 20% of HCV-monoinfected patients, usually 20 years or more from the time of infection. A higher proportion of HIV/HCV-coinfected patients are thought to develop cirrhosis, and at a faster rate. Once patients have developed cirrhosis, approximately 50% will decompensate within the first 5 years. Typically, the first sign of decompensation is the development of ascites. Of patients with cirrhosis, approximately 1-4% per year will develop HCC, or approximately 20% of cirrhotic patients in total. The median survival time from the onset of HCC is approximately 5 months, and the 1-year survival rate is 29%.

S: Subjective

Patients with HCV infection, whether acute or chronic, often have no symptoms, and the infection is discovered via screening tests or on workup of an abnormal liver test result.

Patients with acute HCV infection typically are asymptomatic but may present with symptoms such as jaundice, abdominal pain, and malaise. If symptoms from acute infection develop, they usually do so within 4 weeks after infection has occurred. Most patients with chronic HCV cannot recall a time when they were acutely symptomatic, and HCV is detected because of an incidental finding of abnormal transaminases or through a screening test.

Ask patients with known chronic HCV infection about symptoms that suggest complications of HCV, such as cirrhosis, decompensated cirrhosis, or hepatocellular carcinoma. Additionally, ask patients about any risk factors for other liver injury, such as alcohol and hepatotoxic drugs, and about drugs whose metabolism may be affected by liver disease.

• Fatigue
• Weight loss
• Impaired concentration
• Chronic hepatitis B
• Alcohol intake
• Substance use
• ARVs that may cause hepatotoxicity (didanosine, protease inhibitors, nevirapine, maraviroc)
• Medications with potential for hepatotoxicity, or accumulation in persons with liver disease (e.g., acetaminophen, benzodiazepines, opiates)

O: Objective

Measure vital signs. Calculate body mass index (see chapter Initial Physical Examination).

Perform physical examination to include evaluation of the following:

• Head, eyes, ears, nose, and throat (HEENT): temporal wasting, icterus
• Heart and lungs: signs of congestive heart failure
• Chest: gynecomastia
• Abdomen: caput medusa, venous prominence, distention, signs of ascites, hepatomegaly, splenomegaly
• Extremities: edema
• Neurologic: alertness, mental status, asterixis
• Skin: jaundice, palmar erythema, petechiae, ecchymoses, spider angiomata

P: Plan

Diagnostic Evaluation

Acute HCV infection

After initial exposure, HCV RNA can be detected in blood within 1-3 weeks and is present at the onset of symptoms. Antibodies to HCV can be detected in only 50-70% of patients at the onset of symptoms, but in >90% after 3 months. Within an average of 4-12 weeks, liver cell injury is manifested by elevation of serum alanine aminotransferase (ALT). It is important to understand the timeline of these diagnostic tests in order to appropriately diagnose acute infection and follow for potential resolution versus persistent infection.

In patients with suspected acute HCV infection, check HCV antibody (IgG), HCV RNA, and ALT immediately and then weekly until the ALT has begun to decline and HCV antibody has seroconverted to positive status. The seroconversion of HCV antibody establishes the diagnosis of acute infection. At that point, check the HCV RNA every 2-4 weeks for the following 3 months. If HCV RNA is still present at 3 months, strongly consider starting treatment for acute HCV promptly. If treatment is not initiated and RNA is still present at 6 months after infection, the likelihood of spontaneous clearance is extremely low, and the patient is diagnosed with chronic infection.

Chronic HCV Infection

HCV antibodies

All HIV-infected patients should be tested for HCV infection with the HCV antibody test. Patients with risk factors for HCV infection should be retested at regular intervals. A positive HCV antibody does not establish the diagnosis of active HCV infection but is evidence of exposure; HCV RNA must be checked (see below). In HIV-infected patients, the HCV antibody test result sometimes is falsely negative; therefore, if HCV infection is suspected in spite of a negative HCV antibody finding (e.g., because of a history of high-risk behavior, unexplained elevated ALT, or evidence of cirrhosis), the HCV RNA should be tested even if the HCV antibody test result is negative. A false-negative HCV RNA result is very unlikely in chronic infection.

HCV RNA

All patients who test positive for HCV antibody should have HCV RNA testing performed. As noted above, if patients have negative results on HCV antibody tests but persistently abnormal transaminases or suspected acute or chronic infection, HCV RNA testing should be performed.

The definition of chronic HCV infection is the presence of HCV RNA 6 months after the estimated time of infection. If a patient is HCV antibody positive but HCV RNA negative, the patient has cleared the HCV and does not have chronic HCV infection.

There are quantitative RNA tests and qualitative RNA tests. Although both types of RNA tests are highly sensitive and specific, the qualitative tests can detect lower levels of viremia than the quantitative tests. The choice of RNA test can be important.

The quantitative RNA tests will be reported as a value, with a measured number of international units per milliliter (IU/mL). Quantitative tests are useful for determining the prognosis of HCV treatment and then monitoring while on HCV treatment. Qualitative RNA tests will be reported as a present or absent value, but without a numerical value. They are useful for serial testing during suspected acute infection and for determining whether spontaneous viral clearance has occurred, a sustained virological response has occurred during treatment, or a relapse has occurred after treatment.

Genotyping

The HCV genotype is the strongest predictor of response to HCV treatment and also is a critical determinant of the dosage and duration of treatment. Patients with genotype 1 have poorer responses to treatment than those with genotype 2 or 3. HCV genotyping should be performed once for all patients with detectable HCV RNA; it does not need to be repeated.

Alanine aminotransferase

Monitoring of ALT can be useful to assess acute infection, chronic liver inflammation, and response to HCV treatment. However, ALT does not always correlate with the degree of fibrosis and in addition, ALT can be persistently normal in 25% of HCV patients, including patients with cirrhosis or advanced liver disease. Small fluctuations in ALT usually are not clinically significant in HCV, though trends can be significant during or following HCV treatment.

Additional tests

Check complete blood cell count with platelet count, albumin, total bilirubin, and prothrombin time.

Test all patients for hepatitis B (HBsAg, anti-HBsAb, and anti-HBcAb). For patients with a positive HBsAg or a positive anti-HBcAb result (absent anti-HBsAb), test for active HBV infection (HBV DNA and HBeAg) (see chapter Hepatitis B Infection). Patients with a negative HBsAg and negative anti-HBsAb result should be vaccinated against HBV.

Test for hepatitis A virus (HAV) antibodies (total). All patients with a negative HAV antibody result should be vaccinated against HAV.

Imaging

Ultrasonography can be performed to screen for cirrhosis or focal hepatic masses. Computed tomography (CT), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT) are more expensive and generally are reserved for further evaluation of liver masses detected by ultrasound.

Liver biopsy

Liver biopsy is used to define the degree of inflammation (the grade) and degree of fibrosis (the stage) to determine the need for HCV treatment. Unless there is clear evidence of cirrhosis, laboratory tests and radiology studies are unable to quantitate the degree of fibrosis in the liver. Liver biopsy carries some risk, primarily from bleeding (the risk of significant bleeding or fatality is approximately 1/10,000). Patients with severe thrombocytopenia or coagulopathy should not undergo liver biopsy. Fibrosis is scored from 0 to 4, with 0 indicating no fibrosis and 4 indicating cirrhosis.

Biopsy can be useful in making management decisions for some HCV patients, for example when determining whether to treat a patient, particularly those with genotype 1 virus (see below). If the biopsy reveals only mild-to-moderate fibrosis, it may be preferable to defer treatment and monitor the patient. Conversely, if the biopsy reveals more advanced fibrosis, treatment should be considered more urgently. With genotype 2 or 3 patients, some providers consider biopsy to be unnecessary because treatment outcomes are sufficiently high that findings from a biopsy would not necessarily change the management strategy. For HIV/HCV-coinfected patients, a biopsy may be particularly useful in determining the stage of disease and in planning whether or when to initiate HCV treatment, as the course of liver disease may accelerate. Overall, deciding whether to conduct a biopsy largely is a matter of individual choice. It is not a requirement for treatment of any patient, but may be useful for helping the provider and patient make a decision about whether or when to undergo treatment.

Treatment

Treatment of acute HCV

The presence of HIV infection is not a contraindication to treatment of acute HCV infection. With HIV/HCV-coinfected patients, as with HCV-monoinfected patients, early treatment of acute HCV infection yields a much higher rate of sustained virological response (SVR) than does treatment of chronic HCV infection. In three prospective trials of treatment for acute HCV in HIV-coinfected patients, using pegylated interferon (PEG-IFN) alfa-2a and ribavirin for 24 or 48 weeks, the SVR for genotype 1 HCV was 55-75%, compared with 100% for genotype 3. By contrast, in the largest study of chronic HCV treatment in HIV-coinfected patients (n = 868), the SVR was about 29% for genotype 1 and 62% for genotype 2 or 3.

As mentioned above, RNA should be tested repeatedly for 12 weeks from the time of infection to ascertain whether spontaneous clearance will occur. If RNA is still present at 12 weeks, treatment should be strongly considered.

Treatment of chronic HCV

The goal of HCV treatment is to clear the HCV RNA from the bloodstream -- making the virus undetectable -- in order to slow or halt inflammation, fibrosis, and progression of liver disease, and to reduce risk of cirrhosis and HCC. Treatment success is defined as an SVR, with the HCV RNA becoming undetectable during treatment and remaining undetectable at 6 months after the completion of treatment. Studies show that SVR correlates with clinical outcomes such as decreased risk of decompensation, decreased risk of HCC, and decreased risk of liver-related death.

HIV coinfection is a strong indication for treatment of chronic HCV infection, because the risk of accelerated fibrosis and cirrhosis is higher for coinfected patients. Treatment of chronic HCV infection in HIV/HCV-coinfected patients yields lower rates of SVR than does treatment in monoinfected patients (see below), but HIV-coinfected patients should be strongly considered for HCV treatment. HIV-infected patients with low CD4 cell counts should not be excluded from HCV treatment on the basis of CD4 count alone; this is particularly true for patients already on ART. For timing of HCV treatment, see "Timing of HCV treatment and HIV treatment," below.

Patients with a high risk of progression to cirrhosis, including coinfected patients, should receive higher priority for treatment. For patients with minimal fibrosis, treatment can be deferred, particularly as HCV treatments that are more effective and more tolerable may be available in coming years. Patients who have developed cirrhosis but remain compensated should be treated as soon as possible if they are otherwise candidates. Patients with decompensated liver disease should not receive HCV treatment (likely risks of treatment outweigh potential benefits); appropriate candidates can be considered for liver transplantation.

Until 2011, standard treatment for hepatitis C consisted of pegylated interferon plus ribavirin (PEG-IFN/RBV). However, this treatment has been successful in less than half of patients monoinfected with genotype 1 HCV, and response rates in HIV/HCV-coinfected patients are significantly lower. Additionally, the side effects and contraindications of interferon and ribavirin (RBV) limit treatment eligibility. New types of anti-HCV medications, so-called directly acting antivirals (DAAs), have been advancing through the development process and may significantly improve treatment outcomes. The first two of these, the HCV protease inhibitors (PIs) boceprevir and telaprevir, were approved by FDA in 2011 for treatment of hepatitis C patients with genotype 1. Either of these agents, used in combination with standard therapy (PEG-IFN/RBV), nearly doubles the rates of SVR in genotype 1 HCV-monoinfected patients.

Currently, boceprevir and telaprevir are approved for HCV-monoinfected patients but are not yet approved for treatment of HIV/HCV-coinfected patients. Clinical trials in coinfected genotype 1 patients are currently being conducted and data from these trials are beginning to be reported. For boceprevir, interim analysis of a Phase II randomized controlled study of boceprevir plus PEG-IFN/RBV versus placebo plus PEG-IFN/RBV in patients naive to HCV treatment shows that 63.9% of the boceprevir group had undetectable HCV RNA at week 48, versus 29.4% of the standard therapy group. For telaprevir, 24-week interim data from a Phase II randomized placebo-controlled study of telaprevir plus PEG-IFN/RBV showed that 63% of patients on telaprevir achieved undetectable HCV RNA at weeks 4 and 12, versus 4.5% of those on PEG-IFN/RBV alone. Available data show that each of the HCV PIs greatly improves treatment outcomes in African Americans, a group with very poor responses to standard therapy. It should be noted that the HCV PIs have interactions with many HIV PIs and NNRTIs; both studies excluded patients on certain ARVs in an attempt to avoid interactions with the HCV PIs (see "Potential ARV Interactions," below). Studies on these and other agents in HIV/HCV-coinfected patients are ongoing.

The use of direct antiviral agents in treatment of hepatitis C has potential to greatly increase the likelihood of treatment success, both in patients who are naive to HCV treatment and in those who were treated unsuccessfully in the past. The introduction of these new drugs signals a major advance in HCV therapy, and it has brought about a renewed level of attention to HCV, and with that, an awareness of the need to screen patients at risk of HCV infection, to appropriately diagnose HCV infection, to identify treatment candidates, and to appropriately use these new drugs. It is hoped that, in the future, HCV therapies consisting of all oral medications may be available.

Adverse effects of treatment

HCV therapy may cause significant adverse effects. IFN can cause fatigue, flulike symptoms, thrombocytopenia, nausea, depression, hair loss, weight changes, and many other potential side effects. IFN reduces total white blood cell counts, and can cause neutropenia. It also decreases CD4 cell counts, although the CD4 percentage usually does not change. IFN can reduce HIV RNA somewhat (by approximately 0.5 log₁₀ copies/mL). RBV can cause a hemolytic anemia, sore throat, cough and other side effects. Zidovudine and didanosine should be avoided, if possible, with patients taking RBV, because of the risk of compounded toxicities (anemia with zidovudine, neuropathy, lactic acidosis, liver toxicity, and pancreatitis with didanosine). The side effects of boceprevir and telaprevir can include anemia, rash, and altered taste; telaprevir also can cause anorectal discomfort.

HCV treatment should not be given during pregnancy, and women receiving HCV treatment should avoid pregnancy. IFN may cause fetal growth abnormalities, and it is abortifacient in animals. RBV is teratogenic, and both women and men must use two forms of contraception consistently during treatment with RBV and for 6 months after discontinuation of treatment.

Timing of HCV treatment and HIV treatment

The decision of whether and when to treat HCV among people infected with HIV must be made on an individual basis. When coinfected patients require treatment for both infections, some experts begin with HIV treatment in hope that improved CD4 cell counts will enhance the response to HCV therapy, even though CD4 counts by themselves are not firmly associated with increased likelihood of an SVR. With patients who do not urgently require ART (e.g., because their CD4 counts are very high), many experts recommend treating HCV first, with ART delayed until after completion of HCV treatment. This strategy is intended to simplify treatment and improve the tolerability of both therapies. Patients already on ART generally should remain on ART throughout HCV treatment. Consult with an HCV treatment expert to determine the appropriateness and timing of HCV treatment.

Some patients with HCV will experience worsening of hepatic function during ART, and liver function should be monitored closely. Some ARV medications are hepatotoxic and should be avoided or used cautiously; these include nevirapine, tipranavir, and high-dose ritonavir. Numerous other medications (e.g., fluconazole and isoniazid) are hepatotoxic and can pose problems for patients with impaired liver function.

Other care issues

Acute HAV or HBV infection in persons with chronic HCV can cause fulminant liver disease. All patients with HCV infection should be tested for immunity to HAV and HBV; patients who are not immune should be vaccinated.

Persons with HCV infection should be counseled to avoid exposure to hepatotoxins, including alcohol and hepatotoxic medications (e.g., acetaminophen in large doses, fluconazole, and isoniazid).

As appropriate, all persons with hepatitis C should receive individualized counseling on ways to reduce the risk of infecting others with HCV (including by unprotected sex, by sharing of injection drug equipment, other blood exposures [e.g., from sharing razors or tattoo equipment], and via perinatal exposure).

Patient Education

• Advise patients that most people with HCV will be asymptomatic for many years and may never develop symptoms. However, slow progression of fibrosis can be happening in the absence of symptoms and can progress to cirrhosis.
• Patients can slow the development of fibrosis by avoiding alcohol and obesity, as fat in the liver can add to the liver damage.
• As with HIV, patients must avoid passing HCV to others. Emphasize the importance of safer sex to protect themselves as well as their partners. Instruct patients not to share toothbrushes, dental appliances, razors, sex toys, tattoo equipment, injection equipment, or personal care items that may have blood on them.
• Tell patients to discuss HCV with their sex partners, and suggest partners be tested for HCV.
• Women who are pregnant or considering pregnancy should talk with a specialist in HIV and HCV to discuss ways of decreasing the risk of perinatal transmission.
• HCV is not spread by coughing, sneezing, hugging, sharing food and water, or other casual contact.
• HAV can cause severe illness, liver damage, or even death in people with HCV. Patients who are not immune to HAV need to receive the two-part hepatitis A vaccination series.
• HBV can worsen liver function greatly if it is acquired in addition to HCV. Patients who are not immune to HBV need to receive the three-part hepatitis B vaccination series. If patients have been vaccinated in the past, they should have a blood test to confirm immunity.
• HCV treatment aims to clear the HCV virus from the body. That reduces risk of cirrhosis, end-stage liver disease, hepatocellular carcinoma, and liver-related death.
• HCV treatment is not right for every patient and is not necessary for every patient. Each patient should talk to their health care provider about whether treatment is appropriate for them.
• The HCV treatments include two drugs used together, pegylated interferon-alfa and ribavirin, for all patients being treated. For genotype 1 patients, boceprevir or telaprevir also may be used to create a triple-therapy regimen.
• HCV medications can cause many side effects, including flulike symptoms, body aches, fevers, anemia, neuropathy, and depression. Most of these adverse effects are treatable with medications and resolve after therapy is completed. Additional side effects are associated with the use of boceprevir or telaprevir. Patients should contact their medical provider right away if they experience depression. Antidepressant medications can help to relieve depression.
• It is essential that both men and women who are taking ribavirin should use two forms of contraception consistently during ribavirin therapy and for 6 months after completion of treatment.

References

• Armstrong GL et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Int Med 2006;144:705-14.
• Carrat F, Bani-Sadr F, Pol S, et al., ANRS HCO2 RIBAVIC Study Team. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004 Dec 15;292(23):2909-13.
• Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. April 10, 2009.
• Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004 Jul 29;351(5):451-9.
• Dominguez S, Ghosn J, Valantin MA, et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients. AIDS. 2006 May 12;20(8):1157-61.
• National Institutes of Health. NIH Consensus Development Conference Statement: Management of Hepatitis C: 2002.
• Torriani FJ, Rodriguez Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004 Jul 29;351(5):438-50.
• van de Laar T, Pybus O, Bruisten S, et al. Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men. Gastroenterology. 2009 May;136(5):1609-17.