Author: Rena Fox, MD
Liver disease owing to hepatitis C virus (HCV) infection has become a leading cause of death among HIV-infected patients, as the widespread availability of antiretroviral therapy (ART) has led to a decrease in AIDS-related causes of death. HCV is common among patients 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 in the United States, 70-95% may be coinfected with HCV; among HIV-infected men who have sex with men, 1-12% are coinfected with HCV.
HCV is a single-stranded RNA virus that is transmitted primarily through blood exposure and, less commonly, through sexual or vertical transmission. HCV/HIV coinfection is common because of these shared risk factors. However, 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. Women who are coinfected with HIV and HCV have a higher risk of transmitting HIV to their infants than do women with HIV infection alone. Coinfected women also are more likely than HCV-monoinfected women to pass HCV to their infants. Approximately 20% of babies born to HIV/HCV-coinfected mothers acquire HCV, compared with 5-6% of infants born to HCV-infected women without HIV. Breast-feeding is not known to transmit HCV, although HIV-infected women are advised against breast-feeding because of the risk of transmitting HIV.
Coinfection with HIV adversely impacts the natural history of HCV infection. HIV/HCV-coinfected patients have lower rates of spontaneous HCV clearance, increased HCV viral loads, decreased rates of successful virologic response to HCV treatments, faster progression to cirrhosis, and increased risk of developing liver decompensation, end-stage liver disease, and hepatocellular carcinoma (HCC). HCV coinfection does not appear to increase HIV- and AIDS-related complications or decrease rates of successful HIV antiretroviral (ARV) treatment.
Acute infection can be symptomatic and severe but rarely is fulminant. Patients who do present with 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 25% of patients acutely infected with HCV will clear the virus spontaneously, but 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.
For the majority of HCV patients, other than laboratory abnormalities, there are no clinical manifestations of infection until the development of cirrhosis. Cirrhosis develops in approximately 20% of HCV-monoinfected patients, usually 20 years or more from the time of infection. More than 20% 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%.
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 HCV infection about symptoms that suggest complications of HCV, such as cirrhosis, decompensation, risk factors for worsening liver disease, and hepatotoxins, and about drugs whose metabolism may be affected by liver disease.
Measure vital signs. Calculate body mass index (see chapter Initial Physical Examination).
Perform physical examination to include evaluation of the following:
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.
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. In HIV-Infected patients, the HCV antibody test result sometimes is falsely negative; therefore, if HCV infection is suspected (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.
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.
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. HCV genotyping should be performed once for all patients with detectable HCV RNA; it does not need to be repeated.
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.
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 those 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.
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 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.
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) alpha-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 in 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.
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 has lower rates of SVR than 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, especially those with genotype 1 virus, treatment can be deferred. 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 (risks outweigh benefits); appropriate candidates can be considered for liver transplantation.
The most effective treatment for HCV in patients with or without HIV is combination therapy with pegylated interferon-alfa (PEG-IFN) plus ribavirin. Among HIV-uninfected patients, approximately 45% with genotype 1 achieve HCV viral clearance using this combination. HCV/HIV-coinfected patients have much lower rates of response, from 14-44%, varying by genotype, duration of treatment, and dosage. Several novel drugs, including HCV-specific protease inhibitors, are being investigated as adjuncts to standard therapy.
Data suggest that early virologic response (EVR), defined as a ≥2 log10 decrease in HCV viral load 12 weeks into treatment, predicts SVR; treatment may be stopped if patients do not demonstrate EVR. The recommended duration of treatment in patients with HCV genotype 1 and EVR is 48 weeks. For genotype 2 or 3, the optimal duration of treatment is not clear; some guidelines state that treatment can be limited to 24 weeks, whereas others recommend 48 weeks of treatment for any HIV/HCV-coinfected patient.
HCV therapy may cause significant adverse 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). IFN also may produce flulike symptoms, depression, peripheral neuropathy, and other symptoms. Ribavirin can cause anemia and other adverse effects. Zidovudine and didanosine should be avoided, if possible, with patients taking ribavirin, because of the risk of compounded toxicities (anemia with zidovudine, neuropathy, lactic acidosis, liver toxicity, and pancreatitis with didanosine).
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. Ribavirin is teratogenic, and both women and men must use contraception consistently during treatment with ribavirin and for 6 months after discontinuation of treatment.
The decision of whether and when to treat HCV among people infected with HIV must be determined individually. 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 are not considered to 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 tests 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.
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 HCV transmission to others (including by unprotected sex, sharing of injection drug equipment, other blood exposures (e.g., from sharing razors or tattoo equipment), and via perinatal exposure).