Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 6: Disease-Specific Treatment

Hepatitis C Infection

Background

Hepatitis C virus (HCV) is a single-stranded RNA virus that is transmitted primarily through blood exposure. The virus can also be transmitted perinatally and through sexual contact, although the latter appears to occur rarely. In some populations of HIV-infected injection drug users (IDUs) and hemophiliacs in the United States, up to 90% may be coinfected with HCV. Rates of HCV are approximately 15% among HIV-infected men who have sex with men and 2-3% among monogamous heterosexual partners of HCV-infected individuals. HIV infection appears to increase the rate of progression of chronic HCV, and increases the risk of developing end-stage liver disease. It is not yet clear whether HCV affects the progression of HIV disease.

Impact of Coinfection on Vertical Transmission of HIV and HCV

Women coinfected with HIV and HCV have a higher risk of transmitting HIV to their infants; some studies have shown a 10% (or greater) rate above that of women infected with HIV alone. Coinfected women are also more likely 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.

O: Objective

Acute HCV Infection

Acute HCV infection is usually not recognized. In most cases, patients with acute HCV infection are asymptomatic or have nonspecific symptoms such as fatigue and, occasionally, jaundice and scleral icterus. Acute HCV infection is sometimes discovered on the basis of elevations in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) in asymptomatic patients who receive regular monitoring of hepatic transaminases. Most patients with acute HCV will not resolve the infection and will progress to chronic infection, but symptomatic patients generally have a higher likelihood of clearing the virus than do asymptomatic patients (see "Treatment for Acute HCV", below).

Chronic HCV Infection

About 60-85% of people who become infected with HCV are unable to clear the virus and become chronically infected. Major manifestations are usually not seen in immunocompetent people for 15-20 years, although ALT may be transiently elevated during earlier stages of disease. The virus can cause gradual hepatic fibrosis and eventual cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). Death can occur from decompensated liver disease; the consequences of portal hypertension, esophageal varices, coagulopathy, and thrombocytopenia; HCC; or some combination of these conditions. HIV-infected patients who are not treated with antiretroviral (ARV) medications tend to have faster progression of liver disease than those who are treated.

P: Plan

Diagnostic Evaluation

Enzyme immunoassay

According to the 2002 guidelines of the United States Public Health Service and the Infectious Diseases Society of America, all HIV-infected patients should be tested for anti-HCV antibodies using the enzyme immunoassay (EIA) test. HCV EIA tests are sometimes falsely negative in HIV-infected patients, although the third version of the test is highly sensitive and specific; it is also the least expensive screening test currently available. HIV-infected people who test positive on the EIA should be tested to determine whether they have circulating virus (ie, detectable HCV RNA). Falsely negative HCV viral load testing is uncommon.

Genotyping

Genotyping of HCV is helpful in assessing the likelihood of response to therapy. Patients with genotype 1 have much lower rates of response to treatment than do patients with genotype 2 or 3. Some specialists use the genotype to determine the type and duration of treatment, whereas others treat all HIV/HCV-coinfected patients similarly.

Alanine aminotransferase

Monitoring of ALT is used to assess liver inflammation, although levels may be low in patients with advanced liver disease.

Imaging

Ultrasonography can be performed to screen for cirrhosis or mass lesions. Computed tomography (CT), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT) are more expensive and are generally reserved for evaluation of liver masses. Some specialists recommend screening for HCC every 6 months.

Liver biopsy

Liver biopsy is used to stage the degree of inflammation and fibrosis to determine the need for HCV treatment. Biopsy should be considered in patients who are candidates for HCV treatment, after education about HCV therapy (including the expected success rates given the genotype, potential adverse effects, and the duration and logistics of treatment). Recently, blood tests have been used as noninvasive markers of hepatic fibrosis and have shown reasonable ability to identify patients with either mild or advanced liver fibrosis (currently about 40% of patients with HCV), allowing them to avoid liver biopsies.

Treatment

Treatment of chronic HCV

The recommendations of the National Institutes of Health (NIH) from June 2002 suggest that current alcohol users, pregnant women, patients with untreated depression, patients with renal disease, and patients with advanced cirrhosis are not candidates for HCV treatment. However, more recent data suggest that patients in several of these "special groups" can be treated on a case-by-case basis. Although pregnant women and persons with active alcohol use should not receive HCV treatment, certain individuals with renal disease, depression, injection drug use, and lower degrees of hepatic fibrosis (ie, Child-Pugh class A) should be considered for HCV treatment. These comorbid conditions should, of course, be treated to the degree possible.

HIV-infected patients with low CD4 counts should not be excluded from HCV treatment on the basis of CD4 count alone. Some studies do not support an association between absolute CD4 cell counts and treatment response.

Patients with a high risk of progression to cirrhosis should receive higher priority for treatment. Risk is indicated by portal or bridging cirrhosis, moderate inflammation and necrosis, measurable HCV RNA levels, or persistently elevated ALT levels. However, because ALT levels do not correlate with liver damage and some patients with normal ALT levels have abnormal liver biopsies, many experts treat patients who have normal ALT levels. For patients with minimal findings on liver biopsy and minimal ALT elevations, therapy should be deferred and the patients should be monitored. Patients with decompensated liver disease generally should not receive HCV treatment; appropriate candidates can be considered for clinical studies of liver transplantation in HIV/HCV-coinfected patients.

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 50% with genotype 1 achieve HCV viral clearance using this combination. HCV/HIV-coinfected patients with genotype 1 have a 22% rate of sustained virologic response to PEG-IFN plus ribavirin if treated for 48 weeks, whereas patients with other genotypes have approximately a 55% rate of sustained virologic response. Data suggest that early virologic response (EVR), defined as a ≥2 log₁₀ decrease in HCV viral load 12 weeks into treatment, predicts sustained virologic response to treatment; treatment may be stopped if patients do not demonstrate EVR. The recommended duration of treatment in patients with genotype 1 HCV and EVR is 48 weeks. For genotype 2 or 3, the optimal duration of treatment is not clear; some specialists treat for 24 weeks, whereas others treat for 48 weeks.

Adverse effects of treatment

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 (approximately a 0.5 log₁₀ decrease). IFN may also 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, in patients taking HCV treatment.

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

Treatment of acute HCV

Treatment of acute HCV is associated with a much higher response rate than treatment during the chronic phase. However, delaying therapy for 12 weeks to ascertain whether spontaneous clearance will occur does not affect treatment response rates. Treatment with PEG-IFN monotherapy has been associated with viral eradication in >90% of patients. Treatment for 24 weeks appears to be sufficient to clear HCV.

Timing of HCV treatment and HIV 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 by improving CD4 counts, they may enhance the response to HCV therapy, even though CD4 cell counts by themselves are not firmly associated with an increased likelihood of a sustained virologic response. Other experts choose to treat HCV before initiating ARV therapy (ART) in those with high CD4 counts and low HIV viral loads to simplify treatment and improve the tolerability of ART. 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 (eg, fluconazole and isoniazid) are hepatotoxic and can pose problems for people with impaired liver function.

Other Care Issues

Acute hepatitis A or hepatitis B infection in persons with chronic HCV can cause fulminant liver disease. All patients with HCV infection should be tested for immunity to hepatitis A and hepatitis B; 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 (eg, acetaminophen in large doses, fluconazole, and isoniazid). All patients should be counseled to reduce the risk of transmitting HCV to others. As appropriate, patients should be advised to adopt "safer sex" approaches, avoid blood exposures (eg, from sharing razors or tattoo equipment), practice safe drug injection techniques, and avoid pregnancy.

Patient Education

• Most patients with HCV will remain asymptomatic for several years. However, ongoing injury to the liver occurs during this time and can culminate in liver failure. Patients can slow the damage by avoiding alcohol and any medications (including over-the-counter drugs and recreational drugs) that may damage the liver. Patients should contact their pharmacist or health care provider if they have questions about a specific medication or supplement.
• As with HIV, patients must avoid passing HCV to others. 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. Emphasize the importance of safer sex to protect themselves and their partner(s).
• Tell patients to discuss HCV with their sex partner(s), and suggest that partner(s) get tested for HCV.
• Pregnant women have a high risk of transmitting HIV or HCV infection to the baby because each virus makes it easier to transmit the other. Women who are pregnant or considering pregnancy should talk with a specialist in HIV and HCV to discuss ways to decrease the infection risk for the baby.
• HCV medications (ribavirin and interferon) should not be given during pregnancy. Both men and women who are taking ribavirin should use contraception consistently during ribavirin therapy and for 6 months after completion of treatment.
• If children were born after women were infected with HCV, consider having them tested as well. Even though their risk is low, they should be screened for HCV.
• Certain ARV drugs are more likely to cause problems with the liver because of HCV. Advise patients that if they start an ARV regimen, their liver function tests should be watched carefully to be sure that the body is able to process the medicines.
• Patients who not been vaccinated against hepatitis A need to receive 2 vaccinations 6 months apart. Hepatitis A can cause severe illness damage, or even death, in people with HCV.
• Patients who have not been vaccinated against hepatitis B should complete the vaccine series, which requires 3 shots. If patients have been vaccinated in the past, they should have the anti-HBV titer checked to make sure that they are still protected.
• Hepatitis B can worsen liver function greatly if it is acquired in addition to HCV. Patients who are not immune to hepatitis B should use safer sex (latex barriers) to avoid exposure. Patients who use injection drugs should not share needles or injection equipment.
• Patients who use injection drugs should consider entering a treatment program. Quitting drug use will reduce the strain on the liver, protect patients from other blood borne illnesses that can affect the liver, and help prevent transmission of HCV to others. Patients who are not ready to stop injection drug use should let their providers know so that they can try to help find a source for clean, single-use needles.
• Hepatitis C is not spread by coughing, sneezing, hugging, sharing food and water, or other casual contact.
• The HCV treatments interferon-alfa and ribavirin can cause flulike symptoms, body aches, fevers, anemia, neuropathy, and depression. Most of these adverse effects are treatable with medications. Patients should contact their medical provider right away if they experience depression. Antidepressant medications that can help relieve depression, but the medications take a couple of weeks to become effective.

References

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• Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association/Infectious Diseases Society of America. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents. MMWR Recomm Rep. 2004 Dec 17; 53(RR15);1-112. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=14. Accessed May 19, 2006.
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