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. Without treatment, 15% to 40% of persons living with the virus will develop cirrhosis or cancer, and HCV is the leading cause of liver transplantation in the United States. Hepatitis C-related mortality has been steadily increasing in recent years, and as the baby boomer generation ages, the rates of cirrhosis and hepatocellular carcinoma (HCC) are expected to rise.

As antiretroviral therapy (ART) has reduced AIDS-related mortality among HIV-infected patients, liver disease owing to HCV infection has become a leading cause of death and the sequelae of chronic HCV have increased. HCV is common among persons with HIV infection in the United States. It is estimated that 20-30% 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. The U.S. Centers for Disease Control and Prevention and the U.S. Public Health Service recommend that all HIV-infected persons receive screening for 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 HCV-infected 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 MSM than in the general population, especially among persons who are coinfected with HIV. In HIV-infected MSM, outbreaks of acute HCV have been reported, with sexual activity as the risk factor for transmission. Risk factors associated with sexual transmission of HCV include the presence of coexisting sexually transmitted diseases, unprotected anal receptive sex, and use of recreational drugs.

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 with interferon and ribavirin, 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.

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 (e.g., 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; consider checking interleukin-28B (IL28B ) (see below). 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 prompt initiation of treatment for acute HCV. 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

The following tests are part of the evaluation of 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 who test negative should be retested at regular intervals. A positive HCV antibody test result 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 can be falsely negative, although this is rare. 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 result is negative.

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. False-positive HCV antibody results are possible but rare; they are more likely to occur in the setting of autoimmune disease.

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

There are six main HCV genotypes, numbered 1-6. Genotype 1 infections account for approximately 75% of HCV infections in the United States. In the absence of treatment, HCV genotypes are not associated with prognosis or progression of liver disease. However, the HCV genotype is one of the strongest predictors of response to HCV treatment and is a major factor in determining the appropriate treatment regimen for a patient. HCV genotyping should be performed once for all patients with detectable HCV RNA; it does not need to be repeated.

Subtyping

HCV genotypes are further divided by subtypes. Subtypes are termed 1a, 1b, 2a, 2b, among others. Subtypes are newly being recognized as predictors of treatment response, particularly with genotypes 1a and 1b. Additionally, a polymorphism, Q80K, in genotype 1a patients may become clinically significant in determining treatment regimens using some of the new HCV drugs.

IL28B testing

IL28B is a host genetic polymorphism on chromosome 19. Three different IL28B polymorphisms exist: C/C, C/T, and T/T. Patients with C/C type have higher rates of spontaneous clearance after acute HCV infection, and much higher response rates to interferon-based HCV treatment, whereas patients with the C/T or T/T genotype have lower rates of spontaneous clearance and much lower response rates to treatment with interferon. With non-interferon-based regimens, the role of IL28B has not yet been determined. In regimens containing either sofosbuvir (with or without pegylated interferon) or simeprevir (with interferon), better response rates were seen in patients with IL28B CC than in those with non-CC types, but the differences were much less dramatic than in older regimens.

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; 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) anti-bodies (IgG or total). All patients with a negative HAV antibody result should be vaccinated against HAV.

Imaging

Ultrasonography can be performed to screen for indications of cirrhosis or focal hepatic masses. Repeated ultrasound every 6 months to screen for HCC is recommended for patients with known cirrhosis or advanced fibrosis (stage 3). For noncirrhotic patients, regular repeated ultrasound is not recommended. 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.

Fibrosis staging

For any patient with HCV, it is useful to determine the degree of fibrosis (scarring) in the liver. Fibrosis stage is one of the most important pieces of information in determining a patient's need for HCV treatment. Fibrosis is scored from F0 to F4, with 0 indicating no fibrosis and F4 indicating cirrhosis.

Tools that may be used to determine the severity of chronic liver disease include biopsy, imaging, and serologic tests.

For HIV/HCV-coinfected patients, liver disease may progress quickly. A biopsy or other fibrosis test may be useful in determining the stage of disease and in planning whether or when to initiate HCV treatment. If the test reveals more advanced fibrosis or cirrhosis, treatment should be considered relatively urgently, using currently available therapeutics. Conversely, if the test reveals only mild-to-moderate fibrosis, it may be preferable to defer treatment and monitor the patient, particularly as more effective and more tolerable therapies are anticipated to become available within the next few years.

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. Biopsy has been the gold standard method, and is the main technique used in the United States. 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.

As HCV therapies evolve and demonstrate higher response rates, a biopsy may prove less of a determinant of when to initiate treatment than in years past. At this time, with few directly acting agents (DAA) available, biopsy may still be useful for determining whether a patient can safely wait for more effective regimens.

Fibroscan

Several noninvasive tests to determine fibrosis have been developed. Fibroscan (elastography) is a radiology test used to assesses liver shear wave speed (expressed in meters per second) and equivalent stiffness (expressed in kilopascal) in a rapid, simple, noninvasive, and painless way. The FDA approved the Fibroscan in 2013. For diagnosing cirrhosis (stage F4), the sensitivity and specificity were 87% and 91%, respectively, whereas for diagnosing moderate stages of fibrosis (F2-F3), the sensitivity and specificity were 70% and 84%, respectively.

Serologic tests

Several different scoring systems have been developed to estimate the degree of liver fibrosis based on serum biomarkers and other patient factors. For example, the Fibrosure test uses the measurements of alpha-2-macroglobulin, alpha-2-globulin (haptoglobin), gammaglobulin, apolipoprotein A1, GGT, and total bilirubin, as well as the age and sex of the patient. The currently available serologic tests are not as accurate as liver biopsy in distinguishing different stages of fibrosis, and none of these have been FDA approved.

Treatment

Overview of the Treatment of 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 a sustained virological response (SVR). SVR is achieved when the HCV RNA becomes undetectable during treatment and remains undetectable after the completion of treatment. Originally, SVR was defined as the absence of HCV RNA 24 weeks ("SVR24") after the completion of treatment. SVR12 (12 weeks after the end of treatment) is 99% predictive of SVR24, so recent studies often report this as the outcome measure. SVR correlates with clinical outcomes such as decreased risk of decompensation, decreased risk of HCC, and decreased risk of liver-related death. Most experts consider SVR to represent "cure" of HCV. It is important, however, to remember that this is a cure of the chronic viral hepatitis infection, but it is not the same as "curing" the damage to the liver.

Pegylated interferon and ribavirin

The standard of care in the treatment of chronic HCV from 2001 to 2011 was the combination of pegylated interferon (PEG-IFN) alfa-2a and ribavirin, for both HCV-monoinfected and HIV/HCV-coinfected patients. Response rates varied by host and viral factors, among them HIV coinfection, HCV genotype, stage of liver disease, HCV viral load, race/ethnicity, and IL28B type. Overall, HCV-monoinfected genotype 1 patients have had SVR rates of 42-46% and monoinfected genotype 2/3 patients have had SVR rates of 70-80% with PEG-IFN + ribavirin. HIV/HCV-coinfected patients have had much lower response rates, in the range of 14-38%. Treatment was limited by these poor response rates as well as by multiple complete and relative contraindications to interferon or ribavirin, multiple side effects of both drugs but especially interferon, and the cost and complexity of care for both patients and providers.

Telaprevir and Boceprevir

In 2011, the HCV protease inhibitors boceprevir and telaprevir were approved for genotype 1 HCV. These were the first direct acting antivirals (DAAs) available for treatment of HCV. With use of these agents in combination with PEG-IFN and ribavirin, treatment response rates in HCV-monoinfected genotype 1 patients were much higher than with PEG-IFN + ribavirin alone. In HIV/HCV-coinfected patients, smaller studies of boceprevir and telaprevir (plus PEG-IFN and ribavirin) have shown SVRs in the range of 60-75%, substantially higher than with standard therapy. These triple-therapy regimens, however, are complex and burdened with adverse effects and drug interactions.

Sofosbuvir

Sofosbuvir is an HCV polymerase inhibitor that was FDA approved in late 2013 for treatment of HCV in both HIV-coinfected and HCV-monoinfected patients with genotypes 1-4. It is approved for use with ribavirin alone (for genotypes 2 and 3) or with PEG-IFN + ribavirin (for most patients with genotypes 1 and 4), using specific protocols. It also is being studied in combination with other HCV medications, including in several interferon-free regimens. Use of sofosbuvir-containing regimens has resulted in very high SVR rates (80% to >90%) with 12 or 24 weeks of therapy, in both treatment-experienced and treatment-naive patients and in cirrhotic patients. Few significant drug-drug interactions with ARVs have been identified.

Simeprevir

Simeprevir is a HCV protease inhibitor that was FDA approved in late 2013 for treatment of genotype 1 HCV, in combination with PEG-IFN and ribavirin. Study data have shown SVR rates of 82% in treatment-naive genotype 1 noncirrhotic patients and 58-65% in cirrhotic individuals treated with simeprevir + PEG-IFN + ribavirin. Among patients with the IL28B CC type, 95% achieved SVR. Simeprevir also is being studied in interferon-free regimens.

Simeprevir has markedly reduced efficacy in patients with the Q80K polymorphism, and screening for this is recommended before treatment. Simeprevir also has significant drug-drug interactions with some ARVs, in particular many protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and the pharmacokinetic enhancer cobicistat.

Expansion of DAAs

In 2014-15, several additional HCV DAAs and combinations of DAAs are expected to be considered for FDA approval; many have the potential to be used in regimens that do not include interferon.

Treatment of acute HCV

As mentioned above, in the setting of acute HCV infection, 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 offered.

With HIV/HCV-coinfected patients, as with HCV-monoinfected patients, early treatment of acute HCV infection yields a much higher rate of SVR than does treatment of chronic HCV infection. In three prospective trials of treatment for acute HCV in HIV-coinfected patients, using PEG-IFN + ribavirin for 24 or 48 weeks, the SVR for genotype 1 HCV was 55-75%, and 100% for genotype 3. By contrast, in the largest study of the same regimen for chronic HCV treatment in HIV-coinfected patients (n = 868), the SVR was about 29% for genotype 1 and 62% for genotype 2 or 3. Currently, there are no data on the efficacy of DAAs to treat acute HCV infection in HIV-coinfected patients. Given the relatively high SVR rates that result from treatment of acute HCV with pegylated interferon and ribavirin, and the absence of data in this setting, it is not routinely recommended to use DAAs in acute coinfection at this time.

Treatment of chronic HCV

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. HIV-infected patients with low CD4 cell counts should not be excluded from HCV treatment on the basis of CD4 count alone; this is true particularly for patients already on ART. For timing of HCV treatment, see "Timing of HCV treatment and HIV treatment," below. Traditional treatment of chronic HCV infection in HIV/HCV-coinfected patients with PEG-IFN + ribavirin yields lower rates of SVR than does treatment of monoinfected patients (see above), but use of newer anti-HCV medications has improved the treatment outcomes in coinfected patients.

Patients with a high risk of progression to cirrhosis, including coinfected patients, should receive higher priority for treatment. Patients who have developed cirrhosis but remain compensated should be treated as soon as possible if they otherwise are candidates. Patients with decompensated liver disease should not receive HCV treatment (the likely risks of treatment outweigh potential benefits); appropriate candidates can be considered for liver transplantation. Many patients with minimal fibrosis may be best served by deferring treatment, pending availability of more effective and tolerable therapy options.

Current guidelines recommend treatment of HCV genotype-1-coinfected patients with PEG-IFN + ribavirin + an HCV protease inhibitor for 48 weeks; because of potential drug interactions between HCV protease inhibitors and antiretroviral medications, the selection of HCV protease inhibitor and ARV drugs must be made with great care (see "Drug Interactions," below). HCV genotypes 2-6 should be treated with PEG-IFN + ribavirin. However, as discussed above, the recent FDA approval of new DAA agents and the anticipated approval of others means that the paradigm for HCV treatment is in flux. It is anticipated that currently available and anticipated HCV drugs will be combined to construct a number of effective regimens (including all-oral and "interferon-free" regimens) that can be tailored to the treatment needs of particular patients. Based on current data, the emerging era of HCV treatment is expected to be one of higher response rates, lower side-effect profiles, and perhaps shorter courses of treatment.

To determine an appropriate treatment regimen, consultation with a specialist is recommended.

HCV Directly Acting Antivirals: Classes and Agents

FDA approved:

Protease Inhibitors (NS3/4a)
  • Boceprevir
  • Telaprevir
  • Simeprevir
Nucleoside Polymerase Inhibitors
  • Sofosbuvir

Classes with Agents under Investigation:

  • Protease Inhibitors (NS3/4a)
  • Nucleoside Polymerase Inhibitors
  • NS5A Inhibitors
  • Nonnucleoside Polymerase Inhibitors

Drug Interactions

HCV protease inhibitors and other DAAs may have significant interactions with certain HIV ARVs, particularly with protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and the pharmacokinetic booster cobicistat. Interactions between many DAAs and ARVs have not been studied. Known and expected drug-drug interactions need to be carefully considered before selecting an HCV treatment regimen. Consult with HIV, HCV, and clinical pharmacy specialists. Table 2 shows potential DAA-ARV interactions, based on currently available data.

Table 2. Characteristics of Directly Acting Agents and Potential Interactions with ARVs
DAAMechanismActivity Against HCV GenotypeBarrier to ResistancePotential ARV Interactions
TelaprevirNS3/4A protease inhibitor1Low
  • Contraindicated with all protease inhibitors except atazanavir/ritonavir
  • Contraindicated with elvitegravir/cobicistat
  • Requires increased dosage when administered with efavirenz
  • No dosage adjustment when used with raltegravir
BoceprevirNS3/4A protease inhibitor1Low
  • Contraindicated with all protease inhibitors, and with efavirenz and elvitegravir/cobicistat
SimeprevirNS3/4A protease inhibitor1, 2, 4, 5, 6Low
  • Concentrations decreased by efavirenz, and may be decreased by etravirine and nevirapine; should not be given with these NNRTIs
  • Concentrations increased by darunavir/ritonavir, ritonavir, and cobicistat; should not be given with any PI or cobicistat
  • No clinically significant interactions with raltegravir, rilpivirine, tenofovir
SofosbuvirNS5B RNA polymerase inhibitor1-6High
  • Concentrations decreased by tipranavir/ritonavir
  • No known clinically significant interactions with other ARVs

Adverse effects of treatment

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).

Ribavirin can cause a hemolytic anemia, sore throat, cough, and other side effects. Zidovudine and didanosine should be avoided with patients taking ribavirin, 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. The most commonly reported adverse effects of sofosbuvir + ribavirin regimens were fatigue, headache, insomnia, and nausea. In treatment arms containing sofosbuvir + PEG-IFN + ribavirin, side effects were similar to those reported with PEG-IFN + ribavirin, with the exception of increased rates of fatigue and nausea. The addition of simeprevir to PEG-IFN + ribavirin resulted in an increased incidence of rash including photosensitivity, pruritus, nausea, dyspnea, and hyperbilirubinemia.

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 two forms of contraception consistently during treatment with ribavirin and for 6 months after discontinuation of treatment. Boceprevir and telaprevir are FDA Pregnancy Category B drugs but must be used with PEG-IFN and ribavirin, which are not recommended.

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 based on limited data that improved CD4 cell counts will enhance the response to HCV therapy, and this generally is recommended for patients with CD4 counts of <350 cells/µL. With patients who do not require ART urgently (e.g., because their CD4 counts are very high), consideration could be given to 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, though it brings the risk of HIV disease progression during HCV treatment. Patients already on ART generally should remain on ART throughout the course of HCV treatment, though regimens should be evaluated for adverse drug interactions with HCV drugs (e.g., with boceprevir and telaprevir). 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 dosages >2 g per day, 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 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, so ongoing monitoring is important.
  • 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 that 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 rapidly evolving and it is anticipated that several new regimens will be available over the next few years (2014-15). Each patient should talk to his or her health care provider about whether treatment is appropriate.
  • Standard HCV treatment until 2011 included two drugs used together, pegylated interferon-alfa and ribavirin, for all patients being treated. In 2011, for genotype 1 patients, boceprevir or telaprevir became available to be used to create a triple-therapy regimen.
  • In late 2013, simeprevir was FDA approved for use in combination with pegylated interferon and ribavirin for genotype 1 and 4 patients and sofosbuvir was approved for use in combination with pegylated interferon and ribavirin for genotype 1 patients and for use with ribavirin alone (interferon-free) in genotype 2 or 3 patients and some genotype 1 and 4 patients.
  • Pegylated interferon can cause many side effects, including flulike symptoms, body aches, fevers, leukopenia, neuropathy, and depression. Most of these adverse effects are treatable with medications and resolve after therapy is completed.
  • Ribavirin can cause side effects including rash, sore throat, and anemia.
  • Multiple drug interactions are a concern for direct acting antivirals, including HIV medications. Drug-drug interactions need to be carefully considered before starting HCV treatment and choosing which HCV treatment is right for each patient.
  • 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.

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly