TREATMENT
Acute HCV
To prevent progression of disease from acute to chronic infection, patients diagnosed with acute disease should be treated if
• They are likely to adhere to the treatment plan
• They have no contraindications to pegylated interferon a (PEG-IFN a) treatment.
Contraindications to PEG-IFN a treatment include uncontrolled depression, psychosis, or epilepsy; pregnancy; couples' unwillingness to use effective contraception during treatment; severe concurrent medical disease; and decompensated liver disease.20
For acute HCV infection, treatment with PEG-IFN a-2a 180 µg/wk or PEG-IFN a-2b 1.5 µg/kg/wk for 24 weeks is recommended.20 Treatment results in an SVR greater than 80%.21 Combination therapy with ribavirin (RBV) does not increase SVR in the treatment of acute HCV infection.22
The appropriate time to begin treatment has not been firmly established because, as previously noted, 15% to 25% of those infected will spontaneously clear the virus. The European Association for the Study of the Liver (EASL) suggests that patients who remain HCV positive at 12 weeks from the time of suspected infection should be treated.23
Chronic HCV
Treatment of chronic HCV is based on multiple considerations, many of them patient-specific (see Table 2). One key element in treatment choice is the HCV genotype with which the patient is infected.
The most prevalent in the US are genotypes 1 through 6; further, genotype 1 has two subtypes: 1a and 1b. In the US, genotype 1 is most common, infecting about 70% of patients; genotype 2, 16%; genotype 3, 12%; genotype 4, 1%; genotype 5, < 1%; and genotype 6, 1%.24 Infection with one genotype does not protect an individual from future infection with the same or a different HCV genotype.3
Other factors influencing treatment include viral load, ALT levels, coinfection (eg, HIV, HBV), comorbidities, and treatment contraindications.21 Treatment is recommended for those who have detectable HCV RNA levels, elevated ALT levels, progressive liver disease on biopsy, and the absence of any serious comorbid conditions or contraindications. ALT levels, however, can fluctuate and do not always correlate with disease severity.
For years, the standard treatment for chronic HCV infection has been PEG-IFN a/RBV for 48 weeks. This combination produced an SVR of 50% to 80%, depending on genotype.3,25 Recently, however, treatment protocols have changed considerably with the introduction of two new and very effective direct-acting antiviral agents (DAAs): simeprevir, an HCV NS3/4A protease inhibitor, and sofosbuvir, an HCV NS5B polymerase inhibitor.
Simeprevir was approved by the FDA in October 2013 for use in combination with PEG-IFN/RBV for treatment of chronic HCV genotype 1 infection in adults with compensated liver disease.27 Because the efficacy of simeprevir is reduced in patients with HCV genotype 1a with an NS3 Q80K polymorphism, screening for NS3 Q80K is recommended; alternative therapy should be considered when this mutation is present.27
Sofosbuvir received FDA approval in December 2013 for use in combination with other antiviral drugs for treatment of chronic HCV infection, with established efficacy for treatment of genotypes 1, 2, 3, and 4 and for HCV/HIV coinfection.28 For genotype 1, simeprevir and sofosbuvir achieve SVRs of 80% and 90%, respectively.27,28
Table 3 lists the current medications for treatment of chronic HCV, including their adverse effects, contraindications, and drug interactions.
Updated treatment guidelines
AASLD, IDSA, EASL, WHO, and the Department of Veterans Affairs National Hepatitis C Resource Center Program recently issued updated evidence-based recommendations for the treatment of chronic HCV.4,10,23,26 Highlights of the changes to the guidelines include
• With the introduction of simeprevir and sofosbuvir, the guidelines no longer recommend combination PEG-IFN a/RBV for 48 weeks as the standard treatment for chronic HCV infection11,23,26
• Treatment regimens utilizing the protease inhibitors telaprevir and boceprevir are no longer recommended (with the exception of the WHO guidelines, which include them in a “conditional” recommendation).4
Regimens that include telaprevir and boceprevir are associated with higher rates of serious adverse effects, such as skin reactions and anemia, and involve longer treatment duration, higher pill burden, several drug interactions, frequent dosing, intensive monitoring, and the need to be taken with food (for telaprevir, high-fat food).10,23,26
Finally, the EASL recommends an additional agent, daclatasvir, an NS5A replication complex inhibitor, as an option for treating HCV genotype 1, 3, and 4.23 At this time, it is approved for use in Europe but has not been approved by the FDA.
Regardless of the treatment regimen, all patients receiving HCV antiviral therapy should be tested regularly to assess effectiveness of treatment and to monitor for the occurrence of adverse effects. Recommended periodic laboratory testing should include HCV RNA, complete blood count with differential, liver function, TSH level, renal function, comprehensive metabolic panel, bilirubin level, and pregnancy.29
SPECIAL POPULATIONS
Patients with HIV/HCV coinfection, a history of injection drug use, and renal impairment require management tailored to their individual circumstances.4,23,29
HIV/HCV-coinfected patients
Approximately 25% to 33% of patients infected with HIV are coinfected with HCV. HCV infection progresses more rapidly in HIV-infected patients, and coinfected patients are at greater risk for cirrhosis, liver cancer, and liver failure.30
For patients with HIV/HCV coinfection, the decision to start treatment is more complex because of the high pill burden, overlapping toxicities, and interactions among the drugs used to treat HIV and HCV infections.4 HIV antiviral therapy should be started before HCV treatment to improve immune function, thereby decreasing the risks for both further infections and HIV transmission. This also allows the patient to adjust gradually to each regimen.
One exception to this is when an HIV treatment–naïve patient has a CD4 count > 500 cells/mL.30 In this situation, HCV treatment is sometimes completed prior to the start of HIV treatment.
Recommended treatment for HIV/HCV coinfection, by HCV genotype, is outlined below. For all regimens, the weight-based RBV dosage is calculated as follows:
• Weight < 75 kg, 1,000 mg/d
• Weight ≥ 75 kg, 1,200 mg/d10,30
• Genotypes 1 and 4 (IFN eligible): Sofosbuvir 400 mg/d and weight-based RBV plus weekly PEG-IFN a for 12 weeks
• Genotypes 1 and 4 (IFN ineligible): Sofosbuvir 400 mg/d and weight-based RBV for 24 weeks
• Genotypes 2 and 3 (regardless of IFN eligibility): Sofosbuvir 400 mg/d and weight-based RBV for 12 weeks for genotype 2 and 24 weeks for genotype 3
• Genotypes 5 and 6 (IFN eligible): Sofosbuvir 400 mg/d plus weight-based RBV plus weekly PEG-IFN a for 12 weeks.
Injection drug users
HCV infection among young injection drug users (IDUs) is an emerging epidemic that must be addressed by recognizing at-risk populations, screening for early disease, and providing treatment and education. Globally, it is estimated that approximately 67% of IDUs—approximately 10 million people—are infected with HCV.31 Treatment of HCV in IDUs requires integration of many services and health care professionals, including addiction specialists. Dependence on opiates, alcohol, or other substances is common in this patient population. Patients should be counseled on the importance of abstaining from alcohol. IDUs are at risk for hepatitis A (HAV) and HBV infections and should be vaccinated against these diseases.4
Treatment decisions should be based on an individualized evaluation of the patient’s social, lifestyle, and clinical factors.4,23,29 Consideration must also be given to potential drug interactions.4,23,29 In IDUs, treatment with PEG-IFN a/RBV should be considered because DAA studies have excluded active users.20 Evaluation of the safety and efficacy of new regimens containing PEG-IFN a, as well as PEG-IFN-a–free regimens, in IDUs is needed.20
Renal impairment
Both PEG-IFN a and RBV require dose adjustments in patients with a creatinine clearance less than 30 mL/min.4,10,23,26 Further, simeprevir and sofosbuvir have not been studied in HCV patients with creatinine clearance less than 30 mL/min.10,26
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