WGO GLOBAL PERSPECTIVE—RESOURCE-SENSITIVE GUIDELINES AND “CASCADES”
This guideline will be of interest to all health professionals in primary and secondary care involved in the management of people with hepatitis C infection in different countries of the world. It covers all stages of the disease management pathway: screening, testing, diagnosis, referral, treatment, care, and follow-up of children and adults with, or exposed to, hepatitis C virus (HCV) infection.
Numerous guidelines produced annually by prestigious medical bodies outline “gold standard” practices and are aimed at physicians in resource-rich environments. (See the full version of this guideline for links to the main international guidelines on the management of hepatitis C.) As such, they are inaccessible and irrelevant for many clinicians in developing countries. Any Western guidelines that fail to acknowledge this may be preventing the dissemination of knowledge and evidence to the full global audience. The WGO has developed the concept of “cascades” to make guidelines more applicable to differing resource environments, by providing a collection of related diagnostic and treatment options arranged hierarchically in terms of conditions and available resources.1
WGO guidelines include alternatives for clinicians with limited funding. These alternatives are usually suggested on the basis of cost but may also take account of local availability, technology, and infrastructure. Cascades can range from a simple list of options to more complex parallel diagnostic and treatment pathways and are transformed from being “resource-blind” to “resource-sensitive.” Inevitably, cascades are more heavily based on empirical evidence rather than gold standard options. Research funding is usually spent on trying to improve “best practice” rather than the practicalities of delivery in developing countries. However, with strong involvement from experienced clinicians in developing countries, a consensus is usually reached. More widespread use of cascades in guidelines may also motivate research into the best options for resource-limited services.
EPIDEMIOLOGY—GLOBAL COMPARISON AND RESOURCE FACTORS
When the epidemiology of HCV infection globally is being discussed, it is imperative to discuss “north-west” and “east-south” differences as well. These include a low prevalence of HCV infection in the “north” and the “west”2,3 and a moderate to high prevalence4–6 in the “south” and the “east,” leading to a high health resource and financial burden on already resource-constrained countries. The main risk factor for HCV in the “east” is unsafe therapeutic injections, because of poor practical application of universal infection-control guidelines, including sterilization of equipment. This affects the treatment strategies in developing countries and emphasizes the need for prevention strategies, public awareness, health education, and sensitizing health care staff and concerned authorities in governments.
Another factor is the availability and quality of diagnostic tests for HCV infection, which make screening extremely difficult even in high-risk populations, leading to inaccurate data collection and reporting. Similarly, the standardization and methodology of polymerase chain reaction testing makes the option of “whom to treat” even more difficult.
The natural history of HCV is also different in the “east” and the “west” because of specific risk factors such as alcohol use, addiction, intravenous drug use, coinfections, and superinfections. Other comorbidities and nutritional deficiencies also affect liver histology and progression of the disease.
Data for nonresponders and relapsers will also be different, as conventional interferon (IFN) monotherapy and combination therapy with ribavirin (RBV) are still largely used in developing countries—in comparison with the developed world, where the standard of care is now polyethylene glycol-interferon (PEG-IFN) with RBV (PEG-IFN/RBV) (Table 1).
NATURAL HISTORY AND PREVENTION
The infection can range in severity from a mild illness lasting only a few weeks to a serious (acute infection) or lifelong illness (chronic infection). Approximately 80% of patients infected with HCV will become chronically infected, and most of these patients will show evidence of chronic hepatitis. The incubation period is 14 to 180 days (average 45 d), and no vaccine against hepatitis C is currently available.
Predictors of Chronicity in HCV Infection7
* Male sex
* Age: older than 25 years at the time of infection
* Acute infection is asymptomatic
* African American ethnicity
* HIV infection
Hepatitis C infection is usually slowly progressive over a period of many years, and between 5% and 15% of patients with chronic hepatitis may progress to developing liver cirrhosis over a period of 20 years.8 However, several studies have suggested a more benign course of the disease9 and indicate that fibrosis is a highly unpredictable process.10 A recent publication11 has reported that spontaneous virus elimination occurs in about 50% of newly infected HCV patients.12
Approximately 4% to 9% of patients with cirrhosis will develop progressive liver failure, with a 1% to 4% annual risk of developing primary hepatocellular carcinoma (HCC).13 The mortality rate because of progressive liver failure or HCC will continue to increase during the next few decades. In some countries, HCV infection is the main cause of death from liver disease and is the leading indication for liver transplantation.14
Approximately 70% to 80% of patients with hepatitis C are asymptomatic; in acute or acute-on-chronic hepatitis, the symptoms of all types of viral hepatitis are similar and can include one or more of the following: fatigue, abdominal pain, poor appetite, and jaundice.
Prevention in the Community and Health Care Settings
* All blood donors must be screened for hepatitis C antibodies and/or HCV RNA.
* In health care settings, adherence to universal guidelines for infection control is essential. This should include the use of disposable or adequately sterilized materials for invasive procedures and adequate cleansing and sterilization of instruments.1
* It is important to educate tattooists, barbers, foot/hand care workers, and practitioners of traditional or alternative therapies, about ways of minimizing blood contamination. This involves sterilization techniques for procedures that involve skin penetration or breaks to mucosal surfaces.
* As transmission of HCV by injecting drug use is an increasing trend, it is important to implement an education campaign about the harm of drug use, especially among school-age children. Harm reduction programs such as needle/syringe programs should also be implemented.
* Anyone who has received surgical or dental treatment has a higher risk of HCV infection and should be offered testing.
* Individuals with history of blood transfusion have a higher risk of HCV infection and should be offered testing.
* Chronic hepatitis C patients should be vaccinated against hepatitis B after screening.
* Use of injections by health care professionals and quacks should be discouraged; if necessary, only single-use syringes should be used.
* An appropriate protocol for needle-stick injury should be drawn up and followed in all hospitals (public and private), as recommended by the Centers for Disease Control and Prevention.
* All skin lesions on the hands of health care workers should be covered with waterproof dressing and if possible, double gloving with a blood indicator in the glove.
* Health care workers should be vaccinated for HBV.
1. Rutala WA, Weber DJ and the Healthcare Infection Control Practices Advisory Committee (HICPAC) Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008. Available at http://www.cdc.gov/hicpac/pdf/guidelines/Disinfection_Nov_2008.pdf. Accessed October 11 2013.
DIAGNOSIS AND SCREENING
Infection with HCV is diagnosed by testing for specific antibodies using enzyme-linked immunoassay. The presence of HCV antibody shows that a person has been infected with HCV virus, but it does not indicate whether the infection is acute, chronic, or has resolved. Antibodies may not be detectable during the first few weeks after initial infection because of the “window period,” or if patient is immunocompromised.
In contrast to hepatitis A and hepatitis B virus, in which the diagnosis of acute infection is based on immunoglobulin M antibodies, there is no serologic marker for acute HCV infection. Screening tests for chronic HCV infection are enzyme immunoassay or chemiluminescence immunoassay for anti-HCV and verification by an additional, more specific assay—for example, nucleic acid testing for HCV RNA.
The diagnosis of acute hepatitis C is based on:
* Marked elevation of alanine aminotransferase (ALT; >10×);
* with or without jaundice;
* detectable serum HCV RNA;
* followed by anti-HCV seroconversion weeks later.
If both anti-HCV and HCV RNA are detectable from the start, differential diagnosis between acute and chronic HCV infection with a flare of ALT may be difficult.
Patients with acute hepatitis C should be considered for antiviral therapy (PEG-IFN α-2a, 180 µg/wk or PEG-IFN α-2b, 1.5 µg/kg/wk, for 24 wk) to prevent progression to chronic hepatitis C. High sustained viral response (SVR) rates (nearly 90%) have been reported with PEG-IFN α monotherapy, irrespective of the HCV genotype. Some experts recommend only follow-up in these patients, with HCV RNA quantification every 4 weeks and treatment only being carried out in patients who are still positive at 12 weeks after the initial presentation.
Treatment and cure of hepatitis C has been shown to prevent the long-term risk of complications and is the primary form of management for chronic HCV infection. Not everyone with HCV infection will develop cirrhosis and its complications, and an approach involving monitoring for disease progression will be used in many situations.
Non-1 HCV genotypes are the most common in densely populated countries of South Asia, the Far East, Africa, and the Middle East. Before the era of PEG-IFN, conventional IFN monotherapy or conventional IFN/RBV combination therapy was the mainstay of HCV treatment in most parts of the world. After 2002, PEG-IFN/RBV (the standard of care) became available, but its high cost means that it is available only to a small, affluent proportion of the vast population of resource-constrained countries. The lack of a health-insurance system in these countries further complicates the matter.
Before PEG-IFN/RBV became available, the guidelines in the developed countries also recommended the use of conventional IFN/RBV. Thereafter, dual therapy with PEG-IFN/RBV was recommended. The SVR rate is 40% in genotype 1 (GT1) with PEG-IFN/RBV.15–17 At present, triple therapy with PEG-IFN, RBV and a direct-acting antiviral is recommended (2012). European guidelines do not support general use of triple therapy.
Some older studies18–21 reported a 40% to 50% response to standard IFN/RBV combination therapy in GT1 CHC patients and a viral response of up to 70% to 80% in GT2/3 CHC patients; in acute HCV, the rate is close to 100%.
The data with regard to the SVR rate using conventional IFN/RBV are conflicting, even for GT2a and GT3a.15 Using PEG-IFN/RBV increases the convenience, but not the efficacy, of therapy. In pivotal clinical trials, patients infected with HCV GT2 and GT3 achieved an SVR rate of 80% with PEG-IFN/RBV. However, an SVR rate of 30% to 50% has been reported in different regional studies.22
PEG-IFN α-2a should be used at a dosage of 180 µg once per week, whereas PEG-IFN α-2b should be used at a weight-based dosage of 1.5 µg/kg/wk. The RBV dosage depends on the HCV genotype. Patients with HCV GT1 and GT4-6 should receive a weight-based dose of RBV: 15 mg/kg body weight per day. Patients infected with GT2 and GT3 can be treated with a flat dosage of 800 mg of RBV daily, unless there are baseline factors suggesting low responsiveness—that is, body mass index >25, insulin resistance, metabolic syndrome, severe fibrosis or cirrhosis, older age—in which case they should receive a weight-based dosage of RBV, similar to GT1 and GT4.
The treatment options discussed in this guideline depend on the health care and financial resources available and are based on some empirical evidence from regional experts and societies, without deviating much from evidence-based medical practices. This is an effort to make hepatitis C treatment globally applicable, practically feasible, and updating the knowledge of practicing physicians at all levels, thus allowing maximum benefit to all hepatitis C patients all over the world. It is the role of governments to make treatment affordable to patients in need, as is the case with HIV. A good example is Egypt, where the cost of treatment is about $2000. This has evidently improved access to treatment for >250,000 patients during the last few years, with the majority of them being treated at government expense.
Finally, the guidelines are not fixed rules but represent a dynamic and ever-changing process, guiding physicians to treat patients accordingly and taking into account individualized approaches wherever required. The guidelines always need improvement and updating as newer studies and evidence become available.
Treatment Response Predictors
Patients with the favorable CC genotype at rs12979860 have >2-fold likelihood of spontaneous HCV clearance in comparison with heterozygotes (CT) and TT homozygotes. There is marked ethnic variation in the prevalence of IL28B genotypes. White patients with HCV GT1 and CC IL28B have an approximately 80% chance of SVR, in comparison with just 40% among those with non-CC genotypes.23 The CC genotype is highly prevalent among Asians, has intermediate prevalence in whites and Hispanics, and is relatively uncommon in Africans. Similar associations have been reported for the rs8099917 single nucleotide polymorphism, in which the favorable allele is coded with a T and the unfavorable allele with a G (Table 2).24
Before IFN/RBV therapy is started, the following tests and assessments should be conducted. As individualized treatment helps to save money without losing efficacy, pretreatment quantitative assessment of HCV RNA and HCV genotype is mandatory (Table 3).
Counseling—before antiviral therapy is started, and all patients should receive explanations about:
* The natural history of the disease and liver-related complications.
* Chances and success of all categories of treatments available.
* Adverse effects of the available treatments.
* Cost of the available treatments (especially PEG-IFN) and cost of supportive treatment when required.
The following tests should be carried out during treatment:
* Assessment of side effects and clinical examination at every visit.
* Complete blood count at 2, 4, and 6 weeks and then every 4 weeks until end of treatment.
* Monitoring serum HCV RNA (qualitative) for response-guided therapy quantification at weeks 4 and 12.
* Thyroid-stimulating hormone testing at 3 and 6 months (if clinically indicated) (agreed).
* Psychiatric evaluation (if indicated, for example, depression).
* Chest radiograph, ophthalmic, or audiogram examination (if indicated).
* Cardiac assessment (if indicated).
* Repeated advice regarding the need for contraception during and at least 6 months after the treatment.
* If an end-of-treatment response is achieved, the patient should be followed up and serum HCV RNA (qualitative) should be reassessed 24 weeks after the end of therapy to document SVR (for details, see the algorithm section below).
* Effective birth control should be continued for at least 6 months for patients who have taken RBV.
Treatment With PEG-IFN/RBV—Standard-of-Care Therapy
Who Should be Treated?
* All chronic hepatitis C patients with compensated liver disease with no contraindication to PEG-IFN/RBV should be considered for treatment.
* Treatment with PEG-IFN/RBV is strongly recommended for patients with moderate to advanced fibrosis (grades F2 to F4).
* Patients with mild disease (F0 to F1) should be considered for treatment on an individual basis, taking into account their age, sex, metabolic syndrome, symptoms, and motivation.
Symptomatic cryoglobulinemia is an indication for antiviral therapy, irrespective of the stage of liver disease (Table 4).
Reduced Benefit or Chance of Treatment Response
* Morbidly obese males, body mass index >35
* GT1/4/6 and untypable
* Dual active infection with HCV/HBV
* Relapsers or nonresponders to conventional IFN and RBV
Contraindications for IFN and RBV
* Uncontrolled seizures
* Hepatic decompensation
* Pregnancy (RBV) or couples unwilling to use adequate contraception
* Severe coronary artery diseases and decompensated congestive cardiac failure
Special Caution for IFN Therapy
Special caution is required if IFN is administered in the following circumstances (adapted from APASL/AASLD/EASL guidelines):
* Present or past psychosis or severe depression
* Uncontrolled diabetes mellitus
* Uncontrolled hypertension
* Autoimmune thyroiditis or other active autoimmune disorders, including autoimmune hepatitis
* Symptomatic heart disease or severe vascular disease
* Anemia/ischemic vascular disease
* Renal failure (RBV)
* Neutropenia (neutrophil count <1500 cells/µL)
* Thrombocytopenia (platelet count <85,000/µL)
* Organ transplantation (eg, kidney and heart transplants)
* History of autoimmune disease
* Presence of thyroid autoantibodies
* Comorbidity and the risk of progression in older patients
* History of depression
* Age <5 years
Almost all patients treated with PEG-IFN and RBV experience one or more adverse side effects during the course of treatment, including: influenza-like symptoms, neuropsychiatric side effects, hematologic abnormalities (anemia, neutropenia, and thrombocytopenia), and induction of autoimmune disorders. The use of RBV is associated with hemolytic anemia. As it is cleared by the kidneys, RBV should therefore be used with extreme caution in patients with renal failure. It is also teratogenic, and pregnancy should be avoided during treatment and 6 months thereafter in female patients and female partners of male patients.
Treatment With Protease Inhibitor (PI) TVR/BoC
Treatment of CHC GT1:
* Since 2002, Peg-INF and Ribavirin have been the standard of care (SOC) for CHC patients.
* The SVR rates at 48 weeks are reported to be 80% in GT2 and GT3 and 40% to 50% in those with GT1.
* The development of DAA and availability of telaprevir (TVR) and boceprevir (BOC) have changed the optimal treatment of HCV GT1 infection.
* AASLD26 and APASL27 have updated their treatment guidelines with the introduction of DAA for GT1 HCV infection.
* BOC and TVR are potent inhibitors of HCV GT1 and are commercially available for treatment of patients with chronic hepatitis C.
* To date, the use of protease inhibitors is limited to GT1. Treatment with protease inhibitors is not recommended for the large numbers of patients with GT2 to GT6.
* Second-generation DAAs are being developed to achieve combination antiviral agents with additive potency that lack cross-resistance and have a good safety profile.28
* Different classes of drugs are in the pipeline for treatment of chronic hepatitis C patients. These drugs act on different steps in the HCV life-cycle, including HCV NS3–4 A protease, NS5B polymerase, and NS5A inhibitors. To date, the Food and Drugs Administration has only approved unstructured protein 3/4 A (NS3/4 A) serine protease inhibitors.
PI for Treatment of Untreated (Naive) GT1 HCV Patients
* It is recommended that naive CHC HCV GT1 patients with non-CC+IL28B and fibrosis F3-F4 should be treated with triple therapy (TVR/BoC+PEG-IFN/RBV) for 48 weeks. Naive patients with CC genotype IL28B and F1-F2 receive standard-of-care treatment (PEG-IFN/RBV) for 48 weeks, with almost the same SVR rate.
* Special caution is needed in the treatment of patients with clinically apparent cirrhosis (although they have the greatest need for treatment). The treatment is poorly tolerated and is associated with a 2% mortality rate.29
DAA for Patients With Previous Treatment Failure
* It is recommended that all patients in whom PEG-IFN/RBV treatment has failed, relapsers, partial responders, and null responders should be treated with triple therapy.
* Special caution is needed when treating patients with clinically apparent cirrhosis.
Stopping Rules in Treatment Naive and Treatment Failure Patients
Observing stopping rules and ensuring adherence to treatment are necessary to prevent viral resistance. Table 5 lists futility rules30 for BOC-based or TVR-based triple therapy in treatment naive patients and those in whom treatment has previously failed.
Adverse Effects and Drug Interactions
* Numerous medications have a potential drug-drug interaction with BOC or TVR, including antiarrhythmics, anticoagulants, anticonvulsants, antihistamines, antibacterials, antiretrovirals, statins, herbal products, immunosuppressants, phosphodiesterase inhibitors, and some sedatives/hypnotics.
* Interaction with oral contraceptives can reduce their efficacy, and a second method of contraception should be used during treatment with these agents.
* Fatal and nonfatal serious skin reactions, including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, have been reported in patients receiving TVR combination treatment.
* Anemia has been reported with PEG-IFN α and RBV therapy. The addition of TVR to PEG-IFN α and RBV is associated with an additional decrease in hemoglobin concentrations.
* Patients should be informed that TVR combination treatment may cause a skin rash that can be serious, may be accompanied by fever and skin breakdown, may require urgent treatment in a hospital, and may result in death. Patients should promptly report any skin changes or itching to their health care provider. Patients should not stop TVR because of a rash, unless so instructed by their health care provider.1
1. FDA Highlights of prescribing information for telaprevir (Incivek) (http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/201917s003lbl.pdf).
AN INTERFERON-FREE ALL-ORAL TREATMENT REGIMENS FOR CHC IN 2014 AND BEYOND
* IFN-based therapy has been SOC treatment of CHC for the past 20 years. Combination of PEG-INF and RBV has resulted in SVR in 50% of chronic hepatitis C patients with GT1 and up to 70% to 80% in GT3.1 However, IFN-based therapy is a year-long treatment. It is injectable and associated with severe side effects and poor tolerability. In 2011, first-generation protease inhibitors, TVR and BOC, became available for hepatitis C as a triple therapy (PI plus peg-INF plus RBV). However, these drugs are limited by emergence of resistance, high rates of side effects including rash and cytopenias, as well as less effectiveness in patients with cirrhosis and null responders to SOC therapy.2,3
* The first successful IFN-free DAA therapy was reported with asunaprevir and daclatasvir with SVR rate of 90%. Another study (ELECTRON) using Sofosbuvir in combination with RBV for treatment of CHC patients with GT2 and GT3 achieved SVR rate of 100%, irrespective of previous therapy. Preliminary results of DAA used by different authors showed an SVR rate of 88% to 100% in GT2 and GT3 and 83% to 100% in GT1.4,5
* In light of emerging data from different studies and approval of Sofosbuvir by FDA in December 2013, CHC patients in resource-rich countries will be treated with combination of oral DAA without IFN with good efficacy, better tolerability, and less resistance. In resource-constraint regions with GT2 and GT3 and IL28b-cc positivity, PEG-INF and RBV will continue to be the SOC therapy. Cost and availability will further limit the use of DAA in resource-constraint countries. However, the IFN-free oral therapy must be individualized and tailored care according to the resources available.
Advantages of DAA
1. All Oral therapy, no injection.
2. Pangenotypic. Recent phase 2 studies support the efficacy of DAA in all genotypes (1 to 6).
3. Sofosbuvir is effective in combination with Peg + RBV and monotherpay as well as in combination with other DAA.
4. Absence of viral breakthrough during treatment and high barrier to resistance.
5. Effective in IL28B CT, TT variants.
6. Simple dosage, no relation with foods, minimal side effects and shorter duration of therapy.
7. Effective in Naïve and previously treated patient.
1. Costs is high particularly for resource constrained regions and smaller published studies with little experience of usage in different group of patients.
1. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus Ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002; 347:975-82
2. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011; 346:2405-16.
3. Poordad F, McCone J Jr, Bacon BR, et al. Bocepravir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011; 364:1195-206.
4. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. High rate of sustained virological response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naïve patients chronically infected with HCV genotype 1,2, or 3. Program and abstracts of the 63rd Annual Meeting of the American Association of the study of Liver diseases; Boston, 9-13 November 2012; Abstract LB-2
5. Lawitz E, Gane E, Stedman C, et al. PSI-7977 PROTON and ELECTRON: 100% concordance of SVR4 with SVR24 in HCV GT1, GT2 & GT3. J Hepatol. 2012; 56(suppl.2): S4; A7.
6. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Eng J Med. 2013; 368:34–44.
TREATMENT CATEGORIES AND CASCADES
In this section, patients with chronic hepatitis C who are eligible for treatment in accordance with the diagnostic criteria are stratified following internationally accepted criteria into 6 categories on the basis of genotype, whether or not treatment naive, failure of treatment, treatment response, and stopping rules. These parameters are evidence-based and are an integral part of the AASLD, EASL, APASL, and other regional society treatment guidelines.
The categories include recommendations for high-resource countries, as well as “constrained-resource” alternatives for clinicians with limited resources in terms of cost, local availability of drugs, diagnostic facilities, expertise, and health care infrastructure.
All patients should be treated with PEG-IFN/RBV in accordance with the standard-of-care therapy. Decision making on DAA treatment should take account of the factors mentioned above affecting resource-constrained countries. The alternatives are standard IFN/RBV and in some cases, “wait and watch” policies for minimal and mild disease—based on histology (liver biopsy) or noninvasive markers (FibroScan, FibroTest, FibroSURE, etc.), depending on availability.
Two special categories (sections 5.4. and 5.7) apply to resource-limited countries in which the implementation of gold standard care is not economically feasible but a decision “not to treat” could cause harm to the patient in terms of disease progression and resulting complications, adding significantly to the morbidity and mortality and further increasing the economic burden on already exhausted and depleted health resources in these countries.
CHC GT1—High-resource and Constrained-resource Regions
CHC GT4-6 or “Untypable”
Naive CHC GT2/3
Naive CHC GT2/3—Constrained-resource Regions
CHC Nonresponders to/Relapsers After Standard IFN/RBV
CHC Nonresponders to/Relapsers After PEG-IFN/RBV Therapy
CHC Minimal/Mild Disease F0/F1, Any Genotype—Constrained-resource Regions
CHC Treatment 2014 and Beyond
Summary—Recommendations and Evidence Levels
Recommendations for the treatment of HCV infection—with resource and evidence levels:
Chronic hepatitis C (CHC) GT1 patients:
Treat with PEG-IFN/RBV (SOC) for 48 weeks—resource-sensitive (level B).
Treat with DAA (12 wk) PEG-IFN/RBV±TVR/BoC (48 wk—resource-rich (level A).
Non-responders to/relapsers after PEG-IFN: treat with DAA±DDA±RBV (level A).
Naive CHC GT2 or GT3 infection:
Treat with PEG-IFN/RBV for 24 weeks or 48 weeks, depending on RVR—resource-rich (level A).
Treat with conventional IFN/RBV for 24 weeks, depending on EVR—resource-sensitive (level C).
CHC GT4, GT5, GT6, and untypable:
Treat with PEG-IFN/RBV for 48 weeks (level A).
GT4 can be treated for 24 weeks, depending on RVR in individual patients (level B).
CHC GT2 or GT3 nonresponders to/relapsers after PEG-IFN/RBV:
Can be treated with PEG-IFN for long-duration 72 weeks—resource-sensitive (level C).
Newer IFN—for example, consensus IFN or albinterferon (Albuferon) (not yet available commercially) was found to be noninferior to pegylated interferon-α in a phase 3 randomized trial in GT2 and GT3 CHC patients.1 The cost of treatment is yet to be determined but will be likely exceed the cost of current PEG-INF/RBV treatment—resource-rich (level C).
Interferon Free All Oral treatment with DAA (DAA±DAA±RBV) is the future treatment for all genotypes of chronic HCV infection (Level of Evidence: B).
“Wait and watch” surveillance for cirrhosis and HCC with liver ultrasonography, computed tomography (CT), alpha-fetoprotein (AFP) and platelets as per protocol—resource-sensitive (level C).
1. Nelson DR, Benhamou Y, Chuang WL, Lawitz EJ, et al (ACHIEVE-2/3 Study Team). Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 2 or 3. Gastroenterology. 2010; 139:1267-76.
Treatment of HCV infection in special groups:
Acute HCV infection
Start treatment at the time of diagnosis with PEG-IFN monotherapy or combination therapy for 12 weeks for GT2/3 and 24 weeks for GT1—resource-rich (level A). This treatment strategy prevents the development of chronic hepatitis C in app 90% patients.1
Start treatment at diagnosis with high-dose standard IFN for 24 weeks—resource-sensitive (level C).
Treatment for acute hepatitis C can be delayed for 8 to 16 weeks for spontaneous clearance of HCV infection, especially in symptomatic patients—resource-sensitive (level B).
Treatment of HCV infection in children: The perinatal transmission rate of HCV infections is about 3% to 7%. Diagnosis of perinatally acquired HCV infection is by a positive test for anti-HCV antibody after 18 months of age. HCV RNA becomes positive at the age of 1 or 2 months, and this should be used as a criterion for early diagnosis. The usual age of treatment is 2 to 17 years.
Treat with PEG-IFN/RBV for 24 to 48 weeks, depending on the genotype.
The dose of PEG-IFN should be modified according to body surface area and RBV at a dosage of 15 mg/kg/d.
* Other special groups of CHC patients—for example, patients with renal failure, those with coinfection with HCV/HIV and HBV, organ transplant recipients, and others, are treated in specialized liver units; practice recommendations can be found in other international guidelines (see section 1).
* See the appendix in the longer online version of these guidelines for the evidence grading system used from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.
1. Stefan M, Thomas B, Jürgen R, Christoph S et al, eds. Short Guide to Hepatitis C, 2013 Edition. Germany: The Flying Publisher; 2013. p66-68. Available at: http://pdf.flyingpublisher.com/HepatitisC_guide_2013.pdf. Accessed October 11, 2013.