Journal of Pediatric Gastroenterology & Nutrition:
Chronic Hepatitis C Virus Infection in Children
Mohan, Neelam*; González-Peralta, Regino P†; Fujisawa, Tomoo‡; Chang, Mei-Hwei§; Heller, Solange||; Jara, Paloma¶; Kelly, Deirdre#; Mieli-Vergani, Giorgina**; Shah, Uzma††; Murray, Karen F‡‡
*Department of Pediatrics, Centre of Child Health, Sir Ganga Ram Hospital, New Delhi, India
†Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Florida College of Medicine, Gainesville
‡Children's Center for Health and Development, Yokohama East Hospital, Yokohama City, Kanagawa, Japan
§Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
||Gastroenterology and Nutrition Department, Hospital Infantil de México Federico Gómez, México, DF, Mexico
¶Pediatric University Hospital La Paz, Madrid, Spain
#Liver Unit, Birmingham Children's Hospital NHS Trust and University of Birmingham, Birmingham, UK
**Paediatric Liver Centre, King's College Hospital, London, UK
††Harvard Medical School Dubai Center, Dubai Health Care City, Dubai, UAE
‡‡Hepatobiliary Program, Seattle Children's, Seattle, WA.
Received 5 May, 2009
Accepted 15 September, 2009
Address correspondence and reprint requests to Karen F. Murray, MD, Director, Hepatobiliary Program, Seattle Children's, 4800 Sand Point Way, NE, PO Box 5371/W7830, Seattle, WA 98105 (e-mail: email@example.com).
Drs Murray and González-Peralta have received research funding from Roche.
The other authors report no conflicts of interest.
The importance of hepatitis C viral infection in the health care of children has grown in recent decades. More is now known about the epidemiology of this infection in children and the progression of disease in the pediatric age group, and the treatment options are increasing. In this review, we update readers on the state of our understanding of hepatitis C infection in children, provide the current recommendations for monitoring and treatment, and discuss emerging therapies.
Hepatitis C virus (HCV) was identified in 1989 and since then significant advances have been made in understanding the molecular biology, pathology, and treatment of HCV liver disease. HCV is an enveloped, single-stranded positive-sense RNA virus, belonging to the Hepacivirus genus within the flavivirus family. The HCV genome is approximately 10,000 kilobases with stereotypical genetic heterogeneity. Based on phylogenetic analysis of HCV sequences, 6 major HCV genotypes are recognized, designated 1 to 6, with multiple subtypes within each viral genotype (1). HCV genotypes are geographically clustered, with HCV genotypes 1 and 2 being prevalent worldwide, genotype 3 most common in Australia and the Indian subcontinent, and genotype 4 most common in Egypt, the Middle East, and central Africa, whereas genotypes 5 and 6 are seen in South Africa and southeast Asia, respectively. Genotype 1 is the most common HCV genotype found in the United States (74%) and Europe (64%) (2).
Worldwide prevalence of chronic HCV infection is estimated at 3%, with 150 million people chronically infected. HCV prevalence varies geographically, with rates of 1.7% in the United States, 2.1% in southeast Asia, and 5.3% in Africa, for instance (2).
The frequency of parenteral HCV transmission from infected blood products has been markedly diminished by routine blood screening using anti-HCV antibody in almost all countries. Consequently, mother-to-infant transmission is the primary mode of viral spread in children, now accounting for approximately 60% of children infected. Vertical transmission is almost always confined to pregnant women who have detectable HCV RNA in their serum (3). There has been no report of HCV transmission to an infant born to a woman positive for anti-HCV antibody but negative for HCV RNA (4); however, because serum viral levels may fluctuate during pregnancy, measuring HCV RNA concentration to detect active viremia late in pregnancy is recommended (4). Unlike the high transmission rate seen for hepatitis B virus (HBV) infection, mother-to-infant transmission of HCV occurs in only 5% to 10% of deliveries (4–7). Factors associated with higher HCV vertical transmission rates include maternal serum viral levels above 106 copies per milliliter and co-infection with HIV, prolonged or difficult delivery, and the use of internal fetal monitoring during delivery. Interestingly, HCV vertical transmission rates are lower in children with HLA D13 and detectable HCV-specific CD4 reactivity than in those without these markers, highlighting the potential importance of immune-mediated mechanisms in viral spread (8,9).
HCV infection may occur in utero (10) or at the time of delivery (11). There is conflicting evidence regarding the benefit of delivery by cesarean section to reduce HCV transmission in both HIV-co-infected and noninfected mothers (12). The mother-to-infant transmission rate is low, however, with elective cesarean even when the mother has a high level of HCV RNA in her serum (4).
There is insufficient evidence to discourage breastfeeding because there is little evidence of an increased risk of transmission with breast-feeding (4), despite HCV RNA being frequently detectable in colostrum (13). Additionally, histories of blood transfusion, liver disease, and hepatitis during pregnancy are unrelated to mother-to-infant HCV transmission (4) No difference is also observed in the vertical transmission of different HCV genotypes (4). Furthermore, no consistent relation is observed between the presence or absence of HCV infection in the first versus the second or subsequent infants (4), even in identical twins (14).
Infants are considered infected if the serum HCV RNA is positive on 2 or more occasions (3). Intrauterine infection is suggested in an infant in whom HCV RNA is detected as early as 3 days of age (3); however, in most cases, HCV RNA reaches detectable levels after several weeks of life, suggesting that perinatal HCV transmission is more common than intrauterine acquisition. Regardless of infection, an infant may have detectable anti-HCV antibody in serum until the 18th month of age due to passively transferred antibody from the mother (4). Chronic infection is defined as the persistence of HCV RNA for at least 6 months, and clearance of HCV infection is determined by the persistent disappearance of HCV RNA (3). In perinatally infected infants, loss of HCV RNA may reflect transient viremia or resolved infection, but the distinction is insignificant (3,4).
The natural course of HCV infection in children is not clearly understood, but overall advanced liver disease is rare during childhood. In a study of 359 untreated HCV RNA–positive children, HCV RNA clearance was seen in 7.5% (clearance rate high with genotype 3 rather than 1) and 92.5% showed persistent viremia for more than 10 years of follow-up. Progression to decompensated cirrhosis was seen in 6 (1.8%) of 332 cases with persistent viremia at a mean age of 9.6 years (15). In another study with 157 children with anti-HCV–positive antibody, 28% demonstrated clearance of HCV RNA after 10 years of follow-up, clearance being determined by younger age and normal alanine aminotransferase (ALT) levels (16).
In children with vertically acquired HCV infection, spontaneous HCV clearance rates vary from 0% to 25% in a time frame ranging from 2 to 7 years (16–19). In a large multicenter prospective study of 266 children with vertically acquired HCV infection, 17% showed viral clearance by 2 years of age, 24% by 3 years of age, and 25% by 5 years of age; the median age of clearance of 14.9 months. Positivity of HCV polymerase chain reaction (PCR) in the first year of life was found to be associated with less chance of clearance and more risk of persistent viremia (20). High ALT levels at onset (more than 5 times that of normal) was found by 1 study to be associated with high viral clearance rate (19).
Children with transfusion-acquired infection may have higher rates of spontaneous HCV clearance (3). It is unclear whether these differences in HCV clearance are due to immune tolerance in young infants or whether other factors such as HCV genotype and viral load influence viral resolution (3). In a longitudinal study of 31 children with HCV infection (16 acquired the virus vertically and 15 acquired it by transfusion), overall viral clearance rate was 19% without any significant difference between the 2 groups. Levels of ALT were significantly higher in the vertically acquired group as compared with the transfusion group (21).
Most children with HCV infection are asymptomatic or have mild nonspecific symptoms (3,4). Clinical symptoms are present in approximately 20% of children in the first 4 years of life, with hepatomegaly being the most frequent sign (seen in 10% of HCV-infected individuals) (20). Many, but not all, perinatally infected children will have intermittently or persistently abnormal ALT or aspartate aminotransferase (AST), particularly in the first 2 years of life (3,20,22). Aminotransferase levels do not correlate with histological severity, and there are no reports of acute liver failure with pediatric HCV. In children with vertical HCV infection who have undergone liver biopsy, the histological spectrum reported is usually mild (3,23), although severe liver disease is encountered (24,25). No restriction is required in the daily life of HCV-infected children.
Chronic HCV infection correlates with decrements in health-related quality of life (HR-QOL) and cognitive functioning in adults (26); however, little is known about the impact of HCV infection in children. A recent small pediatric Australian study showed significantly lower global physical and psychosocial scores in 23 HCV-infected children compared with normal controls (27). In a larger analysis, children with HCV had similar overall HR-QOL but worse cognitive functioning than their noninfected peers (28). Moreover, in this study, caregivers were highly distressed about their children's medical circumstances compared with a normative sample.
Laboratory Testing for Hepatitis C Virus Infection
Enzyme immunoassay techniques are used to detect antibody and screen for prior HCV exposure. The presence of antibody shows that the patient has been exposed to the virus but does not discriminate between active or resolved infection. The absence of antibody usually indicates that the patient is not infected. Antibody may also be undetectable within the first few weeks after HCV exposure or in immunocompromised patients. In infants, presence of antibody may be due to passive transplacental passage from the mother, and hence antibody testing for perinatal infection is unreliable until approximately 12 to 18 months of age.
In individuals with detectable anti-HCV antibodies, viral infection is verified by detecting the HCV RNA. Furthermore, the diagnosis of chronic HCV infection is generally made on the basis of persistently detectable HCV RNA for at least 6 months. The specificity of HCV RNA PCR is 98% from birth, and hence the positive predictive value of PCR is high. As in adults, HCV PCR may be intermittently negative. During therapy, serial quantitative HCV RNA determination is mandatory for the monitoring of treatment efficacy.
HCV genotype determination via sequence analysis is recommended before starting treatment to help predict treatment response because different responses to therapy are observed between genotypes (see following sections and Table 1).
TREATMENT OF HCV INFECTION
HCV testing should be considered for all children at risk for this viral infection, including recipients of blood product transfusions and organ transplants before the implementation of effective routine donor screening strategies (1992) or of clotting factor concentrates before the widespread use of reliable sterilizing techniques (1987), infants born to HCV-infected mothers, and those with a history of injection or intranasal drug use. Routine screening of internationally adopted children for HCV is generally not recommended unless the biological mother has a known high-risk factor, such as injection drug use (29).
Although there are no pediatric-specific guidelines (30), periodic assessment of children with chronic HCV infection is recommended. Children with newly diagnosed HCV infection should undergo thorough medical evaluation to detect the presence of liver disease or its sequelae and exclude other potential concomitant causes of hepatic dysfunction.
The need for and timing of a liver biopsy in children with HCV infection is debatable (30) but in general, this procedure should be entertained if the results assist in making sound medical decisions (Table 2). A liver biopsy may be particularly useful to assess degree of liver injury and exclude potential concurrent diseases, particularly in children with normal liver tests who are being considered for antiviral therapy. Even in this setting the liver biopsy is particularly controversial for those with HCV genotype 3 infections whose sustained virological response (SVR) rates exceed 80% (31–35). Indeed, a pretreatment liver biopsy is not generally indicated for adults with HCV genotypes 2 or 3, unless potential contraindications to therapy are present (36). Less invasive tests, such as the use of serologic markers of fibrosis, fibroscan (used for liver stiffness measurement), and magnetic resonance elastography, appear promising in adults (37,38), but so far, little is known about these tools in children.
Screening for hepatocellular carcinoma in children with chronic HCV infection is particularly problematic because this dreaded complication is rare in this population (39,40). In some centers, children with chronic HCV infection will undergo periodic sonographic screening at defined intervals (every 3–5 years), whereas in others, only those with advanced liver disease will undergo regular screening. There are no pediatric-specific guidelines to screen for liver cancer in children with HCV infection, but those with liver fibrosis or cirrhosis should undergo periodic surveillance with ultrasonography and α-fetoprotein concentrations, probably yearly. The recommendation in adults with HCV infection to screen for HCC is ultrasonography at every 6 to 12 months' interval (41).
A frequently overlooked but critical component of the management of children with HCV is to provide information about the virus, including ways to prevent its spread and the implications of infection. Adolescents, in particular, need to understand that alcohol accelerates progression of HCV-related liver disease (42) and should abstain from consumption. The importance of avoiding high-risk behavior such as sharing of intravenous injection needles needs to be openly discussed and appropriate psychosocial assistance offered to those actively engaged in such practices. Sharing potentially tainted personal items such as toothbrushes or razors should be discouraged. Finally, successful completion of hepatitis A virus and HBV vaccination should be confirmed.
Because our knowledge about the natural history of HCV infection and the risk factors associated with progression of liver disease in children is limited, the issue of treating young patients may be controversial, although most experts believe in treatment (Table 3). Given the generally indolent course of HCV infection in children (18,43–50) and the efficacy and safety profile of available therapeutic options, a reasonable approach is to offer treatment only to children with evidence of liver disease, as is recommended in adults. Progressive liver disease, including cirrhosis necessitating liver replacement and HCC, has been reported during childhood (24,39,40). Eradicating HCV to avert these potential hepatic complications in later life, as well as eliminating the social stigma associated with harboring a contagious infection, is a justifiable reason to pursue antiviral therapy in children. It is well known that the shorter the duration of infection, the better the response to treatment (47). Therefore, it may be argued that all children with chronic active viremia (detectable serum HCV RNA for longer than 6 months), irrespective of degree of liver injury, should be considered treatment candidates, particularly if it is administered in the context of a clinical trial. In adults with HCV infection, the American Association for the Study of Liver Diseases (AASLD) recommends therapy in all patients with detectable HCV RNA in serum who are willing to undergo treatment, have compensated liver disease with evidence of chronic hepatitis and significant fibrosis on liver histology, have acceptable hematological and biochemical parameters, and have no known contraindications for initiating therapy (53).
The spontaneous viral clearance rates in children vary considerably, as described earlier. In children with vertically acquired HCV, seroconversion is unlikely to occur after early childhood (6,17,21,43,47,54,55), and it seems prudent to wait until children are 3 to 5 years of age before offering treatment, unless significant liver dysfunction occurs earlier. Although interferon (IFN) is licensed in the United States to treat children with HBV infection as young as 1 year of age, caution should be exercised when treating young infants with this medication because it has been associated with spastic diplegia in this population (56).
The primary goal of treatment is clearance of viral infection as indicated by nondetectablity of HCV RNA in serum by the most sensitive test available. Regression (or delay in progression) of liver fibrosis, prevention of chronic liver disease and development of HCC, and improved quality of life comprise other potential treatment goals.
Certain definitions need to be clarified:
1. Rapid virological response (RVR) is defined as nondetectability of serum HCV RNA (<50 IU/mL) after 4 weeks of therapy.
2. Early virological response (EVR) is defined as undetectable HCV RNA (<50 IU/mL) or at least a 2-log10 decrease in serum HCV RNA from baseline level after 12 weeks of therapy.
3. End-of-treatment virological response (ETVR) is indicated by nondetectability of HCV RNA at the end of therapy.
4. Sustained virological response (SVR) is defined as undetectable serum HCV RNA (<50 IU/mL) 24 weeks after the end of therapy.
5. Nonresponder is defined as failure to clear HCV RNA from serum after 24 weeks therapy.
6. Partial responder is defined as a 2-log decrease in HCV RNA, but still HCV RNA positive at week 24.
SVR is the best correlate of beneficial changes in hepatic fibrosis, prevention of HCC, and improvement in other clinical outcomes. SVR has been shown to have the following beneficial effects: fibrotic regression; substantially reduced rate of HCC; decreased rate of other complications, including liver failure and liver-related death; and improved QOL.
IFN and Ribavirin
For many years IFN was the mainstay of HCV therapy in adults, with SVR rates in the 10% to 15% range (57). The use of different treatment regimens in published small, mostly uncontrolled, clinical trials of IFN for childhood HCV makes direct comparisons to adults difficult, but generally SVR rates are better in children than in adults. In a large review of pediatric IFN trials, SVR occurred in 27% and 71% of those infected with HCV genotypes 1 and HCV genotypes 2 to 3, respectively (58).
The addition of ribavirin to IFN-based treatment regimens results in enhanced rates of SVR in adults with HCV (59,60). Based on the synergistic effects of the combination regimen in adults, several trials assessed the efficacy and safety of IFN-ribavirin in children (32–35), although none included an IFN monotherapy “control” group (Table 1). In aggregate, the reported SVR in children administered combination treatment is 44% and 89% for those infected with HCV genotype 1 and HCV genotype 2 or 3, respectively. Kelly et al (61) have shown that SVR 24 weeks after treatment of chronic HCV in children with standard IFN-α-2b plus ribavirin predicts long-term clearance of HCV because only 1 of 56 SVR patients relapsed during the 5-year follow-up.
The addition of polyethylene glycol (PEG) increases the half-life of IFN allowing once-weekly doses, reduces its volume of distribution, and leads to more sustained plasma levels, resulting in more viral suppression. Studies in adults have shown an increase in SVR to 25% to 39% with use of PEG-IFN as compared with 6% to 11% with IFN alone (62,63). There are 2 PEG-IFN-α preparations available—PEG-IFN-α-2b, with a 12-kDa linear PEG covalently linked to the standard IFN-α-2b molecule, and PEG-IFN-α-2a, with a 40-kDa branched PEG covalently linked to the standard IFN-α-2a molecule (52). The efficacy of both PEG-IFN-α preparations are comparable (64).
In adults with HCV infection, the AASLD recommends the use of a combination of PEG-IFN-α and ribavirin in view of several trials showing the efficacy of this combination. The optimal doses of PEG-IFN-α-2b and -α-2a are 1.5 μg · kg · week and 180 g/week subcutaneously, respectively, whereas that of ribavirin is 800 mg/day orally for genotypes 2 and 3, and 1000 to 1400 mg/day for genotypes 1 and 4, depending on body weight. Duration of therapy also depends on the genotype—for genotypes 1 and 4, therapy is recommended for at least 48 weeks, but if HCV RNA remains detectable between 12 to 24 weeks of therapy, therapy may be extended to 72 weeks; and for genotypes 2 and 3, therapy is recommended for 24 weeks only. In all of the scenarios, retesting for HCV RNA after stoppage of therapy is advised after 24 weeks to determine SVR (53,59,60).
Several clinical trials have assessed PEG-IFN in children with chronic HCV infection. In an initial dose-finding study, 6 (43%) of 14 children (all infected with HCV genotype 1) given PEG-IFN-α-2a alone attained SVR (65). Interestingly, PEG-IFN exposure was about 25% more in children than in adults in this study, based on area-under-the-curve analysis (65). Taken together, results of several subsequent uncontrolled trials show that SVR rates in children treated with combination PEG-IFN with ribavirin are 40% to 53% and 93% to 100% for those infected with HCV genotypes 1 and HCV genotypes 2 or 3, respectively (Table 1).
Pegylated Interferon ± Ribavirin for Children With Hepatitis C (PEDS-C) is the first large-scale controlled trial comparing PEG-IFN alone or with ribavirin for the treatment of children with chronic HCV infection (66). Final results from this collaborative research network showed that 21% of children treated with PEG-IFN alone and 53% receiving PEG-IFN with ribavirin achieved SVR (67), clearly establishing combination therapy as optimal in children.
Factors Associated With Treatment Response
As in adults, in children several important factors are associated with a favorable therapeutic response to IFN-based therapy given alone or in combination with ribavirin, the more important of which are infection with a HCV genotype other than type 1 (Table 1) and low pretreatment serum HCV RNA levels. In 1 report, children younger than 12 years old had better SVR rates than older patients (32), but this was not subsequently confirmed in other studies (68). Also similar to adults, it appears that African American children have poorer virological response rates to combination treatment than whites, but the small number of patients enrolled significantly limits this analysis (32). Importantly, sustained virological response rates are consistently similar for HCV-infected children with normal and abnormal pretreatment serum transaminase levels (31–33,67–69).
Meticulous and statistically robust analyses of randomized clinical trials in adults convincingly demonstrate that SVR rarely occurs in patients who fail to achieve an EVR, defined by at least a 100-fold (2-log) reduction from pretreatment serum HCV RNA levels or loss of detectable HCV RNA after 12 weeks of treatment (63,70). Therefore, antiviral therapy is generally discontinued in adults who do not achieve this virological milestone, thereby minimizing costs and treatment-related toxicity (71). Little is known about the correlation between EVR and SVR in children. Results of a recent pilot study showed that SVR occurred in 21 (72%) of 29 children with at least a 2-log reduction from baseline serum HCV RNA levels after 12 weeks of therapy, but in none of 8 (0%) whose viral levels did not decrease by this magnitude by this time (69). In that report, however, 2 of 14 (14%) children with detectable HCV RNA 12 weeks into treatment achieved SVR (69). Hence, it is possible that these patients, whose HCV RNA cleared by 24 weeks of treatment, may have been disadvantaged by prematurely stopping therapy 12 weeks into treatment. Although these data suggest that reduction in the HCV RNA level after 12 weeks of treatment may be more important than loss of detectable HCV RNA in children, it should be interpreted cautiously until confirmed in larger studies. Importantly, SVR is unlikely to occur in children with detectable HCV RNA after 24 weeks of treatment (31,65), and treatment can be safely stopped in these patients. Adult data also suggest that patients infected with HCV genotypes 2 or 3 can be effectively treated with shorter courses of antivirals (24 weeks) than those infected with HCV genotype 1 (48 weeks) (72). There are little pediatric-specific data assessing treatment duration based on infecting HCV genotype. In 2 recent studies (68,69), SVR rates in children infected with HCV genotypes 2 or 3 treated with combination PEG-IFN with ribavirin for 24 weeks were comparable with those reported in children given IFN or PEG-IFN with ribavirin for 48 weeks (31–33,67,68).
Adverse events are common during treatment with IFN and PEG-IFN–based therapies alone (73) or in combination with ribavirin (25,31–35) (Table 4). These adverse events, particularly those related to leukopenia and neutropenia, may be severe enough that dose reductions are required. Although rare, suicidal ideation attempt occurs in treated children (32). Although autoimmune markers arise during treatment, their pathobiological importance is uncertain. Detectable antithyroid antibodies are particularly common and clinical thyroid disease occurs, which only rarely becomes permanent (74). Based on these potentially clinically significant complications, patients need to be carefully monitored during treatment, which should be prescribed and supervised only by experienced health care providers.
Treatment of Virological Nonresponders and Relapsers
In adult nonresponders to PEG-IFN monotherapy and PEG-IFN plus ribavirin, retreatment with PEG-IFN and ribavirin can achieve an SVR of 40% and 10%, respectively (75,76). Similarly up to 50% of adults who relapse after IFN monotherapy achieve SVR after retreatment with PEG-IFN in combination with ribavirin (59,75,76). Patients with HCV genotypes 2 or 3 and those with low pretreatment viral levels are more likely to respond to retreatment (59,75–77). There is evidence in adults that retreatment may have secondary benefits of reducing inflammation and fibrosis progression, and possibly reversing early cirrhosis. These benefits could translate to a delay in the development of HCC (77).
There are no studies specifically addressing retreatment in children; however, published reports have included children with previous failed response. For example, Wirth et al (33) reported SVR in 6 of 9 patients with recombinant IFN plus ribavirin who had previously not responded to IFN monotherapy. Pawlowska et al (78) reported an end-of-treatment response in 6 of 12 children who had failed IFN plus ribavirin given PEG-IFN plus ribavirin. Interestingly, EVR was more common in children younger than 13 years old and in those with high baseline ALT, low pretreatment HCV RNA levels, and shorter interval from the end of previous therapy (78). Unfortunately, SVR, a better predictor viral response, was not reported in this study. In an open-label trial of PEG-IFN plus ribavirin, Wirth et al (31) included 5 of 62 children who had previously not responded to IFN monotherapy. Of these 5 pediatric nonresponders, 2 achieved SVR with combination therapy; details about the HCV genotype of these prior nonresponders were not provided (31).
TREATMENT OF SPECIAL GROUPS
The prevalence of HCV infection in patients with thalassemia in Asia is high and varies from 20% to 64% (79,80,81). Patients are generally infected with HCV during the first 10 years of life, and persistence of HCV infection is favored by iron overload and the various immune abnormalities underlying susceptibility to infections. HCV infection and iron overload may act as synergistic risk factors for the development of liver cirrhosis and HCC. Clearly, the treatment of chronic HCV in these patients has become imperative, along with the management of iron overload. In an Indian study by Mohan et al (81) with 148 transfusion-dependent β-thalassemics, anti-HCV antibodies were positive in 45.9% and HCV RNA in 20.2%. With IFN monotherapy in HCV RNA–positive patients, SVR was found to be 87.5%. Another study in 63 thalassemic children with HCV receiving IFN monotherapy for a period of 12 months showed an SVR of 58.7%. Absence of cirrhosis, low liver iron content, and infection with non-1b HCV were found to be independently associated with complete sustained response (82). Ribavirin is not generally used in combination with IFN for treatment of such patients because of fear of hemolysis and worsening anemia due to the medication. There are reports of successful usage of ribavirin at the cost of slightly increased blood transfusion rates (83). The prevalence of HCV in patients with hemophilia has been reported to be as high as 72.9%. In adults with hemophilia, monotherapy with IFN has generally been disappointing, with an SVR of 7% to 13%, increasing to 60% with combination therapy (84). Ribavirin has been shown to elevate the activity of factor VIII in these patients through an unknown mechanism, with decreases in spontaneous bleeding (85). No children-specific studies are available.
Routine testing for HCV should be undertaken in children with HIV or HBV infection. In adults, co-infection with HCV and HBV is associated with mutual inhibition of viral replication; however, liver disease is worsened. In adults who are HBsAg and HCV RNA positive, PEG-IFN-α plus ribavirin is recommended. In adults, HCV has little impact on HIV disease progression; conversely, HIV accelerates the natural history of HCV in several aspects. Maintenance of restoration of immune function through highly active antiretroviral therapy reduces the impact of HIV on HCV natural history, particularly progression to cirrhosis and end-stage liver disease. SVR rates following PEG-IFN and ribavirin therapy in HIV/HCV-co-infected patients are 15% to 20% lower than those in HCV monoinfection (84). No studies have been reported in children who are co-infected by HCV and HIV or HBV.
Because there are no pediatric-specific data, preemptively treating HCV-infected children who are being considered for stem cell or solid organ transplantation or those with underlying hematological and renal disease, is especially controversial. The decision to treat (or not) in these usually complex patients should be based on the potential advantages and risks on an individual basis. Adult patients with HCV infection who are operated on for solid organ transplantation showpersistence of HCV viremia and progressive liver disease post transplantation, which may affect their survival. Graft reinfection in adults after liver transplantation is almost universal, and approximately 30% of HCV recipients will die or lose their allograft or develop cirrhosis secondary to HCV recurrence by the fifth postoperative year. Treatment of HCV-related disease following liver transplantation should be initiated in appropriate candidates with caution because there are concerns of intolerance, adverse effects, graft rejection, and mortality (50–52). A review of 10 large trials using combination PEG-IFN and ribavirin for after–liver transplant HCV recurrence in adult recipients has shown an ETVR ranging from 25% to 67% and SVR from 14% to 45%. In the posttransplant setting, 48 weeks of treatment is recommended regardless of genotype (86). In adults with chronic kidney disease with hepatitis C, the current recommendation is to treat before the need for kidney transplantation. Also, treatment is not recommended for patients with chronic HCV infection who have undergone kidney transplantation, unless they develop fibrosing cholestatic hepatitis. In patients who receive other solid organ transplants like heart or lung, administration of antiviral therapy should be made on an individual basis (53).
NOVEL EMERGING AGENTS
Newer antivirals include newer IFN molecules (albumin IFN), ribavirin-like molecules (taribavirin) with better tolerance profile, and agents that specifically target steps in the replication cycle of HCV. Specific targeted antiviral therapy for HCV include inhibitors of critical viral proteins including NS3 serine protease, NS3 helicase, and NS5B RNA-dependent RNA polymerase (the viral replicating enzyme). In the PROVE1 and PROVE2 studies on adult patients with HCV genotype 1, the use of telaprevir, an HCV NS3/4A protease inhibitor, for an initial 12 weeks along with PEG-IFN-α 2a and ribavirin for 24 weeks resulted in SVRs of 61% and 69% as compared to 41% and 46%, respectively, with PEG-IFN-α 2a and ribavirin alone for 48 weeks. There were higher rates of RVR (described as undetectable HCV RNA after 4 weeks of treatment) of 81% versus 11% and 69% versus 13%, with a relapse rate of 14% versus 22%. High RVR was associated with high SVR, shorter duration of therapy, and lesser relapse rates (87,88). Preliminary data from SPRINT-I, which evaluated boceprevir, another NS3 protease inhibitor, in combination with PEG-IFN-α-2b and ribavirin in genotype 1–infected adults demonstrated HCV RNA undectectability in 55% to 57% of patients at follow-up week 12 (89).
Phase 2 trials with nucleoside polymerase inhibitors are in progress with 2 such drugs, R1626 and R7128, demonstrating significant potency as monotherapy and 80% to 85% rate of RVR, competitive with RVR rates observed with protease inhibitors, when combined with PEG-IFN and ribavirin.
With the high global disease burden and public health impact of hepatitis C, development of an effective vaccine against HCV is the need of the hour. However, there are many challenging obstacles—genetic heterogeneity of HCV, high mutation rate, no effective small animal model or cell culture system for HCV, and the observation that convalescent humans and chimpanzees could be reinfected after reexposure. Despite these, several promising approaches have been pursued to develop an HCV vaccine (90). Novel vaccine candidates based on molecular technology such as recombinant proteins (E1 and/or E2 glycoprotein), polypeptides, virus-like particles, plasmid DNA, and recombinant viral vectors including adenovirus, modified vaccinia Ankara, canary pox virus, and alphavirus are being explored. Various novel adjuvants including Toll-like receptor agonists have demonstrated enhanced immunogenicity when applied together with HCV immunogens. Finally, vaccination regimens like prime-boost strategy have shown promise (90,91). Induction of high-titer, long-lasting, and cross-reactive anti-envelope antibodies and a vigorous, multispecific cellular immune response that includes both helper and cytotoxic T lymphocytes may be necessary for an effective vaccine (92). The final vaccine product may thus require multiple components that target various aspects of protective immunity.
Since the discovery of HCV in 1989, great advances have occurred in the understanding of the virus, its infectious epidemiology, the resultant liver injury, and the treatment options available for the disease. Both PEG-IFN and ribavirin are approved therapies for treating children infected with the virus, and a growing body of evidence is developing showing treatment efficacy. Additional therapeutic regimes such as newer IFNs and ribavirin and various protein inhibitors are under trial. With ongoing research of the disease pathogenesis and focusing the treatment of pediatric HCV in trials, the predicted advancements for children infected with HCV are great in the next several years. Progress in the development of a vaccine is most wanted.
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