The Challenge of Treating Children With Hepatitis C Virus Infection

Abstract

The development of oral hepatitis C virus (HCV) direct-acting antivirals (DAAs) has revolutionized the therapeutic field. Nowadays, multiple safe and highly effective antiviral regimens are commercially available to treat adults with hepatitis C infection. These new regimens for the first time genuinely raise the prospects of eradicating HCV. Many challenges, however, remain from identifying infected individuals to optimizing treatment and ensuring global access to antiviral therapy to all population groups, including children. Recently, in April 2017, the association of sofosbuvir with ribavirin and the fixed-dose combination sofosbuvir/ledipasvir have been approved by the Food and Drug Administration for treatment of children with chronic HCV infection 12 years of age and older. The only drugs currently approved for children younger than 12 years are pegylated interferon and ribavirin. There are 6 registered ongoing pediatric trials assessing safety and efficacy of DAAs, but their current completion timelines are years away. Herein, we summarize the state of the art of DAAs’ development for adult and children and highlight the crucial importance of overcoming barriers to treating children with HCV.

What Is Known

• More than 11 million children are anti-hepatitis C virus antibody-positive worldwide and half of them are viremic needing treatment.
• Pegylated interferon in combination with ribavirin is the only currently approved therapy for children younger than 12 years with hepatitis C virus infection. This therapeutic regimen is suboptimally effective, requires subcutaneous injections, and is commonly associated with treatment-related adverse events.
• The association of sofosbuvir and ribavirin and the fixed-dose combination sofosbuvir/ledipasvir have been recently approved by the FDA for pediatric patients 12 years of age and older (or weighing at least 35 kg) with HCV genotype 2 or 3 and 1, 4, 5, or 6 infection, respectively.

What Is New

• Newly developed direct-acting antivirals are highly effective and safe drugs to treat hepatitis C virus. Preliminary data from ongoing pediatric trials show that direct-acting antivirals are similarly effective and safe in children and adolescents.
• Cure of hepatitis C virus infection is possible in almost all patients treated with interferon-free, oral direct-acting antiviral regimens. Hepatitis C virus-infected children need to be targeted for direct-acting antiviral treatment as an integral component of the public health approach to the global eradication of hepatitis C virus infection.
• Serious interplay between pediatric researchers, regulators, and pharmaceutical industry leaders is essential to hasten the process of direct-acting antiviral approval for children with hepatitis C virus infection.

The discovery of hepatitis C virus (HCV) 25 years ago was a major scientific achievement when this elusive virus was isolated via a new expression-cloning technique ⁽¹⁾. Subsequent molecular studies revealed HCV to be an RNA virus that replicates without a DNA intermediate ⁽²⁾. The characterization of HCV nonstructural proteins (NS3–5) is responsible for viral replication allowed for development of direct-acting antiviral (DAA) targeting of NS3/4A protease, NS5A, and both nucleoside and non-nucleoside NS5B polymerase ⁽³⁾. Since the introduction of the first-generation DAAs (ie, protease inhibitors) in 2011, HCV therapy has become one of the great success stories of basic, clinical, and translational viral research. Hence, our focus is to outline the development of DAAs, and to review HCV oral, non-nterferon therapy for adults, older adolescents, and children. Also, we will highlight pediatric barriers that must be overcome to allow children with chronic hepatitis to participate in this rapidly evolving postinterferon era, which has revolutionized HCV therapy.

PREVALENCE OF HEPATITIS C VIRUS

Chronic HCV is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. Throughout this world, 130 million to 170 million people are chronically infected with HCV. In the United States, prevalence is estimated to be 3.2 million individuals ⁽⁴⁾. HCV infection recently eclipsed human immunodeficiency virus infection as a cause of death in the United States; the number of deaths because of HCV are not projected to peak until 2030 ⁽⁵⁾. Globally, 11 million of these infected individuals are younger than 15 years; >50% of all the children are from China, India, Russia, Nigeria, Pakistan, and Egypt ⁽⁶⁾. HCV prevalence in the United States and Europe ranges from 0.05% to 0.36% and 1.8% to 5.8% in developing countries ⁽⁷⁾.

DIRECT-ACTING ANTIVIRAL MEDICATIONS

General Information

The initial monotherapy trials of the first-generation NS3/4A protease inhibitors were hindered by rapid selection of resistant variants ⁽²⁾. It was also recognized that the standard of care with injected interferon-alpha combined with ribavirin showed activity against protease inhibitor-resistant HCV. This antiviral therapy inhibits HCV replication, not by binding viral proteins, but by induction of antiviral and immunomodulatory effects. Therefore, the key first step in the now recognized oral therapeutic revolution against HCV infection was the addition of a NS3/4a protease inhibitor to the standard treatment of peginterferon and ribavirin. This strategy led to enhanced rates of HCV sustained virological rate (SVR) from approximately 45% to 75% among adult patients with genotype 1 HCV infection ⁽²⁾. There was proof, therefore, that use of DAAs was clinically effective but the adverse effects of interferon-based regimens including cytopenias, autoimmune reactions, and depression remained a limiting problem. The subsequent rapid development of HCV NS5A inhibitors, and nucleoside/non-nucleoside NS5B polymerase inhibitors since 2011, is well reported, including new treatment combinations of HCV DAAs. The most recent adult clinical trials have proved that interferon-free, all oral DAA combinations are consistently capable of producing SVR rates >90% (as defined by HCV RNA clearance 12 weeks after cessation of treatment; SVR12) ^(8–10). High optimism now exists for the global eradication of HCV infection ⁽¹¹⁾. Table 1 summarizes DAAs approved to date in adults. First-generation NS3/4 protease inhibitors such as telaprevir and boceprevir are no longer used because of their higher rates of adverse effects and treatment failures in real-world settings ⁽¹¹⁾.

TABLE 1: New direct-acting antivirals approved or in the pipeline for treating HCV infection

Results of Clinical Trials in Adults and “Real-world” Experience

In late 2013, sofosbuvir, a NS5B polymerase inhibitor (in combination with ribavirin), became the first Federal Drug Administration (FDA)-approved DAA that allowed interferon-free therapy for HCV genotypes 2 and 3 ⁽¹²⁾. Then, in early 2014, the “all oral” DAA combination of sofosbuvir with a NS5A inhibitor, daclatasvir, was used for treatment-naïve adults with HCV genotypes 1, 2, and 3 and HCV genotype 1 patients and previous protease inhibitor failure; SVR12 rates were excellent at >93% ⁽¹³⁾. In a subsequent trial, previous nonresponders infected with HCV genotype 1 treated with sofosbuvir and an NS3/4A protease inhibitor, simeprevir, with or without ribavirin achieved excellent SVR12 rates of 90% and 94%, respectively, in addition to a good safety profile and no apparent requirement for ribavirin ⁽¹⁴⁾. Sofosbuvir and ledipasvir, another NS5A inhibitor, were coformulated in 2016, as was the regimen of paritaprevir (NS3/4 protease inhibitor boosted with ritonavir), ombitasvir (NS5A inhibitor), and dasabuvir (NS5B inhibitor).

Two phase III studies were reported in August 2016. In OPTIMIST 1, sofosbuvir and simeprevir were combined to treat a large group of HCV-genotype 1 adults without cirrhosis who were treatment-naïve and treatment-experienced ⁽¹⁵⁾. This regimen for 12 weeks was highly effective in the treatment of genotype 1a-infected individuals without cirrhosis. The overall SVR12 was 97%, superior to the historic rate of 87%. In OPTIMIST 2 ⁽¹⁶⁾, the same 12-week regimen in an open-label fashion was used, but the adult HCV genotype 1a patients had well-compensated cirrhosis. In this difficult-to-treat group, the SVR12 was 83%, and emergent resistance-associated variants occurred based on treatment breakthroughs confirmed to be attributable to NS3/4a region mutation. In a recent phase III DAA trial of untreated and treatment-experienced adults with HCV genotypes 1, 2, 4, 5, and 6, the use of fixed-dose combination sofosbuvir and velpatasvir (a novel NS5A inhibitor) led to an overall high rate of SVR12 of 99% ⁽¹⁷⁾. Similarly, adults given this combination regimen with “difficult-to-treat” HCV genotypes 2 and 3, achieved SVR12 of 99% and 96%, respectively ⁽¹⁸⁾. Thus, these trials showed that treatment with sofosbuvir-velpatasvir was effective regardless of HCV genotype (pan-genotypic). Comprehensive, up-to-date HCV treatment recommendations sanctioned by the American Association for the Study of Liver Diseases, Infectious Disease Society of America, and European and World Health Organization are available ^(8–10).

The potential selection bias inherent to all registration studies raises questions about generalizing trial-derived DAA efficacy and safety results to the adult HCV population at large. Thus, several HCV DAA “real-world” registries including HCV-TARGET, ANRS CO22 Hepather Cohort, and the US Veterans Study were developed. Initial results from these large adult cohorts that include patients with advanced liver disease and those with contraindications to interferon and/or ribavirin and comorbidities confirm that DAA therapy is highly effective and safe outside the registration studies ^(19–21).

PRESENT STANDARD TREATMENT OF HEPATITIS C VIRUS INFECTION IN CHILDREN

Up to April 2017, the standard of care for children and adolescents younger than 18 years with chronic HCV infection was pegylated interferon with ribavirin ^(22–25). This combination therapy results in a SVR of 52% in children with HCV genotype 1 and 4, after 48 weeks of therapy, and 89% in children with genotypes 2 and 3, after 24 weeks of treatment. Interferon regimens, however, are of long duration, requiring injections to deliver medication, and drug effectiveness is limited by the adverse effect profile that includes cytopenias, autoimmunity, and depression. And, it is now clear, as reviewed above, that the noninterferon, oral DAA medications are highly effective and well-tolerated in adults. There are only extremely limited data on DAA treatment in children. In the first “all oral” pediatric trial reported, the use of fixed-dose combination sofosbuvir/ledipasvir in children 12- to 17 years’ old infected with HCV genotype 1 demonstrated satisfactory pharmacokinetic and tolerability profiles and high rates of SVR12 (98%) ⁽²⁶⁾. Similar excellent results were recently reported in abstract form for the combination of sofosbuvir-ribavirin in adolescents with HCV genotype 2 and 3 infection with SVR of 100% and 97%, respectively ⁽²⁷⁾. Basing on these results, the FDA recently approved the use of sofosbuvir and ribavirin and the fixed-dose combination sofosbuvir/ledipasvir for children 12 years of age and older (or weighing at least 35 kg) with HCV genotype 2 or 3 and 1, 4, 5, or 6 infection, respectively.

TREATMENT OF CHILDREN WITH DIRECT-ACTING ANTIVIRALS: IS DELAY OF THERAPY JUSTIFIED?

Our limited ability to risk-stratify patients with minimal HCV disease coupled with a poor understanding of the dynamics progression of chronic HCV infection makes it important to recognize the extraordinary efficacy of new, oral DAA therapy for all patients with HCV. In fact, the DAA therapeutic revolution raises the prospect of genuinely eradicating HCV infection. To achieve this goal; however, DAA cost analyses will be essential in developed and resource-limited countries, in addition to creation of effective HCV screening programs with effective linkage to quality patient care facilities.

In terms of cost-effectiveness, patient age is an important determining factor ⁽²⁸⁾. Treatment of younger individuals, that is, children, is more cost-saving per quality-adjusted life year than treating adults, and pediatric weight-based DAA dosing translates into a need for less medication with subsequent reduced drug costs. Also, the projected long-term cost of medical follow-up is probably less in children than in adults ⁽²⁹⁾. Furthermore, early-in-life eradication of HCV may be important before high-risk adolescent behaviors such as injection-drug use, obtaining tattoos in an unregulated setting, and unprotected sexual activity contribute to the spread of infection. The commitment of motivated parents to adhere to a prescribed antiviral regimen enhances pediatric compliance that is critically important to achieve therapeutic success ⁽³⁰⁾. Moreover, comorbidities such human immunodeficiency virus coinfection, renal impairment, illegal drug and alcohol misuse, and decompensated cirrhosis that may portend unfavorable treatment outcomes are uncommon in children ⁽²⁹⁾. Curing HCV infection in females before they achieve childbearing age might be the best approach to prevent future vertical transmission. Thus, HCV screening of high-risk mothers and their infants should be performed.

Have children been left behind in the HCV treatment revolution? As noted, partial results of only 2 DAA pediatric trials have been reported to date ^(26,27), whereas others are ongoing. In addition, several developmental plans to support authorization of combination DAA regimens for children have been submitted by pharmaceutical companies to the European Medicines Agency (EMA) and FDA, but the current timelines for completion of approved plans are in the distant future. For example, the estimated date of completion of a sofosbuvir with ribavirin trial for children infected with HCV genotype 2 and 3 is January 2018 (clinicaltrial.gov identifier NCT02175758). For children with HCV genotype 1 and 4 infection, the estimated date of completion of a sofosbuvir and ledipasvir ± ribavirin trial (identifier NCT02249182) and a paritaprevir boosted with ritonavir/ombitasvir ± dasabuvir (an NS5B inhibitor) ± ribavirin trial (identifier NCT02486406) are May 2018 and September 2019, respectively. The estimated date of completion of the recently started pangenotypic glecaprevir and pibrentasvir trial (identifier NCT03067129) is September 2019. The long delay is a direct consequence of multiple barriers which impede rapid drug registration and pediatric-regulatory requirements. In many high-HCV prevalent nations, trial recruitment is also hindered by regulations that require either drug approval by EMA and/or FDA. To hasten pediatric access to new DAA therapies, in December 2014, the EMA approved a strategic approach for the registration of children's DAA regimens ⁽³¹⁾. Because of the high efficacy and excellent DAA safety profile in adults, new treatment regimens can now be approved for children in Europe on the basis of preauthorization studies of only 30 to 40 participants. Also, in May 2016, the FDA recommended that pharmaceutical companies focus on development of DAAs for children, especially for the best-studied regimens based on collaborative adult data ⁽³²⁾. The FDA also advocated for earlier development of pediatric DAA drugs, and, more importantly, for the inclusion of younger adolescents in adult phase III trials (40). The above will hopefully accelerate registration of DAA regimens for all children.

The cure of HCV infection is possible for almost all individuals treated with interferon-free, oral DAA combination regimens. Global elimination of HCV is presently hampered by the above-noted barriers, especially poor screening and identification of infected people, and the high price tag of expensive, but very efficacious and safe DAA drugs. We believe that children should be an integral component of the public health approach required for success in realizing global eradication of HCV infection. The close interplay between pediatric researchers, appropriate healthcare regulators, and pharmaceutical industry leaders is essential to accelerate the opportunity for children to receive curative oral DAA therapy to combat chronic HCV infection.