Pediatric HCV

Bridging the Gap: New Clinical Trials Planned for Children with HCV

Yen Pham

Yen Pham

Philip Rosenthal

Philip Rosenthal

Hepatitis C virus infection remains a significant health issue, affecting more than 4 million people in the United States.

The prevalence of HCV infection in children ranges from 0.05% to 0.36% in the United States and Europe, to 1.8% to 5.8% in some developing countries. More children are infected at birth by vertical transmission, with 7,500 new cases reported in the United States each year from vertical transmission.

Spontaneous clearance of the virus can occur in up to 40% of infants infected by vertical transmission, but only in 6% to 12% of older children with HCV. A small subset of children, 20% to 25%, can have more aggressive disease with evidence of cirrhosis or hepatocellular carcinoma.

Current Regimens

The current FDA-approved treatment for HCV in children older than 3 years is the combination of weekly injections of pegylated interferon and twice-daily oral ribavirin. With this regimen, response to treatment in children is similar to that observed in adults. Sustained virologic response occurs in up to 30% to 50% of children with HCV genotype 1 after 48 weeks of treatment and in 80% of children with genotypes 2 and 3 after 24 weeks of treatment.

Adverse effects associated with the current regimen are slightly better tolerated than in adults, but symptoms including fatigue, depression, irritability and nausea almost invariably occur. Interferon can also affect growth, weight loss and neutropenia, making an interferon-free regimen an appealing goal.

The advent of direct-acting antivirals such as non-nucleoside polymerase inhibitors, nucleoside/nucleotide polymerase inhibitors, NS5A inhibitors and/or protease inhibitors demonstrated that much higher cure rates were possible. Telaprevir (Incivek, Vertex Pharmaceuticals) and boceprevir (Victrelis, Merck) were the first two DAAs to receive FDA approval in 2011, which led to the development of the multiple therapies currently under investigation. The nucleoside polymerase inhibitor sofosbuvir (Sovaldi, Gilead) is now FDA-approved for the treatment of HCV in adults with genotypes 1 and 4 (12 weeks with PEG-IFN plus ribavirin, SVR 89%), genotype 2 (12 weeks with ribavirin, SVR 97%) and genotype 3 (24 weeks with ribavirin, SVR 85%).

Future Regimens

Investigations into combination regimens that contain two to four DAAs are achieving SVR rates approaching 100%, with shorter treatment durations and better tolerability than interferon- and ribavirin-containing regimens.

Sofosbuvir plus ledipasvir (Gilead) has been shown to provide 95% or more SVR in patients with HCV genotype 1, irrespective of the treatment history or presence of compensated cirrhosis. The NS5A inhibitor daclatasvir (Bristol-Myers Squibb) produced the best results in combination with sofosbuvir, with a 98% SVR rate in treatment-naive patients with genotype 1 after 12 weeks of treatment. However, additional study looking at a combination of daclatasvir with the NS3 protease inhibitor asunaprevir and the non-nucleoside NS5B inhibitor BMS-791325 (all Bristol-Myers Squibb) yielded a cure rate of more than 90% in the same patient category. AbbVie’s three-drug combination regimen of dasabuvir, ABT-450/ritonavir and ombitasvir yielded an impressively high SVR rate (>95%) in patients with genotype 1a and 1b, including those previously treated with PEG-IFN and ribavirin. For genotype 4, ribavirin is used instead of dasabuvir, since it is only effective against genotype 1; data have shown an SVR rate of 100% with ribavirin and 91% without ribavirin after 12 weeks of treatment. The combination of the NS3/4a protease inhibitor MK-5172 and the NS5A inhibitor MK-8742 (Merck) achieved a 94% to 100% SVR rate with or without ribavirin after 12 weeks of treatment in patients with genotype 1.

Newer therapies in early phases of investigation include the NS3/4A protease inhibitor sovaprevir (ACH-1625; Achillion Pharmaceuticals), the nucleotide NS5B polymerase inhibitor ACH-3422 (Achillion Pharmaceuticals), the NS5A inhibitor samatasvir (Idenix Pharmaceuticals), and the uridine-based nucleotide pro-drugs IDX 21459 and IDX 21437 (Idenix Pharmaceuticals).

These drugs promise the hope of a pan-genotypic cure.

Pediatric Trials

Despite recent advances in the treatment of HCV in adults, treatment options in children are lacking, with dismal SVR rates for the more difficult-to-treat genotype 1 with PEG-IFN and ribavirin alone.

Currently, there is one active trial investigating the pharmacokinetics and efficacy of telaprevir, a protease inhibitor, in combination with PEG-IFN alfa-2b and ribavirin in pediatric patients with genotype 1 infection. A second clinical trial of triple therapy, with boceprevir, for the treatment of children aged 3 to 17 years with genotype 1 was withdrawn in anticipation that newer all-oral therapies would supplant use of this drug by the time the trial was concluded.

The first pediatric interferon-free clinical trial will begin enrollment in the very near future and aims to examine the safety and efficacy of sofosbuvir and ribavirin in children with HCV genotypes 2 and 3. A trial of an all-oral regimen for genotype 1 HCV is also planned and enrollment is expected to begin in the fall.

With multiple rigorous clinical trials of DAA-containing therapies demonstrating efficacy and safety in adult patients, earlier inclusion of children in pharmacokinetic and safety studies is needed to allow children early access to effective therapies. It is expected that the same excellent efficacy and safety profiles for these all-oral regimens will occur in children, and the advent of cures for HCV in children will be a reality in the near distant future.

References:
Afdhal N. N Engl J Med. 2014;370:1483-1493.
Afdhal N. N Engl J Med. 2014;370:1889-1898.
Badizadegan K. Hepatology. 1998;28:1416-1423.
Chak E. Liver Int. 2011;31:1090-1101.
Chou R. Ann Intern Med. 2013;158:114-123.
Denniston MM. Ann Intern Med. 2014;160:293-300.
El-Shabrawi MH. World J Gastroenterol. 2013;19:7880-7888.
Everson GT. Gastroenterology. 2014;146:420-429.
Gonzalez-Peralta RP. J Pediatr Gastroenterol Nutr. 2009;48:630-635.
Hanafiah KM. Hepatology. 2013;57:1333-1342.
Herzode C. Abstract #58. Presented at: The International Liver Congress; April 9-14, 2014; London.
Jara P. Clin Infect Dis. 2003;36:275-280.
Kowdley KV. Lancet. 2013;381:2100-2107.
Kowdley KV. N Engl J Med. 2014;370:1889-1898.
Lawitz E. N Engl J Med. 2013;368:1878-1887.
Lawitz E. Abstract #60. Presented at: The International Liver Congress; April 9-14, 2014; London.
Mack CL. J Pediatr Gastroenterol Nutr. 2012;54:838-855.
Rumbo C. J Pediatr Gastroenterol Nutr. 2006;43:209-216.
Schwarz KB. Gastroenterology. 2011;140:450-458.
Sulkowski MS. N Engl J Med. 2014;370:211-221.
Yeung LT. J Viral Hepatol. 2007;14:797-805.
Zeuzem S. N Engl J Med. 2014;370:1993-2001.
Zeuzem S. N Engl J Med. 2014;370:1604-1614.

For more information:
Yen Pham, MD, is assistant clinical professor at the University of California, San Francisco. Pham can be reached at the University of California, San Francisco, 500 Parnassus Ave., Box 0136, MU 4-East, San Francisco, CA 94143; email: yen.pham@ucsf.edu. Philip Rosenthal, MD, is professor of pediatrics and surgery at the University of California, San Francisco, and is a member of The Liver Center there. He is also an HCV Next Editorial Board member. Rosenthal can be reached at the University of California, San Francisco, 500 Parnassus Ave., Box 0136, MU 4-East, San Francisco, CA 94143;  email: prosenth@peds.ucsf.edu.

Disclosures: Pham reports no relevant financial disclosures. Rosenthal reports associations with Bristol-Myers Squibb, Genentech/Roche, Gilead, Merck and Vertex Pharmaceuticals.

Yen Pham

Yen Pham

Philip Rosenthal

Philip Rosenthal

Hepatitis C virus infection remains a significant health issue, affecting more than 4 million people in the United States.

The prevalence of HCV infection in children ranges from 0.05% to 0.36% in the United States and Europe, to 1.8% to 5.8% in some developing countries. More children are infected at birth by vertical transmission, with 7,500 new cases reported in the United States each year from vertical transmission.

Spontaneous clearance of the virus can occur in up to 40% of infants infected by vertical transmission, but only in 6% to 12% of older children with HCV. A small subset of children, 20% to 25%, can have more aggressive disease with evidence of cirrhosis or hepatocellular carcinoma.

Current Regimens

The current FDA-approved treatment for HCV in children older than 3 years is the combination of weekly injections of pegylated interferon and twice-daily oral ribavirin. With this regimen, response to treatment in children is similar to that observed in adults. Sustained virologic response occurs in up to 30% to 50% of children with HCV genotype 1 after 48 weeks of treatment and in 80% of children with genotypes 2 and 3 after 24 weeks of treatment.

Adverse effects associated with the current regimen are slightly better tolerated than in adults, but symptoms including fatigue, depression, irritability and nausea almost invariably occur. Interferon can also affect growth, weight loss and neutropenia, making an interferon-free regimen an appealing goal.

The advent of direct-acting antivirals such as non-nucleoside polymerase inhibitors, nucleoside/nucleotide polymerase inhibitors, NS5A inhibitors and/or protease inhibitors demonstrated that much higher cure rates were possible. Telaprevir (Incivek, Vertex Pharmaceuticals) and boceprevir (Victrelis, Merck) were the first two DAAs to receive FDA approval in 2011, which led to the development of the multiple therapies currently under investigation. The nucleoside polymerase inhibitor sofosbuvir (Sovaldi, Gilead) is now FDA-approved for the treatment of HCV in adults with genotypes 1 and 4 (12 weeks with PEG-IFN plus ribavirin, SVR 89%), genotype 2 (12 weeks with ribavirin, SVR 97%) and genotype 3 (24 weeks with ribavirin, SVR 85%).

Future Regimens

Investigations into combination regimens that contain two to four DAAs are achieving SVR rates approaching 100%, with shorter treatment durations and better tolerability than interferon- and ribavirin-containing regimens.

Sofosbuvir plus ledipasvir (Gilead) has been shown to provide 95% or more SVR in patients with HCV genotype 1, irrespective of the treatment history or presence of compensated cirrhosis. The NS5A inhibitor daclatasvir (Bristol-Myers Squibb) produced the best results in combination with sofosbuvir, with a 98% SVR rate in treatment-naive patients with genotype 1 after 12 weeks of treatment. However, additional study looking at a combination of daclatasvir with the NS3 protease inhibitor asunaprevir and the non-nucleoside NS5B inhibitor BMS-791325 (all Bristol-Myers Squibb) yielded a cure rate of more than 90% in the same patient category. AbbVie’s three-drug combination regimen of dasabuvir, ABT-450/ritonavir and ombitasvir yielded an impressively high SVR rate (>95%) in patients with genotype 1a and 1b, including those previously treated with PEG-IFN and ribavirin. For genotype 4, ribavirin is used instead of dasabuvir, since it is only effective against genotype 1; data have shown an SVR rate of 100% with ribavirin and 91% without ribavirin after 12 weeks of treatment. The combination of the NS3/4a protease inhibitor MK-5172 and the NS5A inhibitor MK-8742 (Merck) achieved a 94% to 100% SVR rate with or without ribavirin after 12 weeks of treatment in patients with genotype 1.

Newer therapies in early phases of investigation include the NS3/4A protease inhibitor sovaprevir (ACH-1625; Achillion Pharmaceuticals), the nucleotide NS5B polymerase inhibitor ACH-3422 (Achillion Pharmaceuticals), the NS5A inhibitor samatasvir (Idenix Pharmaceuticals), and the uridine-based nucleotide pro-drugs IDX 21459 and IDX 21437 (Idenix Pharmaceuticals).

These drugs promise the hope of a pan-genotypic cure.

Pediatric Trials

Despite recent advances in the treatment of HCV in adults, treatment options in children are lacking, with dismal SVR rates for the more difficult-to-treat genotype 1 with PEG-IFN and ribavirin alone.

Currently, there is one active trial investigating the pharmacokinetics and efficacy of telaprevir, a protease inhibitor, in combination with PEG-IFN alfa-2b and ribavirin in pediatric patients with genotype 1 infection. A second clinical trial of triple therapy, with boceprevir, for the treatment of children aged 3 to 17 years with genotype 1 was withdrawn in anticipation that newer all-oral therapies would supplant use of this drug by the time the trial was concluded.

The first pediatric interferon-free clinical trial will begin enrollment in the very near future and aims to examine the safety and efficacy of sofosbuvir and ribavirin in children with HCV genotypes 2 and 3. A trial of an all-oral regimen for genotype 1 HCV is also planned and enrollment is expected to begin in the fall.

With multiple rigorous clinical trials of DAA-containing therapies demonstrating efficacy and safety in adult patients, earlier inclusion of children in pharmacokinetic and safety studies is needed to allow children early access to effective therapies. It is expected that the same excellent efficacy and safety profiles for these all-oral regimens will occur in children, and the advent of cures for HCV in children will be a reality in the near distant future.

References:
Afdhal N. N Engl J Med. 2014;370:1483-1493.
Afdhal N. N Engl J Med. 2014;370:1889-1898.
Badizadegan K. Hepatology. 1998;28:1416-1423.
Chak E. Liver Int. 2011;31:1090-1101.
Chou R. Ann Intern Med. 2013;158:114-123.
Denniston MM. Ann Intern Med. 2014;160:293-300.
El-Shabrawi MH. World J Gastroenterol. 2013;19:7880-7888.
Everson GT. Gastroenterology. 2014;146:420-429.
Gonzalez-Peralta RP. J Pediatr Gastroenterol Nutr. 2009;48:630-635.
Hanafiah KM. Hepatology. 2013;57:1333-1342.
Herzode C. Abstract #58. Presented at: The International Liver Congress; April 9-14, 2014; London.
Jara P. Clin Infect Dis. 2003;36:275-280.
Kowdley KV. Lancet. 2013;381:2100-2107.
Kowdley KV. N Engl J Med. 2014;370:1889-1898.
Lawitz E. N Engl J Med. 2013;368:1878-1887.
Lawitz E. Abstract #60. Presented at: The International Liver Congress; April 9-14, 2014; London.
Mack CL. J Pediatr Gastroenterol Nutr. 2012;54:838-855.
Rumbo C. J Pediatr Gastroenterol Nutr. 2006;43:209-216.
Schwarz KB. Gastroenterology. 2011;140:450-458.
Sulkowski MS. N Engl J Med. 2014;370:211-221.
Yeung LT. J Viral Hepatol. 2007;14:797-805.
Zeuzem S. N Engl J Med. 2014;370:1993-2001.
Zeuzem S. N Engl J Med. 2014;370:1604-1614.

For more information:
Yen Pham, MD, is assistant clinical professor at the University of California, San Francisco. Pham can be reached at the University of California, San Francisco, 500 Parnassus Ave., Box 0136, MU 4-East, San Francisco, CA 94143; email: yen.pham@ucsf.edu. Philip Rosenthal, MD, is professor of pediatrics and surgery at the University of California, San Francisco, and is a member of The Liver Center there. He is also an HCV Next Editorial Board member. Rosenthal can be reached at the University of California, San Francisco, 500 Parnassus Ave., Box 0136, MU 4-East, San Francisco, CA 94143;  email: prosenth@peds.ucsf.edu.

Disclosures: Pham reports no relevant financial disclosures. Rosenthal reports associations with Bristol-Myers Squibb, Genentech/Roche, Gilead, Merck and Vertex Pharmaceuticals.