IL28B Mutation Linked toTreatment Response in Subset of Hepatitis C Patients

In patients with hepatitis C genotype 2 or 3, a polymorphism in the region of the interleukin 28B gene on chromosome 19 was associated with a sustained virologic response following treatment with peginterferon-alpha and ribavirin, Dr. Alessandra Mangia and her colleagues reported in the September issue of Gastroenterology.

The finding mirrors similar results among genotype 1 hepatitis C patients with the mutation, who are more than twice as likely to respond to prolonged treatment as patients without it, and could point to a “potential role for IL28B genotyping in selecting non-[rapid virologic response] patients for standard 24-week therapy or more prolonged therapy,” she and her colleagues wrote.

Dr. Mangia, of the liver unit at the IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy, studied 213 genotype 2 patients and 55 genotype 3 patients, for a total of 268 patients with hepatitis C, in a multicenter, randomized controlled trial (Gastroenterology 2010 Sept 1 [doi:10.1053/j.gastro.2010.05.079]).

Patients were randomly assigned to either standard 24-week therapy (68 patients) or “variable” treatment, which depended on their response (200 patients). The 122 patients in the variable treatment group who had a rapid virologic response at week 4 received treatment for 12 weeks, while the remaining 78 underwent 24 weeks of therapy. Rapid virologic response was defined as undetectable serum/plasma hepatitis C RNA, according to an assay that has a lower limit of detection of less than 50 IU/mL.

All patients received peginterferon alpha-2b, 1.0 mcg/kg/wk, plus ribavirin, 1,000 mg daily (1,200 mg if body weight was greater than 75 kg).

The researchers then determined the patient genotypes. “The genomic region associated with hepatitis C virus treatment response lies on chromosome 19 and contains multiple [single nucleotide polymorphisms, or SNPs] in linkage disequilibrium around the IL28B gene,” they wrote. “We selected the most strongly associated SNP, rs12979860, located 3 [kilobases] upstream of the IL28B gene, for genotyping in the cohorts.”

Patients could be either homozygous for the gene (CC), heterozygous (CT), or not have it at all (TT).

For all the genotypes combined, 201 patients (75%) attained a sustained virologic response: 51/68 (75%) in the standard treatment arm and 150/200 (75%) in the two variable treatment arms combined, they wrote.

Within the variable treatment arms, 98/122 (80%) of rapid response patients in the 12-week arm had a sustained response, and 52/78 (67%) of the non-rapid response patients in the 24-week arm attained a sustained virologic response (P = .1).

However, when patients were stratified according to genotype, Dr. Mangia found that 82% of those with the CC genotype had a sustained virologic response, compared with 75% with the CT genotype and 58% with the TT genotype (odds ratio 1.8, 95% confidence interval 1.2-2.7, P = .0046).

Moreover, although roughly equivalent proportions of each genotype had a rapid virologic response (165 patients total; 53%, 66%, and 59% for CC, CT, and TT patients, respectively), this effect was “largely driven” by those patients in the variable treatment arm who did not have a rapid response, wrote the authors.

Indeed, among those patients who did not have a rapid response, the link between CC genotype and sustained response was even stronger (87% of CC patients, vs. 67% of CT patients, vs. 29% of TT patients; OR 4.0, 95% CI 1.9-8.5, P = .0002).

The link was independent of whether the patient had hepatitis C genotype 2 or genotype 3.

Current guidelines recommend 12 weeks of therapy for all hepatitis C genotype 2 and 3 patients with a low viral load, irrespective of their IL28B status, according to the authors.

“It is tempting to speculate that such treatment would be most suitable for CC patients,” they said, but “prospective studies randomizing patients according to IL28B-type will be necessary.”

Several authors, not including Dr. Mangia, disclosed that they are coinventors of a patent application based on IL28B. The researchers also reported financial and research support from the Duke Clinical Research Institute, Richard B. Boebel Family Fund, National Health and Medical Research Council of Australia, Gastroenterology Society of Australia, and Royal Australasian College of Physicians.

In patients with hepatitis C genotype 2 or 3, a polymorphism in the region of the interleukin 28B gene on chromosome 19 was associated with a sustained virologic response following treatment with peginterferon-alpha and ribavirin, Dr. Alessandra Mangia and her colleagues reported in the September issue of Gastroenterology.

The finding mirrors similar results among genotype 1 hepatitis C patients with the mutation, who are more than twice as likely to respond to prolonged treatment as patients without it, and could point to a “potential role for IL28B genotyping in selecting non-[rapid virologic response] patients for standard 24-week therapy or more prolonged therapy,” she and her colleagues wrote.

Dr. Mangia, of the liver unit at the IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy, studied 213 genotype 2 patients and 55 genotype 3 patients, for a total of 268 patients with hepatitis C, in a multicenter, randomized controlled trial (Gastroenterology 2010 Sept 1 [doi:10.1053/j.gastro.2010.05.079]).

Patients were randomly assigned to either standard 24-week therapy (68 patients) or “variable” treatment, which depended on their response (200 patients). The 122 patients in the variable treatment group who had a rapid virologic response at week 4 received treatment for 12 weeks, while the remaining 78 underwent 24 weeks of therapy. Rapid virologic response was defined as undetectable serum/plasma hepatitis C RNA, according to an assay that has a lower limit of detection of less than 50 IU/mL.

All patients received peginterferon alpha-2b, 1.0 mcg/kg/wk, plus ribavirin, 1,000 mg daily (1,200 mg if body weight was greater than 75 kg).

The researchers then determined the patient genotypes. “The genomic region associated with hepatitis C virus treatment response lies on chromosome 19 and contains multiple [single nucleotide polymorphisms, or SNPs] in linkage disequilibrium around the IL28B gene,” they wrote. “We selected the most strongly associated SNP, rs12979860, located 3 [kilobases] upstream of the IL28B gene, for genotyping in the cohorts.”

Patients could be either homozygous for the gene (CC), heterozygous (CT), or not have it at all (TT).

For all the genotypes combined, 201 patients (75%) attained a sustained virologic response: 51/68 (75%) in the standard treatment arm and 150/200 (75%) in the two variable treatment arms combined, they wrote.

Within the variable treatment arms, 98/122 (80%) of rapid response patients in the 12-week arm had a sustained response, and 52/78 (67%) of the non-rapid response patients in the 24-week arm attained a sustained virologic response (P = .1).

However, when patients were stratified according to genotype, Dr. Mangia found that 82% of those with the CC genotype had a sustained virologic response, compared with 75% with the CT genotype and 58% with the TT genotype (odds ratio 1.8, 95% confidence interval 1.2-2.7, P = .0046).

Moreover, although roughly equivalent proportions of each genotype had a rapid virologic response (165 patients total; 53%, 66%, and 59% for CC, CT, and TT patients, respectively), this effect was “largely driven” by those patients in the variable treatment arm who did not have a rapid response, wrote the authors.

Indeed, among those patients who did not have a rapid response, the link between CC genotype and sustained response was even stronger (87% of CC patients, vs. 67% of CT patients, vs. 29% of TT patients; OR 4.0, 95% CI 1.9-8.5, P = .0002).

The link was independent of whether the patient had hepatitis C genotype 2 or genotype 3.

Current guidelines recommend 12 weeks of therapy for all hepatitis C genotype 2 and 3 patients with a low viral load, irrespective of their IL28B status, according to the authors.

“It is tempting to speculate that such treatment would be most suitable for CC patients,” they said, but “prospective studies randomizing patients according to IL28B-type will be necessary.”

Several authors, not including Dr. Mangia, disclosed that they are coinventors of a patent application based on IL28B. The researchers also reported financial and research support from the Duke Clinical Research Institute, Richard B. Boebel Family Fund, National Health and Medical Research Council of Australia, Gastroenterology Society of Australia, and Royal Australasian College of Physicians.

In patients with hepatitis C genotype 2 or 3, a polymorphism in the region of the interleukin 28B gene on chromosome 19 was associated with a sustained virologic response following treatment with peginterferon-alpha and ribavirin, Dr. Alessandra Mangia and her colleagues reported in the September issue of Gastroenterology.

The finding mirrors similar results among genotype 1 hepatitis C patients with the mutation, who are more than twice as likely to respond to prolonged treatment as patients without it, and could point to a “potential role for IL28B genotyping in selecting non-[rapid virologic response] patients for standard 24-week therapy or more prolonged therapy,” she and her colleagues wrote.

Dr. Mangia, of the liver unit at the IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy, studied 213 genotype 2 patients and 55 genotype 3 patients, for a total of 268 patients with hepatitis C, in a multicenter, randomized controlled trial (Gastroenterology 2010 Sept 1 [doi:10.1053/j.gastro.2010.05.079]).

Patients were randomly assigned to either standard 24-week therapy (68 patients) or “variable” treatment, which depended on their response (200 patients). The 122 patients in the variable treatment group who had a rapid virologic response at week 4 received treatment for 12 weeks, while the remaining 78 underwent 24 weeks of therapy. Rapid virologic response was defined as undetectable serum/plasma hepatitis C RNA, according to an assay that has a lower limit of detection of less than 50 IU/mL.

All patients received peginterferon alpha-2b, 1.0 mcg/kg/wk, plus ribavirin, 1,000 mg daily (1,200 mg if body weight was greater than 75 kg).

The researchers then determined the patient genotypes. “The genomic region associated with hepatitis C virus treatment response lies on chromosome 19 and contains multiple [single nucleotide polymorphisms, or SNPs] in linkage disequilibrium around the IL28B gene,” they wrote. “We selected the most strongly associated SNP, rs12979860, located 3 [kilobases] upstream of the IL28B gene, for genotyping in the cohorts.”

Patients could be either homozygous for the gene (CC), heterozygous (CT), or not have it at all (TT).

For all the genotypes combined, 201 patients (75%) attained a sustained virologic response: 51/68 (75%) in the standard treatment arm and 150/200 (75%) in the two variable treatment arms combined, they wrote.

Within the variable treatment arms, 98/122 (80%) of rapid response patients in the 12-week arm had a sustained response, and 52/78 (67%) of the non-rapid response patients in the 24-week arm attained a sustained virologic response (P = .1).

However, when patients were stratified according to genotype, Dr. Mangia found that 82% of those with the CC genotype had a sustained virologic response, compared with 75% with the CT genotype and 58% with the TT genotype (odds ratio 1.8, 95% confidence interval 1.2-2.7, P = .0046).

Moreover, although roughly equivalent proportions of each genotype had a rapid virologic response (165 patients total; 53%, 66%, and 59% for CC, CT, and TT patients, respectively), this effect was “largely driven” by those patients in the variable treatment arm who did not have a rapid response, wrote the authors.

Indeed, among those patients who did not have a rapid response, the link between CC genotype and sustained response was even stronger (87% of CC patients, vs. 67% of CT patients, vs. 29% of TT patients; OR 4.0, 95% CI 1.9-8.5, P = .0002).

The link was independent of whether the patient had hepatitis C genotype 2 or genotype 3.

Current guidelines recommend 12 weeks of therapy for all hepatitis C genotype 2 and 3 patients with a low viral load, irrespective of their IL28B status, according to the authors.

“It is tempting to speculate that such treatment would be most suitable for CC patients,” they said, but “prospective studies randomizing patients according to IL28B-type will be necessary.”

Several authors, not including Dr. Mangia, disclosed that they are coinventors of a patent application based on IL28B. The researchers also reported financial and research support from the Duke Clinical Research Institute, Richard B. Boebel Family Fund, National Health and Medical Research Council of Australia, Gastroenterology Society of Australia, and Royal Australasian College of Physicians.