Limits...
Response prediction in chronic hepatitis C by assessment of IP-10 and IL28B-related single nucleotide polymorphisms.

Lagging M, Askarieh G, Negro F, Bibert S, Söderholm J, Westin J, Lindh M, Romero A, Missale G, Ferrari C, Neumann AU, Pawlotsky JM, Haagmans BL, Zeuzem S, Bochud PY, Hellstrand K, DITTO-HCV Study Gro - PLoS ONE (2011)

Bottom Line: High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C.Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL.Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases/Virology, University of Gothenburg, Gothenburg, Sweden. martin.lagging@medfak.gu.se

ABSTRACT

Background: High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C. Several recent studies report that single nucleotide polymorphisms (SNPs) adjacent to IL28B predict spontaneous resolution of HCV infection and outcome of treatment among HCV genotype 1 infected patients.

Methods and findings: In the present study, we correlated the occurrence of variants at three such SNPs (rs12979860, rs12980275, and rs8099917) with pretreatment plasma IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO) involving 253 Caucasian patients. The favorable SNP variants (CC, AA, and TT, respectively) were associated with lower baseline IP-10 (P = 0.02, P = 0.01, P = 0.04) and were less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P = 0.01). Patients carrying favorable SNP genotypes had higher baseline viral load than those carrying unfavorable variants (P = 0.0013, P = 0.029, P = 0.0004 respectively). Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL. In multivariate analyses of genotype 1-infected patients, baseline IP-10 and C genotype at rs12979860 independently predicted the first phase viral decline and RVR, which in turn independently predicted SVR.

Conclusions: Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.

Show MeSH

Related in: MedlinePlus

Mean HCV RNA reduction according to IP-10 in HCV genotype 1 with favorable IL28B genotype.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3044738&req=5

pone-0017232-g004: Mean HCV RNA reduction according to IP-10 in HCV genotype 1 with favorable IL28B genotype.

Mentions: Among genotype 1 infected patients, homozygous carriers of the three favorable IL28B alleles had significantly more pronounced first phase viral decline, as reflected by the reduction of HCV RNA from treatment day 0 to 4, when compared with patients carrying the risk alleles (mean 2.0, 0.9 and 0.6 log10 IU/mL for rs12979860 CC, CT and TT, 1.8, 0.9 and 0.7 log10 IU/mL for rs12980275 AA, AG and TT, and 1.4, 0.8 and 0.6 for rs8099917 TT, TG and GG respectively, P<0.0001 for all 3 SNPs; Kruskal-Wallis test). Among homozygous or heterozygous carriers of the favorable alleles, IP-10 was highly significantly associated with the first phase reduction of HCV RNA (rs = −0.50, P = 0.001 and rs = −0.40, P<0.0001 for rs12979860 CC and CT, rs = −0.29, P = 0.04 and rs = −0.39, P = 0.0003 for rs12980275 AA and AG, and rs = −0.40, P<0.0001 and rs = −0.25, P = 0.046 for rs8099917 TT and TG respectively; Figure 3). This association was also significant for the maximum decline in HCV RNA from day 0 to 4 as well as the decline from day 0 to 1, thus emphasizing an association with the first phase decline in HCV RNA, and translated into a more rapid reduction of HCV RNA during the first 4 weeks of therapy among patients with lower baseline IP-10, and a slower decline among those with higher (Figure 4). Similarly, among genotype 2/3 infected patients, CC carriers of rs12979860 had significantly more pronounced first phase viral decline, as reflected by the reduction of HCV RNA from treatment day 0 to 4, when compared with patients carrying the risk allele (mean 2.7, 2.1 and 1.6 log10 IU/mL for CC, CT and TT, P = 0.04; Kruskal-Wallis test) and IP-10 was significantly correlated with the reduction in HCV RNA from day 0 to 4 in the 22 HCV genotype 2/3 infected patients with rs12979860 CT (rs = −0.45, P = 0.04). In contrast to the first phase reduction in HCV RNA, none of the IL28B-related SNPs or baseline IP-10 predicted the second phase decline after stratification for the first phase decline.


Response prediction in chronic hepatitis C by assessment of IP-10 and IL28B-related single nucleotide polymorphisms.

Lagging M, Askarieh G, Negro F, Bibert S, Söderholm J, Westin J, Lindh M, Romero A, Missale G, Ferrari C, Neumann AU, Pawlotsky JM, Haagmans BL, Zeuzem S, Bochud PY, Hellstrand K, DITTO-HCV Study Gro - PLoS ONE (2011)

Mean HCV RNA reduction according to IP-10 in HCV genotype 1 with favorable IL28B genotype.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044738&req=5

pone-0017232-g004: Mean HCV RNA reduction according to IP-10 in HCV genotype 1 with favorable IL28B genotype.
Mentions: Among genotype 1 infected patients, homozygous carriers of the three favorable IL28B alleles had significantly more pronounced first phase viral decline, as reflected by the reduction of HCV RNA from treatment day 0 to 4, when compared with patients carrying the risk alleles (mean 2.0, 0.9 and 0.6 log10 IU/mL for rs12979860 CC, CT and TT, 1.8, 0.9 and 0.7 log10 IU/mL for rs12980275 AA, AG and TT, and 1.4, 0.8 and 0.6 for rs8099917 TT, TG and GG respectively, P<0.0001 for all 3 SNPs; Kruskal-Wallis test). Among homozygous or heterozygous carriers of the favorable alleles, IP-10 was highly significantly associated with the first phase reduction of HCV RNA (rs = −0.50, P = 0.001 and rs = −0.40, P<0.0001 for rs12979860 CC and CT, rs = −0.29, P = 0.04 and rs = −0.39, P = 0.0003 for rs12980275 AA and AG, and rs = −0.40, P<0.0001 and rs = −0.25, P = 0.046 for rs8099917 TT and TG respectively; Figure 3). This association was also significant for the maximum decline in HCV RNA from day 0 to 4 as well as the decline from day 0 to 1, thus emphasizing an association with the first phase decline in HCV RNA, and translated into a more rapid reduction of HCV RNA during the first 4 weeks of therapy among patients with lower baseline IP-10, and a slower decline among those with higher (Figure 4). Similarly, among genotype 2/3 infected patients, CC carriers of rs12979860 had significantly more pronounced first phase viral decline, as reflected by the reduction of HCV RNA from treatment day 0 to 4, when compared with patients carrying the risk allele (mean 2.7, 2.1 and 1.6 log10 IU/mL for CC, CT and TT, P = 0.04; Kruskal-Wallis test) and IP-10 was significantly correlated with the reduction in HCV RNA from day 0 to 4 in the 22 HCV genotype 2/3 infected patients with rs12979860 CT (rs = −0.45, P = 0.04). In contrast to the first phase reduction in HCV RNA, none of the IL28B-related SNPs or baseline IP-10 predicted the second phase decline after stratification for the first phase decline.

Bottom Line: High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C.Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL.Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases/Virology, University of Gothenburg, Gothenburg, Sweden. martin.lagging@medfak.gu.se

ABSTRACT

Background: High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C. Several recent studies report that single nucleotide polymorphisms (SNPs) adjacent to IL28B predict spontaneous resolution of HCV infection and outcome of treatment among HCV genotype 1 infected patients.

Methods and findings: In the present study, we correlated the occurrence of variants at three such SNPs (rs12979860, rs12980275, and rs8099917) with pretreatment plasma IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO) involving 253 Caucasian patients. The favorable SNP variants (CC, AA, and TT, respectively) were associated with lower baseline IP-10 (P = 0.02, P = 0.01, P = 0.04) and were less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P = 0.01). Patients carrying favorable SNP genotypes had higher baseline viral load than those carrying unfavorable variants (P = 0.0013, P = 0.029, P = 0.0004 respectively). Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL. In multivariate analyses of genotype 1-infected patients, baseline IP-10 and C genotype at rs12979860 independently predicted the first phase viral decline and RVR, which in turn independently predicted SVR.

Conclusions: Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.

Show MeSH
Related in: MedlinePlus