2009年8月21日-研究人員確定了一個遺傳變異體，這個遺傳變異體可以預測黑人和白人對於丙肝治療的不同反應。這種對治療起到雙倍效果的理想基因型，在白人中更爲常見，佔據了兩個做種族對於治療有效性差異的一半。
一項8月21日出現在《自然》雜誌上的新研究，從1600名美國丙肝感染者中，確定了全部基因序列中的單個核苷酸多形態現象。選出來的大部分患者都是服用利巴韋林和聚丙二醇干擾素進行抗病毒治療的患者。
這個成功治療的標準是持續性病毒學應答，定義爲在評估後期病毒值少到無法精確檢測。據估計，持續性病毒學應答在治療結束後的24周，對實時聚合酶鏈反應進行分析。
基因型定義爲rs12979860，在接近IL28B的19號染色體上出現單核苷酸多態性--IL28B是干擾素-λ-3的基因代碼-與每一個羣組的持續性病毒學應答有關。在每一個組中，在CC基因型病人身上出現很高的持續性病毒學應答比例，CT基因型病人的比例居中，而TT基因型病人的比例最低。
"應答良好的病人百分之八十能根除病毒，"資深作者大衛・噶德斯坦，杜克大學人類基因差異研究中心主任說，"而應答性不好的病人，只有百分之三十能根除病毒，考慮到這一差異，在病人開始治療之前，應該先知曉自己的基因類型。"
研究者評論，這一發現獲得了證實，中東種族顯示出比白人更高的應答比例，C等位基因更多。實際上，應答百分率和白人、黑人、西班牙人、中東人身體內C等位基因出現的頻度呈現着一種線性關係。
"因爲CC基因型在白人中出現的頻度多於黑人，我們認爲他可以解釋白人和黑人對於應答所呈現出的差異性"噶德斯坦博士說，"這告訴我們個體基因構成對於治療來說是比種族更重要的決定因素。"
慢性丙肝感染的治療需要使用利巴韋林和干擾素結合治療48周。很多病人只有輕微的反應，但是其他人都不能完成整個治療。副作用是類似感冒、抑鬱、反胃、嘔吐、脫水、乏力、貧血、白細胞增多、食慾不振、皮膚反應和腹瀉。"肝病治療的副作用很嚴重，百分之五十的治療都是不能根除病毒的。"
但是，瑪麗・噶裏頓，美國馬里蘭州國家癌症機構SAIC's基礎研究計劃的主任，在一封給Medscape Gastroenterology的郵件中評論了治療的重要性。
"總體來說，丙肝感染的治療比較困難" 噶裏頓博士說，但是她補充道："假如我唄感染了，我希望獲得一種與基因型無關的治療方式。假如我有一段時間必須忍受治療的痛苦，假如我有CC基因型，我會堅持。這次研究的亮點就是干擾素可能成爲備選治療方式，這種方式更容易忍受，更容易清除病毒" 噶裏頓博士也提到，用干擾素進行的第二階段研究暗示這產品副作用會有所降低。
研究者說，最近的研究說明多形性對於拉美裔人、白人、黑人，在丙肝治療的效果一致。應答率和C基因型頻度相關，對於中東種族也是一樣的。雖然IL28B中至少有兩個其它的SNPs與rs12979860緊密聯繫，共同決定着治療效果。IL28B的多形性對於多個種族的應答率差異作用顯著，這一點顯而易見。
"這個發現讓我們能給患者提供更有價值的信息，能幫助他們和他們的醫生決策最佳治療方案" 噶裏頓博士說，"這就是個性化治療的意義所在。"
原文：
Genetic Variant Predicts Success of Treatment in Chronic Hepatitis C
Jacquelyn K. Beals, PhD
Authors and Disclosures
August 21, 2009 - Researchers have identified a genetic variant that predicts the difference between white and black patients' responses to treatment for hepatitis C. The favorable genotype, which is associated with a 2-fold better response to treatment, is more common in white populations and accounts for about half the difference between the 2 ethnic groups with respect to treatment efficacy.
The new study, published online August 16 in Nature, identified a single nucleotide polymorphism (SNP) in a genomewide association study of more than 1600 American patients with chronic hepatitis C infection. Most patients were drawn from a study that compared treatment regimens including peginterferon-α-2b (PegIFN-α-2b) or PegIFN-α-2a in combination with ribavirin.
The criterion for successful treatment was sustained virological response (SVR), defined as the absence of detectable virus at the end of follow-up evaluation. SVR was assessed by a real-time polymerase chain reaction assay 24 weeks after the end of treatment (or by undetectable viral levels after 12 weeks if follow-up was unavailable).
Genotyping identified rs12979860, a SNP on chromosome 19 near IL28B - the gene that codes for interferon-λ-3 - that is highly associated with SVR in each population group (P = 1.06 × 10-25 in white patients; P = 2.06 × 10-3 in black patients; P for combined populations = 1.37 × 10-28). In each group, the highest percentage SVR occurred in patients with the CC genotype, response rates were intermediate in patients with the CT genotype, and patients with the TT genotype demonstrated the lowest percentage SVR.
"Eighty percent of those [patients] with the favorable response genotype eradicated the virus," senior author David Goldstein, PhD, director of the Center for Human Genome Variation, Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, said in a statement. "[O]nly about 30 percent with the less favorable response genotype did so. With differences of that magnitude, patients considering therapy may want to know what their genotype is before they start treatment," he suggested.
The findings gain further support from the observation that patients of East Asian ancestry show higher SVR rates than do whites, and the C-allele is more frequent in East Asian populations, the researchers comment. In fact, a nearly linear relationship exists between percentage SVR and the C-allele frequency for (in ascending order) blacks, Hispanics, whites, and East Asians.
"Because [the CC genotype] appears significantly more often among Caucasian populations than it does among African populations, we feel it explains much of the difference in response rates we see between African-Americans and those of European ancestry," observed Dr. Goldstein. "This tells us that individual genetic makeup is a much more important determinant of response to treatment than is race or ethnicity."
Treatment for chronic hepatitis C infection typically requires 48 weeks of PegIFN-α-2b or PegIFN-α-2a in combination with ribavirin. Many patients experience only mild reactions, but others are unable to complete the therapy. Among the side effects are flulike symptoms, depression, nausea and vomiting, dehydration, fatigue, anemia, neutropenia, loss of appetite, skin reactions, and diarrhea. "The side effects of hepatitis treatment can be brutal, and about half the time the treatment fails to eradicate the virus," said Dr. Goldstein.
However, Mary Carrington, PhD, director of SAIC's Basic Research Program, SAIC-Frederick, Inc, National Cancer Institute, Frederick, Maryland, commented on the importance of treatment in an email to Medscape Gastroenterology. "Permanent liver damage and liver cancer can be fatal, so treatment is generally a good option, especially since its success rate is about 40 to 80 percent, though [it is] more like 30 percent in African-Americans," she said.
"[T]reatment for HCV infection overall can be awfully difficult," said Dr. Carrington, but he added: "If I were infected, I would want treatment regardless of my genotype. If I had a very difficult time tolerating the drugs, I would feel more inclined to continue if I had the CC genotype. One of the beauties of this study is that it presents the possibility that interferon-λ-3 may provide an alternative treatment regimen that could be easier to tolerate and that may be more successful in clearing the virus." Dr. Carrington also mentioned that a recent phase 2 study with interferon-λ-1 suggests that this product may have fewer side effects.
The present study demonstrated that the effect of the polymorphism on the efficacy of hepatitis C treatment was consistent in the Hispanics, whites, and blacks studied, and the SVR rates correlated strongly with the C-allele frequency in these groups, as well as in East Asians, say the researchers. Although at least 2 other SNPs in IL28B were too closely correlated with rs12979860 to completely resolve their effects, it seems clear that a polymorphism in IL28B contributes significantly to the variation in SVR rates across multiple ethnic groups.
"This discovery enables us to give patients valuable information that will help them and their doctors decide what is best for them," concluded Dr. Goldstein. "This is what personalized medicine is all about."
Dr. Goldstein is a paid consultant for Schering-Plough, which markets the interferon treatment. He is also an inventor on a patent for the IL28B polymorphisms as a potential diagnostic for interferon treatment response and would receive royalties if such tests are marketed. Dr. Carrington has disclosed no relevant financial relationships.
Nature. Published online August 16, 2009.
Authors and Disclosures
Journalist
Jacquelyn K. Beals, PhD
Jacqueline K. Beals, PhD, is a freelance writer for Medscape.
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