Sex, genotype, and IL28B pattern predict spontaneous HCV clearance

Women, people with hepatitis C virus (HCV) genotype 1, and those with a favourable IL28B gene pattern are more likely to spontaneously clear HCV without treatment, while those with unfavourable patterns are more likely to benefit from earlier therapy, according to two recent studies.

Approximately 20 to 40% of people initially infected with HCV will go on to clear the virus without treatment, while the rest will develop chronic infection lasting longer than 6 months. Over years or decades, chronic hepatitis C can lead to severe liver disease including cirrhosis and liver cancer.

As described in the August 2, 2013, online edition of Hepatology, Jason Grebely from the Kirby Institute at the University of New South Wales in Sydney and colleagues aimed to learn more about the time course and factors associated with spontaneous HCV clearance.

The researchers looked at data from an international collaboration of nine prospective cohorts evaluating outcomes after acute HCV infection in Australia, Canada, Europe, and the US. The analysis included 632 participants with acute hepatitis C. About two-thirds were men, about 80% were white, and most had a history of injection drug use; 5% were co-infected with HIV.

Just under half of participants (47%) had HCV genotype 1 and a similar proportion (49%) had the IL28B CC gene pattern (single nucleotide polymorphism rs12979860). Genotype 1 HCV is more difficult to treat than genotypes 2 or 3, while the IL28B CC pattern is associated with better response to interferon-based therapy than the CT or TT patterns.

The main endpoint was spontaneous HCV clearance, defined as two consecutive tests at least four weeks apart showing undetectable HCV RNA.

• 28% of participants were anti-HCV antibody negative but HCV RNA positive when HCV was detected, indicating early acute infection.
• 173 out of 632 participants (27%) spontaneously cleared HCV during a median follow-up period of 0.6 years.
• At one year after infection, 25% of participants had cleared HCV.
• Among people who experienced spontaneous clearance, the median time to clearance was 16.5 weeks.
• Within this group, 34% demonstrated clearance at three months, 67% did so at six months, and 83% did so at 12 months.
• After adjusting for age, factors independently associated with spontaneous HCV clearance included:

o   HCV genotype 1 vs non-1: adjusted hazard ratio (HR) 1.56, or about half again as likely;

o   Female sex vs male: adjusted HR 2.16, or just over twice as likely;

o   IL28B CC vs CT or TT: adjusted HR 2.26, or more than twice as likely.

• Furthermore, the effect of HCV genotype and IL28B pattern had a greater effect on spontaneous clearance among women compared with men, and CC women were more than five times as likely to clear HCV than CT or TT men.
• Both IL28B CC and HCV genotype 1 were independent predictors of clearance for women, but only IL28B CC was a significant predictor for men.

"Female sex, favorable IL28B genotype, and HCV genotype 1 are independent predictors of spontaneous clearance," the researchers concluded. "Further research is required to elucidate the observed sex-based differences in HCV control."

In the second study, described in the August 2013 Journal of Hepatology, Alessandra Mangia from IRCCS Casa Sollievo della Sofferenza Hospital and colleagues in Italy explored whether IL28B rs12979860 – alone or in combination with human leukocyte antigen (HLA) class 2 alleles, or genetic variants – could both predict spontaneous HCV clearance and help individualize treatment for people with persistent hepatitis C.

Most people with acute hepatitis C have no symptoms, or only general flu-like symptoms, so infection is not usually diagnosed at this early stage in typical clinical practice. A majority of people who undergo treatment have been infected for at least a year, and often much longer. Studies have shown that interferon-based therapy is very effective if started during acute infection, but clinicians do not want to start too early and unnecessarily treat people who would have cleared the virus on their own.

This analysis included 178 participants with acute HCV infection who were treated with interferon alone or interferon plus ribavirin starting either within or after 48 weeks from the time of acute hepatitis C diagnosis; 169 patients had data available for genetic testing.

In this study, 28% of participants achieved spontaneous HCV clearance. Factors associated with natural clearance included development of jaundice, or yellowing of the skin due to elevated bilirubin levels (odds ratio 2.75, or nearly three times more likely) and having the IL28B CC pattern (odds ratio 3.87, or nearly four times more likely). HLA alleles, however, were not a significant predictor.

Among people with the IL28B CT or TT patterns who did not have jaundice, the negative predictive value for HCV persistence was 98%, meaning they had only a 2% likelihood of spontaneous clearance.

Among CT or TT patients, those who started treatment within 48 weeks of diagnosis had a much higher likelihood of sustained virological response than those who started treatment after 48 weeks (100 vs 28%, respectively). In contrast, the difference in response rates between people with the CC pattern who were treated early or late did not reach statistical significance (85 vs 65%, respectively).

Based on these findings, the study authors concluded, "In patients with acute HCV hepatitis, lack of viral clearance may be predicted by absence of jaundice and IL28B [CT or TT] genotype; in patients with these characteristics, treatment needs to be started immediately."