Genetic variation associated with response to hepatitis C therapy in HIV co-infected patients

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The presence of a genetic variation in the IL28B gene is associated with better response rates to hepatitis C therapy in patients who are co-infected with HIV and hepatitis C, Spanish investigators report in the online edition of AIDS.

However, the beneficial effect of the variation in the  IL28B gene was restricted to patients who were infected with hepatitis C gentoypes 1 and 4, which are generally harder to treat.

Separate research conducted at the same hospital showed that the genetic variation, or polymorphism, also affected response rates in co-infected patients being re-treated with anti-hepatitis C drugs.

Glossary

gene

A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

log

Short for logarithm, a scale of measurement often used when describing viral load. A one log change is a ten-fold change, such as from 100 to 10. A two-log change is a one hundred-fold change, such as from 1,000 to 10.

The researchers believe that their findings will help to guide decisions about hepatitis C therapy.

HIV and hepatitis C have shared modes of transmission and in some regions of the wrold a large proportion of HIV-positive patients are co-infected with hepatitis C. Liver disease caused by hepatitis C is a leading cause of serious illness and death in co-infected patients.

Standard therapy for hepatitis C consists of pegylated interferon and ribavirin. It can cause unpleasant side-effects and only a minority of HIV-positive patients with chronic hepatitis C successfully respond to this treatment.

In hepatitis C mono-infected patients, the IL28B genetic variation has been associated with better treatment outcomes. Several studies in HIV/HCV co-infected patients have also shown that the IL28B polymorphism predicts treatment response.

Investigators from the Carlos III Hospital in Madrid wished to see if the genetic variant also influenced therapeutic responses in co-infected patients.

They therefore tested stored blood samples obtained from 196 co-infected people who had completed hepatitis C therapy and analysed the response rates of their patients.

All the patients were of European origin, 75% were men and their average age was 42.

Median CD4 cell count was 483 cells/mm3, and three-quarters of patients treated with anti-HIV drugs had an undetectable viral load.

Over two-thirds (69%) of patients were infected with the harder to treat hepatitis C genotypes. However, 70% of patients had only mild liver damage.

Analysis of frozen blood samples showed that 44% of patients carried the IL28B genetic variation.

Overall, 54% of patients had a successful response to treatment – an undetectable hepatitis C viral load six months after the completion of therapy, or sustained virological response (SVR).

A rapid virological response (RVR) – an undetectable hepatitis C viral load after four weeks of treatment – was observed in 21% of patients. An early virological response (EVR, 2 log drop in viral load at week 12) was achieved by 80% of patients, and 59% had undetectable hepatitis C at this time (complete early virological response, or cEVR). On the completion of therapy (EOTR), 65% of patients had an undetectable hepatitis C viral load.

Patients carrying the IL28B polymorphism had higher treatment response rates at all time intervals than those who did not have this gene.

  • RVR = 51 vs 17%, p < 0.0001.

  • EVR = 100 vs 62%, p < 0.0001.

  • cEVR = 82 vs 41%, p < 0.0001.

  • EOTR = 87 vs 48%, p < 0.0001.

  • SVR = 76 vs 36&, p < 0.0001.

However, higher treatment response rates were only seen in patients with the IL28B polymorphism who were infected with hepatitis C genotypes 1 and 4 (p < 0.0001 at all time points). Treatment outcomes rates for patients with genotypes 2 and 3 were comparable regardless of carriage of the gene.

The beneficial effect of the IL28B gene for patients with genotypes 1 and 4 appeared to be associated with early responses to therapy.

Patients carrying the gene had significantly greater declines in hepatitis C viral load at weeks 4 and 12 than individuals who did not (both p < 0.0001).

Nevertheless, presence of the IL28B polymorphism was associated with higher sustained treatment response rates even in patients who did not achieve an early response to therapy (64 vs 27%, p = 0.001).

“Our results suggest that although the effect of the IL28B polymorphism on SVR is largely mediated by its impact on early viral responses on treatment, as RVR and EVR they exert its action beyond that, influencing the SVR regardless of the achievement of RVR,” write the authors.

They conclude, “our study demonstrates an important role for IL28B genotypes in predicting on-treatment virological responses to therapy in HIV/HCV-coinfected individuals…knowledge at baseline of the IL28B genotype may helpfully assist in treatment decisions.”

IL28b and re-treatment response rates

Separate research conducted at the same hospital showed that the presence of the genetic variant was also associated with increased rates of treatment responses in co-infected patients who received a second course of hepatitis C therapy.

The study involved 62 patients. A sustained virological response was achieved in 57% of patients carrying the variant and only 24% of individuals without it (p = 0.006). Once again, the beneficial effect of the genetic variant was restricted to patients infected with hepatitis C genotypes 1 and 4.

“A favourable IL28B genotype plays a major role in the outcome of re-treatment,” write the researchers.

References

Rallon NI et al. IL28B gene polymorphisms and viral kinetics in HIV/hepatitis C virus-coinfected patients treated with pegylated interferon and ribavirin. AIDS 26, online edition: doi: 10.1097/QAD.0b013e3283471cae, 2011 (click here for the free abstract).

Labarga P et al. Impact of IL28B polymorphisms on response to preginterferon plus ribavirin in HIV-HCV coinfected patients with prior non-response or relapse. AIDS 25, online edition: doi: 10.1097/QAD.0b013e3283471d83, 2011 (click here for the text [£]).

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