Investigators identify genetic profile associated with better treatment outcomes in people with HIV/HCV co-infection

Michael Carter
Published: 29 July 2013

Several genetic characteristics are associated with a successful response to treatment for hepatitis C virus (HCV) in people with HIV co-infection, Spanish researchers report in the online edition of AIDS. The study involved people with the difficult-to-treat HCV genotypes 1 and 4, who received dual therapy with pegylated interferon and ribavirin.

The treatment response rate was almost 80% for participants with the most favourable genetic profile compared to a response rate of just 7% for people with the least favourable profile. The investigators hope their research will help doctors and patients predict the likely outcome of HCV therapy prior to its initiation.

Large numbers of people with HIV have HCV co-infection. Liver disease related to HCV is an important cause of serious illness and death in this group.

The majority of HCV infections in Europe involve genotypes 1 and 4. These genotypes are associated with poorer treatment outcomes. HCV therapy is lengthy and can involve unpleasant side-effects. It is therefore important to identify the factors associated with a greater likelihood of a successful outcome (a sustained virological response – an SVR – which is considered achieved with an undetectable HCV viral load six months after the completion of therapy). This enables people to make informed decisions about risks and benefits of therapy.

It is already known that the IL28B gene is predictive of treatment outcomes in co-infected peope who have the harder-to-treat HCV genotypes. Variations in a specific genetic sequence (single nucleotide polymorphism [SNP] rs14158) at the low-density lipoprotein receptor (LDLR) gene have also been shown to increase the predictive capacity of IL28B.

Investigators in Spain wanted to see if other genetic variations improved on the ability of IL28B to predict treatment outcomes.

They therefore designed a study involving 205 people with co-infection receiving care between 2000 and 2010, who all received dual HCV therapy with pegylated interferon and weight-based ribavirin. All had genotype 1 (79%) or genotype 4 (21%) and received treatment for 48 weeks.

Blood samples and peripheral blood mononuclear cells were examined in the laboratory for the presence of 118 genetic variations.

The participants had well-controlled HIV. Median baseline CD4 cell count was 521 cells/mm3 and 82% had an undetectable viral load. The median age was 42 years, 83% of participants were male and 85% had a history of injecting drug use. There was a high prevalence of factors associated with poorer treatment outcomes. Almost half the participants had advanced liver fibrosis and a third had an HCV viral load above 600,000 copies iu/ml.

Overall, 36% of participants achieved an SVR. The SVR rate differed according to IL28B status. The SVR rate was 56% for participants with IL28B-CC, 30% for participants with IL28B-TT and 21% for those with IL28B-CT. Lower baseline HCV viral load and higher LDL cholesterol were also associated with treatment response.

Laboratory analysis also showed that several other genetic variations were similarly associated with an increase in the chances of achieving an SVR.

These included several variations in the LDLR gene (rs10415811, p = 0.047; rs11672123, p = 0.0067; rs1433099, p = 0.0019; rs2569540, p = 0.0044; rs5930, p = 0.046).

Other genes increasing treatment response rates were transforming growth factor β (TGF-β, p = 0.0087); aquaporine 2 (AQP-2, p =0.01), very-low-density lipoprotein receptor (VLDLR, p = 0.015), Sp 110 nuclear body protein (SP110; rs919178, p = 0.045); 2’-5’-oligoadenylate synthase 1 (OAS1; rs1131454, p = 0.047); interferon alpha/beta receptor 1 (IFNAR1; rs2243592; p = 0.036) and apolipoprotein B (APO-B; rs11126598, p = 0.0094).

There was a strong synergy between genetic variations at IL28B, TGF-β and AQP-2.

The SVR rate was 79% for participants with the most favourable genetic profile (IL28B CC; TGF-β non-AA; AQP-2 non-GG) compared to a 7% SVR rate among participants with the least favourable profile (IL28B non-CC; TGF-β AA; AQP-2 GG).

Analysis that controlled for potential confounders confirmed that the three most favourable genetic variations had a significant relationship with the chances of achieving an SVR (IL28B CC, p = 0.001; TGF-β non-AA, p = 0.024; AQP-2 non-GG, p = 0.005).

“These pharmacogenomic parameters improve the predictive capacity of IL28B genotype and may therefore play a role in the development of a tool to accurately predict response to therapy against HCV,” comment the investigators. “The predictive performance of IL28B genotype can be markedly enhanced by using other genomic predictors concomitantly.”

The authors note that only 14% of participants had the genetic profile associated with the best outcomes, and just 6% had the three genes associated with the poorest chances of a SVR.

Nevertheless, they call for further research to explore the ability of these genes to predict responses to HCV therapy based on new direct-acting agents.

 

Reference

Neukam K et al. Variations in multiple genes improve interleukin 28b genotype predictive capacity for response to therapy against hepatitis C genotype 1 or 4 infection. AIDS 27, online edition, doi: 10.1097/01.aids.0000432459.36970.a9, 2013.

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