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.
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
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
Spain wanted to see if other genetic variations improved on the ability of
IL28B to predict treatment outcomes.
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.
analysis also showed that several other genetic variations were similarly
associated with an increase in the chances of achieving an SVR.
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).
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;
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