IL28B Predict Outcomes for HIV/HCV Coinfected People?
HIV/HCV coinfected people with the favorable IL28B CC genotype
respond better to interferon-based therapy for chronic hepatitis
C, but may be more like to develop liver cirrhosis if left
growing body of research has explored the association between
variations in the IL28B gene and outcomes among hepatitis
C virus (HCV) monoinfected individuals, including response
to interferon treatment and liver disease progression. These
links have not been as extensively studied in HIV/HCV
2009 researchers first
reported that variations in the human genome near the IL28B
gene can help predict spontaneous HCV clearance and response
to interferon therapy. The IL28B gene encodes interleukin 28,
or interferon lambda. Interferons produced by the body are key
to the immune response against HCV; injected interferon strengthens
this natural response.
nucleotide polymorphisms, or SNPs, are substitutions of a single
nucleotide building block at a specific position in the genome.
Each person carries 2 copies of every gene, one from each parent.
A SNP known as rs12979860 located "upstream" of the
IL28B gene has 2 variations, or alleles, C and T. Thus, individuals
can have 3 patterns: CC, TT, or CT.
C patients with the CC pattern are more likely to spontaneously
clear HCV and have better treatment outcomes. People with the
TT pattern have the least favorable response, while those with
the mixed CT pattern fall in between.
pair of studies by overlapping Spanish research teams, reported
in the May 15, 2011 issue of AIDS, examined relationships
between IL28B patterns and treatment outcomes in HIV/HCV coinfected
study, Norma Rallon from Hospital Carlos III in Madrid and
colleagues looked at the influence of the rs12979860 SNP on
early viral kinetics during interferon-based therapy.
The analysis included 196 HIV/HCV coinfected patients who completed
a course of hepatitis C treatment with pegylated
interferon plus ribavirin and were evaluated for sustained
virological response (SVR), usually assessed 24 weeks after
completion of therapy. More than half (57%) were infected with
hard-to-treat HCV genotype 1, 30% had genotype 3, 12% had genotype
4, and only 1% had genotype 2.
The researchers looked at viral load reductions at various points,
including rapid virological response (RVR) at week 4, early
virological response (EVR) at week 12, and end-of-treatment
response (EOT), typically at 24 weeks for people with HCV genotypes
2 or 3 and 48 weeks for those with genotypes 1 or 4, though
many experts recommend 48 weeks regardless of genotype for HIV/HCV
overall SVR rate for the study population was 54%.
had the favorable IL28B CC genotype.
CC genotype was associated with significantly higher response
rates at all time points compared with CT and TT, after
adjusting for other response predictors including HCV genotype,
viral load, and fibrosis stage:
51% for CC patients vs 17% for those with non-CC patterns;
100% vs 62%, respectively;
87% vs 48%, respectively;
76% vs 36%, respectively.
CC genotype remained a predictor of SVR among patients who
did not achieve RVR or complete EVR.
the association between IL28B and viral kinetics and treatment
outcomes was significant only for HCV genotypes 1 and 4.
CC genotype is a strong predictor of virological response to
therapy in HIV/HCV-coinfected patients," the study authors
concluded. "This effect is mediated by an increase in viral
clearance during the first 12 weeks of treatment and is mainly
seen in patients infected with HCV genotypes 1 and 4."
In the second
study, Pablo Labarga, also from Hospital Carlos III, looked
at the link between IL28B patterns and treatment response among
62 HIV/HCV coinfected patients who failed to achieve sustained
response with prior suboptimal therapy (e.g., conventional interferon
or inadequate doses of ribavirin) and underwent re-treatment
with pegylated interferon plus weight-adjusted ribavirin.
Most were male injection drug users, almost all were on antiretroviral
therapy (ART) with undetectable HIV viral load, and the
average CD4 count was about 650 cells/mm3. About 75% had HCV
genotypes 1 or 4 and more than half had advanced liver fibrosis.
The overall SVR or cure rate in this analysis was 40%. Significant
predictors of sustained response were HCV genotype 2 or 3, prior
relapse after stopping treatment (as opposed to failure to respond
at all), and ribavirin plasma trough concentration at week 4.
Participants with the IL28B CC pattern were more likely to achieve
SVR than people with other patterns (57% vs 24%, respectively).
As in the previous study, however, IL28B was only a significant
predictor of response in prior non-responders with HCV genotypes
1 or 4.
In summary, "re-treatment of chronic hepatitis C in HIV/HCV-coinfected
patients must ensure optimal ribavirin exposure, especially
in prior relapsers and/or in patients infected with HCV genotype
2 or 3," the researchers concluded. "In contrast,
in prior true non-responders infected with HCV genotype 1 or
4, which is the most prevalent and difficult-to-treat population,
optimization of ribavirin exposure seems to have little impact
on SVR, while a favorable IL28B genotype plays a major role
in the outcome of re-treatment."
Finally, as described in the June
1, 2011, Journal of Infectious Diseases (abstract),
Pablo Barreiro and colleagues looked at the link between IL28B
patterns and liver fibrosis progression. Because HIV/HCV coinfected
people tend to experience accelerate fibrosis progression, they
hypothesized that any influence of IL28B on the risk of developing
cirrhosis might be more easily recognized in this population.
This retrospective analysis included 304 coinfected patients
at 2 Spanish clinics who underwent transient elastography (FibroScan)
before starting treatment with pegylated interferon plus ribavirin.
Again, most were men and 85% were on ART. Nearly half (46%)
had the favorable IL28B CC pattern.
was significantly more common among people with the CC compared
with CT or TT gene patterns (24% vs 13%, respectively). In a
multivariate analysis, older age, history of alcohol abuse,
and CC IL28B pattern were independent predictors of cirrhosis.
Interestingly, the researchers noted, mean alanine aminotransferase
(ALT) levels were higher over the past 5 years in people with
the CC pattern.
The study authors concluded that HIV/HCV coinfected people with
the CC pattern may experience a more rapid progression of HCV-related
fibrosis, perhaps as result of increased liver inflammation.
Thus, they recommended, "access to HCV treatment is of
utmost importance in IL28B CC carriers, in whom treatment response
is better and in whom progression to cirrhosis might occur more
Rallon study: Infectious Diseases Department, Hospital Carlos
III, Madrid, Spain; Duke Clinical Research Institute, Durham,
NC; Institute for Genome Sciences and Policy, Durham, NC.
Labarga study: Hospital Carlos III, Madrid, Spain; Hospital
Valme, Seville, Spain; Hospital Reina Sofía, Córdoba,
Spain; Universidad de Jaén, Jaén, Spain; Hospital
San Pedro, Logroño, Spain.
Barreiro study: Infectious Diseases Department, Hospital Carlos
III, Madrid, Spain; Infectious Diseases Unit, Hospital de Valme,
Seville, Spain; Infectious Diseases Unit, Hospital Reina Sofía,
Córdoba, Spain; Immunogenetics Unit, Faculty of Sciences,
Jaen University, Spain; Duke Clinical Research Institute, Durham,
NI Rallon, V Soriano, S Naggie, et al. IL28B gene polymorphisms
and viral kinetics in HIV/hepatitis C virus-coinfected patients
treated with pegylated interferon and ribavirin. AIDS
May 15, 2011.
P Labarga, P Barreiro, JA Mira, et al. Impact of IL28B polymorphisms
on response to peginterferon and ribavirin in HIV-hepatitis
C virus-coinfected patients with prior nonresponse or relapse.
AIDS 25(8):1131-1133 (abstract).
May 15, 2011.
P Barreiro, JA Pineda, N Rallón, et al. Influence of
interleukin-28B single nucleotide polymorphisms on progression
to liver cirrhosis in human immunodeficiency virus-hepatitis
C virus-coinfected patients receiving antiretroviral therapy.
Journal of Infectious Diseases 203(11):1629-1636 (abstract).
June 1, 2011.