Does IL28B Predict Outcomes for HIV/HCV Coinfected People?

SUMMARY 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 untreated.

By Liz Highleyman

A 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 coinfected patients.

In 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.

Single 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.

Hepatitis 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.

Treatment Response

A 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 individuals.

In the first 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 coinfected people.

Results

	The overall SVR rate for the study population was 54%.
	44% had the favorable IL28B CC genotype.
	The 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:
	RVR: 51% for CC patients vs 17% for those with non-CC patterns; EVR: 100% vs 62%, respectively; EOT: 87% vs 48%, respectively; SVR: 76% vs 36%, respectively.
	The CC genotype remained a predictor of SVR among patients who did not achieve RVR or complete EVR.
	However, the association between IL28B and viral kinetics and treatment outcomes was significant only for HCV genotypes 1 and 4.

"IL28B 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."

Fibrosis Progression

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.

Cirrhosis 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 rapidly."

Investigator affiliations:

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, NC.

6/3/11

References

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 25(8):1025-1033 (abstract). 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.