Thursday, September 1, 2011

Hepatitis C in Minority Populations

September issue of Gastroenterology

Hepatitis C in Minority Populations

These presentations were given at Digestive Disease Week 2011 in Chicago.

About 3.2 million people in the United States arechronically infected with hepatitis C virus (HCV), the leading cause of cirrhosis and hepatocellular carcinomaand the leading indication for liver transplant.

HCVprevalence is highest in minorities, especially black men,but blacks have poorer response to peginterferon/ribavirin than whites. VIRAHEP-C, astudy of black and white patients with genotype 1 HCV treated with peginterferon alfa-2a, found lower sustained virologic response(SVR) rates in blacks compared to whites(28% vs. 52%) (Gastroenterology 2006;131:470-7).

Blacks also have lower SVR to peg-interferonalfa-2b, and lower SVR when infected with HCV genotypes 2 and 3.

The impact of Hispanic ethnicity on HCV treatment response is largely unknown.

The LATINO study found significantly lower SVR(34%) to peginterferon/ribavirin in white Hispanics withHCV genotype 1 compared to non-Hispanic whites (49%)(N. Engl. J. Med. 2009;360:257-67). However, the LATINO results may not be generalizable, because inclusion/exclusion criteria were narrow, and investigators did not measure insulin resistance, which is linked to lower SVR andis prevalent in Hispanics.

One mechanism for poorer response of blacks and possibly Hispanics to peginterferon/ribavirin was elucidated recently. Genome-wide association studies in HCV-infected patients uncovered single nucleotide polymorphisms in IL28B (IFN-gamma-3 gene) that are strongly associated with race and SVR.

The favorable IL28B CC genotype occurs in highest frequency in East Asians and whites (and is associated with SVR above 80%), intermediate frequency in Hispanics, and lowest frequency in blacks (SVR 53%). In contrast, the unfavorable TT genotype is most frequent in blacks, and is associated with anSVR of 12%.

Investigators estimate that variable frequency of the IL28B C-allele explains half the racial differences in SVR to peginterferon/ribavirin.

We have entered a new era of HCV therapy with the recent approval of two direct acting antiviral (DAA) drugs, boceprevir and telaprevir. DAA use was linked to increased side effects, but DAA/peginterferon/ribavirin significantly improved SVR in patients withHCV genotype 1, and shortened treatmentin many patients.

Data on DAAs in minorities are limited, but promising. In every trial, addition of the DAA improved the SVR for all ethnic groups.

In ADVANCE, SVR in the telaprevir/peginterferon/ribavirin arms (69%-75%) was significantly higher than the peginterferon/ribavirin arm(44%) (N. Engl. J. Med. 2011;364:2405-16).
In blacks, SVRwith telaprevir/peginterferon/ribavirin (62%) was significantly higher than with peginterferon/ribavirin (25%).In SPRINT II, SVR was significantly higher in boceprevir/peginterferon/ribavirin arms (63%-66%) than in the peginterferon/ribavirin arm (37%). (N. Engl. J.Med. 2011;364:1195-206).

Among 159 blacks (14.4% ofpatients), SVR was 42%-53% in boceprevir/peginterferon/ribavirin arms compared to 23% in the peginterferon/ribavirin arm. In each DAA trial, blacks had lower SVR than whites, but the number of blacks was small, and statistical comparison between blacks andn on-blacks was not performed.

The impact of the IL28B genotype on responsivenessto the DAAs is unknown. Data from DAA trials suggest that IL28B genotype is a stronger predictor of response than race. However, the strongest predictor of responseis receiving DAA.
Triple therapy with DAA/peginterferon/ribavirin improves SVR for all ethnicities and IL28B genotypes, narrowing the SVR gap between groups.

Accordingly,the relative importance of the IL28B genotype may diminish, but further studies are needed to determine its role in HCV treatment paradigms.

As DAAs enter the marketplace, several unresolved issues relevant to minority populations remain. The impactof IL28B, race/ethnicity, and other host factors on treatment responsiveness must be explored in well-designed trials with larger representation of minorities. Innovative strategies are needed to improve minority recruitment into these trials, and care must be taken to ensure that minority patients with hepatitis C have equal access to DAAs.

■ANDREA EWING REID, M.D., M.P.H., is Program Director,Gastroenterology Training, Gastroenterology, Hepatology and Nutrition Section, Washington DC VA Medical Center.

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