African Americans and Hepatitis C: background on Schering controversy

We'll be providing some additional context and perspectives on the controversy surrounding Schering-Plough's initial exclusion of African Americans from its phase II study of SCH 503034, a new hepatitis C protease inhibitor (see previous post).  Today, here's some background on African Americans and hepatitis C, focusing on epidemiology and response to treatment.

What do we know about African Americans and hepatitis C?

Epidemiology: African Americans have a higher rate of hepatitis C than other racial/ethnic groups – 3.0% of African Americans have been infected with hepatitis C, twice as high as the rate among whites.  Hepatitis C prevalence is highest among black males ages 45-49: an alarming 17.9% have been infected, according to statistics from the Centers for Disease Control and Prevention (CDC), a federal agency.  Though African Americans make up roughly 12% of the U.S. population, they account for an estimated 22% of all people with chronic hepatitis C in the country.

Treatment: Hepatitis C treatment is much less effective in African Americans compared to other racial/ethnic groups.  Part of the decreased success of treatment is linked to genotype – among people with chronic hepatitis C, roughly 90% of African Americans have genotype 1, the strain of hepatitis C least responsive to interferon-based treatment, compared to about 70% of whites.  However, even among people with genotype 1, African Americans are less likely to respond to treatment than whites.

Initial studies of pegylated interferon/ribavirin treatment did not enroll enough African Americans to draw meaningful conclusions about difference in response by race/ethnicity.  However, three major trials specifically designed to compare treatment responses between whites and African Americans confirmed that treatment success rates* were about twice as high in whites (39-52%) vs. African Americans (19-26%), even when all study participants had genotype 1.

The reasons for African Americans’ decreased responsiveness to interferon-based treatment remain under investigation.  Speculation centers on possible genetic differences that influence immune responses, since interferon is believed to operate in part by strengthening the immune system’s ability to fight hepatitis C.  Some differences between whites and African Americans in patterns of immune response to hepatitis C have been described, though their relevance to treatment outcomes is not clear.

* Treatment success is defined as a sustained virologic response (SVR) – when hepatitis C remains undetectable 6 months after the end of treatment.

For references, click on the link below.

General review:

Pearlman BL. Hepatitis C Virus Infection in African Americans. Clinical Infectious Diseases 2006 Jan 1;42(1):82-91. Abstract; full text courtesy of NATAP.

Epidemiology:

Estrada AL. Health disparities among African-American and Hispanic drug injectors--HIV, AIDS, hepatitis B virus and hepatitis C virus: a review. AIDS 2005 Oct;19 Suppl 3:S47-52. Abstract.

Armstrong GL, Simard EP, Wasley A, et al. The prevalence of hepatitis C virus (HCV) infection in the United States, 1999-2002. Program and abstracts of the 55th Annual Meeting of the American Association for the Study of Liver Diseases; October 29 - November 2, 2004; Boston, Massachusetts. 2004. Abstract 31. See abstract below.

Treatment:

Jeffers LJ, Cassidy W, Howell CD, et al. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology. 2004 Jun;39(6):1702-8. Abstract.

Muir AJ, Bornstein JD, Killenberg PG, et al. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004 May 27;350(22):2265-71. Abstract.

Jacobson I, Brown R Jr, McCone J, et al. Weight based ribavirin dosing improves virologic response in HCV-infected genotype 1 African-Americans compared to flat dose ribavirin with peginterferon alfa-2b combination therapy. Program and abstracts of the 55th Annual Meeting of the American Association for the Study of Liver Diseases; October 29 - November 2, 2004; Boston, Massachusetts. Abstract 125. Abstract courtesy of HIVandHepatitis.com.

See also:

VIRAHEP-C (Viral Resistance to Antiviral Therapy of Chronic Hepatitis C): a research study examining differences and factors involved in response to treatment between whites and African Americans, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health.

Immune responses by race/ethnicity:

Sugimoto K, Stadanlick J, Ikeda F, et al. Influence of ethnicity in the outcome of hepatitis C virus infection and cellular immune response. Hepatology. 2003 Mar;37(3):590-9. Abstract.

Kaplan DE, Sugimoto K, Ikeda F, et al. T-cell response relative to genotype and ethnicity during antiviral therapy for chronic hepatitis C. Hepatology. 2005 Jun;41(6):1365-75. Abstract.

The Prevalence of Hepatitis C Virus (HCV) Infection in the United States, 1999-2002

Gregory L. Armstrong, Edgar P. Simard, Annemarie Wasley, Centers for Disease Control and Prevention, Atlanta, GA; Geraldine M. McQuillan, Centers for Disease Control and Prevention, Hyattsville, MD; Wendi L. Kuhnert, Miriam J. Alter, Centers for Disease Control and Prevention, Atlanta, GA.

Introduction: To examine trends in HCV prevalence, we analyzed data from the current, ongoing National Health and Nutrition Examination Survey (NHANES) conducted during 1999-2002 and compared prevalence with that from NHANES III, approximately 10 years earlier.

Methods: The civilian non-institutionalized population was surveyed using a multistage sampling design. Serum specimens were obtained from 15,079 participants aged 6 years and older and tested for anti-HCV by 3rd generation EIA (Ortho) and RIBA (Chiron). Specimens positive by RIBA were tested by quantitative and (if negative) qualitative RNA tests (Roche, 2nd version). Differences were considered statistically significant where p<0.05.

Results: The prevalence of anti-HCV was 1.6% (95% CI 1.3-1.9%), corresponding to 3.8 million positive persons, and was higher in males (2.1%) than females (1.1%) and higher among Blacks (3.0%) than Whites (1.5%) or Mexican Americans (1.3%). Prevalence was lowest among participants 6-29 years-old (0.4%) and highest among participants 45-49 years-old (7.1% among men, 2.3% among women). Among Black men in this age group 17.9% tested anti-HCV-positive. Of all anti-HCV positive persons, 69.9% were between age 35 and 54 years. Compared with NHANES III, the overall prevalence of anti-HCV was unchanged but peaked in an older age group (45-49 years in current NHANES vs. 35-39 years in NHANES III). Prevalence varied with several demographic and risk factors. Persons who had ever used injection drugs had a higher prevalence (57.3%) than those who had used non-injection drugs (3.5%) or those who had never used these drugs (0.7%). Prevalence increased with increasing numbers of lifetime sexual partners from 0.5% among persons with 0-1 lifetime partners to 1.0%, 4.7% and 12.1% among those with 2-9, 10-49 and 50+ partners, respectively. Prevalence was higher among those with a history of blood transfusion before 1990 (4.2%) than among those without (1.4%). Of the 148 anti-HCV positive specimens available for RNA testing, 82.4% were HCV RNA-positive, including 67.5% of specimens from persons under 40-years-old and 88.0% of those aged 40 years and older. Of all RNA-positive specimens, 68.0% had titers above 2M copies/ml. In RNA-positive specimens, ALT levels abnormal in 59.9%; 41.0% were 40-79 U/L and 18.9% were 80+ U/L. Among the RNA-positive participants, 63% stated that they had never been told they had “any kind of liver condition.”

Conclusions: The overall prevalence of HCV infection has not changed during the past 10 years but the peak in age-specific prevalence has shifted to older age groups, with very low prevalence in persons under 30 years old. Taken together, these data are consistent with a past epidemic of acute HCV infection, the result of which is a cohort of people, now aged 40-59 years, with a high prevalence of infection.

Comments

[Hepster]

What most of these tests always seem to leave out is that for most of the fraction of people that are cured by interferon it is simply cured long enough to register on Schering Test Results. The bulk of the cured relapse within 6 months and get to enjoy severe side effects like brain damage for the rest of their lives.

[Daniel Raymond]

I'd like to offer a clarification about relapse rates: for people on hepatitis C treatment, an undetectable viral load at the end of their course of treatment (usually 48 weeks) is called an End of Treatment Response (ETR). That's good news, but it doesn't mean that you're cured -- as Hepster notes, a proportion of people experience a viral "relapse" after treatment. This means that the hepatitis C virus returns to detectable levels after the person finishes their course of medication. That's why people have to get their viral load measured six months after stopping their medications: if it's still undetectable, that's considered a sustained virologic response (SVR).

Not everyone whose virus becomes undetectable by the end of treatment will ultimately have an SVR, but the majority will. I looked back at 3 pivotal clinical trials that resulted in the FDA approvals of pegylated interferon, to see what the breakdown was:

Fried et al. (NEJM 2002): ETR - 69%; SVR - 56%
Hadziyannis et al. (AnnIntMed 2004): ETR - 69%; SVR - 52%
Manns et al. (Lancet 2001): ETR - 65%; SVR - 54%

Based on these numbers, people who have an ETR (undetectable at the end of treatment) have a 75-83% chance of an SVR (still undetectable six months later). In other words, the majority of people with an ETR stay undetectable.

For a detailed discussion of these studies, see Treatment Action Group's comprehensive report, especially the chapter on treatment:
http://aidsinfonyc.org/tag/coinf/hcv2004/chap5.html

Virtually everyone who achieves an SVR will remain undetectable on standard viral load tests. A recent study reported at a major liver disease conference looked at nearly 1,000 people who had achieved an SVR (undetectable 6 months after treatment) and found that 99% remained undetectable after several years of follow up (averaging over 4 years). The hepatitis C virus became detectable again in only 8 out of the 997 people studied.

For a report on this study, see NATAP's write up here:
http://www.natap.org/2007/EASL/EASL_34.htm

So people are increasingly comfortable calling an SVR a cure, with a minimal risk of relapse.

As Hepster notes, some side effects do persist after the end of treatment -- I've heard people refer to an interferon "hangover" from lingering depression, though the people that I've talked to generally say that it clears up after a few months off of treatment. I've also heard about rare cases of people developing permanent side effects -- including a couple people who developed diabetes on treatment.

To the best of my knowledge, permanent/life-long side effects from hepatitis C treatment are extremely rare -- and not unique to interferon: medications for many other conditions and diseases can also pose a risk for long-term damage. But a lot of people have a rough time on hepatitis C treatment. I always encourage people who are considering treatment to carefully consider the risk of side effects, talk with their doctor about how they'd manage or prevent the more common ones, and talk to other people who've gone through treatment about what worked for them.