The last post discussed the role of viral factors (genotype and viral load) in determining the chance of success for hepatitis C treatment. These factors account for by far the greatest proportion of differences in treatment outcomes, but they don’t account for all variation. Here I’ll look at the role of patient (or “host”) factors, including age, weight, race, and cirrhosis.
Several studies have reported that treatment is more likely to be successful in people below the age of 40. People younger than 40 were about 2 ½ times more likely to achieve a sustained virologic response (SVR) than people over 40 in one major study that compared pegylated interferon, with or without ribavirin, to standard interferon and ribavirin (Fried et al., Peginterferon alfa-2a Plus Ribavirin for Chronic Hepatitis C Virus Infection, New England Journal of Medicine vol. 347 no. 113, September 26 2002 – abstract). Similar results have been reported in other large studies (e.g. Manns et al., Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial, Lancet vol. 358 issue 9286, September 22 2001 – summary [free registration required]).
It’s not clear why age affects treatment outcomes; older people usually have been infected longer, and may have more liver damage (see cirrhosis below). The quality and magnitude of immune responses can also change or decline as people get older, though the impact of this on response to hepatitis C treatment is at best hypothetical. However, the data seem to suggest a modest advantage in treating hepatitis C sooner, rather than delaying therapy. But bear in mind that age is only one of several variables to consider.
Heavier weight or higher body mass index (BMI, a way of calculating fat based on weight and height) also affects response to treatment. The Fried study cited above found that people weighing less than 75 kg (about 165 pounds) were nearly twice as likely to achieve an SVR than people weighing over 75 kg. A retrospective analysis of 253 people treated with standard interferon, with or without ribavirin, found that obesity [a BMI >30mg/m(2)] reduced the chances of treatment success by about 75% (Bressler et al., High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C, Hepatology vol. 38 issue 3, September 2003 – abstract).
Obesity has been linked to increased fibrosis, and can lead to an accumulation of fat in liver cells (hepatic steatosis). Either of these factors may in theory make it harder to achieve an SVR. Alternately, weight and BMI may affect the distribution of interferon and ribavirin in the body—perhaps heavier or obese people simply don’t get effective drug levels and should receive higher doses. Indeed, the prescribed dose of ribavirin typically depends on weight, and one of the pegylated interferons (Schering-Plough’s Peg-Intron) is also dosed by weight (see the next entry on potential differences between drugs for more on this subject). Finally, obesity can lead to changes in immune function, which could hypothetically undermine some of the effects of interferon and ribavirin.
All of this suggests that obese persons may benefit from weight loss prior to starting hepatitis C treatment. While this idea has not been tested, some evidence suggests that weight loss may be beneficial even without treatment. A small Australian study recently reported that people with hepatitis C who lost weight (and maintained their weight loss) through diet and exercise experienced a reduction in liver enzyme (ALT) levels and an improvement in quality of life (Hickman et al., Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life, Gut vol. 53 no. 3, March 2004 – abstract). An earlier small study from these researchers found that weight loss also resulted in an improvement in the condition of the liver, using liver biopsies to demonstrate reduced fibrosis (Hickman et al., Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C, Gut vol. 51 no. 1, July 2002 – abstract).
Most research indicates that African-Americans tend have worse responses to hepatitis C treatment than whites, though large studies often fail to include enough African-American participants for meaningful analysis. A recent study, presented by Lennox Jeffers at the 2003 annual meeting of the American Association for the Study of Liver Diseases (AASLD), looked at response to treatment in 78 African-Americans and 26 Caucasians, all with genotype 1. Only 26% of African-Americans had SVRs, compared with 39% of Caucasians.
The reasons for impaired response to treatment in African-Americans have not been established. In general, 90% of African-Americans with hepatitis C have genotype 1 – the hardest to treat. But genotype doesn’t seem to account for all of the differences in treatment response. Some viral kinetics data suggest that interferon is less effective at suppressing hepatitis C in African-Americans (Layden-Almer et al., Viral dynamics and response differences in HCV-infected African American and white patients treated with IFN and ribavirin, Hepatology vol. 37 issue 6, June 2003 – abstract).
The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK, part of the National Institutes of Health) is currently sponsoring a larger study of treatment outcomes in African-Americans and whites, called VIRAHEP-C (Viral Resistance to Antiviral Therapy of Chronic Hepatitis C), to look at these issue. Because of its large size (400 people enrolled—200 African-American), VIRAHEP-C should provide definitive answers to whether and to what degree African-Americans have a lower SVR rate, and a better understanding of the reasons for the difference. The study won’t be complete until 2006, but hopefully preliminary results will come out sooner.
In the meantime, African-Americans will have to make difficult decisions about the risks and benefits of hepatitis C treatment. So far, few if any differences in SVR rates have been reported for other racial/ethnic groups, but more research is needed.
People with advanced liver damage, particularly cirrhosis (serious scarring), are less likely to achieve an SVR from hepatitis C treatment. The Hadziyannis study (abstract) cited in the previous post found that in people with genotype 1 receiving standard treatment, SVRs were seen in 41% of people with cirrhosis or bridging fibrosis, compared to 57% of people without cirrhosis or bridging fibrosis. For people with genotype 2 or 3, SVR rates were 73% for people with cirrhosis or bridging fibrosis, vs. 83% for people with less severe liver damage. Other studies have shown similar results.
These findings reveal a paradox in hepatitis C treatment: people with less advanced liver disease are more likely to benefit from treatment, but people with more liver damage are more likely to need treatment.
Some additional issues may influence treatment response. In particular, adherence to treatment seems important – generally defined in hepatitis C therapy as the 80% rule: taking 80% of the prescribed interferon and ribavirin doses 80% of the time (McHutchison et al., Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C, Gastroenterology vol. 123 no. 4, October 2002 – abstract). In many cases, people skip doses or quit treatment early because of side effects, so good monitoring and management of side effects is important. In practical terms, this means good communication between people and their doctors and nurses, education to help people know in advance what to watch for and expect, and support (and support groups) for people going through treatment. In some cases, adherence may improve by having a health care provider directly administer the weekly dose of pegylated interferon. This would also give people a chance to talk about any side effects or difficulties with treatment more frequently.
Doctors also decrease the dose of interferon and/or ribavirin based on side effects and laboratory abnormalities (e.g., dangerous drops in red blood cell, white blood cell, or platelet counts). Dose reductions seem likely to lower the chances of achieving an SVR. so doctors are increasingly using EPO (epoetin alfa, sold as Epogen or Procrit) to counteract the effects of ribavirin on red blood cell counts, which can cause anemia. Use of EPO offsets the need to reduce ribavirin dosing and appears to reverse anemia and may improve quality of life (Dieterich et al., Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa, American Journal of Gastroenterology vol. 98 issue 11, November 2003 – abstract). The big question is whether use of EPO to preserve full dosing of ribavirin will lead to better SVR.
One other major “host factor” affects response to hepatitis C treatment: HIV status. People with HIV show consistently lower SVR rates in all major studies. This issue will be the subject of a future post; for now, more information is available in a recent article I wrote for the newsletter of Chicago’s Test Positive Aware Network (TPAN - https://www.tpan.com/), and another article (see also chart) by Tracy Swan of the Treatment Action Group (TAG).
Next: Is it about the drugs?