• Introduction
• Early Virologic Response
• Persistently Normal Aminotransferases (PNALT)
• Liver Biopsy
• Cirrhosis and Maintenance Therapy
• HCV and HIV Co-Infection
• African-Americans and Hepatitis C
• References

Introduction

The Hepatitis C virus (HCV) is a major public health problem and the most common cause of death from liver disease in the United States.¹ According to population-based studies, HCV accounts for more than 40% of chronic liver disease in the U.S., and causes about 10,000 deaths per year.² Although the proportion of these deaths that occur in correctional facilities is believed by many to be as high as 30% and rising, the exact numbers of deaths due to HCV that occur in the U.S. correctional system is unknown. Despite the declining incidence of HCV infection, the prevalence of HCV-related chronic liver disease is increasing because of a substantial time lag between infection and clinical manifestations.

Although the estimated prevalence of hepatitis C in the U.S. is about 2%,³ it is significantly higher in state and federal correctional facilities (16-49%).^4-6 According to a U.S. Justice Department study, 1.3 to 1.4 million inmates released from prison in 1996 were infected with HCV, or about 30% of the total in the U.S. population with the condition.⁷ As in the general population, injection drug use (IDU) accounts for most HCV infections in the correctional setting, as up to two-thirds of inmates have a history of IDU before incarceration.⁵ Since there is such a high prevalence of HCV among inmates, the correctional environment affords an opportunity to diagnose and treat the virus in many of those who are infected.

The following topics are among the most important in the realm of HCV treatment as published in medical literature or presented at scientific meetings in the past two years. For more essentials on HCV epidemiology, natural history and treatment, the reader is encouraged to consult prior issues of HEPP Report.^8-10

Early Virologic Response

The best therapy currently available for treatment-naive patients is weekly injections of pegylated-interferon alpha-2a coupled with twice daily oral ribavirin. Sustained virologic response (SVR is defined as undetectable HCV RNA 24 weeks after the completion of therapy) can be achieved in more than half of those treated.^11,12 However, early identification of treatment non-responders is warranted to spare the expense and side effects of unnecessary medication. Consequently, the use of the early virologic response (EVR) has been popularized.

The best marker of EVR in terms of sensitivity (capture the largest number of responders) and negative predictive value (eliminate the largest number of non-responders) is a decline in the HCV viral load of at least 2-log from baseline after 12 weeks of therapy. Patients not achieving this treatment milestone have almost no chance of achieving a SVR,¹³ and therefore can be spared an additional 12 to 36 weeks of unnecessary therapy. In a recently published economic analysis, the use of EVR decreased costs by 45% when compared to a full course of therapy.¹⁴ Based on these data, many experts recommend terminating therapy for patients who do not reach an EVR at 12 weeks.

There are several caveats to bear in mind when utilizing EVR. Because most patients with genotypes other than 1 achieve an EVR, using a 12-week cut-off reduces costs only marginally in patients with other genotypes.¹³ Secondly, variations of up to one 1 log unit can occur with any assay, so a patient with a 1.8-log RNA drop at 12 weeks, for example, may still achieve a sustained response.¹⁵ Moreover, histologic benefits may be achieved despite patients not reaching early or sustained virologic responses.¹⁶ Although many insurance companies have justified stopping coverage of medications for patients who do not reach this threshold, a patient may still show significant hepatic histologic improvement or at least delayed histologic progression without reaching an EVR/SVR. This topic will be discussed in greater detail below. Accordingly, use of EVR should be viewed as an individualized tool and not a hard and fast rule for terminating therapy.

Persistently Normal Aminotransferases (PNALT)

HCV is usually associated with elevated alanine aminotransferase (ALT) levels, yet about 30% of patients with chronic HCV have persistently normal ALT levels.¹⁷ The study of this patient subset has been compounded by differing definitions of a "normal" ALT.^18,19 The definition of a normal ALT used in the phase III clinical trial of peginterferon alfa-2b and ribavirin was <43 IU/L for men and <34 IU/L for women.¹¹ Patients with PNALT were defined as those with three separate blood tests drawn at least one month apart that demonstrated ALT measurement at or below the upper limit of the normal level.

Although many patients with PNALT have a slow progression of fibrosis,²⁰ some PNALT patients have relatively advanced fibrosis on liver biopsies.²¹ In a recent study of 91 HCV RNA-positive patients with PNALT (all of whom had liver biopsy), one in six patients had significant, progressive liver disease that was only identified on liver biopsy.²²

Treatment for the HCV patient with PNALT has been controversial. An older study of interferon monotherapy for those with PNALT showed that therapy caused elevations in ALT, and was therefore not beneficial.²³ However, subsequent studies treating those with PNALT using standard interferon/ribavirin showed sustained response rates without ALT "flares" in 47% of the patients.^24,25

The 2002 NIH Consensus Guidelines on the Management of HCV recommended that treatment for HCV patients with PNALT should be individualized, taking into account factors such as liver histology, HCV genotype, patient age, motivation for therapy and co-morbid conditions.²⁶ A recently completed multicenter, multinational, randomized trial showed that HCV-infected PNALT patients had similar rates of sustained response compared to those with elevated ALTs when treated with pegylated-interferon/ribavirin.²⁷

In a recent study by Ghany, et al., 123 patients with chronic HCV underwent two liver biopsies, each at extended, but variable intervals. The biopsy reports were correlated with serum aminotransferases. The authors concluded that the best predictors of fibrosis progression in these patients were the extent of serum aminotransferase elevations and the degree of hepatocellular necrosis and inflammation on liver biopsy. Consequently, they felt these findings support the recommendation that patients with PNALT and mild liver histology can safely defer treatment.²⁸ As a result of these studies and others, some specialists believe that all PNALT patients who are otherwise candidates for treatment should undergo liver biopsy, and that treatment should be based on histology results.

Liver Biopsy

The necessity of liver biopsy prior to treatment is also a subject of debate. Despite drawbacks like the potential for complications and sampling error, biopsy is the only reliable predictor of natural history of disease.^29,30 Nearly all patients with high-grade necroinflammation and most of patients with intermediate-grade on biopsy develop cirrhosis.³¹ Nonetheless, the cost-effectiveness of treating patients without fibrosis on biopsy has been questioned.³² Expert consensus groups from the U.S. and Europe have previously recommended the routine performance of liver biopsy prior to antiviral therapy initiation.^33,34 However, recent guidelines from the American Association for the Study of Liver Diseases (AASLD) are less dogmatic: "biopsy is not mandatory to initiate therapy ... yet a liver biopsy should be done when results will influence the recommendation to treat."³⁵

Different prison systems take different approaches to liver biopsy. The Federal Bureau of Prisons, Louisiana, and Georgia require a biopsy prior to treatment, and only treat those with significant fibrosis. On the other hand, Texas and Pennsylvania systems do not mandate biopsy for those who desire treatment and do not have contraindications.³⁶ A recent cost-effectiveness study of HCV-infected inmates was carried out at the Louisiana State Penitentiary in which 501 patients were evaluated, approximately half of whom had pre-treatment liver biopsies. In an analysis of those patients infected with HCV genotype 1 who received pegylated-interferon/ribavirin, the cost of HCV treatment was $16,826 per patient treated with liver biopsy and $14,389 for those treated without liver biopsy. The authors concluded that a protocol using liver biopsy as a means to determine eligibility for therapy does in fact balance costs and complies with current recommendations.³⁷

Cirrhosis and Maintenance Therapy

Patients with HCV-related cirrhosis have a high risk of dying from end-stage liver disease (30% over 10 years³⁵), and thus have much to gain from successful treatment. Patients with advanced liver disease can be successfully treated with interferon-based therapies, but sustained response rates are lower and medication dose reductions are needed more frequently in this population relative to those with less advanced disease.

Most of the data supporting the treatment of compensated cirrhotics comes from subgroup analysis of larger trials in which 43% of those treated with pegylated-interferon/ribavirin achieve an SVR.^11,12 Only one published treatment trial examined patients with advanced liver disease exclusively; cirrhotic patients on pegylated-interferon monotherapy achieved an SVR in 30% of cases.³⁸ In patients who achieve SVR, the risk of developing hepatocellular carcinoma or liver failure may also be diminished.³⁹

Despite some data supporting the treatment of compensated cirrhotics, there is little evidence supporting therapy for those with decompensated liver disease (ascites, encephalopathy, etc.). These patients should be referred to liver transplantation centers or be enrolled in clinical trials. (See HEPP Report December 2003 issue at www.hivcorrections.org for the management of decompensated liver patients in the correctional setting.)

Even if patients do not achieve an SVR, both cirrhotics and non-cirrhotics may still have significant hepatic histologic improvement or at least delayed histologic progression following treatment with combination therapy. In an analysis of data from over 3,000 patients receiving sequential liver biopsies, interferon-based treatment reduced the rate of fibrosis progression. Despite only a third of patients achieving SVR, nearly half had reversal of their cirrhosis. 73% of patients had improvement of necrosis and inflammation, irrespective of achieving SVR.¹⁸ In a more recent meta-analysis of over 1,000 treatment-naive patients, pegylated-interferon alfa-2a significantly reduced fibrosis relative to standard interferon.⁴⁰

Based upon the above two studies and others like them, some specialists support the concept of "maintenance therapy" in which patients with cirrhosis who do not achieve an SVR continue therapy in hopes of achieving a regression or slowing of their liver disease. Although many providers are utilizing maintenance therapy in their practices, this approach is still experimental since it has not been proven in well-controlled trials. Large multi-center trials such as HALT-C, COPILOT and EPIC are underway and will likely provide guidance on this issue.

HCV and HIV Co-Infection

HCV is common in HIV-infected patients because of shared routes of transmission. In fact, the U.S. Public Health Service and the Infectious Disease Society of America advocate screening all HIV-infected individuals for HCV.⁴¹ HIV seropositivity accelerates the rate of HCV-progression by about three-fold.⁴²

Many providers are treating co-infected patients for both diseases. The more intact the immune system (CD4+ count >200 cells/mm³), the higher likelihood of sustained response to HCV therapy.⁴³ Several authors have recommended liver biopsy prior to initiating treatment for HCV in co-infected patients.⁴⁴ Co-infected patients should be monitored closely because the concomitant use of nucleoside analogs and ribavirin increases the risk of pancreatitis, anemia and lactic acidosis.^45-47 Furthermore, ribavirin is contraindicated with didanosine (ddI) since it increases risks of side effects associated with ddI. Finally, the potential for antiretroviral medication-induced hepatotoxicity is compounded in HCV-infected patients.

The results of recently completed trials of over 400 co-infected patients treated with pegylated-interferon alfa-2a/ribavirin have been made available. Sustained response rates ranged from 27 to 40%, yet discontinuation rates ranged from 12 to 25%.^48-50 Both response rates and termination rates are significantly higher when compared to those from monoinfected HCV patients. However, in co-infected patients, the rates of SVR are better with treatment with pegylated-interferon alfa-2a than with treatment with standard non-pegylated interferon alpha-2a/ribavirin.

African-Americans and Hepatitis C

Compared with Caucasians, U.S. minority populations are disproportionately affected by chronic HCV infection.³ Furthermore, African-Americans are more likely to be infected with HCV genotype 1 and develop chronic infection than are Caucasians.^51,52 Efforts to assess the natural history of HCV-infected African-Americans have been hampered by inadequate representation of African-Americans in HCV prospective trials. A retrospective study of over 350 patients showed that African-Americans had significantly less necrosis and cirrhosis on liver biopsy compared to Caucasians.⁵³ However, another retrospective analysis of over 300 inmates from the Virginia Department of Corrections showed there were no clinically significant differences between Caucasians and African-Americans on liver biopsy.⁵⁴ Nonetheless, African-Americans with HCV-related cirrhosis may have up to a six times higher risk of developing hepatocellular carcinoma compared to their cirrhotic Caucasian counterparts.⁵⁵

With respect to interferon-based therapy, most studies have reported lower response rates among African-Americans compared to Caucasians. Ongoing studies of standard interferon/ribavirin combination therapy have shown lower sustained responses in African-Americans compared to Caucasians.^56,57 The lower response rate may be due, in part, to an impaired ability of African-Americans to inhibit viral production and clear virus with therapy,⁵⁸ but the reason for the discrepant response rates are still unclear.

Preliminary results are available from the first well-controlled clinical trial conducted exclusively in African-Americans infected with genotype 1. This trial evaluated the safety and efficacy of pegylated-interferon alpha-2a/ribavirin treatment. When compared to the historical control group (genotype 1 patients of similar weight to those in the study), there was a lower rate of SVR, 26% versus 39%, respectively, for the trial participants and controls. The utility of EVR was confirmed in this population; i.e., EVR had a good negative predictive value in both studies involving African-Americans and non-African-Americans. Although no unexpected adverse effects were noted in this trial, African-Americans in this trial developed more neutropenia than did controls.⁵⁹ For unknown reasons, the significance of neutropenia-related treatment was less clinically significant than previously thought, especially in African-Americans.⁶⁰ Finally, the study showed that even the patients without an SVR achieved a benefit with respect to hepatic histology.⁶¹ In summary, although the likelihood of an SVR is decreased among African-Americans, are less than those of non-African-Americans, HCV treatment may be beneficial, and ethnicity should not be a criterion on which to base suitability of therapy.

Since there is such a high prevalence of HCV among inmates, the correctional environment affords an opportunity to diagnose and treat the virus in many of those who are infected. In this month's Spotlight (David Thomas, J.D., M.D.) discusses the complex medical, legal, and financial issues surrounding HCV treatment in prisons and jails. The absence of any formal guidelines for treatment of HCV in correctional settings remains the most significant roadblock to providing good care to all HCV-infected inmates. The time is ripe for either the Society for Correctional Physicians or the National Commission on Correctional Health Care to develop these much-needed benchmark standards.

Brian L. Pearlman, M.D., F.A.C.P, is Medical Director at the Center for Hepatitis C, Atlanta Medical Center, Atlanta, GA, and Associate Professor of Medicine at Medical College of Georgia, Augusta, GA. Disclosures: Speakers' Bureau: Schering-Plough.

Joseph E. Paris, Ph.D., M.D., C.C.H.P., F.S.C.P., is Medical Director at the Georgia Department of Corrections. Disclosures: Nothing to disclose.

References

1. Kim WR. Hepatology. 2002;36(Suppl 1):S30-34.

2. Alter MJ. 1997;26(Suppl 1):S62-65.

3. Alter MJ, et al. N Engl J Med. 1999;341:556-62.

4. Spaulding A, et al. Prev Med. 1999;28:92-100.

5. Reindollar RW. Am J Med. 1999;107:S100-S103.

6. Baillargeon J, et al. Public Health. 2003;117(1);43-8.

7. NCCHC, National Institute of Justice (2002). The health status of soon-to-be released inmates. Washington D.C. United States Department of Justice.

8. HEPP Report. 2003;6:4.

9. HEPP Report. 2002;5:8-9.

10. HEPP Report. 2002;5:4.

11. Manns MP, et al. Lancet. 2001;358:958-65.

12. Fried MW, et al. N Engl J Med. 2002;347:975-82.

13. Davis GL, et al. Hepatology. 2003;38:645-52.

14. Wong JB, et al. 2003;98:2354-62.

15. Shiffman JL, et al. Am J Gastroenterol. 2003;98:1159-66.

16. Poynard T, et al. 2002;122:1303-13.

17. Conry-Cantilena C, et al. N Engl J Med. 1996;334:1691-96.

18. Prati D, et al. Ann Intern Med. 2002;137:1-9.

19. Piton A, et al. Hepatology. 1998:27:1213-19.

20. Persico M, et al. Gastroenterology. 2000;118:760-64.

21. Gholson CF, et al. Am J Gastroenterol. 1997:92:1788-92.

22. Kyrlagkitsis I, et al. Am J Gastroenterol. 2003;98:1588-93.

23. Marcellin P, et al. 51st AASLD. Oct 27-31, 2000; Dallas, TX. Abstract 883.

24. Silverman AL, et al. 52nd AASLD; Nov 9-13, 2001;Dallas, TX.

25. Lee SS, et al. J Viral Hepat. 2001;8:202-205.

26. National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C: 2002. Gastroenterology. 2002:123:2082-99.

27. Zeuzem S, et al. Hepatology. 2003;38(Suppl 1):208A.

28. Ghany MG, et al. Gastroenterology. 2003;124:97-104.

29. Garcia-Tsao G. Ann Intern Med. 1993;118:150-153.

30. Regev A, et al. Am J Gastroenterol. 2002;97:2614-18.

31. Yano M, et al. Hepatology. 1996;23:13334-40.

32. Salomon JA, et al. JAMA. 2003;290:228-37.

33. National Institute of Health Consensus Development Conference. Hepatology. 1997;26(Supl 1):2S-10S.

34. EASL. J Hepatol. 1999;30:956-61.

35. Strader D, et al. AASLD Practice Guidelines. 2004.

36. Cassidy W. Hepatitis C infections in prisons. Available at: http://hcvadvocate.org. Accessed July 22, 2003.

37. Marino MJ. Abstract T1256. Digestive Disease Week. 2003. May 17-22, 2003.

38. Heathcote EJ, et al. N Engl J Med. 2000;343:1673-80.

39. Heathcote EJ. J Clin Gastroenterol. 2003;37:395-98.

40. Camma C, et al. Hepatology. 39(2):333-42.

41. USPHS and IDSA. 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus.

42. Graham CS, et al. Clin Infect Dis. 2001;33:562-9.

43. Boyle B. http://hivandhepatitis.com. Accessed December 29, 2003.

44. Sulkowski MS et al. Ann Intern Med. 2003;138:197-207.

45. Soriano V, et al. AIDS. 2004;18:1-12.

46. Butt AA. AIDS Reader. 2003;13:344-48.

47. Lafeuillade A, et al. Lancet. 2001:357:280-1.

48. Chung R, et al. 11th CROI; 2004 February 8-11; San Francisco, California. Abstract 110.

49. Perez-Olmeda M, et al. AIDS. 2003;17:1023-28.

50. Torriani FJ, et al. 11th CROI; 2004 February 8-11; San Francisco, California. Abstract 112.

51. McHuthison JF, et al. Gastroenterology. 2000;119:1317-23.

52. Reddy KR, et al. Hepatology. 1999;30:787-93.

53. Wiley TE, et al. Am J Gastroenterol. 2002;97:700-706.

54. Sterling RK, et al. Digestive Disease Week; 2003 May 17-22; Orlando, FL. Abstract 252.

55. Mindie H, et al. Digestive Disease Week; 2003 May 17-22; Orlando, FL. Abstract 121.

56. Lawitz EJ, et al. Hepatology. 2001;34:1000A.

57. Siddiqui FA, et al. Hepatology. 2001;34:1637A.

58. Layden-Almer JE, et al. Hepatology. 2003;37(6):1343-50.

59. Jeffers LJ, et al. Hepatology. 2003;38(Suppl 1):190A.

60. Soza A, et al. Hepatology. 2002;36:1273-79.

61. Cassidy W, et al. Hepatology. 2003;38(Suppl 1):303A.