|
|
|
| ||
| ||
|
||
|
||
|
||
| ||||||||||||||||||||||||
|
SEPTEMBER 2007
Main Article:
Incorporation of the AST Platelet Ratio Index (APRI) into the HCV Evaluation and Treatment Pathway in the Texas Department of Criminal Justice (TDCJ)
David Paar, MD Director, Clinical Virology The University of Texas Medical Branch- Correctional Managed Care Disclosures: Speaker's Bureau: Vircus, Tibotec Therapeutics, and Boehringer Ingelheim; Advisor: Tibotec Therapeutics Introduction Prisons and jails in the U.S. bear a disproportionate share of the total United States population with hepatitis C virus (HCV) infection. The primary source of HCV infections in the U.S. is illegal injection drug use.1 Since drug offenders make up 21% of state and 55% of federal prison populations and even greater percentages of offenders report past drug use 2, it is not surprising that the prevalence of HCV infection in correctional facilities (15% - 40%) is significantly higher than in the general population (1.8%).1,3 Additionally, it has been estimated that at least a third of all HCV-infected persons in the U.S. pass through a correctional facility in any given year.4 These circumstances provide a unique opportunity for correctional systems to identify, treat, educate, and ultimately interrupt the transmission of HCV by prisoners who are released back into the community since HCV is acquired primarily from risk behaviors occurring outside of the correctional setting.5 Scarce health care funding for HCV treatment within corrections is one reason why this opportunity has not been exploited. With an estimated 400,000 HCV-infected offenders behind bars at any one time, the potential cost of comprehensive screening, testing, treatment, and prevention programs would be enormous.3 Nonetheless correctional systems are assuming responsibility for treating many of these inmates who have chronic HCV infection since courts have found that it is an Eighth Amendment violation to deny HCV treatment to an offender who has significant liver disease that is amenable to antiviral treatment.6 Consequently, correctional systems are facing challenges in developing evaluation and treatment guidelines that address logistical and financial limitations to treating HCV infections among offenders. For example, since continued HCV care for inmates after release is generally not available, duration of incarceration has been adopted as an exclusionary criterion for treatment by many correctional jurisdictions. Likewise, among offenders with chronic HCV infection and no medical or psychiatric contraindications to treatment, ALT levels may be used to decide who should be considered for antiviral therapy because of the geographical and security challenges of transporting patients to a facility where liver biopsy can be done.7 Logistically, using ALTs may make sense; yet one large collaborative study demonstrated that ALT levels lack adequate sensitivity and specificity on which to base treatment decisions in the correctional setting or elsewhere.8 Liver biopsy remains the gold standard in making treatment decisions regarding HCV infection; and it should be emphasized that deferral of treatment is appropriate and cost effective for those with little or no evidence of fibrosis provided that appropriate follow up conducted periodically to assess disease progression.9 But there is a general consensus that even the gold standard is not perfect. First, liver biopsy is expensive and associated with low, but predictable rates of morbidity and mortality.10 Further, the histopathological samples obtained by percutaneous liver biopsy are often not representative of the overall condition of the liver or may not be large enough to make an accurate diagnosis.11 Finally, the interpretation of fibrosis is dependent upon the skill and experience of the pathologist reading the biopsy specimen.12 For all of these reasons, there has been a great deal of basic and clinical research aimed at identifying noninvasive markers of hepatic fibrosis that can be used to accurately predict significant fibrosis for patients with HCV infection as well as other conditions associated with hepatic fibrosis. Although many serum markers of hepatic fibrosis have been identified, none has been identified that can entirely replace the need for liver biopsy. This article describes why and how The Texas Department of Criminal Justice (TDCJ) incorporated one of these serum markers of hepatic fibrosis, the AST Platelet Ratio Index (APRI), into its HCV evaluation and treatment guideline. Serum Markers of Hepatic Fibrosis Serum markers of hepatic fibrosis reflect the state of fibrosis and fibrogenesis within the liver. These markers can be divided into two groups: Indirect and direct markers. Indirect markers include common clinical tests such as platelet counts, serum transaminases, glutamyl transpeptidase (GGT), and total bilirubin - all of which measure hepatic function. In contrast, the direct serum markers more accurately reflect the complex process of fibrogenesis. Fibrogenesis is a dynamic process characterized by deposition and degradation of the extracellular matrix (ECM) of the liver by stellate and other fibrogenic cells within the liver. Many serum markers of ECM remodeling are under investigation. A few examples are hyaluronic acid, metalloproteinases (MMPs), specific tissue inhibitors of metalloproteinases (TIMPs), macroglobulin, apolipoprotein A1, and haptoglobin.13,14 Many clinical studies have documented the correlation between serum markers of hepatic fibrosis with stage of fibrosis on liver biopsy to determine which markers, or more accurately, combinations of markers can accurately predict insignificant fibrosis (F0, F1), which does not require treatment, from significant fibrosis (F2, F3, F4), which does require treatment.15-21 See HCV 101 for an explanation of the fibrosis staging score.22 Not all of these tests are directly comparable because existing studies differ in their definition of fibrosis staging as well as in the population in which they have been validated. Given these limitations, it can generally be stated that using many of these tests, approximately 50% of patients can be classified as having either insignificant fibrosis or significant fibrosis obviating the need for further evaluation by liver biopsy. The other 50% of patients will require liver biopsy to determine extent of fibrosis. Of course, even the best serum marker tests are not 100% accurate. Thus the decision not to biopsy based on a serum marker assay alone is incorrect. Other factors that might be taken into account when assessing the accuracy of a serum marker of fibrosis include historical data such as alcohol intake, physical examination findings such as enlarged spleen, or laboratory data such as prolonged coagulation times that suggest that the serum marker assay is inaccurate.9 Table 1 lists and characterizes the serum markers of hepatic fibrosis generally available to clinicians practicing in the U.S. APRI in the TDCJ Until January 2007, the University of Texas Medical Branch - Correctional Managed Care (UTMB-CMC), which provides health care to approximately 80% of offenders incarcerated in the TDCJ, followed an HCV treatment guideline that relied on hepatic transaminase elevations rather than liver biopsy to determine suitability for HCV treatment. This guideline was recently modified after studies conducted within prisons suggested that it was more cost effective to base HCV treatment decisions on liver biopsies rather than on transaminase elevations.23 In addition, it was decided to incorporate a non-invasive marker of fibrosis into the guideline in order to reduce the number of biopsies needed for treatment decisions. The APRI score was selected because it is a simple formula (AST divided by platelet count) based on commonly ordered and inexpensive laboratory tests and has been prospectively validated, in part, with prisoner liver biopsy specimens and laboratory values at UTMB.20,24 In previous studies, using lower and upper cut-off values of 0.42 and 1.2, respectively, the APRI accurately classifies 60% of people with HCV as having either insignificant fibrosis (F0, F1) or significant fibrosis (F2, F3, F4).20 In the other 40% of patients, percutaneous liver biopsy must be used to assign stage of fibrosis in order to make a treatment decision. By using the APRI, it was anticipated that the number of biopsies performed on HCV positive offenders would be reduced by approximately 50% in comparison to a guideline that did not incorporate the APRI or other serum marker of hepatic fibrosis. The IDCR-O-Gram shows how the APRI has been incorporated into the UTMB - CMC HCV management guideline. Because HCV genotype II and III infections respond well to a six month course of pegylated interferon plus ribavirin, all genotype II and III patients are considered potential candidates for therapy regardless of APRI score. This makes sense from a public health view point as well; eliminating these infections leads to a decrease in the overall reservoir of infection. All HIV/HCV co-infected patients are candidates for treatment and receive a liver biopsy to aid in treatment decisions. Since this guideline was adopted, Snyder, et al.24 have published an algorithm in which the APRI and the FIBROSpect II (see Table 1) are used to sequentially screen a prospective cohort of patients undergoing liver biopsy for evaluation of HCV infection. The APRI was used as an initial screening tool for the prediction of fibrosis. The FIBROSpect II was used to assess the group of patients whose APRI score was indeterminate. Using this strategy the percentage of 93 prospectively assessed patients whose fibrosis could be accurately predicted, using liver biopsy as the standard, was 74.2 %. This suggests that it may be possible to combine these tests to further reduce the number of biopsies necessary to make accurate diagnosis of stage of fibrosis. Summary Correctional institutions are treating increasing numbers of offenders with HCV infections. Treatment guidelines can promote cost effective means of evaluating and treating HCV infections through judicious application of non-invasive means of assessing fibrosis. UTMB-CMC has incorporated the APRI into its evaluation and treatment regimen and will assess its effectiveness in ongoing quality assurance programs. References: 1.Armstrong GL, Wasley A, Simard EP, et al. The Prevalence of Hepatitis C Virus Infection in the United States, 1999 through 2002. Ann Intern Med. 2006:144:705-14. 2.Mumola CJ, Karberg, JC. Drug Use and Dependence, State and Federal Prisoners, 2004. Bureau of Justice Statistics Special Report. October 2006, NCJ 213530. 3.Murray OJ, Pulvino J, Baillargeon J, et al. Managing Hepatitis C in or Prisons. Correct Care, Spring 2007;21(2):1,11. 4.Boutwell AE, Allen SA, Rich, JD. Opportunities to Address the Hepatitis C Epidemic in the Correctional Setting. Clinical Infectious Disease. 2005:S367-72. 5.Weinbaum CM, Sabin K, Santibanez S. Hepatitis B, Hepatitis C, and HIV in Correctional Po;ulations: A review of Epidemiology and Prevention. AIDS 2005;19(suppl3-S41-S46). 6.United States Court of Appeals for the Second Circuit. Docket No. 04-3234-pr. 412F.3d 398; 2005. 7.Spaulding AC, Weinbaum CM, Lau DT-Y, et al. A Framework for Management of Hepatitis C in Prisons. Ann Intern Med;144:762-89. 8.Pradat P, Alberti A, Poynard T, et al. Predictive Value of ALT levels for Histologic Findings in Chronic Hepatitis C: A European Collaborative Study. Hepatology. 2002;36:973-77. 9.Strader DB, Wright T, Thomas DL, et al. Diagnosis, Management, and Treatment of Hepatitis C. Hepatology. 2004;39:1147-71. 10.Cadranel JF, Rufat P, Degos F. Practices of Liver Biopsy in France: Results of a Prospective Nationwide Survery. Hepatology. 2005;41:257-64. 11.Bedossa P, Dargere D, Paradis, V. Sampling Variability of Liver Fibrosis in Chronic Hepatitis C. Hepatology. 2003;38:1449-57. 12.Rousselet M-C, Michalak S, Dupre F, et al. Hepatitis Network 49. Sources of Variability in Histological Scoring of Chronic Viral Hepatitis. Hepatology 2005;41:257-64. 13.Friedman SL, Rockey DC, Bissell DM. Hepatic Fibrosis 2006: Report of the Third AASLD Single Topic Conference. Hepatology 2007;45:242-49. 14.Rockey, DC, Bissell DM. Noninvasive measures of Liver Fibrosis. Hepatology 2006;43:S113-S120. 15.Forns X, Ampurdanes S, Llovet JM, et al. Identification of Chronic Hepatitis C Patients Without Hepatic Fibrosis by a Simple Predictive Model. Hepatology 2006;36:986-92. 16.mbert-Bismut F, Ratziu V, Pieroni L, et al. Biochemical Markers of Liver Fibrosis in Patients with Hepatitis C Virus Infection : A Prospective Study. Lancet 2001;357:1069-75. 17.Zaman A, Rosen HR, Ingram K, et al. Assessment of FIBROSpect II to Detect hepatic Fibrosis in Chronic Hepatitis C Patients. The American Journal of Medicine 2007;120:280.e9-280.e14. 18.Liver Fibrosis Panel, HepaScoreŽ Test Summary. Quest Diagnostics. http://www.questdiagnositics.com. Last accessed 9/2/2007. 19.Wai C-T, Greenson JK, Fontana RJ. A Simple Noninvasive Index Can Predict Both Significant Fibrosis and Cirrhosis in Patients with Chronic Hepatitis C. Hepatology 2003;38:518-26. 20.Snyder, N, Gajula, L, Xiao, S-Y, et al. APRI: An Easy and Validated Predictor of hepatic Fibrosis in Chronic Hepatitis C. J Clin Gastroenterol 2006;40:535-42. 21.Sterling RK, Lissen E, Clumeck N, et al. Development of A simple Noninvasive Index to Predict Significant Fibrosis in Patients with HIV/HCV Coinfection. Hepatology 2006;43:1317-25. 22.Goodman ZD. Grading and Staging Systems for Inflammation and Fibrosis in Chronic Liver Diseases. Journal of Hepatology (in press) 2007,doi:10.1016/jhep.2007.07.006. 23.Paris J, Pradan MM, Allen S, et al. Cost of Hepatitis C Treatment in the Correctional Setting. Journal of Correctional Health Care. 2005;11(2):199-212. 24.Snyder N, Nguyen A, Gajula L, et al. The APRI May Be Enhanced by the Use of the FIBROSpect II in the Estimation of Fibrosis in Chronic Hepatitis C. Clinica Chimica Acta 2007;381:119-23. |
| |||||||||||||||||||||||
