Predictors of referral for HCV care
In the unadjusted analyses, when compared with those not referred for HCV care by their primary HIV care provider, referred patients were significantly less likely to be African American and less likely to have injected drugs in the preceding 6 months (P < 0.05; Table 1). At the time of referral, those who were referred were more likely to be in active psychiatric care, be on antiretroviral therapy (ART), tended to have lower HIV RNA levels, higher CD4 cell counts, higher alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin levels and lower albumin levels (P < 0.05). There were no differences in referral by age, gender, alcohol use or drug treatment in the prior 6 months or prior AIDS diagnosis. In logistic regression analysis, independent predictors of referral to HCV care were being in active psychiatric care, undetectable HIV RNA, CD4 cell count > 200 cells/μl, being on ART, persistently elevated ALT levels, having an albumin < 3.5 mg/dl and having a bilirubin > 1.2 mg/dl. In the subsample that also had data on recent drug and alcohol use, undetectable HIV RNA, CD4 cell count > 200 cells/μl and elevated ALT remained independent predictors of referral. Further, in comparison with those who reported no drug use, those who reported recently using any drugs by injection were significantly less likely to be referred. However, enrollment in drug treatment programs (e.g., methadone maintenance) was not associated with referral status.
Predictors of clinic attendance and treatment initiation
Among the 277 who were referred for care, compared with those who did not complete their first appointment (n = 92), people who completed their first appointment (n = 185) were significantly less likely to have used or injected drugs in the prior 6 months (63 versus 100%, P = 0.01) and were significantly more likely to be on ART (68 versus 47% taking ART at the time of referral, P < 0.01). Those who kept their appointment were also more likely to have persistently elevated ALT levels [median percentage ALT > 1.25 × ULN, 50 versus 30%, P = 0.06) and persistently elevated AST levels (median percentage AST > 1.25 × ULN, 57 versus 48%, P = 0.07). There were no differences with respect to other factors including CD4 cell count, HIV RNA level, albumin or bilirubin, all of which were associated with referral.
Among the 125 (of 185) patients who had a complete pre-treatment evaluation, we further examined the characteristics associated with treatment initiation (Table 2). In comparison with those who did not initiate treatment, those who did were less often African American (P = 0.05), less likely to have ever injected drugs (P = 0.03), more likely to have persistently elevated ALT and AST levels (P < 0.05), more likely to have CD4 cell counts > 200 cells/μl (P = 0.08) and more likely to have significant fibrosis on biopsy (P = 0.03) (Table 2).
The proportion of individuals referred increased over time from < 1% in 1998 to 28% in 2003 (Table 3). By contrast, the proportion of individuals who were referred and completed their appointment increased only from < 1% in 1998 to 13% in 2003, reflecting the observation that while the rate of referral increased over time, many of these referred patients failed to attend their scheduled hepatitis C appointment. Indeed, the ‘no show’ percentage increased steadily over time: 1999, 0%; 2000, 2%; 2001; 8%; 2002, 44%; and 2003, 53%. In comparison with those referred in earlier years, individuals referred in later years had lower CD4 cell counts, were less likely to be on antiretroviral therapy and more likely to have used or injected drugs in the prior 6-month interval (Table 3). Despite the observed increase in referral rate, even in 2003, 65% of patients with a CD4 cell count > 200 cells/μl and 30% of patients with undetectable HIV RNA were not referred for HCV care during the study time period.
In an urban setting with high rates of HCV genotype 1 co-infection, African American ethnicity and polysubstance abuse, we observed relatively low rates of referral for HCV care, HCV treatment initiation and limited effectiveness of antiviral treatment for hepatitis C despite the establishment of a dedicated, on-site clinic. Among those patients who initiated HCV treatment with standard or peg-IFN plus RBV, 21% achieved a SVR, which is similar to the SVR rate observed in pivotal clinical trials among patients with HIV/HCV genotype 1 co-infection [8,9,21]. However, while efficacy was comparable with that observed in controlled trials, real world effectiveness in this population was negligible as less than 1% of the full cohort of co-infected patients in HIV care achieved an SVR.
Low rates of overall treatment effectiveness have been observed in other co-infected populations as well. Among patients in HIV care in Rhode Island, only one of approximately 400 co-infected patients achieved SVR (overall treatment effectiveness, 0.2%) . Similarly among 182 co-infected patients in a cohort study in San Francisco, only one person achieved SVR (overall treatment effectiveness, 0.5%) . Interestingly, these rates are also similar to those reported in some HCV mono-infected populations. Among 1470 HCV-infected patients enrolled in the Kaiser Permanente Northern California Health System from 1999–2004, less than 17% underwent HCV treatment and the overall treatment effectiveness was less than 4% . Similarly, in a study of 293 HCV mono-infected patients who were referred for treatment, only 28% were treated; of whom, 13% achieved SVR . Comparable rates were observed in our population with 23% of those fully evaluated for treatment initiating treatment and 21% achieving SVR.
Multiple factors contribute to the exceedingly low impact of hepatitis C treatment in this and other settings. Despite financial access to on-site HCV care, nearly 67% of HIV/HCV co-infected patients were not referred by their primary HCV care provider. This low rate of referral is also consistent with what has been reported in other co-infected populations [14–17]. In general, HIV care providers in our setting tended to refer patients who had well-controlled HIV (e.g. undetectable HIV RNA, CD4 > 200 cells/μl and on HAART) and were not actively using drugs. Individuals with these characteristics were also more likely to initiate treatment. However, our data also indicate that many co-infected patients with well controlled HIV disease were not referred for HCV care. This finding suggests that additional programs to educate both health care providers and patients on HCV and its treatment should be developed and evaluated in this and similar settings.
Providers were also more likely to refer those with higher levels of liver inflammation as reflected by serum ALT and AST levels. Although it is important for those patients with more active liver disease to be referred, it is also well-established that ALT measurements are not necessarily predictive of underlying liver disease and patients with cirrhosis may have normal hepatic enzyme levels . In fact, published guidelines for the management of co-infected patients indicate that serum ALT level should not substantially influence the decision to evaluate or treat hepatitis C . Moreover, nearly 20% of patients evaluated in the HCV clinic had already progressed to end-stage disease by the time of their referral evaluation, rendering them ineligible for treatment. For these patients and others with significant liver disease, it is important that early referral afford them the opportunity to be evaluated for HCV treatment since current therapies are strictly contraindicated in the setting of end-stage liver disease and access to orthotropic liver transplantation is very limited.
It was encouraging that the rate of referral steadily increased each year, with a substantial rise in 2003 following the recommendation from the US National Institutes of Health Consensus Panel that HIV-infected patients, particularly those with stable HIV disease, should be considered for HCV treatment. However, our data indicate that referral for HCV care is necessary but not sufficient for effective hepatitis C treatment as nearly one-third of referred patients did not attend their HCV appointment. Indeed, whereas the absolute numbers of referrals and patients evaluated increased over time, actual attendance rate declined over time most notably in 2003, the same year that the referral rate had nearly tripled from the previous years. Whereas providers appeared to be following the revised guidelines by referring more patients with less stable HIV disease (e.g., CD4 cell counts < 350 cells/μl who were not on ART) and who were actively using drugs, these same patients were significantly less likely to attend their appointment.
Interestingly, psychiatric disease was not associated with lower rates of provider referral or patient compliance with HCV care appointments. In fact, in comparison with other co-infected patients, those actively seen in the psychiatry clinic were more likely to enter hepatitis C care. On the other hand, although psychiatric care appeared to facilitate entry into HCV care, active treatment of drug addiction did not, perhaps because whereas psychiatric care is available on-site at the JHU HIV clinic, drug treatment, and specifically methadone maintenance, is received in geographically and organizationally distinct off-site centers. Prior studies have shown that HCV can be successfully delivered in methadone maintenance treatment settings . However, integrated care strategies that address all patient medical and psychosocial needs, while incorporating patient education, peer support, case-management along with on-site drug treatment are needed to truly improve show rates among persons actively using drugs. Some centers are beginning to launch such pilot programs; however few patients have been treated under this model thus far .
Patient eligibility for and willingness to take IFN plus RBV therapy were also important factors, as was the medical necessity of treatment. In our study, many patients who were fully evaluated for hepatitis C did not initiate HCV treatment either due to direct contraindication to the safe administration of these medications (e.g. decompensated liver disease, advanced AIDS, uncontrolled psychiatric disease) or indirect factors such as active substance use which precluded treatment adherence. These data regarding treatment eligibility are consistent with observations in other co-infected [10,14] and mono-infected populations , although definitions of eligibility tend to vary across studies. In addition, more than 75% of treatment-eligible patients in our clinic with minimal histologic disease did not initiate therapy, choosing to defer a potentially toxic, relatively ineffective therapy in the setting of other comorbidities (e.g. drug use and psychiatric disease). Conversely, 53% of those with significant fibrosis were treated. However, this and multiple other studies suggest that SVR rates are lower among persons with cirrhosis in comparison with those with minimal histologic disease, which lends support to the hypothesis that HIV-infected patients should be treated even in the setting of minimal histologic disease .
Overall, consistent with published guidelines, treatment decisions were based on case-by-case assessments of potential risk and benefits of HCV therapies, a reasonable strategy until more efficacious therapies become available. The current standard of care, peg-IFN-α plus RBV, has relatively low efficacy in persons infected with HCV genotype 1, particularly those with high levels of hepatitis C viremia, African American ethnicity and HIV co-infection. Indeed, among carefully selected patients enrolled in clinical trials, SVR has been observed in only 14–29% of such patients [8,29–31]. Thus, our SVR rate (21%) compares favorably with similar therapies in these other populations and reinforces that the efficacy of the currently available medications is only one factor that reduces overall treatment effectiveness. However, even with more efficacious therapies, much work is needed before the efficacy rates observed in clinical trials translate into effectiveness at the level of the co-infected patient population. Given that 67% of co-infected patients in the clinic population were not even referred for HCV care and less than 15% underwent such a systematic assessment of HCV disease risk and need for HCV treatment, efforts should focus first on improving referral and attendance rates. In this regard, given that the major barriers to being referred for HCV care appeared to be uncontrolled HIV and drug use, further integration of HCV care with HIV care and substance abuse treatment would likely improve referral and attendance rates.
We were limited in this analysis by not having HCV RNA data on the full sample of participants and it is likely that some of the 845 patients did not need to be referred for care based on the absence of detectable HCV RNA. However, data from a random sample of the same clinic observed that only 11% of HIV/HCV co-infected persons were HCV RNA negative (unpublished data). Further, given that HCV RNA testing is not part of routine HIV clinical care in this clinic, it is unlikely that this issue significantly impacted HCV clinic referral patterns. We were also limited by not having drug use data on the full sample of patients which prohibited multivariate analysis of predictors of appointment attendance and treatment initiation.
In conclusion, we observed limited effectiveness of HCV therapy in a population of HIV/HCV co-infected individuals engaged in regular health care with the ability to access HCV care in the absence of financial or geographical barriers. New paradigms for HCV care are urgently needed in these populations, ones that incorporate patient and provider education as well as case management to address competing needs including substance abuse, psychiatric illness and HIV. Our findings further underscore the well-documented low efficacy of current HCV therapeutics in persons co-infected with HIV and HCV genotype 1, particularly African Americans. Novel therapies, such as HCV polymerase and protease inhibitors are currently under investigation and our data highlight the urgent medical need of co-infected patients for access to such novel anti-HCV agents.
Financial support for this study came from DA-11602, DA-16065 and DA-3806 from the National Institute on Injection Drug Abuse, grant HS 07–809 from the Agency for Health Care Policy and Research and MO1-RR00052.
1. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C Virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis 2002; 34:831–837.
2. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, et al
. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33:562–569.
3. Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC, et al
. End-stage liver disease in persons with hemophilia and transfusion-associated infections. Blood 2002; 100:1584–1589.
4. Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, et al
. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32:492–497.
5. Selik RM, Byers RH Jr, Dworkin MS. Trends in diseases reported on US death certificates that mentioned HIV infection, 1987–1999. J Acquir Immune Defic Syndr 2002; 29:378–387.
6. NIH. NIH Consensus Statement on Management of Hepatitis C: 2002
. NIH Consens State Sci Statements
7. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004; 39:1147–1171.
8. Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, et al
. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351:451–459.
9. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, et al
. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:438–450.
10. Fleming CA, Craven DE, Thornton D, Tumilty S, Nunes D. Hepatitis C virus and human immunodeficiency virus coinfection in an urban population: low eligibility for interferon treatment. Clin Infect Dis 2003; 36:97–100.
11. Butt AA, Wagener M, Shakil AO, Ahmad J. Reasons for non-treatment of hepatitis C in veterans in care. J Viral Hepat 2005; 12:81–85.
12. Restrepo A, Johnson TC, Widjaja D, Yarmus L, Meyer K, Clain DJ, et al
. The rate of treatment of chronic hepatitis C in patients co-infected with HIV in an urban medical centre. J Viral Hepat 2005; 12:86–90.
13. Rauch A, Egger M, Reichen J, Furrer H. Chronic hepatitis C in HIV-infected patients: low eligibility and applicability of therapy with pegylated interferon-alpha plus ribavirin. J Acquir Immune Defic Syndr 2005; 38:238–240.
14. Fultz SL, Justice AC, Butt AA, Rabeneck L, Weissman S, Rodriguez-Barradas M. Testing, referral, and treatment patterns for hepatitis C virus coinfection in a cohort of veterans with human immunodeficiency virus infection. Clin Infect Dis 2003; 36:1039–1046.
15. Shim M, Khaykis I, Park J, Bini EJ. Low physician referral rates and high no-show rates are major barriers to HCV therapy among patients coinfected with HIV and HCV
. American Association for the Study of Liver Diseases 55th Annual Meeting
, 2004 [abstract 386].
16. Fishbein DA, Lo Y, Reinus JF, Gourevitch MN, Klein RS. Factors associated with successful referral for clinical care of drug users with chronic hepatitis C who have or are at risk for HIV infection. J Acquir Immune Defic Syndr 2004; 37:1367–1375.
17. Fleming CA, Tumilty S, Murray JE, Nunes D. Challenges in the treatment of patients coinfected with HIV and hepatitis C virus: need for team care. Clin Infect Dis 2005; 40(Suppl 5):S349–S354.
18. Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA 2002; 288:199–206.
19. Moore RD. Understanding the clinical and economic outcomes of HIV therapy: the Johns Hopkins HIV clinical practice cohort. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17(Suppl 1):S38–S41.
20. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al
. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22:696–699.
21. Bobbola M, Momi J, Lim J, Ready J, Cheung R. Practice patterns and treatment outcomes in the management of chronic hepatitis C (CHC) infection in a large managed care cohort
. American College of Gastroenterology 70th Annual Scientific Meeting
, Honolulu, Hawaii. 2005 [abstract 785].
22. Taylor LE. Delivering care to injection drug users coinfected with HIV and hepatitis C virus. Clin Infect Dis 2005; 40(Suppl 5):S355–S361.
23. Hall CS, Charlebois ED, Hahn JA, Moss AR, Bangsberg DR. Hepatitis C Virus infection in San Francisco's HIV-infected urban poor. J Gen Intern Med 2004; 19:357–365.
24. Falck-Ytter Y, Kale H, Mullen KD, Sarbah SA, Sorescu L, McCullough AJ. Surprisingly small effect of antiviral treatment in patients with hepatitis C. Ann Intern Med 2002; 136:288–292.
25. Pradat P, Alberti A, Poynard T, Esteban JI, Weiland O, Marcellin P, et al
. Predictive value of ALT levels for histologic findings in chronic hepatitis C: a European collaborative study. Hepatology 2002; 36:973–977.
26. Sylvestre DL. Approaching treatment for hepatitis C virus infection in substance users. Clin Infect Dis 2005; 41(Suppl 1):S79–S82.
27. Litwin AH, Soloway I, Gourevitch MN. Integrating services for injection drug users infected with hepatitis C virus with methadone maintenance treatment: challenges and opportunities. Clin Infect Dis 2005; 40(Suppl 5):S339–S345.
28. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al
. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975–982.
29. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, 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 2001; 358:958–965.
30. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004; 350:2265–2271.
31. Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology 2004; 39:1702–1708.
Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
HIV; hepatitis C; referral; intravenous drug abuse; antiviral therapy