Epidemiology and Social
Limited effectiveness of antiviral treatment for hepatitis C in an urban HIV clinic
Mehta, Shruti Ha; Lucas, Gregory Ma,b; Mirel, Lisa Ba; Torbenson, Michaelb; Higgins, Yvonneb; Moore, Richard Da,b; Thomas, David La,b; Sulkowski, Mark Sa
From the aDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, USA
bDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Received 11 May, 2006
Revised 3 August, 2006
Accepted 5 September, 2006
Correspondence to Mark S. Sulkowski, MD, Department of Medicine, 1830 E Monument St, Suite 455, Baltimore, MD 21287, USA. E-mail: firstname.lastname@example.org
Objective: To evaluate predictors and trends of referral for hepatitis C virus (HCV) care, clinic attendance and treatment in an urban HIV clinic.
Design and methods: A retrospective cohort analysis in which 845 of 1318 co-infected adults who attended the Johns Hopkins HIV clinic between 1998 and 2003 after an on-site viral hepatitis clinic was opened, attended regularly (≥ 1 visit/year for ≥ 2 years). Logistic regression was used to examine predictors of referral.
Results: A total of 277 (33%) of 845 were referred for HCV care. Independent predictors of referral included percentage elevated alanine aminotransferase levels [adjusted odds ratio (AOR) for 10% increase,1.16; 95% confidence interval (CI), 1.10–1.22] and CD4 cell count > 350 cells/μl (AOR, 3.20; 95% CI, 2.10–4.90), while injection drug use was a barrier to referral (AOR, 0.26; 95% CI, 0.11–0.64). Overall referral rate increased from < 1% in 1998 to 28% in 2003; however, even in 2003, 65% of those with CD4 cell count > 200 cells/μl were not referred. One hundred and eighty-five (67%) of 277 referred kept their appointment, of whom 32% failed to complete a pre-treatment evaluation. Of the remaining 125, only 69 (55%) were medically eligible for treatment, and 29 (42%) underwent HCV treatment. Ninety percent of 29 were infected with genotype 1 and 70% were African American; six (21%) achieved sustained virologic response (SVR). Only 0.7% of the full cohort achieved SVR.
Conclusions: Although the potential for SVR and the recent marked increase in access to HCV care are encouraging, overall effectiveness of anti-HCV treatment in this urban, chiefly African American, HCV genotype 1 HIV clinic is extremely low. New therapies and treatment strategies are an urgent medical need.
Because of shared routes of transmission, 15–30% of HIV-infected persons are co-infected with hepatitis C virus (HCV) . In comparison with those infected with HCV alone, HIV/HCV co-infected patients progress more often and more rapidly to significant liver disease or cirrhosis [2,3]. With widespread use of antiretroviral therapy for HIV infection, co-infection with HCV has become a growing cause of morbidity and mortality among HIV-infected patients and in fact, in one center, it was estimated that 50% of deaths among HIV-infected patients were attributable to liver disease [4,5].
These data support prompt treatment of HCV among co-infected patients. Current treatment guidelines recommend combination therapy with pegylated interferon (pegIFN) plus ribavirin (RBV) for the treatment of HCV among co-infected persons [6,7]. Data from clinical trials suggest that HIV/HCV co-infected patients treated with this regimen have a sustained virologic response (SVR) rate ranging from 15% (genotype 1 or 4) to 70% (genotype 2 or 3) [8,9]. However, the uptake of HCV treatment among HIV/HCV co-infected patients has remained low among most populations. A number of studies have suggested that these low rates of treatment stem from high rates of treatment ineligibility due to medical and psychiatric contraindications, non-adherence to medical visits and concomitant alcohol and/or drug use [10–13]. Low referral rates of co-infected patients for hepatitis C care may further contribute to low treatment rates [14–17].
The Johns Hopkins University (JHU) HIV clinic is composed of over 3000 HIV-infected persons of whom approximately 50% are HCV-co-infected . An on-site viral hepatitis clinic was established in 1998. The objective of this study was to examine trends and characteristics of HIV/HCV co-infected persons who were referred for HCV care after the establishment of this clinic. Among those referred, we also examined characteristics associated with clinic attendance and treatment initiation.
The population for this study derives from HIV/HCV co-infected members of the JHU HIV clinic cohort in Baltimore, Maryland . Individuals were eligible for this analysis if they were seen in the JHU HIV clinic after 30 June 1998 when the Viral Hepatitis Clinic was opened and had their first visit to the HIV clinic by 31 December 2001, thus allowing for sufficient follow-up (n = 1318). The analysis was truncated in December 2003 because a clinical trial began in 2004 and recruited over 165 co-infected patients in 2004 from the HIV clinic. As many individuals received biopsies and treatment through this clinical trial, the estimates of referral for 2004 were likely to be lower. To be further eligible for analysis, it was required that individuals be in regular care for their HIV infection, defined as having at least one visit per year for at least 2 consecutive years. Of the 1318 HIV/HCV co-infected patients who were seen during the eligible period, 157 (12%) died within 2 years of their first visit after 1998 and 316 (24%) had insufficient follow-up (e.g. only one visit), leaving 845 who were included in the HCV referral and treatment analysis. With regard to sociodemographic characteristics, these 845 were not significantly different from other co-infected individuals in the clinic population who were not eligible for this study (n = 473, data not shown).
Hepatitis C virus clinic
The HCV clinic is located physically within the JHU HIV clinic and care is delivered by five specialists (four physicians and one nurse practitioner). The clinic provides comprehensive evaluation and treatment of HCV infection on a referral basis that routinely includes an assessment of HCV RNA viral load and genotype. Those who are determined to be eligible for treatment are routinely recommended to undergo liver biopsy. Treatment eligibility is determined on a case-by-case basis taking into account medical and psychiatric co-morbidities as well as baseline laboratory values. Importantly, neither former nor active injection drug and/or alcohol use excludes an individual from treatment. Standard clinical practice is to offer treatment to all individuals regardless of stage of fibrosis on biopsy; however, emphasis is on treating individuals with significant liver disease disease (≥ stage 2 fibrosis). HCV treatment with interferon (IFN; standard or pegylated) plus RBV is available to all treatment-eligible patients through commercial insurance or state and federal government assistance programs (e.g., Medicaid and the AIDS Drugs Assistance Program).
For all HIV/HCV co-infected persons in the study sample, information on prescribed medications and laboratory parameters was obtained from the JHU clinical and laboratory database. As previously described, data on patient demographics, social practices, clinical and laboratory parameters and prescribed antiretroviral and other medications are collected and abstracted from patient charts by trained personnel and transferred electronically from the JHU laboratory database at enrollment and subsequent 6-month intervals . Validity checks are performed periodically on a 5% sample of abstracted fields in the database and to date errors have only been found in 0.2% of variable fields. Longitudinal data on drug and alcohol use was only available on a subset of individuals who underwent an additional audio computer-assisted self interview (ACASI) that collected detailed information about these behaviors at 6-month intervals (n = 419 for alcohol data and 203 for drug-related data). The study was approved by the Johns Hopkins Medicine Intitutional Review Board and written informed consent was obtained from all participants.
First, characteristics of persons who were referred for HCV care were compared with those not referred using chi-squared tests for categorical variables and Mann–Whitney tests for continuous variables. Multiple logistic regression was used to determine independent predictors of referral. For individuals who were referred, covariates were taken from the last HIV clinic visit prior to referral and for those not referred the covariates were taken from the last HIV clinic visit prior to 2004. Using the same analytical techniques, we further compared characteristics of patients who completed and did not complete their appointment among those who were referred and of patients who initiated treatment compared with those who did not among those who had a complete evaluation. We also examined trends by calculating annual referral and completion rates considering in the denominator all individuals who were still in follow-up at the HIV clinic within the calendar year and had not been previously referred. Finally, association of calendar year of referral and characteristics that predicted referral were examined using an exact chi-squared test based on the Monte-Carlo method. Two-sided P values < 0.05 were deemed statistically significant. Data were analyzed using SAS software, version 9.1 (SAS Institute Inc., Cary, North Carolina, USA).
Study population and outcomes
Among the 845 HIV/HCV co-infected individuals eligible for this analysis, the median age was 40 years, 63% were men and 85% were African American. Overall, 277 (33%) were referred for HCV clinical care (Fig. 1) and 185 (67%) of the 277 completed at least one appointment with the viral hepatitis clinic. Of the 185 who entered HCV care, 60 (32%) failed to complete the medical evaluation required to determine HCV treatment eligibility, leaving 125 fully evaluated patients. Of the 125, 56 (45%) were ineligible for treatment because of: no detectable HCV RNA (n = 9); end-stage liver disease (n = 19); advanced AIDS or less than 2-year life expectancy (n = 16); severe psychiatric disease (n = 6); and drug or alcohol use which precluded treatment adherence (n = 6). Of the 69 patients eligible for HCV treatment, 65 (94%) were infected with genotype 1 and 4 (6%) were infected with genotype 2/3. Liver biopsy results were available on 38, of whom 12 (31%) had no fibrosis (F0), 17 (44%) had mild-moderate fibrosis (F1–F2) and nine (24%) had cirrhosis (F5–F6). HCV treatment with standard or peg IFN plus RBV was initiated in 29 patients representing 23% of 125 fully-evaluated patients and 42% of eligible patients. Ninety percent of treated patients were infected with HCV genotype 1 and 70% were African American. Sustained virologic response (SVR) was achieved in six treated patients (21%) including 100% of those infected with genotype 2/3 (n = 3) and 12% of those infected with genotype 1 (n = 26). Reasons for not treating hepatitis C among treatment-eligible patients included mild liver disease (n = 30, 75%), and patient refusal or deferment (n = 10, 25%). Among all HIV/HCV co-infected patients receiving regular HIV care (n = 845), less than 1% were effectively treated for hepatitis C, defined as having achieved a treatment-related SVR (Fig. 2).
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.
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